Membranous Nephropathy

**49**

**Chapter 4**

**Abstract**

pathic MN.

**1. Introduction**

**2. Epidemiology**

calcineurin inhibitor, rituximab

*and David Johnson*

Membranous Nephropathy

*Bhadran Bose, Sunil V. Badve, Vivekanand Jha, Chen Au Peh* 

Membranous nephropathy (MN) is a glomerular disease that is the leading cause of nephrotic syndrome in non-diabetic Caucasian adults. MN is most often primary (idiopathic) and the remaining is secondary to systemic disease or exposure to infection or drugs. The majority of patients with MN have circulating antibodies to the podocyte antigens phospholipase A2 receptor (PLA2R) (70%) and thrombospondin type-1 domain-containing 7A (THSD7A) (3–5%). Immunologic remission (depletion of PLA2R antibodies) often precedes and may predict clinical remission. Untreated, about one-third of patients undergo spontaneous remission, one-third have persistent proteinuria but maintain kidney function and the remaining one-third will develop end stage kidney failure. All patients with idiopathic MN should be treated with conservative care from the time of diagnosis to minimise proteinuria. Immunosuppressive therapy is traditionally reserved for patients who have persistent nephrotic-range proteinuria despite conservative care. Immunosuppressive agents for primary MN include combination of corticosteroids/ alkylating agent or calcineurin inhibitors and rituximab. This chapter will review the epidemiology, diagnosis and treatment of MN, particularly focusing on idio-

**Keywords:** membranous nephropathy, PLA2R antibody, cytotoxic agents,

Idiopathic membranous nephropathy (MN) remains the leading cause of nephrotic syndrome in Caucasian adults and one of the most common primary glomerular diseases to progress to end-stage kidney disease (ESKD) [1, 2]. Secondary MN is associated with autoimmune diseases (e.g., systemic lupus erythematosus), infections (e.g., hepatitis B and C), medications (e.g., nonsteroidal anti-inflammatory drugs, d-penicillamine, gold), and neoplasias [3]. As idiopathic and secondary forms have similar clinical presentations, the designation of idiopathic is made only after ruling out secondary causes by a careful history, physical examination, and laboratory

MN accounts for 20–30% of cases of nephrotic syndrome in Caucasian adults [4, 5]. Although the disease affects patients of all ages, all ethnicities and both sexes, it is more common in white men [4, 6]. MN has a peak incidence during

evaluation. This chapter will primarily focus on idiopathic MN.

### **Chapter 4**

## Membranous Nephropathy

*Bhadran Bose, Sunil V. Badve, Vivekanand Jha, Chen Au Peh and David Johnson*

#### **Abstract**

Membranous nephropathy (MN) is a glomerular disease that is the leading cause of nephrotic syndrome in non-diabetic Caucasian adults. MN is most often primary (idiopathic) and the remaining is secondary to systemic disease or exposure to infection or drugs. The majority of patients with MN have circulating antibodies to the podocyte antigens phospholipase A2 receptor (PLA2R) (70%) and thrombospondin type-1 domain-containing 7A (THSD7A) (3–5%). Immunologic remission (depletion of PLA2R antibodies) often precedes and may predict clinical remission. Untreated, about one-third of patients undergo spontaneous remission, one-third have persistent proteinuria but maintain kidney function and the remaining one-third will develop end stage kidney failure. All patients with idiopathic MN should be treated with conservative care from the time of diagnosis to minimise proteinuria. Immunosuppressive therapy is traditionally reserved for patients who have persistent nephrotic-range proteinuria despite conservative care. Immunosuppressive agents for primary MN include combination of corticosteroids/ alkylating agent or calcineurin inhibitors and rituximab. This chapter will review the epidemiology, diagnosis and treatment of MN, particularly focusing on idiopathic MN.

**Keywords:** membranous nephropathy, PLA2R antibody, cytotoxic agents, calcineurin inhibitor, rituximab

#### **1. Introduction**

Idiopathic membranous nephropathy (MN) remains the leading cause of nephrotic syndrome in Caucasian adults and one of the most common primary glomerular diseases to progress to end-stage kidney disease (ESKD) [1, 2]. Secondary MN is associated with autoimmune diseases (e.g., systemic lupus erythematosus), infections (e.g., hepatitis B and C), medications (e.g., nonsteroidal anti-inflammatory drugs, d-penicillamine, gold), and neoplasias [3]. As idiopathic and secondary forms have similar clinical presentations, the designation of idiopathic is made only after ruling out secondary causes by a careful history, physical examination, and laboratory evaluation. This chapter will primarily focus on idiopathic MN.

#### **2. Epidemiology**

MN accounts for 20–30% of cases of nephrotic syndrome in Caucasian adults [4, 5]. Although the disease affects patients of all ages, all ethnicities and both sexes, it is more common in white men [4, 6]. MN has a peak incidence during

the fourth and fifth decades of life, and is relatively uncommon in patients aged under 20 years [4, 6]. The incidence of ESKD is about 35% at 10 years [7].

#### **3. Pathogenesis**

In the past decade, the understanding of the pathogenesis of idiopathic MN has significantly improved. In 2009, phospholipase A2 receptor (PLA2R) was identified as the major antigen responsible for autoantibody binding in idiopathic MN [8]. PLA2R is a transmembrane receptor that is highly expressed in glomerular podocytes and anti-PLA2R (typically of IgG4 subtype) was initially identified in 70% of patients with idiopathic MN [8]. Subsequent studies from various cohorts have shown that PLA2R antibodies are positive in 50–80% of patients with idiopathic MN [4, 6, 9–12]. PLA2R antibodies are uncommon in patients with MN associated with malignancies [13, 14]. PLA2R antibody has been reported in hepatitis-B associated membranous nephropathy [15] and also in hepatitis-C associated membranous nephropathy [14]. In genetic studies, there was association with HLA-DQA1 risk alleles [16, 17] and PLA2R1 alleles [16]. Furthermore, the presence of HLA DQA1\* 05:01 and DQB1\* 02:01 alleles are associated with higher PLA2R antibody levels [18].

PLA2R is a 180-kDa membrane receptor with a large extracellular region comprising 10 distinct globular domains, including a cysteine-rich domain, a fibronectin type II domain, and eight distinct C-type lectin domains (CTLD1–8) [19]. Each domain is separated by a small linker sequence of <10 amino acids. CysR is the immunodominant epitope for PLA2R [20]. Epitope spreading refers to the development of immune responses to endogenous epitopes secondary to the release of self-antigens during a chronic autoimmune or inflammatory response. In MN, epitope-spreading starts with the cysteine-rich domain then extends to CTLD1, CTLD7 or other nearby regions. This results in an augmented immune response through heightened antibody diversity. In a study of 69 patients with MN from five French centres, Seitz-Polski et al. demonstrated that higher anti-PLA2R antibody titres and serum reactivity to CTLD1 and/or CTLD7 in addition to the cysteine-rich domain were associated with a higher rate of kidney failure [21].

A second IgG4 auto-antibody against thrombospondin type-1 domain-containing 7A (THSD7A) was identified in a smaller number of patients with MN. THSD7A, like PLA2R, is also a protein highly expressed in podocytes and was identified in European and North American patients with anti-PLA2R-negative idiopathic MN but not in healthy controls or patients with other glomerular diseases [22]. It occurred in 2–5% of all patients with idiopathic membranous nephropathy, which corresponded to 8–14% of patients who were seronegative for anti-PLA2R antibodies. A recent meta-analysis of 10 studies involving 4121 patients showed that the prevalence of THSD7A was low at 3% (95% CI 2–4%) of all patients with idiopathic MN, which corresponded to 10% (95% CI 6–15%) of anti-PLA2R antibody negative patients [23]. However, this meta-analysis was limited by a limited number of studies and small sample size. This meta-analysis also showed that cancer may be more common in patients with THSD7A antibodies and the incidence varied from 6 to 25%. Further studies to elucidate the role of THSD7A as a marker of prognosis and response to therapy are required.

Antibodies against both PLA2R and THSD7A can coexist but only in 1% of cases [24].

#### **4. Pathology**

Despite the availability of anti-PLA2R antibody, kidney biopsy remains the standard of care in diagnosing MN. In early MN, glomeruli may appear normal by

**51**

**Figure 2.**

*glomerular basement membrane.*

**Figure 1.**

*in MN (silver-methamine stain).*

*Membranous Nephropathy*

*DOI: http://dx.doi.org/10.5772/intechopen.87051*

light microscopy. However, with time, the glomerular basement membrane thickens and there is formation of subepithelial "spikes" of basement membrane on the outer surface of the capillary wall. These "spikes" are more apparent with silver methenamine staining (**Figure 1**). Immunofluorescence microscopy reveals diffuse, uniform, finely granular deposits of IgG4 along the outer surfaces of capillary walls (**Figure 2**). Complement components, including C3, C4d and C5b-9, are also

*Glomerulus showing thickening of glomerular basement membrane and subepithelial "spikes" (see arrowhead)* 

*Immunofluorescence showing diffuse fine granular distribution pattern of immunoglobulin G (IgG) along the* 

#### *Membranous Nephropathy DOI: http://dx.doi.org/10.5772/intechopen.87051*

light microscopy. However, with time, the glomerular basement membrane thickens and there is formation of subepithelial "spikes" of basement membrane on the outer surface of the capillary wall. These "spikes" are more apparent with silver methenamine staining (**Figure 1**). Immunofluorescence microscopy reveals diffuse, uniform, finely granular deposits of IgG4 along the outer surfaces of capillary walls (**Figure 2**). Complement components, including C3, C4d and C5b-9, are also

#### **Figure 1.**

*Glomerulonephritis and Nephrotic Syndrome*

**3. Pathogenesis**

the fourth and fifth decades of life, and is relatively uncommon in patients aged under 20 years [4, 6]. The incidence of ESKD is about 35% at 10 years [7].

In the past decade, the understanding of the pathogenesis of idiopathic MN has significantly improved. In 2009, phospholipase A2 receptor (PLA2R) was identified as the major antigen responsible for autoantibody binding in idiopathic MN [8]. PLA2R is a transmembrane receptor that is highly expressed in glomerular podocytes and anti-PLA2R (typically of IgG4 subtype) was initially identified in 70% of patients with idiopathic MN [8]. Subsequent studies from various cohorts have shown that PLA2R antibodies are positive in 50–80% of patients with idiopathic MN [4, 6, 9–12]. PLA2R antibodies are uncommon in patients with MN associated with malignancies [13, 14]. PLA2R antibody has been reported in hepatitis-B associated membranous nephropathy [15] and also in hepatitis-C associated membranous nephropathy [14]. In genetic studies, there was association with HLA-DQA1 risk alleles [16, 17] and

PLA2R is a 180-kDa membrane receptor with a large extracellular region comprising 10 distinct globular domains, including a cysteine-rich domain, a fibronectin type II domain, and eight distinct C-type lectin domains (CTLD1–8) [19]. Each domain is separated by a small linker sequence of <10 amino acids. CysR is the immunodominant epitope for PLA2R [20]. Epitope spreading refers to the development of immune responses to endogenous epitopes secondary to the release of self-antigens during a chronic autoimmune or inflammatory response. In MN, epitope-spreading starts with the cysteine-rich domain then extends to CTLD1, CTLD7 or other nearby regions. This results in an augmented immune response through heightened antibody diversity. In a study of 69 patients with MN from five French centres, Seitz-Polski et al. demonstrated that higher anti-PLA2R antibody titres and serum reactivity to CTLD1 and/or CTLD7 in addition to the cysteine-rich

A second IgG4 auto-antibody against thrombospondin type-1 domain-containing 7A (THSD7A) was identified in a smaller number of patients with MN. THSD7A, like PLA2R, is also a protein highly expressed in podocytes and was identified in European and North American patients with anti-PLA2R-negative idiopathic MN but not in healthy controls or patients with other glomerular diseases [22]. It occurred in 2–5% of all patients with idiopathic membranous nephropathy, which corresponded to 8–14% of patients who were seronegative for anti-PLA2R antibodies. A recent meta-analysis of 10 studies involving 4121 patients showed that the prevalence of THSD7A was low at 3% (95% CI 2–4%) of all patients with idiopathic MN, which corresponded to 10% (95% CI 6–15%) of anti-PLA2R antibody negative patients [23]. However, this meta-analysis was limited by a limited number of studies and small sample size. This meta-analysis also showed that cancer may be more common in patients with THSD7A antibodies and the incidence varied from 6 to 25%. Further studies to elucidate the role

Antibodies against both PLA2R and THSD7A can coexist but only in 1% of cases [24].

Despite the availability of anti-PLA2R antibody, kidney biopsy remains the standard of care in diagnosing MN. In early MN, glomeruli may appear normal by

05:01 and DQB1\*

02:01

PLA2R1 alleles [16]. Furthermore, the presence of HLA DQA1\*

domain were associated with a higher rate of kidney failure [21].

of THSD7A as a marker of prognosis and response to therapy are required.

alleles are associated with higher PLA2R antibody levels [18].

**50**

**4. Pathology**

*Glomerulus showing thickening of glomerular basement membrane and subepithelial "spikes" (see arrowhead) in MN (silver-methamine stain).*

#### **Figure 2.**

*Immunofluorescence showing diffuse fine granular distribution pattern of immunoglobulin G (IgG) along the glomerular basement membrane.*

**Figure 3.** *Electron microscopy showing diffuse subepithelial electron dense deposits (see arrowheads) in MN.*

commonly present, but not C1q. The antigens, PLA2R and THSD7A, co-localise with IgG4 in most patients with idiopathic MN.

Electron microscopy shows diffuse subepithelial electron-dense deposits and also glomerular basement membrane thickening (**Figure 3**). The deposits are gradually incorporated within new glomerular basement membrane and become more electron-lucent as they are resorbed before eventually disappearing in patients following the development of complete remission (CR).

#### **5. Clinical manifestations**

At presentation, 60–70% of patients will have nephrotic syndrome [25, 26]. The remaining one-third is presented with sub nephrotic-range proteinuria (<3.5 g/day) [27]. Microscopic hematuria also occurs in approximately one-third of patients; however, macroscopic hematuria is unusual and should prompt consideration of alternative diagnoses [28]. Hypertension and moderate-to-severe kidney failure occur in a minority of patients and tend to occur more commonly in older individuals [29]. Dyslipidaemia is common and venous thromboembolism has been reported to occur in approximately 7% [30].

#### **6. Natural history**

MN is a chronic disease, with spontaneous remission and relapses. There is great variability in the rate of disease progression, and the natural course is difficult to assess [31–33]. Spontaneous remissions are said to occur in up to 30% of cases. The proportion of patients going into spontaneous remission is much lower when patients have higher grades of proteinuria or high anti-PLA2R antibody titre (>85 RU/mL) at presentation [34]. The remaining two-thirds of patients who do not undergo spontaneous remission either have persistent proteinuria with stable kidney function long-term or will progress to kidney failure. Even patients who do not progress but remain nephrotic are at an increased risk for life-threatening

**53**

logical remission.

**9. Treatment**

pressive therapy.

*Membranous Nephropathy*

**7. Predicting factors**

antibodies.

**8. Response measurements**

immunocompromised patient.

*DOI: http://dx.doi.org/10.5772/intechopen.87051*

thromboembolic and cardiovascular events [30, 35, 36]. A rapid decline in kidney function should raise the possibility of a superimposed condition, such as interstitial nephritis, renal vein thrombosis or acute tubular necrosis due to sepsis in an

Many individual factors, such as advanced age, male sex, degree of kidney impairment on presentation, degree of chronicity in the kidney biopsy (e.g., degree of interstitial fibrosis, tubular atrophy, vascular damage and glomerulosclerosis), degree of proteinuria and anti-PLA2R antibody titre have all been reported to be predictors of prognosis and/or response to immunosuppressive therapy in patients with MN [34, 37]. Pei et al. observed a 47% higher risk of kidney disease progression in patients with proteinuria exceeding 4 g/24 hour for longer than 18 months and a 66% higher risk in patients with proteinuria exceeding 8 g/24 hour for more than 6 months [38]. Similarly, PLA2R antibodies appear to correlate with disease activity, response to therapy and also prognosis [18, 34, 39, 40]. In particular, higher antibody levels are linked to a higher risk of declining kidney function, suggesting that these affected individuals may benefit from earlier initiation of immunosuppression [18]. Conversely, favourable outcomes have been shown in patients who are negative for anti-PLA2R

The best-accepted responses are improved kidney survival and CR of proteinuria. CR is defined as a urine protein excretion of <0.3 g/24 hour accompanied by a normal serum albumin concentration and normal serum creatinine [41]. Partial remission (PR) has been also recognised as a positive outcome and is defined as urine protein excretion of <3.5 g/24 hour or reduced by at least 50% from peak values accompanied by an improvement or normalisation of the serum albumin concentration and stable serum creatinine [41]. Approximately 30% of MN cases will relapse subsequent to a CR [42]. The great majority who do, however, will relapse to sub-nephrotic-range proteinuria and will have stable long-term function [42]. A review of 350 nephrotic patients with MN found that the 10-year kidney survival was 100% in the CR group, 90% in the PR group, and 45% in the no-remission group [43]. Respective rates of glomerular filtration rate decline were −0.12 ± 0.40, −0.17 ± 0.50 and −0.86 ± 1.08 mL/minute/month, such that the attainment of CR or PR independently predicted a much more favourable kidney function prognosis [43]. In patients who are anti-PLA2R antibody positive, reduction in circulating antibody titre precedes clinical remission, and furthermore, persistence of antibody despite treatment is associated with clinical resistance [44]. Future definitions of remission of this disease may well incorporate elements of both clinical and sero-

Based on the predictive factors described above, patients can be rationally assigned to either conservative (non-immunosuppressive) therapy or immunosupthromboembolic and cardiovascular events [30, 35, 36]. A rapid decline in kidney function should raise the possibility of a superimposed condition, such as interstitial nephritis, renal vein thrombosis or acute tubular necrosis due to sepsis in an immunocompromised patient.

#### **7. Predicting factors**

*Glomerulonephritis and Nephrotic Syndrome*

commonly present, but not C1q. The antigens, PLA2R and THSD7A, co-localise

*Electron microscopy showing diffuse subepithelial electron dense deposits (see arrowheads) in MN.*

Electron microscopy shows diffuse subepithelial electron-dense deposits and also glomerular basement membrane thickening (**Figure 3**). The deposits are gradually incorporated within new glomerular basement membrane and become more electron-lucent as they are resorbed before eventually disappearing in patients

At presentation, 60–70% of patients will have nephrotic syndrome [25, 26]. The remaining one-third is presented with sub nephrotic-range proteinuria (<3.5 g/day) [27]. Microscopic hematuria also occurs in approximately one-third of patients; however, macroscopic hematuria is unusual and should prompt consideration of alternative diagnoses [28]. Hypertension and moderate-to-severe kidney failure occur in a minority of patients and tend to occur more commonly in older individuals [29]. Dyslipidaemia is common and venous thromboembolism has been reported

MN is a chronic disease, with spontaneous remission and relapses. There is great variability in the rate of disease progression, and the natural course is difficult to assess [31–33]. Spontaneous remissions are said to occur in up to 30% of cases. The proportion of patients going into spontaneous remission is much lower when patients have higher grades of proteinuria or high anti-PLA2R antibody titre (>85 RU/mL) at presentation [34]. The remaining two-thirds of patients who do not undergo spontaneous remission either have persistent proteinuria with stable kidney function long-term or will progress to kidney failure. Even patients who do not progress but remain nephrotic are at an increased risk for life-threatening

with IgG4 in most patients with idiopathic MN.

**5. Clinical manifestations**

**Figure 3.**

to occur in approximately 7% [30].

**6. Natural history**

following the development of complete remission (CR).

**52**

Many individual factors, such as advanced age, male sex, degree of kidney impairment on presentation, degree of chronicity in the kidney biopsy (e.g., degree of interstitial fibrosis, tubular atrophy, vascular damage and glomerulosclerosis), degree of proteinuria and anti-PLA2R antibody titre have all been reported to be predictors of prognosis and/or response to immunosuppressive therapy in patients with MN [34, 37]. Pei et al. observed a 47% higher risk of kidney disease progression in patients with proteinuria exceeding 4 g/24 hour for longer than 18 months and a 66% higher risk in patients with proteinuria exceeding 8 g/24 hour for more than 6 months [38]. Similarly, PLA2R antibodies appear to correlate with disease activity, response to therapy and also prognosis [18, 34, 39, 40]. In particular, higher antibody levels are linked to a higher risk of declining kidney function, suggesting that these affected individuals may benefit from earlier initiation of immunosuppression [18]. Conversely, favourable outcomes have been shown in patients who are negative for anti-PLA2R antibodies.

#### **8. Response measurements**

The best-accepted responses are improved kidney survival and CR of proteinuria. CR is defined as a urine protein excretion of <0.3 g/24 hour accompanied by a normal serum albumin concentration and normal serum creatinine [41]. Partial remission (PR) has been also recognised as a positive outcome and is defined as urine protein excretion of <3.5 g/24 hour or reduced by at least 50% from peak values accompanied by an improvement or normalisation of the serum albumin concentration and stable serum creatinine [41]. Approximately 30% of MN cases will relapse subsequent to a CR [42]. The great majority who do, however, will relapse to sub-nephrotic-range proteinuria and will have stable long-term function [42]. A review of 350 nephrotic patients with MN found that the 10-year kidney survival was 100% in the CR group, 90% in the PR group, and 45% in the no-remission group [43]. Respective rates of glomerular filtration rate decline were −0.12 ± 0.40, −0.17 ± 0.50 and −0.86 ± 1.08 mL/minute/month, such that the attainment of CR or PR independently predicted a much more favourable kidney function prognosis [43]. In patients who are anti-PLA2R antibody positive, reduction in circulating antibody titre precedes clinical remission, and furthermore, persistence of antibody despite treatment is associated with clinical resistance [44]. Future definitions of remission of this disease may well incorporate elements of both clinical and serological remission.

#### **9. Treatment**

Based on the predictive factors described above, patients can be rationally assigned to either conservative (non-immunosuppressive) therapy or immunosuppressive therapy.

#### **10. Conservative therapy**

Conservative therapy includes controlling oedema, dietary protein intake, blood pressure, and hyperlipidaemia. MN patients develop significant oedema and to control the oedema, loop diuretic is the mainstay of treatment along with low-salt diet. High salt diet intake, apart from worsening the oedema, can also significantly impair the beneficial effects of renin-angiotensin blockade, which are one of the key components of conservative therapy. A normal dietary protein intake (0.75–1.0 g/kg/day) is usually recommended. A recent meta-analysis including 44,989 participants showed more intensive blood pressure-lowering (mean blood pressure levels of 133/76 mm Hg, compared with 140/81 mm Hg in the less intensive treatment group) achieved a relative risk reduction of albuminuria by 10% [45]. Anti-proteinuric agents, such as angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs), should be used as first-line antihypertensive agents [46, 47]. In patients with lower levels of proteinuria (<4 g/24 hour), treatment with an ACEi or an ARB may be sufficient to reduce proteinuria to sub-nephrotic levels thereby appreciably mitigating kidney and cardiovascular risks. However, in patients with higher degrees of proteinuria, the use of these medications alone is unlikely to result in a substantial reduction in proteinuria or preservation of kidney function [48].

Statins should be prescribed to control hypercholesterolaemia and attenuate the heightened cardiovascular risk observed in patients with MN [49].

Patients with severe nephrotic syndrome are at increased risk of thromboembolic complications. Lionaki et al. reported that clinically apparent venous thromboembolism occurred in 7% of patients with MN and the risk was higher if the serum albumin was below 2.8 g/dL [30]. In a retrospective review of MN patients with nephrotic range proteinuria, use of prophylactic anticoagulation has been shown to be associated with a reduction in fatal thromboembolic episodes and benefits of anticoagulation outweigh the risk of bleeding [50]. In general, MN patients who are severely nephrotic (proteinuria >10 g/24 hour and serum albumin of <2.5 g/dL) should be considered for anticoagulation [30].

#### **11. Immunosuppressive therapy**

Several treatment strategies using immunosuppressive therapy have been shown to be successful in reducing proteinuria in MN [51]. Based on their risk factor profiles, patients are grouped into low, medium and high-risk categories.

#### **12. Treatment of low-risk patients**

Patients in the low-risk group are categorised by a <5% risk of kidney disease progression over 5 years of observation. Patients in this group would have normal kidney function and proteinuria of ≤4 g/24 hours over a 6-month observation period. Evidence to support this approach comes from published validation studies [43, 52]. Such patients therefore do well with a conservative treatment approach, as outlined above [53].

#### **13. Treatment of medium-risk patients**

Patients in this group have preserved renal function and daily urinary protein excretion rates of 4–8 g/24 hours which continue unabated following a 6 month

**55**

*Membranous Nephropathy*

*DOI: http://dx.doi.org/10.5772/intechopen.87051*

with one or more of the following options:

**13.1 Corticosteroid monotherapy**

alternate day prednisone (45 mg/m2

period of conservative therapy. These patients warrant immunosuppressive therapy

An early collaborative randomized study of 72 adult patients with idiopathic nephrotic syndrome demonstrated that a 2–3 month course of high-dose alternateday prednisone when compared to placebo resulted in a significant reduction in progression to kidney failure but there was no effect on the degree of proteinuria. Ten of the 38 placebo-treated and one of the 34 prednisone-treated patient were in renal failure (creatinine more than 5 mg/dL [440 μmol/L]) or dead (*p* < 0.02) [54]. A subsequent prospective randomised study comparing a 6-month course of

idiopathic MN showed no significant benefit of corticosteroid treatment alone in either induction of remission or preservation of kidney function over a mean follow-up period of 48 months [55]. Hence, corticosteroid monotherapy have been

A number of randomised trials have suggested that alternating monthly regimen of steroids and cytotoxic agents is more likely to induce CR of nephrotic syndrome, and halt disease progression compared to no therapy or corticosteroids alone. The first study by Ponticelli's group compared the effects of corticosteroids alternating monthly with chlorambucil to conservative treatment in 67 adult patients with MN [56]. The regimen was given over a 6-month period. It consists of 1 g of intravenous methylprednisolone (MTP)/day for first 3 days of months 1, 3 and 5 followed by 27 days of oral methylprednisolone 0.5 mg/kg/day for the remainder of the month. In the alternating months (months 2, 4 and 6), chlorambucil 0.2 mg/ kg/day is used instead of corticosteroids. Compared with controls, patients in the intervention group experienced higher rates of CR or PR (72 vs. 30%, *p* = 0.001) and significantly better preserved kidney function at 1 year (*p* = 0.011) and 2 years (*p* < 0.0001). After 10 years of follow-up, patients treated with combination

therapy had a 92% probability of kidney survival compared with 60% in the control group (*p* = 0.004), and the probability of achieving a CR or PR was 83% in the treatment group, and only 38% in the controls (*p* = 0.000) [57]. A second study by the same group, compared the original chlorambucil regimen (45 patients) as described above to MTP pulses plus steroid alone for 6 months (47 patients) [58]. Compared to the steroids alone regimen, treatment with the chlorambucil regimen resulted in higher proportions of patients without nephrotic syndrome at 3 years (66 vs. 40%, *p* = 0.011), although the result was no longer statistically significant by 4 years (62 vs. 42%, *p* = 0.102) chlorambucil-treated patients also had longer mean ratios of months in remission (0.52 vs. 0.31, *p* = 0.008) [58]. In a third study from the same investigators, patients were enrolled in a 6-month study comparing corticosteroids (1 gm of intravenous MTP day for first 3 days of months 1, 3 and 5 followed by 27 days of oral methylprednisolone 0.5 mg/kg/day for the remainder of the month) alternating monthly with either chlorambucil (0.2 mg/kg/day) or oral cyclophosphamide (2.5 mg/kg/day) in months 2, 4 and 6 [59]. No significant differences were observed between the two groups with respect to remission rate (CR or PR) at 1 year (82 vs. 93%, respectively, *p* = 0.116), subsequent relapse rate (31 vs. 25%, or changes in proteinuria or reciprocal serum creatinine over time. In an open-label, parallel-arm, randomised controlled trial, Jha and colleagues compared the effects of alternating monthly prednisolone and cyclophosphamide

shown to be ineffective inducing remission in patients with MN.

**13.2 Cytotoxic agents combined with corticosteroids**

) or no specific treatment in 158 patients with

*Glomerulonephritis and Nephrotic Syndrome*

in proteinuria or preservation of kidney function [48].

heightened cardiovascular risk observed in patients with MN [49].

of <2.5 g/dL) should be considered for anticoagulation [30].

**11. Immunosuppressive therapy**

**12. Treatment of low-risk patients**

**13. Treatment of medium-risk patients**

Conservative therapy includes controlling oedema, dietary protein intake, blood pressure, and hyperlipidaemia. MN patients develop significant oedema and to control the oedema, loop diuretic is the mainstay of treatment along with low-salt diet. High salt diet intake, apart from worsening the oedema, can also significantly impair the beneficial effects of renin-angiotensin blockade, which are one of the key components of conservative therapy. A normal dietary protein intake (0.75–1.0 g/kg/day) is usually recommended. A recent meta-analysis including 44,989 participants showed more intensive blood pressure-lowering (mean blood pressure levels of 133/76 mm Hg, compared with 140/81 mm Hg in the less intensive treatment group) achieved a relative risk reduction of albuminuria by 10% [45]. Anti-proteinuric agents, such as angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs), should be used as first-line antihypertensive agents [46, 47]. In patients with lower levels of proteinuria (<4 g/24 hour), treatment with an ACEi or an ARB may be sufficient to reduce proteinuria to sub-nephrotic levels thereby appreciably mitigating kidney and cardiovascular risks. However, in patients with higher degrees of proteinuria, the use of these medications alone is unlikely to result in a substantial reduction

Statins should be prescribed to control hypercholesterolaemia and attenuate the

Several treatment strategies using immunosuppressive therapy have been shown

Patients in the low-risk group are categorised by a <5% risk of kidney disease progression over 5 years of observation. Patients in this group would have normal kidney function and proteinuria of ≤4 g/24 hours over a 6-month observation period. Evidence to support this approach comes from published validation studies [43, 52]. Such patients therefore do well with a conservative treatment approach, as

Patients in this group have preserved renal function and daily urinary protein excretion rates of 4–8 g/24 hours which continue unabated following a 6 month

to be successful in reducing proteinuria in MN [51]. Based on their risk factor profiles, patients are grouped into low, medium and high-risk categories.

Patients with severe nephrotic syndrome are at increased risk of thromboembolic complications. Lionaki et al. reported that clinically apparent venous thromboembolism occurred in 7% of patients with MN and the risk was higher if the serum albumin was below 2.8 g/dL [30]. In a retrospective review of MN patients with nephrotic range proteinuria, use of prophylactic anticoagulation has been shown to be associated with a reduction in fatal thromboembolic episodes and benefits of anticoagulation outweigh the risk of bleeding [50]. In general, MN patients who are severely nephrotic (proteinuria >10 g/24 hour and serum albumin

**10. Conservative therapy**

**54**

outlined above [53].

period of conservative therapy. These patients warrant immunosuppressive therapy with one or more of the following options:

#### **13.1 Corticosteroid monotherapy**

An early collaborative randomized study of 72 adult patients with idiopathic nephrotic syndrome demonstrated that a 2–3 month course of high-dose alternateday prednisone when compared to placebo resulted in a significant reduction in progression to kidney failure but there was no effect on the degree of proteinuria. Ten of the 38 placebo-treated and one of the 34 prednisone-treated patient were in renal failure (creatinine more than 5 mg/dL [440 μmol/L]) or dead (*p* < 0.02) [54]. A subsequent prospective randomised study comparing a 6-month course of alternate day prednisone (45 mg/m2 ) or no specific treatment in 158 patients with idiopathic MN showed no significant benefit of corticosteroid treatment alone in either induction of remission or preservation of kidney function over a mean follow-up period of 48 months [55]. Hence, corticosteroid monotherapy have been shown to be ineffective inducing remission in patients with MN.

#### **13.2 Cytotoxic agents combined with corticosteroids**

A number of randomised trials have suggested that alternating monthly regimen of steroids and cytotoxic agents is more likely to induce CR of nephrotic syndrome, and halt disease progression compared to no therapy or corticosteroids alone. The first study by Ponticelli's group compared the effects of corticosteroids alternating monthly with chlorambucil to conservative treatment in 67 adult patients with MN [56]. The regimen was given over a 6-month period. It consists of 1 g of intravenous methylprednisolone (MTP)/day for first 3 days of months 1, 3 and 5 followed by 27 days of oral methylprednisolone 0.5 mg/kg/day for the remainder of the month. In the alternating months (months 2, 4 and 6), chlorambucil 0.2 mg/ kg/day is used instead of corticosteroids. Compared with controls, patients in the intervention group experienced higher rates of CR or PR (72 vs. 30%, *p* = 0.001) and significantly better preserved kidney function at 1 year (*p* = 0.011) and 2 years (*p* < 0.0001). After 10 years of follow-up, patients treated with combination therapy had a 92% probability of kidney survival compared with 60% in the control group (*p* = 0.004), and the probability of achieving a CR or PR was 83% in the treatment group, and only 38% in the controls (*p* = 0.000) [57]. A second study by the same group, compared the original chlorambucil regimen (45 patients) as described above to MTP pulses plus steroid alone for 6 months (47 patients) [58]. Compared to the steroids alone regimen, treatment with the chlorambucil regimen resulted in higher proportions of patients without nephrotic syndrome at 3 years (66 vs. 40%, *p* = 0.011), although the result was no longer statistically significant by 4 years (62 vs. 42%, *p* = 0.102) chlorambucil-treated patients also had longer mean ratios of months in remission (0.52 vs. 0.31, *p* = 0.008) [58]. In a third study from the same investigators, patients were enrolled in a 6-month study comparing corticosteroids (1 gm of intravenous MTP day for first 3 days of months 1, 3 and 5 followed by 27 days of oral methylprednisolone 0.5 mg/kg/day for the remainder of the month) alternating monthly with either chlorambucil (0.2 mg/kg/day) or oral cyclophosphamide (2.5 mg/kg/day) in months 2, 4 and 6 [59]. No significant differences were observed between the two groups with respect to remission rate (CR or PR) at 1 year (82 vs. 93%, respectively, *p* = 0.116), subsequent relapse rate (31 vs. 25%, or changes in proteinuria or reciprocal serum creatinine over time.

In an open-label, parallel-arm, randomised controlled trial, Jha and colleagues compared the effects of alternating monthly prednisolone and cyclophosphamide for 6 months versus conservative treatment (salt restriction, blood pressure control and diuretic therapy) on remission, kidney disease progression and quality of life in adult patients with MN and nephrotic syndrome [60]. Compared with controls, those who received cyclophosphamide and steroids were more likely to achieve remission (72 vs. 35%, *p* < 0.001) and have better kidney survival, defined as not experiencing doubling of serum creatinine, dialysis or death (79 vs. 44%, *p* = 0.0006) [60]. They also had higher mean quality of life scores at 10 years, as measured by a visual analogue scale (7.31 ± 0.76 vs. 6.61 ± 1.08, *p* < 0.01). Infectious complications were similar between the groups.

Adverse effects associated with these agents, particularly infertility and malignancy, are the major drawbacks of cytotoxics combined with corticosteroids. The risk of malignancy is not increased for patients treated with cumulative cyclophosphamide doses of up to 36 g but increases significantly thereafter [61].

#### **13.3 Cyclosporine**

Early uncontrolled studies of cyclosporine (CSA) suggested an initial benefit but a high relapse rate [62, 63]. In the first single-blind randomised controlled study, 51 patients with steroid-resistant MN were treated with low-dose prednisone (0.15 mg/kg/day up to a maximum dose of 15 mg and reduced after 26 weeks by thirds at 4-week intervals) plus CsA (3.5 mg/kg/day in two divided doses and aiming for a trough level between 125 and 225 μg/L) and compared to patients treated with placebo plus prednisone (similar dose to treatment arm) [64]. At the end of 26 weeks of treatment, 75% of patients (21 of 28) in the CsA group versus only 22% of patients (5 of 23) in the controls had achieved a CR or PR (*P* < 0.001). Relapses occurred in about 40% of patients within 1 year of discontinuation of CsA treatment. In an observational study of 36 adults with idiopathic MN and steroiddependent or -resistant nephrotic syndrome treated with CsA (5.54 ± 0.81 mg/kg/ day), the German Cyclosporine in Nephrotic Syndrome Study Group reported that prolonging CsA treatment (>1 year) resulted in a higher (34% CR at 1 year) and more sustained rate of remission [65]. Prolonged low-dose CsA (~1.5 mg/kg/day) could be considered for long-term maintenance of patients who achieve CR or PR, especially in patients at high risk of relapse [66]. However, this needs to be weighed against the risk of renal scarring from long-term exposure to CsA.

#### **13.4 Tacrolimus**

Tacrolimus is also a reasonable consideration for the treatment of MN. In an open-label, randomised controlled trial of tacrolimus versus conservative therapy in 48 patients with MN, normal kidney function and nephrotic syndrome from 13 Spanish centres, Praga et al. demonstrated that tacrolimus monotherapy resulted in a higher probability of remission (CR or PR) at 12 months (76 vs. 22%, *p* < 0.001) with shorter mean time to remission (61. vs. 11.3 months, *p* = 0.003) [67]. In patients with CR or PR at 18 months who subsequently had their tacrolimus withdrawn, 47% of patients experienced a relapse of nephrotic syndrome within a mean period of 4.2 months.

#### **14. Treatment of high-risk patients**

This group of patients is characterised by worsening kidney failure, extremely high anti-PLA2R antibodies or persistent high proteinuria (≥8 g/day).

**57**

*Membranous Nephropathy*

**14.1 Corticosteroids**

treatment group.

**14.3 Cyclosporine**

(*p* = 0.02).

**14.4 Mycophenolate mofetil**

*DOI: http://dx.doi.org/10.5772/intechopen.87051*

**14.2 Cytotoxic agents combined with corticosteroids**

chlorambucil group (52 vs. 46 vs. 29%, respectively).

nine clearance of these patients was 51 mL/minute/1.73 m2

A prospective double-blind randomised controlled trial by the UK Medical Research assessed the medium-term effect of an 8-week course of high-dose prednisolone (100–150 mg on alternate day) in a high risk MN population [68]. A total of 103 patients with preserved kidney function (average creatinine clearance 88 ± 30 mL/minute) were randomised to the treatment group (*n* = 52) or to the control group (*n* = 51). At 36 months, there was no significant difference regarding the degree of proteinuria or loss of kidney function between the control and the

Another randomised controlled trial by the same group assessed whether immunosuppression preserved kidney function in patients with idiopathic MN and declining kidney function [69]. The study randomised patients to either combination of prednisolone and chlorambucil (intravenous methyl prednisolone 1 g per day for 3 consecutive days then oral prednisolone 0·5 mg/kg per day for 28 days during months 1, 3, and 5. During months 2, 4, and 6, patients received oral chlorambucil at a starting dose of 0·15 mg/kg per day) (*n* = 33) or CsA (12 months of CsA received a starting dose of 5 mg/kg per day, aiming for trough level of 100–200 μg/L) (*n* = 37) or supportive therapy alone (*n* = 38). The primary endpoint was a further 20% decline in Cockcroft-Gault estimated creatinine clearance and occurred less frequently in the prednisolone and chlorambucil group than in either the cyclosporin or supportive therapy groups (58 vs. 81 vs. 84%, respectively, *p* = 0.003). Serious adverse events were also most common in the prednisolone and

So far, there has been only one controlled trial with CsA in patients with highgrade proteinuria and progressive kidney failure. In this study, patients with high risk features were randomly assigned to either CsA (3.5 mg/kg/day taken in two divided doses, and aiming for trough level between 110 and 170 μg/L) treatment (nine patients) or placebo (eight patients) for 12 months) [70]. The average creati-

daily urine protein excretion of 11.5 g/day. After 12 months, there was a significant improvement in renal function as measured by the change in slopes, being greater in the CsA versus placebo patients [70 vs. 7% improvement, mean difference 1.5 (95% CI 0.2–3.1)]. Proteinuria in the CsA group was reduced by an average of 4.5 g/day, where in the placebo group there was an increase of 0.7 g/day by month 3

In a pilot study, Miller et al. treated 16 medium or high risk MN patients with 1.5–2 g/day of mycophenolate mofetil for a mean period of 8 months [71]. There were no significant changes in mean serum creatinine or albumin levels over the course of the study. Similar results were reported in a retrospective analysis of 17 patients with MN [72], in which treatment with mycophenolate mofetil for 12 months combined with steroids resulted in a 61% reduction of proteinuria.

Kidney function improved in three of six patients with kidney failure.

and they had an average

#### **14.1 Corticosteroids**

*Glomerulonephritis and Nephrotic Syndrome*

complications were similar between the groups.

**13.3 Cyclosporine**

**13.4 Tacrolimus**

period of 4.2 months.

**14. Treatment of high-risk patients**

for 6 months versus conservative treatment (salt restriction, blood pressure control and diuretic therapy) on remission, kidney disease progression and quality of life in adult patients with MN and nephrotic syndrome [60]. Compared with controls, those who received cyclophosphamide and steroids were more likely to achieve remission (72 vs. 35%, *p* < 0.001) and have better kidney survival, defined as not experiencing doubling of serum creatinine, dialysis or death (79 vs. 44%, *p* = 0.0006) [60]. They also had higher mean quality of life scores at 10 years, as measured by a visual analogue scale (7.31 ± 0.76 vs. 6.61 ± 1.08, *p* < 0.01). Infectious

Adverse effects associated with these agents, particularly infertility and malignancy, are the major drawbacks of cytotoxics combined with corticosteroids. The risk of malignancy is not increased for patients treated with cumulative cyclophos-

Early uncontrolled studies of cyclosporine (CSA) suggested an initial benefit but a high relapse rate [62, 63]. In the first single-blind randomised controlled study, 51 patients with steroid-resistant MN were treated with low-dose prednisone (0.15 mg/kg/day up to a maximum dose of 15 mg and reduced after 26 weeks by thirds at 4-week intervals) plus CsA (3.5 mg/kg/day in two divided doses and aiming for a trough level between 125 and 225 μg/L) and compared to patients treated with placebo plus prednisone (similar dose to treatment arm) [64]. At the end of 26 weeks of treatment, 75% of patients (21 of 28) in the CsA group versus only 22% of patients (5 of 23) in the controls had achieved a CR or PR (*P* < 0.001). Relapses occurred in about 40% of patients within 1 year of discontinuation of CsA treatment. In an observational study of 36 adults with idiopathic MN and steroiddependent or -resistant nephrotic syndrome treated with CsA (5.54 ± 0.81 mg/kg/ day), the German Cyclosporine in Nephrotic Syndrome Study Group reported that prolonging CsA treatment (>1 year) resulted in a higher (34% CR at 1 year) and more sustained rate of remission [65]. Prolonged low-dose CsA (~1.5 mg/kg/day) could be considered for long-term maintenance of patients who achieve CR or PR, especially in patients at high risk of relapse [66]. However, this needs to be weighed

phamide doses of up to 36 g but increases significantly thereafter [61].

against the risk of renal scarring from long-term exposure to CsA.

Tacrolimus is also a reasonable consideration for the treatment of MN. In an open-label, randomised controlled trial of tacrolimus versus conservative therapy in 48 patients with MN, normal kidney function and nephrotic syndrome from 13 Spanish centres, Praga et al. demonstrated that tacrolimus monotherapy resulted in a higher probability of remission (CR or PR) at 12 months (76 vs. 22%, *p* < 0.001) with shorter mean time to remission (61. vs. 11.3 months, *p* = 0.003) [67]. In patients with CR or PR at 18 months who subsequently had their tacrolimus withdrawn, 47% of patients experienced a relapse of nephrotic syndrome within a mean

This group of patients is characterised by worsening kidney failure, extremely

high anti-PLA2R antibodies or persistent high proteinuria (≥8 g/day).

**56**

A prospective double-blind randomised controlled trial by the UK Medical Research assessed the medium-term effect of an 8-week course of high-dose prednisolone (100–150 mg on alternate day) in a high risk MN population [68]. A total of 103 patients with preserved kidney function (average creatinine clearance 88 ± 30 mL/minute) were randomised to the treatment group (*n* = 52) or to the control group (*n* = 51). At 36 months, there was no significant difference regarding the degree of proteinuria or loss of kidney function between the control and the treatment group.

#### **14.2 Cytotoxic agents combined with corticosteroids**

Another randomised controlled trial by the same group assessed whether immunosuppression preserved kidney function in patients with idiopathic MN and declining kidney function [69]. The study randomised patients to either combination of prednisolone and chlorambucil (intravenous methyl prednisolone 1 g per day for 3 consecutive days then oral prednisolone 0·5 mg/kg per day for 28 days during months 1, 3, and 5. During months 2, 4, and 6, patients received oral chlorambucil at a starting dose of 0·15 mg/kg per day) (*n* = 33) or CsA (12 months of CsA received a starting dose of 5 mg/kg per day, aiming for trough level of 100–200 μg/L) (*n* = 37) or supportive therapy alone (*n* = 38). The primary endpoint was a further 20% decline in Cockcroft-Gault estimated creatinine clearance and occurred less frequently in the prednisolone and chlorambucil group than in either the cyclosporin or supportive therapy groups (58 vs. 81 vs. 84%, respectively, *p* = 0.003). Serious adverse events were also most common in the prednisolone and chlorambucil group (52 vs. 46 vs. 29%, respectively).

#### **14.3 Cyclosporine**

So far, there has been only one controlled trial with CsA in patients with highgrade proteinuria and progressive kidney failure. In this study, patients with high risk features were randomly assigned to either CsA (3.5 mg/kg/day taken in two divided doses, and aiming for trough level between 110 and 170 μg/L) treatment (nine patients) or placebo (eight patients) for 12 months) [70]. The average creatinine clearance of these patients was 51 mL/minute/1.73 m2 and they had an average daily urine protein excretion of 11.5 g/day. After 12 months, there was a significant improvement in renal function as measured by the change in slopes, being greater in the CsA versus placebo patients [70 vs. 7% improvement, mean difference 1.5 (95% CI 0.2–3.1)]. Proteinuria in the CsA group was reduced by an average of 4.5 g/day, where in the placebo group there was an increase of 0.7 g/day by month 3 (*p* = 0.02).

#### **14.4 Mycophenolate mofetil**

In a pilot study, Miller et al. treated 16 medium or high risk MN patients with 1.5–2 g/day of mycophenolate mofetil for a mean period of 8 months [71]. There were no significant changes in mean serum creatinine or albumin levels over the course of the study. Similar results were reported in a retrospective analysis of 17 patients with MN [72], in which treatment with mycophenolate mofetil for 12 months combined with steroids resulted in a 61% reduction of proteinuria. Kidney function improved in three of six patients with kidney failure.

Branten et al. reported 32 patients with MN and kidney insufficiency treated with mycophenolate mofetil (1 g twice a day) plus steroids (IV MTP 1 g for 3 consecutive days at the beginning of months 1, 3, and 5 and oral prednisone, 0.5 mg/kg every other day, for 6 months with subsequent tapering for 12 months) and compared the results with those obtained for 32 patients from a historic control group treated for the same period of time with oral cyclophosphamide (1.5 mg/kg/day) and steroids (similar steroid schedule to above) [73]. Overall, 21 mycophenolatetreated patients developed PR of proteinuria, six patients experienced at least 50% reduction in proteinuria, and five patients experienced no response. No significant differences were observed between the intervention and control groups at 12 months with respect to the occurrence of CR or PR (66 vs. 72%, respectively, *p* = 0.30) or adverse drug reactions (75 vs. 69%, *p* = 0.60), although relapse occurred more frequently in those who received mycophenolate mofetil (38 vs. 13%, *p* < 0.01).

#### **14.5 Rituximab**

In a pilot study of eight MN patients treated with four weekly courses of rituximab (375 mg/m2 ), two achieved CR and three achieved PR by 12 months [74, 75]. Mean 24-hour urinary protein excretion rates fell by 66% from 8.6 to 3.0 g (*p* < 0.005). Kidney function remained stable in all patients. Adverse effects were reported as mild and included chills, fever and an anxiety reaction.

In another prospective open-label pilot trial, 15 patients with idiopathic MN and proteinuria of >4 g/24 hour despite conservative therapy for >3 months received two doses of rituximab (1 g) 2 weeks apart [76]. At 6 months, another two fortnightly doses of rituximab were administered to patients with measured 24-hour urinary protein excretion rates exceeding 3 g and total CD19<sup>+</sup> B-cell counts exceeding 15 cells/μL. Mean proteinuria levels decreased by 54% from 13.0 g/24 hour at baseline to 6.0 g/24 hour at 12 months. At 12 months, two patients achieved CR, six achieved PR, five did not respond and two progressed to ESKD. Rituximab was well-tolerated and was effective in reducing proteinuria in patients with idiopathic MN.

The Evaluate Rituximab Treatment for Idiopathic Membranous Nephropathy (GEMRITUX) study was a French multicentre, randomised, controlled trial which evaluated the efficacy of rituximab in inducing remission in medium- to high-risk patients with idiopathic membranous nephropathy [77]. Thirty-seven patients received both rituximab (375 mg/m2 on days 1 and 8) and conservative therapy and 38 patients received conservative therapy alone. There was no significant difference in remission rates at 6 months (35.1% in rituximab group compared to 21.1% in conservative group, *p* = 0.21). However, with extended follow up (median 17.0 months), remission rates were significantly higher in the rituximab group (64.9 vs. 34.2%, *p* < 0.01).

The Membranous Nephropathy Trial Of Rituximab (MENTOR) study (NCT01180036) was a multicentre, randomised controlled trial comparing the efficacy and safety of rituximab to CsA in medium to high-risk patients with idiopathic MN [78]. Patients with proteinuria ≥5 g/24 hour following a minimum period of 3 months of conservative non-immunosuppressive therapy were randomised to receive IV rituximab 1000 mg (day 1 and 15, then repeated at 6 months) or oral CsA (3.5 mg/kg/day for 12 months). Patients who received CsA had a higher rate of treatment failure at 24 months compared with those who received rituximab (79.4 vs. 37.5%), and CR or PR occurred in 62.5% of the rituximab cohort compared with 20.6% of those who received CsA (odds ratio 6.0, 95% CI 2.7–13.2, *P* < 0.0001).

**59**

another four patients.

course of immunosuppression.

*Membranous Nephropathy*

**14.6 Eculizumab**

*DOI: http://dx.doi.org/10.5772/intechopen.87051*

**14.7 Adrenocorticotropic hormone**

Numerous prospective uncontrolled studies have been performed evaluating the efficacy of rituximab in idiopathic MN and are summarised in **Table 1** [75, 77–87].

Eculizumab is a humanised anti-C5 monoclonal antibody designed to prevent the cleavage of C5 into its proinflammatory by-products. In a randomised placebocontrolled trial in 200 patients with MN, eculizumab, although well-tolerated, failed to show any significant reduction of proteinuria. There were concerns that the dosing schedules were inadequate as inhibition of complement was not uniformly demonstrated. Patients in the eculizumab arm were treated every 2 weeks with two different intravenous dose regimens over a total of 16 weeks [88]. Neither of the active drug regimens of eculizumab showed any significant effect on proteinuria or kidney function compared to placebo. More encouraging results were seen in a continuation of the original study, in which eculizumab was used for up to 1 year, with a significant reduction in proteinuria in some patients (including two patients who went into CR). More long-term studies need to be performed with anti-C5 monoclonal antibody to determine its role in the treatment of MN.

In a study by Berg and colleagues, synthetic adrenocorticotropic hormone (ACTH) administered 1 mg twice per week for 1 year decreased proteinuria in patients with idiopathic MN [89, 90]. Ponticelli et al. conducted a randomised pilot study comparing methylprednisolone plus a cytotoxic agent versus synthetic ACTH in 32 patients with idiopathic MN [91]. In this study, 16 patients were randomly assigned to receive three cycles of MTP (IV MTP 1 g, administered for 3 consecutive days, and then 0.4 mg/kg body weight per day for 27 days, administered orally) and each cycle was followed by 1 month of treatment with either chlorambucil (0.2 mg/kg/day orally) or cyclophosphamide (2.5 mg/kg/ day orally), and 16 were assigned to receive ACTH 1 mg intramuscular injections administered initially one injection every other week to two injections per week for a total treatment period of 1 year. No significant differences were observed in remission rates between the ACTH and control groups (87 vs. 93%, respectively), Medication discontinuation rates due to lack of efficacy or adverse drug reactions were 12.5% in both groups. A pilot study by Hladunewich et al. administered 20 idiopathic MN patients with either 40 or 80 IU twice-weekly dose of Acthar® gel and found a significant improvement in proteinuria at 12 months in the entire cohort [92]. There was >50% decrease in proteinuria in 65% of patients and no significant adverse effects were documented. Improvement in serum anti-PLA2R antibodies was not noted in all patients. Measured anti-PLA2R antibodies became undetectable in three out of 15 patients and appreciably declined in

A suggested, risk-based treatment algorithm is displayed in **Figure 4**. It is intended as a guide only and should additionally take into account individual patient circumstances and preferences. Patients who do not respond well or relapse after a first course of immunosuppression therapy may benefit from a second

Patients with severe kidney insufficiency (serum creatinine of ≥3.5 mg/dL or 309 μmol/L) are less likely to benefit from immunosuppression therapy and more likely to experience treatment-related harm, such that consideration should be given to conservative therapy only and plans made for transplantation in the future [41].

Numerous prospective uncontrolled studies have been performed evaluating the efficacy of rituximab in idiopathic MN and are summarised in **Table 1** [75, 77–87].

#### **14.6 Eculizumab**

*Glomerulonephritis and Nephrotic Syndrome*

(38 vs. 13%, *p* < 0.01).

rituximab (375 mg/m2

patients with idiopathic MN.

(64.9 vs. 34.2%, *p* < 0.01).

received both rituximab (375 mg/m2

**14.5 Rituximab**

Branten et al. reported 32 patients with MN and kidney insufficiency treated with mycophenolate mofetil (1 g twice a day) plus steroids (IV MTP 1 g for 3 consecutive days at the beginning of months 1, 3, and 5 and oral prednisone, 0.5 mg/kg every other day, for 6 months with subsequent tapering for 12 months) and compared the results with those obtained for 32 patients from a historic control group treated for the same period of time with oral cyclophosphamide (1.5 mg/kg/day) and steroids (similar steroid schedule to above) [73]. Overall, 21 mycophenolatetreated patients developed PR of proteinuria, six patients experienced at least 50% reduction in proteinuria, and five patients experienced no response. No significant differences were observed between the intervention and control groups at 12 months with respect to the occurrence of CR or PR (66 vs. 72%, respectively, *p* = 0.30) or adverse drug reactions (75 vs. 69%, *p* = 0.60), although relapse occurred more frequently in those who received mycophenolate mofetil

In a pilot study of eight MN patients treated with four weekly courses of

reported as mild and included chills, fever and an anxiety reaction.

24-hour urinary protein excretion rates exceeding 3 g and total CD19<sup>+</sup>

counts exceeding 15 cells/μL. Mean proteinuria levels decreased by 54% from 13.0 g/24 hour at baseline to 6.0 g/24 hour at 12 months. At 12 months, two patients achieved CR, six achieved PR, five did not respond and two progressed to ESKD. Rituximab was well-tolerated and was effective in reducing proteinuria in

and 38 patients received conservative therapy alone. There was no significant difference in remission rates at 6 months (35.1% in rituximab group compared to 21.1% in conservative group, *p* = 0.21). However, with extended follow up (median 17.0 months), remission rates were significantly higher in the rituximab group

The Membranous Nephropathy Trial Of Rituximab (MENTOR) study (NCT01180036) was a multicentre, randomised controlled trial comparing the efficacy and safety of rituximab to CsA in medium to high-risk patients with idiopathic MN [78]. Patients with proteinuria ≥5 g/24 hour following a minimum period of 3 months of conservative non-immunosuppressive therapy were randomised to receive IV rituximab 1000 mg (day 1 and 15, then repeated at 6 months) or oral CsA (3.5 mg/kg/day for 12 months). Patients who received CsA had a higher rate of treatment failure at 24 months compared with those who received rituximab (79.4 vs. 37.5%), and CR or PR occurred in 62.5% of the rituximab cohort compared with 20.6% of those who received CsA (odds ratio 6.0, 95% CI 2.7–13.2, *P* < 0.0001).

The Evaluate Rituximab Treatment for Idiopathic Membranous Nephropathy (GEMRITUX) study was a French multicentre, randomised, controlled trial which evaluated the efficacy of rituximab in inducing remission in medium- to high-risk patients with idiopathic membranous nephropathy [77]. Thirty-seven patients

[74, 75]. Mean 24-hour urinary protein excretion rates fell by 66% from 8.6 to 3.0 g (*p* < 0.005). Kidney function remained stable in all patients. Adverse effects were

In another prospective open-label pilot trial, 15 patients with idiopathic MN and proteinuria of >4 g/24 hour despite conservative therapy for >3 months received two doses of rituximab (1 g) 2 weeks apart [76]. At 6 months, another two fortnightly doses of rituximab were administered to patients with measured

), two achieved CR and three achieved PR by 12 months

on days 1 and 8) and conservative therapy

B-cell

**58**

Eculizumab is a humanised anti-C5 monoclonal antibody designed to prevent the cleavage of C5 into its proinflammatory by-products. In a randomised placebocontrolled trial in 200 patients with MN, eculizumab, although well-tolerated, failed to show any significant reduction of proteinuria. There were concerns that the dosing schedules were inadequate as inhibition of complement was not uniformly demonstrated. Patients in the eculizumab arm were treated every 2 weeks with two different intravenous dose regimens over a total of 16 weeks [88]. Neither of the active drug regimens of eculizumab showed any significant effect on proteinuria or kidney function compared to placebo. More encouraging results were seen in a continuation of the original study, in which eculizumab was used for up to 1 year, with a significant reduction in proteinuria in some patients (including two patients who went into CR). More long-term studies need to be performed with anti-C5 monoclonal antibody to determine its role in the treatment of MN.

#### **14.7 Adrenocorticotropic hormone**

In a study by Berg and colleagues, synthetic adrenocorticotropic hormone (ACTH) administered 1 mg twice per week for 1 year decreased proteinuria in patients with idiopathic MN [89, 90]. Ponticelli et al. conducted a randomised pilot study comparing methylprednisolone plus a cytotoxic agent versus synthetic ACTH in 32 patients with idiopathic MN [91]. In this study, 16 patients were randomly assigned to receive three cycles of MTP (IV MTP 1 g, administered for 3 consecutive days, and then 0.4 mg/kg body weight per day for 27 days, administered orally) and each cycle was followed by 1 month of treatment with either chlorambucil (0.2 mg/kg/day orally) or cyclophosphamide (2.5 mg/kg/ day orally), and 16 were assigned to receive ACTH 1 mg intramuscular injections administered initially one injection every other week to two injections per week for a total treatment period of 1 year. No significant differences were observed in remission rates between the ACTH and control groups (87 vs. 93%, respectively), Medication discontinuation rates due to lack of efficacy or adverse drug reactions were 12.5% in both groups. A pilot study by Hladunewich et al. administered 20 idiopathic MN patients with either 40 or 80 IU twice-weekly dose of Acthar® gel and found a significant improvement in proteinuria at 12 months in the entire cohort [92]. There was >50% decrease in proteinuria in 65% of patients and no significant adverse effects were documented. Improvement in serum anti-PLA2R antibodies was not noted in all patients. Measured anti-PLA2R antibodies became undetectable in three out of 15 patients and appreciably declined in another four patients.

A suggested, risk-based treatment algorithm is displayed in **Figure 4**. It is intended as a guide only and should additionally take into account individual patient circumstances and preferences. Patients who do not respond well or relapse after a first course of immunosuppression therapy may benefit from a second course of immunosuppression.

Patients with severe kidney insufficiency (serum creatinine of ≥3.5 mg/dL or 309 μmol/L) are less likely to benefit from immunosuppression therapy and more likely to experience treatment-related harm, such that consideration should be given to conservative therapy only and plans made for transplantation in the future [41].


**61**

**Author/year** Ruggenenti/2012

Prospective

High

100

RTX 375 mg/m2 weekly ×4

[84]

Fervenza/2010

Prospective

Medium

20

RTX 375 mg/m2 weekly ×4, repeated at 6 months

Not

specified

[85]

Fervenza/2008

Prospective

High

14

RTX 1000 mg on day 1 and 15, repeated at 6 months if

12

At 6 months, four achieved PR. At

12 months, two achieved CR and 6 PR.

At 24 months, CR or PR in RTX arm was 62.5

vs. 20.6% in the CsA arm

Treatment failure higher in CsA group

compared to RTX group (79.4 vs. 37.5%).

Results awaited

proteinuria >3 g/24 hours and CD9 + B cell >15 cells/μL

RTX 1000 mg on day 1 and 15, repeated at 6 months vs.

24

CsA 3.5–5 mg/kg/day for 6 months

[86]

Fervenza/2015

RCT

High

130

[78]

Results from

abstract

Rojas-Rivera/2015 [87]

RCT

High

MTP 1 g IV day 1–3 then MTP PO 0.5 mg/kg/day for day 4–30 on months 1, 3 and 5 and cyclophosphamide

PO 2.0 mg/kg/day for 30 days on months 2, 4 and 6 vs.

tacrolimus 0.05 mg/kg/day for 6 months, then tapered

to withdrawal by 9 months + RTX 1 g at day 180.

*Abbreviations are: RCT, randomised controlled trial; RTX, rituximab; NIAT, non-immunosuppressive antiproteinuric therapy; CsA, cyclosporine; CR, CR; PR, partial remission; MTP, methylprednisolone;* 

*PO, per oral.*

**Table 1.**

*Rituximab treatment of idiopathic MN.*

**Level of evidence**

**Risk group**

**N**

**Treatment regimens**

**Median** 

**Outcomes/comments**

**follow-up** 

**(months)**

29 (median)

At end of follow up, 65% achieved CR or

PR. Median time to remission 7.1 months.

Kidney function improved in those who

achieved CR.

*Membranous Nephropathy*

*DOI: http://dx.doi.org/10.5772/intechopen.87051*

Proteinuria reduced from 11.9 g/24 hours to

4.2 and 2.0 g/24 hours at 12 and 24 months,

respectively. At 24 months, 4 of 18 achieved

CR, 12 of 18 achieved PR and 1 relapsed.

Remission rates higher than fortnightly

dosing.


**Table 1.**

*Rituximab treatment of idiopathic MN.*

#### *Membranous Nephropathy DOI: http://dx.doi.org/10.5772/intechopen.87051*

*Glomerulonephritis and Nephrotic Syndrome*

**60**

**Author/year** Dahan/2017 [77]

Fiorentino/2016

Prospective

Mediumhigh

38

RTX 375 mg/m2 monthly × 6

15

uncontrolled

[79]

Bagchi/2018 [80]

Moroni [81] Waldman/2016

Prospective

High

13

CsA 3 mg/kg/day for 6 months then tapered by 50 mg/

41 (mean)

By 6 months 85% achieved remission

(CR + PR). By 12 months, 54% achieved CR.

2 relapsed by 24 months. Treatment well

tolerated.

day every 3 weeks plus RTX 1000 mg day 1 and 15, then

after 6 months when CD19+ B cell count ≥5 cells/μL.

[82]

Ruggenenti/2015

Prospective

High

132

RTX 375 mg/m2 weekly ×4

30.8

84 of 132 (63.6%) achieved remission

(CR + PR), 43 (32.6%) achieved CR. Anti-

R antibody depletion preceded 2

PLA remission.

[83]

Ruggenenti/2003

Prospective

Medium

8

RTX 375 mg/m2 weekly ×4

Not

Significant reduction in proteinuria. Kidney

function stabilised. two achieved CR and

three achieved PR.

specified

[75]

Prospective

Mediumhigh

34 (*n* = 16)

RTX 375 mg/m2 × 1 dose (*n* = 18) or ×2 2 weeks apart

23.9 (mean)

At 12 months, 5 (14.7%) CR, 10 (29.4%) PR

and 19 (55.8%) no response. Outcome similar

for one vs. two doses.

uncontrolled

Retrospective

High

21

RTX 500 mg × 2 doses 7–10 days apart ± 3rd dose after

13

4–6 weeks if CD19 not depleted

uncontrolled

RCT

Mediumhigh

75

RTX 375 mg/m2 on day 1 and 8 + NIAT vs. NIAT alone

17

At 6 months, 13 of 37 (35.1%) treated with RTX + NIAT achieved remission vs. 8 of 38

(21.1%) controls (*p* = 0.21). Significantly

higher rates of PLA

and 6 months in RTX + NIAT group.

29 of 38 (76.3%) achieved remission −15 (39.5%) CR and 14 (36.8%) PR. Proteinuria

significantly reduced. Kidney function

stable. No significant adverse events.

13 of 21 (61.9%) achieved remission −4

(19.05) CR and 9 (42.9%) PR. One patient

relapsed after achieving PR. Kidney survival

was significantly better in responders (*p*

−0.0037).

R antibody depletion at 3 2

**Level of** 

**Risk** 

**N**

**Treatment regimens**

**Median** 

**Outcomes/comments**

**follow-up** 

**(months)**

**group**

**evidence**

#### **Figure 4.**

*Treatment algorithm for idiopathic MN. Based on the renal function and degree of proteinuria at presentation, patients with MN can be classified in to low, medium and high risk category for progression. Patients in the low risk category should be managed with conservative therapy alone but during follow up if they transform in to medium or high risk category then they should be considered for immunosuppressive therapy. Patients in the medium risk category should be treated with conservative therapy for at least 6 months and despite that if they still have more than 4 g/ day of proteinuria then they should be considered for immunosuppressive therapy. Patients in the high risk category shouldn't wait for 6 months before starting immunosuppressive therapy. Patients in the medium or high risk category could be treated with either cytotoxics plus corticosteroids or CNI plus corticosteroids or rituximab with or without CNI. If there is no response to one agent, consider alternate agent. If the patient is refractory to all three agents, then they could be treated either with MMF or ACTH.* <sup>⋆</sup> *Conservative treatment involves the use of ACEi ± ARB blocker to maintain BP < 125/75 mmHg, lipid control with HMG-CoA reductase inhibitor, dietary protein restriction (0.6–0.8 g/kg ideal body weight/day), dietary NaCl intake (goal is 2–3 g Na) to optimise antiproteinuric effects of ACEi and ARBs, smoking cessation, and attempt to reduce obesity, if present. Abbreviations are: anti-PLA2R, phospholipase A2 receptor antibody; ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CNI, calcineurin inhibitor; ACTH, adrenocorticotrophic hormone; MMF, mycophenolate mofetil.*

#### **15. Conclusion**

In conclusion, controlling proteinuria (either CR or PR) in MN is clearly associated with a slower rate of kidney disease progression. Newer biomarkers, such anti-PLA2R antibody and THSD7A, are showing some promising role in differentiating between primary versus secondary MN, predicting prognosis and response to therapy. There are no standard or universal first-line specific therapeutic options for idiopathic MN. Supportive or conservative care, including dietary salt restriction, anti-proteinuric therapy with ACEi or ARB, optimisation of blood pressure and serum cholesterol, and management of cardiovascular and thromboembolic risks, should be given in all cases. Immunosuppressive therapy, such as cytotoxic agents and steroids, calcineurin inhibitors and steroids, rituximab (with or without calcineurin inhibitors), and ACTH, should be considered in patients at medium or high risk of kidney disease progression, cardiovascular disease or thromboembolic complications, as evidenced by heavy proteinuria (>4 g/day) and/or deteriorating kidney function.

#### **Acknowledgements**

The authors would like to thank Dr. Jasveen Renthawa for providing the renal biopsy images.

**63**

*Membranous Nephropathy*

**Author details**

Australia

and David Johnson2,10,11\*

*DOI: http://dx.doi.org/10.5772/intechopen.87051*

Bhadran Bose1,2, Sunil V. Badve2,3,4, Vivekanand Jha5,6,7, Chen Au Peh8,9

1 Department of Nephrology, Nepean Hospital, Kingswood, Australia

3 Department of Nephrology, St George Hospital, Sydney, Australia

4 The George Institute for Global Health, Sydney, Australia

5 The George Institute for Global Health, New Delhi, India

7 University of New South Wales, Sydney, Australia

11 Translational Research Institute, Brisbane, Australia

\*Address all correspondence to: david.johnson2@health.qld.gov.au

9 University of Adelaide, Adelaide, Australia

provided the original work is properly cited.

6 University of Oxford, Oxford, UK

2 Australasian Kidney Trials Network, University of Queensland, Brisbane,

8 Department of Renal Medicine, Royal Adelaide Hospital, Adelaide, Australia

10 Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

#### **Conflict of interest**

Authors declare no conflict of interest.

### **Author details**

*Glomerulonephritis and Nephrotic Syndrome*

**62**

**15. Conclusion**

*they could be treated either with MMF or ACTH.* <sup>⋆</sup>

**Figure 4.**

**Acknowledgements**

**Conflict of interest**

Authors declare no conflict of interest.

biopsy images.

In conclusion, controlling proteinuria (either CR or PR) in MN is clearly associ-

*Conservative treatment involves the use of ACEi ± ARB blocker* 

*Treatment algorithm for idiopathic MN. Based on the renal function and degree of proteinuria at presentation, patients with MN can be classified in to low, medium and high risk category for progression. Patients in the low risk category should be managed with conservative therapy alone but during follow up if they transform in to medium or high risk category then they should be considered for immunosuppressive therapy. Patients in the medium risk category should be treated with conservative therapy for at least 6 months and despite that if they still have more than 4 g/ day of proteinuria then they should be considered for immunosuppressive therapy. Patients in the high risk category shouldn't wait for 6 months before starting immunosuppressive therapy. Patients in the medium or high risk category could be treated with either cytotoxics plus corticosteroids or CNI plus corticosteroids or rituximab with or without CNI. If there is no response to one agent, consider alternate agent. If the patient is refractory to all three agents, then* 

*to maintain BP < 125/75 mmHg, lipid control with HMG-CoA reductase inhibitor, dietary protein restriction (0.6–0.8 g/kg ideal body weight/day), dietary NaCl intake (goal is 2–3 g Na) to optimise antiproteinuric effects of ACEi and ARBs, smoking cessation, and attempt to reduce obesity, if present. Abbreviations are: anti-PLA2R, phospholipase A2 receptor antibody; ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CNI, calcineurin inhibitor; ACTH, adrenocorticotrophic hormone; MMF, mycophenolate mofetil.*

The authors would like to thank Dr. Jasveen Renthawa for providing the renal

ated with a slower rate of kidney disease progression. Newer biomarkers, such anti-PLA2R antibody and THSD7A, are showing some promising role in differentiating between primary versus secondary MN, predicting prognosis and response to therapy. There are no standard or universal first-line specific therapeutic options for idiopathic MN. Supportive or conservative care, including dietary salt restriction, anti-proteinuric therapy with ACEi or ARB, optimisation of blood pressure and serum cholesterol, and management of cardiovascular and thromboembolic risks, should be given in all cases. Immunosuppressive therapy, such as cytotoxic agents and steroids, calcineurin inhibitors and steroids, rituximab (with or without calcineurin inhibitors), and ACTH, should be considered in patients at medium or high risk of kidney disease progression, cardiovascular disease or thromboembolic complications, as evidenced by heavy proteinuria (>4 g/day) and/or deteriorating kidney function.

Bhadran Bose1,2, Sunil V. Badve2,3,4, Vivekanand Jha5,6,7, Chen Au Peh8,9 and David Johnson2,10,11\*

1 Department of Nephrology, Nepean Hospital, Kingswood, Australia

2 Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia

3 Department of Nephrology, St George Hospital, Sydney, Australia

4 The George Institute for Global Health, Sydney, Australia

5 The George Institute for Global Health, New Delhi, India

6 University of Oxford, Oxford, UK

7 University of New South Wales, Sydney, Australia

8 Department of Renal Medicine, Royal Adelaide Hospital, Adelaide, Australia

9 University of Adelaide, Adelaide, Australia

10 Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia

11 Translational Research Institute, Brisbane, Australia

\*Address all correspondence to: david.johnson2@health.qld.gov.au

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Swaminathan S, Leung N, Lager DJ, Melton LJ 3rd, Bergstralh EJ, Rohlinger A, et al. Changing incidence of glomerular disease in Olmsted County, Minnesota: A 30-year renal biopsy study. Clinical Journal of the American Society of Nephrology. 2006;**1**(3):483-487

[2] Haas M, Meehan SM, Karrison TG, Spargo BH. Changing etiologies of unexplained adult nephrotic syndrome: A comparison of renal biopsy findings from 1976-1979 and 1995-1997. American Journal of Kidney Diseases. 1997;**30**(5):621-631

[3] Glassock RJ. Secondary membranous glomerulonephritis. Nephrology, Dialysis, Transplantation. 1992;**7** (Suppl 1):64-71

[4] Cattran DC, Brenchley PE. Membranous nephropathy: Integrating basic science into improved clinical management. Kidney International. 2017;**91**(3):566-574

[5] Debiec H, Ronco P. Immunopathogenesis of membranous nephropathy: An update. Seminars in Immunopathology. 2014;**36**(4):381-397

[6] De Vriese AS, Glassock RJ, Nath KA, Sethi S, Fervenza FC. A proposal for a serology-based approach to membranous nephropathy. Journal of the American Society of Nephrology. 2017;**28**(2):421-430

[7] Hogan SL, Muller KE, Jennette JC, Falk RJ. A review of therapeutic studies of idiopathic membranous glomerulopathy. American Journal of Kidney Diseases. 1995;**25**(6):862-875

[8] Beck LH, Bonegio RGB, Lambeau G, Beck DM, Powell DW, Cummins TD, et al. M-type phospholipase A2 receptor as target antigen in idiopathic

membranous nephropathy. The New England Journal of Medicine. 2009;**361**(1):11-21

[9] Francis JM, Beck LH Jr, Salant DJ. Membranous nephropathy: A journey from bench to bedside. American Journal of Kidney Diseases. 2016;**68**(1):138-147

[10] Debiec H, Ronco P. Immune response against autoantigen PLA2R is not gambling: Implications for pathophysiology, prognosis, and therapy. Journal of the American Society of Nephrology. 2016;**27**(5):1275-1277

[11] Ronco P, Debiec H. Pathophysiological advances in membranous nephropathy: Time for a shift in patient's care. Lancet. 2015;**385**(9981):1983-1992

[12] Sinico RA, Mezzina N, Trezzi B, Ghiggeri GM, Radice A. Immunology of membranous nephropathy: From animal models to humans. Clinical and Experimental Immunology. 2016;**183**(2):157-165

[13] Hoxha E, Kneissler U, Stege G, Zahner G, Thiele I, Panzer U, et al. Enhanced expression of the M-type phospholipase A2 receptor in glomeruli correlates with serum receptor antibodies in primary membranous nephropathy. Kidney International. 2012;**82**(7):797-804

[14] Larsen CP, Messias NC, Silva FG, Messias E, Walker PD. Determination of primary versus secondary membranous glomerulopathy utilizing phospholipase A2 receptor staining in renal biopsies. Modern Pathology. 2013;**26**(5):709-715

[15] Xie Q, Li Y, Xue J, Xiong Z, Wang L, Sun Z, et al. Renal phospholipase A2 receptor in hepatitis B virusassociated membranous nephropathy.

**65**

*Membranous Nephropathy*

2015;**41**(4-5):345-353

2011;**364**(7):616-626

2013;**24**(8):1323-1329

2013;**83**(5):940-948

1995;**270**(15):8963-8970

*DOI: http://dx.doi.org/10.5772/intechopen.87051*

[22] Tomas NM, Beck LH, Meyer-Schwesinger C, Seitz-Polski B, Ma H, Zahner G, et al. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. The New England Journal of Medicine.

[23] Ren S, Wu C, Zhang Y, Wang AY, Li G, Wang L, et al. An update on clinical significance of use of THSD7A in diagnosing idiopathic membranous nephropathy: A systematic review and meta-analysis of THSD7A in IMN. Renal

[24] Larsen CP, Cossey LN, Beck LH. THSD7A staining of membranous glomerulopathy in clinical practice reveals cases with dual autoantibody positivity. Modern Pathology.

[25] Gluck MC, Gallo G, Lowenstein J,

[26] Schieppati A, Mosconi L, Perna A, Mecca G, Bertani T, Garattini S, et al. Prognosis of untreated patients with idiopathic membranous nephropathy. The New England Journal of Medicine.

[27] Hladunewich MA, Troyanov S, Calafati J, Cattran DC, Metropolitan Toronto Glomerulonephritis Registry. The natural history of the nonnephrotic membranous nephropathy patient. Clinical Journal of the American Society of Nephrology.

[28] Ramzy MH, Cameron JS, Turner DR, Neild GH, Ogg CS, Hicks J. The long-term outcome of idiopathic membranous nephropathy. Clinical Nephrology. 1981;**16**(1):13-19

[29] O'Callaghan CA, Hicks J, Doll H, Sacks SH, Cameron JS. Characteristics

2014;**371**(24):2277-2287

Failure. 2018;**40**(1):306-313

2016;**29**(4):421-426

1993;**329**(2):85-89

2009;**4**(9):1417-1422

Baldwin DS. Membranous glomerulonephritis. Evolution of clinical and pathologic features. Annals of Internal Medicine. 1973;**78**(1):1-12

American Journal of Nephrology.

[16] Stanescu HC, Arcos-Burgos M, Medlar A, Bockenhauer D, Kottgen A, Dragomirescu L, et al. Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy. The New England Journal of Medicine.

[17] Lv J, Hou W, Zhou X, Liu G, Zhou F, Zhao N, et al. Interaction between PLA2R1 and HLA-DQA1 variants associates with anti-PLA2R antibodies and membranous nephropathy. Journal of the American Society of Nephrology.

[18] Kanigicherla D, Gummadova J, McKenzie EA, Roberts SA, Harris S, Nikam M, et al. Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy. Kidney International.

[19] Ancian P, Lambeau G, Mattei MG, Lazdunski M. The human 180-kDa receptor for secretory phospholipases A2. Molecular cloning, identification of a secreted soluble form, expression, and chromosomal localization. The Journal of Biological Chemistry.

[20] Fresquet M, Jowitt TA, Gummadova J, Collins R, O'Cualain R, McKenzie EA, et al. Identification of a major epitope recognized by PLA2R autoantibodies in primary membranous nephropathy. Journal of the American Society of Nephrology. 2015;**26**(2):302-313

[21] Seitz-Polski B, Dolla G, Payre C, Girard CA, Polidori J, Zorzi K, et al. Epitope spreading of autoantibody response to PLA2R associates with poor prognosis in membranous nephropathy. Journal of the American Society of Nephrology. 2016;**27**(5):1517-1533

*Membranous Nephropathy DOI: http://dx.doi.org/10.5772/intechopen.87051*

American Journal of Nephrology. 2015;**41**(4-5):345-353

[16] Stanescu HC, Arcos-Burgos M, Medlar A, Bockenhauer D, Kottgen A, Dragomirescu L, et al. Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy. The New England Journal of Medicine. 2011;**364**(7):616-626

[17] Lv J, Hou W, Zhou X, Liu G, Zhou F, Zhao N, et al. Interaction between PLA2R1 and HLA-DQA1 variants associates with anti-PLA2R antibodies and membranous nephropathy. Journal of the American Society of Nephrology. 2013;**24**(8):1323-1329

[18] Kanigicherla D, Gummadova J, McKenzie EA, Roberts SA, Harris S, Nikam M, et al. Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy. Kidney International. 2013;**83**(5):940-948

[19] Ancian P, Lambeau G, Mattei MG, Lazdunski M. The human 180-kDa receptor for secretory phospholipases A2. Molecular cloning, identification of a secreted soluble form, expression, and chromosomal localization. The Journal of Biological Chemistry. 1995;**270**(15):8963-8970

[20] Fresquet M, Jowitt TA, Gummadova J, Collins R, O'Cualain R, McKenzie EA, et al. Identification of a major epitope recognized by PLA2R autoantibodies in primary membranous nephropathy. Journal of the American Society of Nephrology. 2015;**26**(2):302-313

[21] Seitz-Polski B, Dolla G, Payre C, Girard CA, Polidori J, Zorzi K, et al. Epitope spreading of autoantibody response to PLA2R associates with poor prognosis in membranous nephropathy. Journal of the American Society of Nephrology. 2016;**27**(5):1517-1533

[22] Tomas NM, Beck LH, Meyer-Schwesinger C, Seitz-Polski B, Ma H, Zahner G, et al. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. The New England Journal of Medicine. 2014;**371**(24):2277-2287

[23] Ren S, Wu C, Zhang Y, Wang AY, Li G, Wang L, et al. An update on clinical significance of use of THSD7A in diagnosing idiopathic membranous nephropathy: A systematic review and meta-analysis of THSD7A in IMN. Renal Failure. 2018;**40**(1):306-313

[24] Larsen CP, Cossey LN, Beck LH. THSD7A staining of membranous glomerulopathy in clinical practice reveals cases with dual autoantibody positivity. Modern Pathology. 2016;**29**(4):421-426

[25] Gluck MC, Gallo G, Lowenstein J, Baldwin DS. Membranous glomerulonephritis. Evolution of clinical and pathologic features. Annals of Internal Medicine. 1973;**78**(1):1-12

[26] Schieppati A, Mosconi L, Perna A, Mecca G, Bertani T, Garattini S, et al. Prognosis of untreated patients with idiopathic membranous nephropathy. The New England Journal of Medicine. 1993;**329**(2):85-89

[27] Hladunewich MA, Troyanov S, Calafati J, Cattran DC, Metropolitan Toronto Glomerulonephritis Registry. The natural history of the nonnephrotic membranous nephropathy patient. Clinical Journal of the American Society of Nephrology. 2009;**4**(9):1417-1422

[28] Ramzy MH, Cameron JS, Turner DR, Neild GH, Ogg CS, Hicks J. The long-term outcome of idiopathic membranous nephropathy. Clinical Nephrology. 1981;**16**(1):13-19

[29] O'Callaghan CA, Hicks J, Doll H, Sacks SH, Cameron JS. Characteristics

**64**

*Glomerulonephritis and Nephrotic Syndrome*

[1] Swaminathan S, Leung N, Lager DJ, Melton LJ 3rd, Bergstralh EJ, Rohlinger membranous nephropathy. The New England Journal of Medicine.

[9] Francis JM, Beck LH Jr, Salant DJ. Membranous nephropathy: A journey from bench to bedside. American Journal of Kidney Diseases.

[10] Debiec H, Ronco P. Immune response against autoantigen PLA2R is not gambling: Implications for pathophysiology, prognosis, and

therapy. Journal of the American Society of Nephrology. 2016;**27**(5):1275-1277

2009;**361**(1):11-21

2016;**68**(1):138-147

[11] Ronco P, Debiec H.

2015;**385**(9981):1983-1992

2016;**183**(2):157-165

2012;**82**(7):797-804

Pathophysiological advances in membranous nephropathy: Time for a shift in patient's care. Lancet.

[12] Sinico RA, Mezzina N, Trezzi B, Ghiggeri GM, Radice A. Immunology of membranous nephropathy: From animal models to humans. Clinical and Experimental Immunology.

[13] Hoxha E, Kneissler U, Stege G, Zahner G, Thiele I, Panzer U, et al. Enhanced expression of the M-type phospholipase A2 receptor in glomeruli

correlates with serum receptor antibodies in primary membranous nephropathy. Kidney International.

[14] Larsen CP, Messias NC, Silva FG, Messias E, Walker PD. Determination of primary versus secondary membranous glomerulopathy utilizing phospholipase A2 receptor staining in renal biopsies. Modern Pathology. 2013;**26**(5):709-715

[15] Xie Q, Li Y, Xue J, Xiong Z, Wang L, Sun Z, et al. Renal phospholipase A2 receptor in hepatitis B virusassociated membranous nephropathy.

[2] Haas M, Meehan SM, Karrison TG, Spargo BH. Changing etiologies of unexplained adult nephrotic syndrome: A comparison of renal biopsy findings from 1976-1979 and 1995-1997. American Journal of Kidney Diseases.

[3] Glassock RJ. Secondary membranous glomerulonephritis. Nephrology, Dialysis, Transplantation. 1992;**7**

Membranous nephropathy: Integrating basic science into improved clinical management. Kidney International.

Immunopathogenesis of membranous nephropathy: An update. Seminars in Immunopathology. 2014;**36**(4):381-397

[6] De Vriese AS, Glassock RJ, Nath KA, Sethi S, Fervenza FC. A proposal for a serology-based approach to membranous nephropathy. Journal of the American Society of Nephrology.

[7] Hogan SL, Muller KE, Jennette JC, Falk RJ. A review of therapeutic studies of idiopathic membranous glomerulopathy. American Journal of Kidney Diseases. 1995;**25**(6):862-875

[8] Beck LH, Bonegio RGB, Lambeau G, Beck DM, Powell DW, Cummins TD, et al. M-type phospholipase A2

receptor as target antigen in idiopathic

[4] Cattran DC, Brenchley PE.

A, et al. Changing incidence of glomerular disease in Olmsted County, Minnesota: A 30-year renal biopsy study. Clinical Journal of the American Society of Nephrology.

2006;**1**(3):483-487

**References**

1997;**30**(5):621-631

(Suppl 1):64-71

2017;**91**(3):566-574

2017;**28**(2):421-430

[5] Debiec H, Ronco P.

and outcome of membranous nephropathy in older patients. International Urology and Nephrology. 2002;**33**(1):157-165

[30] Lionaki S, Derebail VK, Hogan SL, Barbour S, Lee T, Hladunewich M, et al. Venous thromboembolism in patients with membranous nephropathy. Clinical Journal of the American Society of Nephrology. 2012;**7**(1):43-51

[31] Donadio JV Jr, Torres VE, Velosa JA, Wagoner RD, Holley KE, Okamura M, et al. Idiopathic membranous nephropathy: The natural history of untreated patients. Kidney International. 1988;**33**(3):708-715

[32] Erwin DT, Donadio JV Jr, Holley KE. The clinical course of idiopathic membranous nephropathy. Mayo Clinic Proceedings. 1973;**48**(10):697-712

[33] Glassock RJ. Diagnosis and natural course of membranous nephropathy. Seminars in Nephrology. 2003;**23**(4):324-332

[34] Timmermans SA, Abdul Hamid MA, Cohen Tervaert JW, Damoiseaux JG, van Paassen P, Limburg Renal Registry. Anti-PLA2R antibodies as a prognostic factor in PLA2R-related membranous nephropathy. American Journal of Nephrology. 2015;**42**(1):70-77

[35] Trew PA, Biava CG, Jacobs RP, Hopper J Jr. Renal vein thrombosis in membranous glomerulonephropathy: Incidence and association. Medicine (Baltimore). 1978;**57**(1):69-82

[36] Wagoner RD, Stanson AW, Holley KE, Winter CS. Renal vein thrombosis in idiopathic membranous glomerulopathy and nephrotic syndrome: Incidence and significance. Kidney International. 1983;**23**(2):368-374

[37] Wehrmann M, Bohle A, Bogenschutz O, Eissele R, Freislederer A, Ohlschlegel C, et al. Long-term

prognosis of chronic idiopathic membranous glomerulonephritis. An analysis of 334 cases with particular regard to tubulo-interstitial changes. Clinical Nephrology. 1989;**31**(2):67-76

[38] Pei Y, Cattran D, Greenwood C. Predicting chronic renal insufficiency in idiopathic membranous glomerulonephritis. Kidney International. 1992;**42**(4):960-966

[39] Oh YJ, Yang SH, Kim DK, Kang SW, Kim YS. Autoantibodies against phospholipase A2 receptor in Korean patients with membranous nephropathy. PLoS ONE. 2013;**8**(4):e62151

[40] Hoxha E, Harendza S, Pinnschmidt H, Panzer U, Stahl RA. PLA2R antibody levels and clinical outcome in patients with membranous nephropathy and non-nephrotic range proteinuria under treatment with inhibitors of the renin-angiotensin system. PLoS ONE. 2014;**9**(10):e110681

[41] KDIGO clinical practice guidelines for glomerulonephritis. Kidney International. Supplement. 2012;(S2):139-274

[42] Ponticelli C, Passerini P, Altieri P, Locatelli F, Pappalettera M. Remissions and relapses in idiopathic membranous nephropathy. Nephrology, Dialysis, Transplantation. 1992;**7**(Suppl 1):85-90

[43] Troyanov S, Wall CA, Miller JA, Scholey JW, Cattran DC, Toronto Glomerulonephritis Registry Group. Idiopathic membranous nephropathy: Definition and relevance of a partial remission. Kidney International. 2004;**66**(3):1199-1205

[44] Ramachandran R, Yadav AK, Kumar V, Inamdar N, Nada R, Gupta KL, et al. Temporal association between PLA2R antibodies and clinical outcomes in primary membranous nephropathy. Kidney International Reports. 2018;**3**(1):142-147

**67**

*Membranous Nephropathy*

2016;**387**(10017):435-443

et al. Blood pressure control, proteinuria, and the progression of renal disease. The modification of diet in renal disease study. Annals of Internal

Medicine. 1995;**123**(10):754-762

[47] Ruggenenti P, Perna A, Gherardi G, Garini G, Zoccali C, Salvadori M, et al. Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet.

1999;**354**(9176):359-364

[48] Gansevoort RT, Heeg JE, Vriesendorp R, de Zeeuw D, de Jong PE. Antiproteinuric drugs in patients with idiopathic membranous glomerulopathy. Nephrology, Dialysis, Transplantation. 1992;**7**(Suppl 1):91-96

[49] Spitalewitz S, Porush JG, Cattran D, Wright N. Treatment of hyperlipidemia

American Journal of Kidney Diseases.

[51] Perna A, Schieppati A, Zamora J, Giuliano GA, Braun N, Remuzzi G. Immunosuppressive treatment for idiopathic membranous nephropathy: A systematic review. American Journal of Kidney Diseases. 2004;**44**(3):385-401

[52] Cattran DC, Pei Y, Greenwood CM, Ponticelli C, Passerini P, Honkanen E.

in the nephrotic syndrome: The effects of pravastatin therapy.

[50] Sarasin FP, Schifferli JA. Prophylactic oral anticoagulation in nephrotic patients with idiopathic membranous nephropathy. Kidney International. 1994;**45**(2):578-585

1993;**22**(1):143-150

*DOI: http://dx.doi.org/10.5772/intechopen.87051*

Validation of a predictive model of idiopathic membranous

1997;**51**(3):901-907

(Suppl 1):48-52

nephropathy: Its clinical and research implications. Kidney International.

[53] Cattran DC, Pei Y, Greenwood C. Predicting progression in membranous glomerulonephritis. Nephrology, Dialysis, Transplantation. 1992;**7**

[54] A controlled study of shortterm prednisone treatment in adults with membranous nephropathy. Collaborative study of the adult idiopathic nephrotic syndrome. The New England Journal of Medicine.

[55] Cattran DC, Delmore T, Roscoe J, Cole E, Cardella C, Charron R, et al. A randomized controlled trial of prednisone in patients with idiopathic membranous nephropathy. The New England Journal of Medicine.

[56] Ponticelli C, Zucchelli P, Imbasciati E, Cagnoli L, Pozzi C, Passerini P, et al. Controlled trial of methylprednisolone

[57] Ponticelli C, Zucchelli P, Passerini P, Cesana B, Locatelli F, Pasquali S, et al. A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney International.

[58] Ponticelli C, Zucchelli P, Passerini P, Cesana B. Methylprednisolone plus chlorambucil as compared with methylprednisolone alone for the treatment of idiopathic membranous nephropathy. The Italian Idiopathic Membranous Nephropathy Treatment Study Group. The New England Journal of Medicine. 1992;**327**(9):599-603

and chlorambucil in idiopathic membranous nephropathy. The New England Journal of Medicine.

1979;**301**(24):1301-1306

1989;**320**(4):210-215

1984;**310**(15):946-950

1995;**48**(5):1600-1604

[45] Xie X, Atkins E, Lv J, Bennett A, Neal B, Ninomiya T, et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: Updated systematic review and meta-analysis. Lancet.

[46] Peterson JC, Adler S, Burkart JM, Greene T, Hebert LA, Hunsicker LG,

#### *Membranous Nephropathy DOI: http://dx.doi.org/10.5772/intechopen.87051*

*Glomerulonephritis and Nephrotic Syndrome*

International Urology and Nephrology.

prognosis of chronic idiopathic membranous glomerulonephritis. An analysis of 334 cases with particular regard to tubulo-interstitial changes. Clinical Nephrology. 1989;**31**(2):67-76

[38] Pei Y, Cattran D, Greenwood C. Predicting chronic renal insufficiency

[39] Oh YJ, Yang SH, Kim DK, Kang SW,

[40] Hoxha E, Harendza S, Pinnschmidt H, Panzer U, Stahl RA. PLA2R antibody levels and clinical outcome in patients with membranous nephropathy and non-nephrotic range proteinuria under treatment with inhibitors of the renin-angiotensin system. PLoS ONE.

Kim YS. Autoantibodies against phospholipase A2 receptor in Korean patients with membranous nephropathy.

PLoS ONE. 2013;**8**(4):e62151

2014;**9**(10):e110681

2012;(S2):139-274

2004;**66**(3):1199-1205

2018;**3**(1):142-147

Kidney International Reports.

[41] KDIGO clinical practice guidelines for glomerulonephritis. Kidney International. Supplement.

[42] Ponticelli C, Passerini P, Altieri P, Locatelli F, Pappalettera M. Remissions and relapses in idiopathic membranous nephropathy. Nephrology, Dialysis, Transplantation. 1992;**7**(Suppl 1):85-90

[43] Troyanov S, Wall CA, Miller JA, Scholey JW, Cattran DC, Toronto Glomerulonephritis Registry Group. Idiopathic membranous nephropathy: Definition and relevance of a partial remission. Kidney International.

[44] Ramachandran R, Yadav AK, Kumar V, Inamdar N, Nada R, Gupta KL, et al. Temporal association between PLA2R antibodies and clinical outcomes in primary membranous nephropathy.

in idiopathic membranous glomerulonephritis. Kidney International. 1992;**42**(4):960-966

[30] Lionaki S, Derebail VK, Hogan SL, Barbour S, Lee T, Hladunewich M, et al. Venous thromboembolism in patients with membranous nephropathy. Clinical Journal of the American Society of Nephrology. 2012;**7**(1):43-51

[31] Donadio JV Jr, Torres VE, Velosa JA, Wagoner RD, Holley KE, Okamura M,

[32] Erwin DT, Donadio JV Jr, Holley KE.

membranous nephropathy. Mayo Clinic Proceedings. 1973;**48**(10):697-712

nephropathy. Seminars in Nephrology.

[34] Timmermans SA, Abdul Hamid MA, Cohen Tervaert JW, Damoiseaux JG, van Paassen P, Limburg Renal Registry. Anti-PLA2R antibodies as a prognostic factor in PLA2R-related membranous nephropathy. American Journal of Nephrology. 2015;**42**(1):70-77

[35] Trew PA, Biava CG, Jacobs RP, Hopper J Jr. Renal vein thrombosis in membranous glomerulonephropathy: Incidence and association. Medicine (Baltimore). 1978;**57**(1):69-82

[36] Wagoner RD, Stanson AW, Holley KE, Winter CS. Renal vein thrombosis in idiopathic membranous glomerulopathy and nephrotic syndrome: Incidence and significance. Kidney International.

Bogenschutz O, Eissele R, Freislederer A, Ohlschlegel C, et al. Long-term

et al. Idiopathic membranous nephropathy: The natural history of untreated patients. Kidney International. 1988;**33**(3):708-715

The clinical course of idiopathic

[33] Glassock RJ. Diagnosis and natural course of membranous

2003;**23**(4):324-332

1983;**23**(2):368-374

[37] Wehrmann M, Bohle A,

and outcome of membranous nephropathy in older patients.

2002;**33**(1):157-165

**66**

[45] Xie X, Atkins E, Lv J, Bennett A, Neal B, Ninomiya T, et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: Updated systematic review and meta-analysis. Lancet. 2016;**387**(10017):435-443

[46] Peterson JC, Adler S, Burkart JM, Greene T, Hebert LA, Hunsicker LG, et al. Blood pressure control, proteinuria, and the progression of renal disease. The modification of diet in renal disease study. Annals of Internal Medicine. 1995;**123**(10):754-762

[47] Ruggenenti P, Perna A, Gherardi G, Garini G, Zoccali C, Salvadori M, et al. Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet. 1999;**354**(9176):359-364

[48] Gansevoort RT, Heeg JE, Vriesendorp R, de Zeeuw D, de Jong PE. Antiproteinuric drugs in patients with idiopathic membranous glomerulopathy. Nephrology, Dialysis, Transplantation. 1992;**7**(Suppl 1):91-96

[49] Spitalewitz S, Porush JG, Cattran D, Wright N. Treatment of hyperlipidemia in the nephrotic syndrome: The effects of pravastatin therapy. American Journal of Kidney Diseases. 1993;**22**(1):143-150

[50] Sarasin FP, Schifferli JA. Prophylactic oral anticoagulation in nephrotic patients with idiopathic membranous nephropathy. Kidney International. 1994;**45**(2):578-585

[51] Perna A, Schieppati A, Zamora J, Giuliano GA, Braun N, Remuzzi G. Immunosuppressive treatment for idiopathic membranous nephropathy: A systematic review. American Journal of Kidney Diseases. 2004;**44**(3):385-401

[52] Cattran DC, Pei Y, Greenwood CM, Ponticelli C, Passerini P, Honkanen E.

Validation of a predictive model of idiopathic membranous nephropathy: Its clinical and research implications. Kidney International. 1997;**51**(3):901-907

[53] Cattran DC, Pei Y, Greenwood C. Predicting progression in membranous glomerulonephritis. Nephrology, Dialysis, Transplantation. 1992;**7** (Suppl 1):48-52

[54] A controlled study of shortterm prednisone treatment in adults with membranous nephropathy. Collaborative study of the adult idiopathic nephrotic syndrome. The New England Journal of Medicine. 1979;**301**(24):1301-1306

[55] Cattran DC, Delmore T, Roscoe J, Cole E, Cardella C, Charron R, et al. A randomized controlled trial of prednisone in patients with idiopathic membranous nephropathy. The New England Journal of Medicine. 1989;**320**(4):210-215

[56] Ponticelli C, Zucchelli P, Imbasciati E, Cagnoli L, Pozzi C, Passerini P, et al. Controlled trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy. The New England Journal of Medicine. 1984;**310**(15):946-950

[57] Ponticelli C, Zucchelli P, Passerini P, Cesana B, Locatelli F, Pasquali S, et al. A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney International. 1995;**48**(5):1600-1604

[58] Ponticelli C, Zucchelli P, Passerini P, Cesana B. Methylprednisolone plus chlorambucil as compared with methylprednisolone alone for the treatment of idiopathic membranous nephropathy. The Italian Idiopathic Membranous Nephropathy Treatment Study Group. The New England Journal of Medicine. 1992;**327**(9):599-603

[59] Ponticelli C, Altieri P, Scolari F, Passerini P, Roccatello D, Cesana B, et al. A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy. Journal of the American Society of Nephrology. 1998;**9**(3):444-450

[60] Jha V, Ganguli A, Saha TK, Kohli HS, Sud K, Gupta KL, et al. A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy. Journal of the American Society of Nephrology. 2007;**18**(6):1899-1904

[61] Faurschou M, Sorensen IJ, Mellemkjaer L, Loft AG, Thomsen BS, Tvede N, et al. Malignancies in Wegener's granulomatosis: Incidence and relation to cyclophosphamide therapy in a cohort of 293 patients. The Journal of Rheumatology. 2008;**35**(1):100-105

[62] Ambalavanan S, Fauvel JP, Sibley RK, Myers BD. Mechanism of the antiproteinuric effect of cyclosporine in membranous nephropathy. Journal of the American Society of Nephrology. 1996;**7**(2):290-298

[63] Guasch A, Suranyi M, Newton L, Hall BM, Myers BD. Short-term responsiveness of membranous glomerulopathy to cyclosporine. American Journal of Kidney Diseases. 1992;**20**(5):472-481

[64] Cattran DC, Appel GB, Hebert LA, Hunsicker LG, Pohl MA, Hoy WE, et al. Cyclosporine in patients with steroidresistant membranous nephropathy: A randomized trial. Kidney International. 2001;**59**(4):1484-1490

[65] Meyrier A, Noel LH, Auriche P, Callard P. Long-term renal tolerance of cyclosporin A treatment in adult idiopathic nephrotic syndrome.

Collaborative Group of the Societe de Nephrologie. Kidney International. 1994;**45**(5):1446-1456

[66] Alexopoulos E, Papagianni A, Tsamelashvili M, Leontsini M, Memmos D. Induction and long-term treatment with cyclosporine in membranous nephropathy with the nephrotic syndrome. Nephrology, Dialysis, Transplantation. 2006;**21**(11):3127-3132

[67] Praga M, Barrio V, Juarez GF, Luno J. Grupo Espanol de Estudio de la Nefropatia M. Tacrolimus monotherapy in membranous nephropathy: A randomized controlled trial. Kidney International. 2007;**71**(9):924-930

[68] Cameron JS, Healy MJ, Adu D. The Medical Research Council trial of short-term high-dose alternate day prednisolone in idiopathic membranous nephropathy with nephrotic syndrome in adults. The MRC Glomerulonephritis Working Party. The Quarterly Journal of Medicine. 1990;**74**(274):133-156

[69] Howman A, Chapman TL, Langdon MM, Ferguson C, Adu D, Feehally J, et al. Immunosuppression for progressive membranous nephropathy: A UK randomised controlled trial. Lancet. 2013;**381**(9868):744-751

[70] Cattran DC, Greenwood C, Ritchie S, Bernstein K, Churchill DN, Clark WF, et al. A controlled trial of cyclosporine in patients with progressive membranous nephropathy. Canadian Glomerulonephritis Study Group. Kidney International. 1995;**47**(4):1130-1135

[71] Miller G, Zimmerman R 3rd, Radhakrishnan J, Appel G. Use of mycophenolate mofetil in resistant membranous nephropathy. American Journal of Kidney Diseases. 2000;**36**(2):250-256

[72] Choi MJ, Eustace JA, Gimenez LF, Atta MG, Scheel PJ, Sothinathan R,

**69**

*Membranous Nephropathy*

2007;**50**(2):248-256

2002;**360**(9337):923-924

2003;**14**(7):1851-1857

[75] Ruggenenti P, Chiurchiu C,

*DOI: http://dx.doi.org/10.5772/intechopen.87051*

et al. Mycophenolate mofetil treatment for primary glomerular diseases. Kidney International. 2002;**61**(3):1098-1114

Gesualdo L, et al. Treatment with rituximab in idiopathic membranous nephropathy. Clinical Kidney Journal.

[81] Moroni G, Depetri F, Del Vecchio L, Gallelli B, Raffiotta F, Giglio E, et al. Low-dose rituximab is poorly effective in patients with primary membranous nephropathy. Nephrology, Dialysis, Transplantation.

[82] Waldman M, Beck LH, Braun M, Wilkins K, Balow JE, Austin HA. Membranous nephropathy: Pilot study of a novel regimen combining cyclosporine and rituximab. Kidney International Reports. 2016;**1**(2):73-84

[83] Ruggenenti P, Debiec H, Ruggiero B, Chianca A, Pellé T, Gaspari F, et al. Anti-phospholipase A2 receptor antibody titer predicts post-rituximab outcome of membranous nephropathy. Journal of the American Society of Nephrology. 2015;**26**(10):2545

[84] Ruggenenti P, Cravedi P, Chianca A, Perna A, Ruggiero B, Gaspari F, et al. Rituximab in idiopathic membranous nephropathy. Journal of the American Society of Nephrology. 2012;**23**(8):1416

[85] Fervenza FC, Abraham RS, Erickson SB, Irazabal MV, Eirin A, Specks U, et al. Rituximab therapy in idiopathic membranous nephropathy: A 2-year study. Clinical Journal of the American Society of Nephrology.

[86] Fervenza FC, Cosio FG, Erickson SB, Specks U, Herzenberg AM, Dillon JJ, et al. Rituximab treatment of idiopathic membranous nephropathy. Kidney International. 2008;**73**(1):117-125

2010;**5**(12):2188

2017;**32**(10):1691-1696

[80] Bagchi S, Subbiah AK, Bhowmik D, Mahajan S, Yadav RK, Kalaivani M, et al. Low-dose rituximab therapy in resistant idiopathic membranous nephropathy: Single-center experience. Clinical Kidney Journal. 2018;**11**(3):337-341

2016;**9**(6):788-793

[73] Branten AJ, du Buf-Vereijken PW, Vervloet M, Wetzels JF. Mycophenolate mofetil in idiopathic membranous nephropathy: A clinical trial with comparison to a historic control group treated with cyclophosphamide. American Journal of Kidney Diseases.

[74] Remuzzi G, Chiurchiu C, Abbate M, Brusegan V, Bontempelli M,

Ruggenenti P. Rituximab for idiopathic membranous nephropathy. Lancet.

Brusegan V, Abbate M, Perna A, Filippi C, et al. Rituximab in idiopathic membranous nephropathy: A oneyear prospective study. Journal of the American Society of Nephrology.

[76] Fervenza FC, Cossio FG, Leung N, Wasiluk A, Cohen I, Wochos D, et al. A pilot study on the use of rituximab for the treatment of idiopathic

membranous nephropathy: Preliminary results. Journal of the American Society

of Nephrology. 2005;(16):555A

L, et al. Rituximab for severe

SJ, Lafayette RA, Rovin BH, Aslam N, et al. A multicenter randomized controlled trial of rituximab versus cyclosporine in the treatment of idiopathic membranous nephropathy (MENTOR). Nephron.

[79] Fiorentino M, Tondolo F, Bruno F, Infante B, Grandaliano G,

2015;**130**(3):159-168

2017;**28**(1):348

[77] Dahan K, Debiec H, Plaisier E, Cachanado M, Rousseau A, Wakselman

membranous nephropathy: A 6-month trial with extended follow-up. Journal of the American Society of Nephrology.

[78] Fervenza FC, Canetta PA, Barbour

#### *Membranous Nephropathy DOI: http://dx.doi.org/10.5772/intechopen.87051*

*Glomerulonephritis and Nephrotic Syndrome*

[59] Ponticelli C, Altieri P, Scolari F, Passerini P, Roccatello D, Cesana B, et al. A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy. Journal of the American Society of Nephrology.

Collaborative Group of the Societe de Nephrologie. Kidney International.

[66] Alexopoulos E, Papagianni A, Tsamelashvili M, Leontsini M, Memmos D. Induction and long-term treatment with cyclosporine in membranous nephropathy with the nephrotic syndrome. Nephrology, Dialysis, Transplantation. 2006;**21**(11):3127-3132

[67] Praga M, Barrio V, Juarez GF, Luno J. Grupo Espanol de Estudio de la Nefropatia M. Tacrolimus monotherapy

in membranous nephropathy: A randomized controlled trial. Kidney International. 2007;**71**(9):924-930

Medicine. 1990;**74**(274):133-156

[70] Cattran DC, Greenwood C, Ritchie S, Bernstein K, Churchill DN, Clark WF, et al. A controlled trial of cyclosporine in patients with progressive membranous nephropathy.

Canadian Glomerulonephritis Study Group. Kidney International.

[71] Miller G, Zimmerman R 3rd, Radhakrishnan J, Appel G. Use of mycophenolate mofetil in resistant membranous nephropathy. American

[72] Choi MJ, Eustace JA, Gimenez LF, Atta MG, Scheel PJ, Sothinathan R,

Journal of Kidney Diseases.

2000;**36**(2):250-256

1995;**47**(4):1130-1135

[69] Howman A, Chapman TL, Langdon MM, Ferguson C, Adu D, Feehally J, et al. Immunosuppression for

progressive membranous nephropathy: A UK randomised controlled trial. Lancet. 2013;**381**(9868):744-751

[68] Cameron JS, Healy MJ, Adu D. The Medical Research Council trial of short-term high-dose alternate day prednisolone in idiopathic membranous nephropathy with nephrotic syndrome in adults. The MRC Glomerulonephritis Working Party. The Quarterly Journal of

1994;**45**(5):1446-1456

1998;**9**(3):444-450

[60] Jha V, Ganguli A, Saha TK, Kohli HS, Sud K, Gupta KL, et al. A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy. Journal of the American Society of Nephrology. 2007;**18**(6):1899-1904

[61] Faurschou M, Sorensen IJ,

2008;**35**(1):100-105

1996;**7**(2):290-298

1992;**20**(5):472-481

2001;**59**(4):1484-1490

Mellemkjaer L, Loft AG, Thomsen BS, Tvede N, et al. Malignancies in Wegener's granulomatosis: Incidence and relation to cyclophosphamide therapy in a cohort of 293 patients. The Journal of Rheumatology.

[62] Ambalavanan S, Fauvel JP, Sibley RK, Myers BD. Mechanism of the antiproteinuric effect of cyclosporine in membranous nephropathy. Journal of the American Society of Nephrology.

[63] Guasch A, Suranyi M, Newton L, Hall BM, Myers BD. Short-term responsiveness of membranous glomerulopathy to cyclosporine. American Journal of Kidney Diseases.

[64] Cattran DC, Appel GB, Hebert LA, Hunsicker LG, Pohl MA, Hoy WE, et al. Cyclosporine in patients with steroidresistant membranous nephropathy: A randomized trial. Kidney International.

[65] Meyrier A, Noel LH, Auriche P, Callard P. Long-term renal tolerance of cyclosporin A treatment in adult idiopathic nephrotic syndrome.

**68**

et al. Mycophenolate mofetil treatment for primary glomerular diseases. Kidney International. 2002;**61**(3):1098-1114

[73] Branten AJ, du Buf-Vereijken PW, Vervloet M, Wetzels JF. Mycophenolate mofetil in idiopathic membranous nephropathy: A clinical trial with comparison to a historic control group treated with cyclophosphamide. American Journal of Kidney Diseases. 2007;**50**(2):248-256

[74] Remuzzi G, Chiurchiu C, Abbate M, Brusegan V, Bontempelli M, Ruggenenti P. Rituximab for idiopathic membranous nephropathy. Lancet. 2002;**360**(9337):923-924

[75] Ruggenenti P, Chiurchiu C, Brusegan V, Abbate M, Perna A, Filippi C, et al. Rituximab in idiopathic membranous nephropathy: A oneyear prospective study. Journal of the American Society of Nephrology. 2003;**14**(7):1851-1857

[76] Fervenza FC, Cossio FG, Leung N, Wasiluk A, Cohen I, Wochos D, et al. A pilot study on the use of rituximab for the treatment of idiopathic membranous nephropathy: Preliminary results. Journal of the American Society of Nephrology. 2005;(16):555A

[77] Dahan K, Debiec H, Plaisier E, Cachanado M, Rousseau A, Wakselman L, et al. Rituximab for severe membranous nephropathy: A 6-month trial with extended follow-up. Journal of the American Society of Nephrology. 2017;**28**(1):348

[78] Fervenza FC, Canetta PA, Barbour SJ, Lafayette RA, Rovin BH, Aslam N, et al. A multicenter randomized controlled trial of rituximab versus cyclosporine in the treatment of idiopathic membranous nephropathy (MENTOR). Nephron. 2015;**130**(3):159-168

[79] Fiorentino M, Tondolo F, Bruno F, Infante B, Grandaliano G, Gesualdo L, et al. Treatment with rituximab in idiopathic membranous nephropathy. Clinical Kidney Journal. 2016;**9**(6):788-793

[80] Bagchi S, Subbiah AK, Bhowmik D, Mahajan S, Yadav RK, Kalaivani M, et al. Low-dose rituximab therapy in resistant idiopathic membranous nephropathy: Single-center experience. Clinical Kidney Journal. 2018;**11**(3):337-341

[81] Moroni G, Depetri F, Del Vecchio L, Gallelli B, Raffiotta F, Giglio E, et al. Low-dose rituximab is poorly effective in patients with primary membranous nephropathy. Nephrology, Dialysis, Transplantation. 2017;**32**(10):1691-1696

[82] Waldman M, Beck LH, Braun M, Wilkins K, Balow JE, Austin HA. Membranous nephropathy: Pilot study of a novel regimen combining cyclosporine and rituximab. Kidney International Reports. 2016;**1**(2):73-84

[83] Ruggenenti P, Debiec H, Ruggiero B, Chianca A, Pellé T, Gaspari F, et al. Anti-phospholipase A2 receptor antibody titer predicts post-rituximab outcome of membranous nephropathy. Journal of the American Society of Nephrology. 2015;**26**(10):2545

[84] Ruggenenti P, Cravedi P, Chianca A, Perna A, Ruggiero B, Gaspari F, et al. Rituximab in idiopathic membranous nephropathy. Journal of the American Society of Nephrology. 2012;**23**(8):1416

[85] Fervenza FC, Abraham RS, Erickson SB, Irazabal MV, Eirin A, Specks U, et al. Rituximab therapy in idiopathic membranous nephropathy: A 2-year study. Clinical Journal of the American Society of Nephrology. 2010;**5**(12):2188

[86] Fervenza FC, Cosio FG, Erickson SB, Specks U, Herzenberg AM, Dillon JJ, et al. Rituximab treatment of idiopathic membranous nephropathy. Kidney International. 2008;**73**(1):117-125

[87] Rojas-Rivera J, Fernandez-Juarez G, Ortiz A, Hofstra J, Gesualdo L, Tesar V, et al. A European multicentre and open-label controlled randomized trial to evaluate the efficacy of Sequential treatment with TAcrolimus-Rituximab versus steroids plus cyclophosphamide in patients with primary MEmbranous Nephropathy: The STARMEN study. Clinical Kidney Journal. 2015;**8**(5):503-510

[88] Appel G, Nachman P, Hogan S, Radhakrishnan J, Old C, Hebert L, et al. Eculizumab (C5 complement inhibitor) in the treatment of idiopathic membranous nephropathy (abstract). Journal of the American Society of Nephrology. 2002;(13):668A

[89] Berg AL, Nilsson-Ehle P, Arnadottir M. Beneficial effects of ACTH on the serum lipoprotein profile and glomerular function in patients with membranous nephropathy. Kidney International. 1999;**56**(4):1534-1543

[90] Berg AL, Arnadottir M. ACTHinduced improvement in the nephrotic syndrome in patients with a variety of diagnoses. Nephrology, Dialysis, Transplantation. 2004;**19**(5):1305-1307

[91] Ponticelli C, Passerini P, Salvadori M, Manno C, Viola BF, Pasquali S, et al. A randomized pilot trial comparing methylprednisolone plus a cytotoxic agent versus synthetic adrenocorticotropic hormone in idiopathic membranous nephropathy. American Journal of Kidney Diseases. 2006;**47**(2):233-240

[92] Hladunewich MA, Cattran D, Beck LH, Odutayo A, Sethi S, Ayalon R, et al. A pilot study to determine the dose and effectiveness of adrenocorticotrophic hormone (H.P. Acthar(R) Gel) in nephrotic syndrome due to idiopathic membranous nephropathy. Nephrology, Dialysis, Transplantation. 2014;**29**(8):1570-1577

**71**

**Chapter 5**

**Abstract**

in autoimmunity.

**1. Introduction**

anti-PLA2R

significant.

Primary Membranous

Autoimmune Disease

Nephropathy as a Model of

*Patrick Hamilton, Durga Kanigicherla and Paul Brenchley*

Membranous nephropathy is the most common cause of adult nephrotic syndrome worldwide with a significant health care burden. There has been a leap in our understanding of the disease mechanism over the last decade with a remarkably strong genetic component to the development of the disease and its strong association with high affinity antibody—in the form of anti-PLA2R autoantibody in the majority of cases, with a smaller proportion associated with anti-THSD7A autoantibody. New evidence is now providing confirmation of specific elements in the development of the disease pathogenesis, such as involvement of loss of peripheral tolerance. There is a striking correlation between disease activity and anti-PLA2R antibody levels, along with response to treatment; evidence points strongly to these antibodies being pathogenic. The development of membranous nephropathy therefore follows the well appreciated multi-hit step-wise path to autoimmune clinical disease. Given its strong genetic basis and putative pathogenic antibody the disease provides an invaluable model for understanding of autoimmunity. This chapter focuses on the most up to date knowledge of autoimmune membranous nephropathy and provides a paradigm for understanding the underlying disease mechanisms

**Keywords:** autoimmune disease, membranous nephropathy, nephrotic syndrome,

Autoimmune disease is a term that covers a range of conditions in which the immune system recognises the body as a foreign pathogen, and encompasses over 80 conditions affecting almost every organ [1]. Individually, many of these conditions are rare but taken together they represent a significant mortality and morbidity affecting approximately 9% of the population worldwide with the prevalence rising [1, 2]. Given that the majority of conditions have no cure and potentially require lifelong treatment, and that most patients are diagnosed during young adulthood or in middle age, the cost to healthcare systems is particularly

Despite the variation of organs affected and clinical presentation, many of the conditions that appear distinct will share a common theme of disease pathogenesis. Underscoring many of the conditions is a genetic susceptibility that taken in concert with an environmental trigger sets off an immune cascade resulting in the

#### **Chapter 5**

*Glomerulonephritis and Nephrotic Syndrome*

[87] Rojas-Rivera J, Fernandez-Juarez G, Ortiz A, Hofstra J, Gesualdo L, Tesar V, et al. A European multicentre and open-label controlled randomized trial to evaluate the efficacy of Sequential treatment with TAcrolimus-Rituximab versus steroids plus cyclophosphamide in patients with primary MEmbranous

Nephropathy: The STARMEN study. Clinical Kidney Journal.

[88] Appel G, Nachman P, Hogan S, Radhakrishnan J, Old C, Hebert L, et al. Eculizumab (C5 complement inhibitor) in the treatment of idiopathic membranous nephropathy (abstract). Journal of the American Society of Nephrology. 2002;(13):668A

[89] Berg AL, Nilsson-Ehle P, Arnadottir M. Beneficial effects of ACTH on the serum lipoprotein profile and glomerular function in patients with membranous nephropathy. Kidney International. 1999;**56**(4):1534-1543

[90] Berg AL, Arnadottir M. ACTHinduced improvement in the nephrotic syndrome in patients with a variety of diagnoses. Nephrology, Dialysis, Transplantation. 2004;**19**(5):1305-1307

[91] Ponticelli C, Passerini P, Salvadori M, Manno C, Viola BF, Pasquali S, et al. A randomized pilot trial comparing methylprednisolone plus a cytotoxic agent versus synthetic adrenocorticotropic hormone in idiopathic membranous nephropathy. American Journal of Kidney Diseases.

[92] Hladunewich MA, Cattran D, Beck LH, Odutayo A, Sethi S, Ayalon R, et al. A pilot study to determine the dose and effectiveness of adrenocorticotrophic hormone (H.P. Acthar(R) Gel) in nephrotic syndrome due to

idiopathic membranous nephropathy. Nephrology, Dialysis, Transplantation.

2006;**47**(2):233-240

2014;**29**(8):1570-1577

2015;**8**(5):503-510

**70**

## Primary Membranous Nephropathy as a Model of Autoimmune Disease

*Patrick Hamilton, Durga Kanigicherla and Paul Brenchley*

#### **Abstract**

Membranous nephropathy is the most common cause of adult nephrotic syndrome worldwide with a significant health care burden. There has been a leap in our understanding of the disease mechanism over the last decade with a remarkably strong genetic component to the development of the disease and its strong association with high affinity antibody—in the form of anti-PLA2R autoantibody in the majority of cases, with a smaller proportion associated with anti-THSD7A autoantibody. New evidence is now providing confirmation of specific elements in the development of the disease pathogenesis, such as involvement of loss of peripheral tolerance. There is a striking correlation between disease activity and anti-PLA2R antibody levels, along with response to treatment; evidence points strongly to these antibodies being pathogenic. The development of membranous nephropathy therefore follows the well appreciated multi-hit step-wise path to autoimmune clinical disease. Given its strong genetic basis and putative pathogenic antibody the disease provides an invaluable model for understanding of autoimmunity. This chapter focuses on the most up to date knowledge of autoimmune membranous nephropathy and provides a paradigm for understanding the underlying disease mechanisms in autoimmunity.

**Keywords:** autoimmune disease, membranous nephropathy, nephrotic syndrome, anti-PLA2R

#### **1. Introduction**

Autoimmune disease is a term that covers a range of conditions in which the immune system recognises the body as a foreign pathogen, and encompasses over 80 conditions affecting almost every organ [1]. Individually, many of these conditions are rare but taken together they represent a significant mortality and morbidity affecting approximately 9% of the population worldwide with the prevalence rising [1, 2]. Given that the majority of conditions have no cure and potentially require lifelong treatment, and that most patients are diagnosed during young adulthood or in middle age, the cost to healthcare systems is particularly significant.

Despite the variation of organs affected and clinical presentation, many of the conditions that appear distinct will share a common theme of disease pathogenesis. Underscoring many of the conditions is a genetic susceptibility that taken in concert with an environmental trigger sets off an immune cascade resulting in the end organ damage and clinical signs and symptoms that bring the patient to the attention of their healthcare provider, the so-called multi-hit hypothesis. As science progresses and we gain greater insight into these disease processes, it is becoming more apparent that there are similarities in many of the conditions. At present, most management strategies attempt to globally restrict the immune system, a strategy that has been shown to help control the disease but comes with a significant side effect profile. Despite the accelerating knowledge we are gaining of the underlying pathogenesis, there remains a lack of directed novel therapies for patients at present, although in many conditions there are signs that this is changing.

Membranous nephropathy represents a particularly interesting basis to understand this process given its clear pathological classification, strong genetic contribution, putative pathogenic antibody and evidence for the loss of tolerance that is now emerging. In this chapter, we review the current understanding of autoimmune membranous nephropathy and use it as a basis for the understanding of autoimmune disease in general.

#### **2. Background**

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults worldwide but despite this remains a rare disease. Incidence is estimated at 1.2 per 100,000 in European cohorts with a peak incidence in the fifth and sixth decades, although it can affect any age, and has a slight male preponderance [3]. The classical presentation of the disease is with nephrotic syndrome, that is, the tetrad of leg swelling, proteinuria and serum hypoalbuminemia, with or without hypercholesterolemia. A number of patients have also been known to present with venous thrombosis. This can be in the form of deep vein thrombosis (DVT) and, not uncommonly as the first presentation of the disease, with acute kidney injury (AKI) as a result of renal vein thrombosis. Hypercoagulopathy as a result of the loss of anti-thrombotic factors such as anti-thrombin III and plasminogen due to proteinuria, an increased level of factor VIII and fibrinogen, along with an increased platelet hyperaggregability has been noted in nephrotic syndrome whatever the cause. However, compared to other conditions that have a similar degree of proteinuria, MN has a relatively higher risk of venous thrombosis and its associated risks; the mechanism for this association has not been ascertained [4–6].

Clinically there are two distinct forms of MN, but these can be histologically very similar and difficult to differentiate. Both require very different treatment strategies and therefore distinguishing them is imperative. Primary MN accounts for the majority of patients (approximately 75–80%) and has now been shown to be an autoimmune disease. Secondary MN is caused by a multitude of causes including medications, systemic disorders and toxins, and its treatment is therefore aimed at the underlying trigger or condition [7].

It is one of the idiosyncrasies of MN that up to a third of patients if left untreated will achieve spontaneous remission within the first 2 years following diagnosis, and this potential for spontaneous remission has informed the current treatment options, especially for those patients without rapidly progressive renal decline [8]. The mainstay of treatment at present has a focus on the reduction of proteinuria with the use of an renin-angiotensin pathway blockade or immunosuppression if this fails [7]. It has also meant that for many studies, patients undergo three to 6 months of supportive care before they are eligible, in case any response to treatment seen is actually as a result of spontaneous remission. However, with the increasing use, understanding and monitoring of biomarkers such as anti-PLA2R, treatments are likely to be less empiric in the future.

**73**

*Primary Membranous Nephropathy as a Model of Autoimmune Disease*

If patients do reach ESRD and receive a renal transplant, it has been well demonstrated that this can provide a dramatic improvement to not only life expectancy but also quality of life [9–11]. However, this comes with the risk of recurrence of MN following transplantation (up to 34% of patients) despite the judicial use of immunosuppression and can lead to the loss of the graft in up to 50% of these cases. There is some evidence to suggest that receiving a transplant from a living related donor increases the risk of recurrence, but this is far outweighed by the complications associated with remaining on dialysis [12]. Current practice therefore, is to attempt to match HLA antigens as closely as

For many patients, MN remains a relapsing and remitting disease, requiring lifelong follow up under the care of specialists in tertiary care. Despite being a rare condition, its chronicity, current standard treatments and their associated side-effects, the risk of ESRD, and disease recurrence means it is a disease that has a significant impact on both a patient's quality of life and a healthcare system with

Recent advances in biomarker research for MN have shown promising results but at present diagnosis requires biopsy confirmation. Histologically the disease is characterised by thickening of the glomerular basement membrane and spikes seen on silver stain. Immunofluorescence almost universally shows coarse granular immunoglobulin IgG and complement C3 deposition on the capillary wall. Electron microscopy (EM) will show sub-epithelial immune complex deposition (**Figure 1**). It has become apparent over the years that the dominant IgG subclass found histologically (and for antibodies to PLA2R as described below) in primary MN is IgG4 [13–15]. This appears to differ from secondary MN where IgG1 predominates [16]. IgG makes up a significant proportion of serum protein in humans contributing approximately 10–20% of circulating proteins. It can be further subdivided into four subclasses with differing effects. IgG4 is the least abundant of these subclasses and is generally found

in response to allergens or in response to repeated exposure to an antigen [17]. New research findings suggest that there may be a class switch involved in primary membranous nephropathy. Here it has been shown that in early MN (stage I of the Ehrenreich and Churg scale) the predominant subclass of antibody is IgG1

but as the disease progresses this changes so that IgG4 predominates [16].

In primary MN, disease activity is still measured by proteinuria level and renal excretory function despite the advances in anti-PLA2R research. Proteinuria level has been shown to be not only a marker for remission when it is low but also predicts progression to ESRD when increased. If proteinuria reduces through either spontaneous remission or with treatment, then the risk of CKD progression also falls. It is for this reason that the main focus of treatment in primary MN is concerned with control of proteinuria, with or without the use of immunosuppression, generally in the form of the Ponticelli regime (or calcineurin inhibitors if cyclophosphamide is not tolerated or is contraindicated). This regime of rotating high dose intravenous steroids and immunosuppression was first described in the mid-1980s and has been the recommended regime since [7, 18–20]. Despite its success in treating the condition, the Ponticelli regime comes with a significant side effect burden, including an increased risk of infection, osteoporosis, diabetes mellitus, weight gain,

possible to reduce the reliance on immunosuppression to minimise rejection.

*DOI: http://dx.doi.org/10.5772/intechopen.88003*

finite resources.

**3. Diagnosis**

**4. Treatment**

#### *Primary Membranous Nephropathy as a Model of Autoimmune Disease DOI: http://dx.doi.org/10.5772/intechopen.88003*

If patients do reach ESRD and receive a renal transplant, it has been well demonstrated that this can provide a dramatic improvement to not only life expectancy but also quality of life [9–11]. However, this comes with the risk of recurrence of MN following transplantation (up to 34% of patients) despite the judicial use of immunosuppression and can lead to the loss of the graft in up to 50% of these cases. There is some evidence to suggest that receiving a transplant from a living related donor increases the risk of recurrence, but this is far outweighed by the complications associated with remaining on dialysis [12]. Current practice therefore, is to attempt to match HLA antigens as closely as possible to reduce the reliance on immunosuppression to minimise rejection.

For many patients, MN remains a relapsing and remitting disease, requiring lifelong follow up under the care of specialists in tertiary care. Despite being a rare condition, its chronicity, current standard treatments and their associated side-effects, the risk of ESRD, and disease recurrence means it is a disease that has a significant impact on both a patient's quality of life and a healthcare system with finite resources.

#### **3. Diagnosis**

*Glomerulonephritis and Nephrotic Syndrome*

mune disease in general.

**2. Background**

end organ damage and clinical signs and symptoms that bring the patient to the attention of their healthcare provider, the so-called multi-hit hypothesis. As science progresses and we gain greater insight into these disease processes, it is becoming more apparent that there are similarities in many of the conditions. At present, most management strategies attempt to globally restrict the immune system, a strategy that has been shown to help control the disease but comes with a significant side effect profile. Despite the accelerating knowledge we are gaining of the underlying pathogenesis, there remains a lack of directed novel therapies for patients at

present, although in many conditions there are signs that this is changing.

Membranous nephropathy represents a particularly interesting basis to understand this process given its clear pathological classification, strong genetic contribution, putative pathogenic antibody and evidence for the loss of tolerance that is now emerging. In this chapter, we review the current understanding of autoimmune membranous nephropathy and use it as a basis for the understanding of autoim-

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults worldwide but despite this remains a rare disease. Incidence is estimated at 1.2 per 100,000 in European cohorts with a peak incidence in the fifth and sixth decades, although it can affect any age, and has a slight male preponderance [3]. The classical presentation of the disease is with nephrotic syndrome, that is, the tetrad of leg swelling, proteinuria and serum hypoalbuminemia, with or without hypercholesterolemia. A number of patients have also been known to present with venous thrombosis. This can be in the form of deep vein thrombosis (DVT) and, not uncommonly as the first presentation of the disease, with acute kidney injury (AKI) as a result of renal vein thrombosis. Hypercoagulopathy as a result of the loss of anti-thrombotic factors such as anti-thrombin III and plasminogen due to proteinuria, an increased level of factor VIII and fibrinogen, along with an increased platelet hyperaggregability has been noted in nephrotic syndrome whatever the cause. However, compared to other conditions that have a similar degree of proteinuria, MN has a relatively higher risk of venous thrombosis and its associated

risks; the mechanism for this association has not been ascertained [4–6].

the underlying trigger or condition [7].

treatments are likely to be less empiric in the future.

Clinically there are two distinct forms of MN, but these can be histologically very similar and difficult to differentiate. Both require very different treatment strategies and therefore distinguishing them is imperative. Primary MN accounts for the majority of patients (approximately 75–80%) and has now been shown to be an autoimmune disease. Secondary MN is caused by a multitude of causes including medications, systemic disorders and toxins, and its treatment is therefore aimed at

It is one of the idiosyncrasies of MN that up to a third of patients if left untreated will achieve spontaneous remission within the first 2 years following diagnosis, and this potential for spontaneous remission has informed the current treatment options, especially for those patients without rapidly progressive renal decline [8]. The mainstay of treatment at present has a focus on the reduction of proteinuria with the use of an renin-angiotensin pathway blockade or immunosuppression if this fails [7]. It has also meant that for many studies, patients undergo three to 6 months of supportive care before they are eligible, in case any response to treatment seen is actually as a result of spontaneous remission. However, with the increasing use, understanding and monitoring of biomarkers such as anti-PLA2R,

**72**

Recent advances in biomarker research for MN have shown promising results but at present diagnosis requires biopsy confirmation. Histologically the disease is characterised by thickening of the glomerular basement membrane and spikes seen on silver stain. Immunofluorescence almost universally shows coarse granular immunoglobulin IgG and complement C3 deposition on the capillary wall. Electron microscopy (EM) will show sub-epithelial immune complex deposition (**Figure 1**). It has become apparent over the years that the dominant IgG subclass found histologically (and for antibodies to PLA2R as described below) in primary MN is IgG4 [13–15]. This appears to differ from secondary MN where IgG1 predominates [16]. IgG makes up a significant proportion of serum protein in humans contributing approximately 10–20% of circulating proteins. It can be further subdivided into four subclasses with differing effects. IgG4 is the least abundant of these subclasses and is generally found in response to allergens or in response to repeated exposure to an antigen [17].

New research findings suggest that there may be a class switch involved in primary membranous nephropathy. Here it has been shown that in early MN (stage I of the Ehrenreich and Churg scale) the predominant subclass of antibody is IgG1 but as the disease progresses this changes so that IgG4 predominates [16].

#### **4. Treatment**

In primary MN, disease activity is still measured by proteinuria level and renal excretory function despite the advances in anti-PLA2R research. Proteinuria level has been shown to be not only a marker for remission when it is low but also predicts progression to ESRD when increased. If proteinuria reduces through either spontaneous remission or with treatment, then the risk of CKD progression also falls. It is for this reason that the main focus of treatment in primary MN is concerned with control of proteinuria, with or without the use of immunosuppression, generally in the form of the Ponticelli regime (or calcineurin inhibitors if cyclophosphamide is not tolerated or is contraindicated). This regime of rotating high dose intravenous steroids and immunosuppression was first described in the mid-1980s and has been the recommended regime since [7, 18–20]. Despite its success in treating the condition, the Ponticelli regime comes with a significant side effect burden, including an increased risk of infection, osteoporosis, diabetes mellitus, weight gain,

#### **Figure 1.**

*Histological appearance of membranous nephropathy (a) haematoxylin and eosin stain (H&E) showing marked capillary loop thickening (b) silver staining showing spikes (c) electron microscopy of MN showing sub-epithelial immune complex deposition (d) immunofluorescence showing IgG deposition on the capillary wall. Figures courtesy of Dr. Lorna Williams, Consultant Histopathologist, Manchester University Hospitals Foundation Trust, UK.*

haemorrhagic cystitis, infertility and malignancy [18]. It is this that has led many researchers to search for an alternative therapy including mycophenolate mofetil and tacrolimus but with variable evidence to show an improvement in outcomes.

Rituximab is a monoclonal antibody against CD20, found on the B-cells, which leads to a reduction in B-cell numbers and has been used extensively in cancer therapy and autoimmune diseases since its introduction in the 1990s. A number of case series and studies have shown the potential that Rituximab can have for primary MN, but so far there has only been one randomised controlled trial (RCT) [21–24]. Here it has been shown that compared to standard anti-proteinuric therapy, patients treated with rituximab show a greater reduction in anti-PLA2R levels at month 3, followed by a later reduction in proteinuria, increase in serum albumin and are more likely to enter remission [24]. Combined with the high cost of the medication itself, its widespread use has been restricted in resource-limited, evidence-based healthcare systems, such as the NHS in UK [25]. The use of Rituximab therapy is currently under investigation in the MENTOR study in North America and via the Commissioning through Evaluation pathway run under the auspices of the National Institute for Health and Care Excellence (NICE) in the UK. It is possible that based on these two studies the use of Rituximab will become more ubiquitous in the near future.

#### **5. Future novel treatments**

The use of many of these medications comes with side effects that can be unpalatable to the patient and physician and the search for treatments with a reduced

**75**

*Primary Membranous Nephropathy as a Model of Autoimmune Disease*

side-effect profile is on-going. Treatments such as immunoadsorption (IA) allow for the controlled removal of antibodies without the side effects associated with immunosuppression. Immunoadsorption RCTs in MN though, are non-existent and certainly not in the anti-PLA2R era. Immunoadsorption is a method of removing specific circulating immunoglobulins from the blood and has been shown to remove over 80% of circulating IgG with a single session adsorption of 2.5 plasma volumes, with albumin and antithrombin III almost unaffected [26]. With multiple sessions, this can rise to over 98% [27]. These are removed in the absorber through binding Peptide-GAM. Using two columns per machine, one regenerating whilst the other is removing antibodies; the process can occur indefinitely until the required level of

Post IA it appears that autoantibodies can be slow to re-emerge. Use in dilated cardiomyopathy for the removal of β1-adreno-receptor autoantibodies (β1-AAB) has shown that only a small minority of patients (0% in the first year and 15% by 3 years) will show an increase in significant β1-AAB autoantibodies [28, 29].

To our knowledge, there has only been one publication using immunoadsorption for the treatment of MN [30]. In 1999, Esnault et al. successfully used IA for the treatment of various aetiologies of Nephrotic syndrome including four patients with MN [31]. Here they showed that not only is the procedure safe but that there was a significant improvement in proteinuria in all patients with membranous nephropathy. The main side effect in this group of patients was headache, which resolved without sequelae. Since that time the treatment has been used in numerous other autoimmune conditions including Focal Segmental Glomerulosclerosis (FSGS) [32], systemic lupus nephritis (SLE) [33, 34], ANCA-associated small vessel vasculitides [35, 36], Anti-glomerular basement membrane antibody disease [37]

In conditions such as SLE, the use of immunoadsorption can dramatically reduce the level of circulating immune complexes and autoantibodies leading to clinical improvement in even severe life-threatening SLE. These results have been shown with as little as two sessions within 3 days and repeated every 3 weeks if patients remain with active disease [33]. With the current understanding of primary MN's autoimmune process, the use of IA could provide the ability to rapidly remove the pathogenic antibodies leading to remission. Current IA machines can remove the different classes such as IgG4 with an increased specificity but cannot differentiate further than that. If IA is proved to work for primary MN, it may be possible to develop an IA column that is specific only for anti-PLA2R, therefore allowing for an

Until recently autoimmune (or primary) MN was known as idiopathic MN as its cause remained unclear. It was generally a diagnosis of exclusion, once a patient had biopsy confirmation of MN and all causes of secondary MN had been ruled out. It was for a long time postulated to be an autoimmune disease, but the target antigen in humans remained elusive. In the late 1970s, work on the Heymann Nephritis rat model of experimental MN showed that circulating IgG antibodies could bind to the podocytes [41–43]. The target antigen was found to be megalin, but this was not present on human podocytes, so the search for the target antigen continued. It was not until 2009, almost 40 years later that this was discovered. Here Beck et al. used western blotting with MN patient sera, to show that antibodies bound to a 185 kDa protein band from glomerular extracts. This band was only seen in the primary MN group and not seen in normal patients or other proteinuric conditions including

*DOI: http://dx.doi.org/10.5772/intechopen.88003*

antibody has been removed.

and in renal transplantation [38–40].

even more targeted and personalised treatment.

**6. Autoimmune membranous nephropathy**

#### *Primary Membranous Nephropathy as a Model of Autoimmune Disease DOI: http://dx.doi.org/10.5772/intechopen.88003*

*Glomerulonephritis and Nephrotic Syndrome*

haemorrhagic cystitis, infertility and malignancy [18]. It is this that has led many researchers to search for an alternative therapy including mycophenolate mofetil and

*Histological appearance of membranous nephropathy (a) haematoxylin and eosin stain (H&E) showing marked capillary loop thickening (b) silver staining showing spikes (c) electron microscopy of MN showing sub-epithelial immune complex deposition (d) immunofluorescence showing IgG deposition on the capillary wall. Figures courtesy of Dr. Lorna Williams, Consultant Histopathologist, Manchester University Hospitals* 

Rituximab is a monoclonal antibody against CD20, found on the B-cells, which leads to a reduction in B-cell numbers and has been used extensively in cancer therapy and autoimmune diseases since its introduction in the 1990s. A number of case series and studies have shown the potential that Rituximab can have for primary MN, but so far there has only been one randomised controlled trial (RCT) [21–24]. Here it has been shown that compared to standard anti-proteinuric therapy, patients treated with rituximab show a greater reduction in anti-PLA2R levels at month 3, followed by a later reduction in proteinuria, increase in serum albumin and are more likely to enter remission [24]. Combined with the high cost of the medication itself, its widespread use has been restricted in resource-limited, evidence-based healthcare systems, such as the NHS in UK [25]. The use of Rituximab therapy is currently under investigation in the MENTOR study in North America and via the Commissioning through Evaluation pathway run under the auspices of the National Institute for Health and Care Excellence (NICE) in the UK. It is possible that based on these two studies the

The use of many of these medications comes with side effects that can be unpalatable to the patient and physician and the search for treatments with a reduced

tacrolimus but with variable evidence to show an improvement in outcomes.

use of Rituximab will become more ubiquitous in the near future.

**74**

**Figure 1.**

*Foundation Trust, UK.*

**5. Future novel treatments**

side-effect profile is on-going. Treatments such as immunoadsorption (IA) allow for the controlled removal of antibodies without the side effects associated with immunosuppression. Immunoadsorption RCTs in MN though, are non-existent and certainly not in the anti-PLA2R era. Immunoadsorption is a method of removing specific circulating immunoglobulins from the blood and has been shown to remove over 80% of circulating IgG with a single session adsorption of 2.5 plasma volumes, with albumin and antithrombin III almost unaffected [26]. With multiple sessions, this can rise to over 98% [27]. These are removed in the absorber through binding Peptide-GAM. Using two columns per machine, one regenerating whilst the other is removing antibodies; the process can occur indefinitely until the required level of antibody has been removed.

Post IA it appears that autoantibodies can be slow to re-emerge. Use in dilated cardiomyopathy for the removal of β1-adreno-receptor autoantibodies (β1-AAB) has shown that only a small minority of patients (0% in the first year and 15% by 3 years) will show an increase in significant β1-AAB autoantibodies [28, 29].

To our knowledge, there has only been one publication using immunoadsorption for the treatment of MN [30]. In 1999, Esnault et al. successfully used IA for the treatment of various aetiologies of Nephrotic syndrome including four patients with MN [31]. Here they showed that not only is the procedure safe but that there was a significant improvement in proteinuria in all patients with membranous nephropathy. The main side effect in this group of patients was headache, which resolved without sequelae. Since that time the treatment has been used in numerous other autoimmune conditions including Focal Segmental Glomerulosclerosis (FSGS) [32], systemic lupus nephritis (SLE) [33, 34], ANCA-associated small vessel vasculitides [35, 36], Anti-glomerular basement membrane antibody disease [37] and in renal transplantation [38–40].

In conditions such as SLE, the use of immunoadsorption can dramatically reduce the level of circulating immune complexes and autoantibodies leading to clinical improvement in even severe life-threatening SLE. These results have been shown with as little as two sessions within 3 days and repeated every 3 weeks if patients remain with active disease [33]. With the current understanding of primary MN's autoimmune process, the use of IA could provide the ability to rapidly remove the pathogenic antibodies leading to remission. Current IA machines can remove the different classes such as IgG4 with an increased specificity but cannot differentiate further than that. If IA is proved to work for primary MN, it may be possible to develop an IA column that is specific only for anti-PLA2R, therefore allowing for an even more targeted and personalised treatment.

#### **6. Autoimmune membranous nephropathy**

Until recently autoimmune (or primary) MN was known as idiopathic MN as its cause remained unclear. It was generally a diagnosis of exclusion, once a patient had biopsy confirmation of MN and all causes of secondary MN had been ruled out. It was for a long time postulated to be an autoimmune disease, but the target antigen in humans remained elusive. In the late 1970s, work on the Heymann Nephritis rat model of experimental MN showed that circulating IgG antibodies could bind to the podocytes [41–43]. The target antigen was found to be megalin, but this was not present on human podocytes, so the search for the target antigen continued. It was not until 2009, almost 40 years later that this was discovered. Here Beck et al. used western blotting with MN patient sera, to show that antibodies bound to a 185 kDa protein band from glomerular extracts. This band was only seen in the primary MN group and not seen in normal patients or other proteinuric conditions including

patients with secondary MN. Using mass spectrometry this band was found to contain the M-type phospholipase A2 receptor 1 (PLA2R) [15]. Since then, the increased interest and research into MN has led to the discovery of a second minor target antigen in thrombospondin type-1 domain containing 7A (THSD7A) [44].

#### **7. M-type phospholipase A2 receptor 1**

The landmark paper by Beck et al. describing the discovery of autoantibodies to PLA2R found on human podocytes transformed our understanding of the MN disease process. Here was evidence that for the majority of patients with MN, the condition was, as had been postulated, an autoimmune disease [15].

PLA2R is a transmembrane receptor for Phospholipase A2, a protein from the mannose receptor family, one of four described in humans; Endo180, DEC205, Mannose Receptor (MR) and PLA2R [45–47]. As with all the mannose receptor family, the transmembrane glycoprotein has an extracellular component, in the case of PLA2R, this is made up of an N-terminal ricin rich domain, a fibronectin type II domain and 8 C-type lectin domains (CTLDs) [48]. In the kidney, it is found almost exclusively on the podocytes, but it has also been found on neutrophils and in the lung [49, 50]. Its function in the kidney remains unknown, however, and how the anti-PLA2R antibodies alter its normal function leading to proteinuria, if indeed that is what is part of the process, also remains unknown [15, 51].

The predominant antibody to PLA2R is IgG and in particular IgG4, which is the major component of immune complex deposition in primary MN [13, 14]. These immune complexes appear to form in the kidney with the IgG4 antibodies and the PLA2R antigen being co-localised, giving further evidence for the role of PLA2R in the disease process [52, 53]. The fact that the complexes form in situ in the kidney may explain why some patients with biopsy-proven MN and clinical evidence for the disease are serum anti-PLA2R negative. Debiec and Ronco showed in 2011 that there were a number of patients who were serum anti-PLA2R negative but had detectable PLA2R in glomerular deposits. They did also find a few patients with no PLA2R in the glomerular deposits but who were serologically positive [54]. We know that anti-PLA2R antibodies have a high affinity for PLA2R in the podocytes and it may be that a certain level of deposition is required to overload the system before the anti-PLA2R antibodies become serologically detectable [48].

Much of the excitement surrounding anti-PLA2R is due to its apparent pathogenicity with the resultant potential for use as a biomarker and as a treatment target. Several studies have provided evidence for its pathogenicity showing that a high titre correlates with disease activity. For patients who go into remission either spontaneously or through the use of immunosuppression, the anti-PLA2R level falls months before this becomes clinically apparent with a fall in proteinuria. If a patient relapses, this again is predated by a rise in antibody titres [55–60].

Outcomes can also be predicted with high titres predicting a worse outcome in regards to renal function and an improved outcome with low titres [55]. If treatment does not result in antibody negativity, then they are left with a high risk of relapse [51, 57]. Ruggenenti et al. have shown similar results with a reduction in anti-PLA2R levels strongly predicting remission and increasing titres following this, predicting relapse [59].

With the increasingly strong evidence for the involvement of anti-PLA2R antibodies in the pathogenesis of primary MN, the focus has now shifted to trying to understand the antigen and its interaction with the autoantibody. Work carried out in Manchester has now determined the major epitope on the PLA2R antigen

**77**

*Primary Membranous Nephropathy as a Model of Autoimmune Disease*

**8. Thrombospondin type-1 domain-containing 7A**

that is recognised by the anti-PLA2R antibodies. Four different sized fragments of extracellular PLA2R (full-length N-C8, N-terminus to C-type lectin domain (CTLD) 3 (N-C3), N-terminus to CTLD2 (N-C2) and a ricin rich domain) were used to investigate the reactivity of human anti-PLA2R autoantibodies. It was found that the major epitope was located in the N-C3 region of the receptor. The antibodies were also found to bind with an equal affinity to the four different fragments, confirming the existence of a single epitope. The epitope itself is a 31-mer peptide made up of the beta-1 and beta-3 strands and encompassing the

Leading on from this the Manchester team also constructed a 3D model of the structure of the immune complex incorporating the extracellular N-C8 PLA2R and the autoantibody with the binding site [48]. This work has been further confirmed by Kao et al. who found that the dominant epitope is in the N-terminal region as well, in particular in the region from the ricin rich domain through the fibronectin-

The fact that anti-PLA2R antibodies are found in up to 80% of patients with primary MN raises a number of possibilities. It is known that some patients with secondary membranous can develop malignancies years after the diagnosis of MN and it may be that these patients fall into this category. Whether these patients represent a cohort who have two separate conditions and it is coincidental that one is known to cause the other is still up for debate. A second possibility is that there are more pathogenic antigens leading to the formation of autoantibodies than previously thought. In fact, for a small number of patients with primary MN, this seems

Using western blotting, Thomas et al. discovered a glomerular protein of 250 kDa in patients with anti-PLA2R negative biopsy-proven membranous nephropathy. This corresponded to THSD7A, a protein found in the podocyte foot

They went on to show that the predominant antibody to this antigen was IgG4 in keeping with a diagnosis of primary MN, and on histological staining, in a similar fashion to anti-PLA2R, the immune complexes were co-localised with the antigen. Levels of the antibody were shown to correlate with disease activity, being higher in active disease and lower as the clinical manifestations of the disease improved. Interestingly, there appeared to be no statistical significance in the clinical presentation or demographics between the anti-PLA2R positive and the anti-THSD7A positive patients, except for a slightly higher number of women in the anti-THSD7A group, although this is believed to be due to the small num-

This evidence suggests that for a minority of primary MN patients, approximately 2.5–5% in this study, a second unrelated and discrete antigen is involved with the pathogenesis of the disease [44]. Whether this all represents a separate disease and whether there are other minor antigens still to be discovered remains unknown as does the major epitope in THSD7A. However, for PLA2R, in addition to the major epitope in the CysR domain, evidence from the work of Fresquet et al. on the identification of the major epitope of PLA2R, showed that 10% of anti-PLA2R positive sera reacted with an epitope at CTLD4-8. This suggests that there may be a further, as yet unidentified, antibody to this minor epitope [48]. This idea of epitope spreading has been suggested by Lambeau et al. who have defined additional

*DOI: http://dx.doi.org/10.5772/intechopen.88003*

beta-2 strand [48].

to be the case.

processes [44].

bers involved.

epitopes in CTLD1 and CTLD7 domains [62].

like type to the CTLD1 [61].

#### *Primary Membranous Nephropathy as a Model of Autoimmune Disease DOI: http://dx.doi.org/10.5772/intechopen.88003*

*Glomerulonephritis and Nephrotic Syndrome*

**7. M-type phospholipase A2 receptor 1**

patients with secondary MN. Using mass spectrometry this band was found to contain the M-type phospholipase A2 receptor 1 (PLA2R) [15]. Since then, the increased interest and research into MN has led to the discovery of a second minor target antigen in thrombospondin type-1 domain containing 7A (THSD7A) [44].

The landmark paper by Beck et al. describing the discovery of autoantibodies to PLA2R found on human podocytes transformed our understanding of the MN disease process. Here was evidence that for the majority of patients with MN, the

PLA2R is a transmembrane receptor for Phospholipase A2, a protein from the mannose receptor family, one of four described in humans; Endo180, DEC205, Mannose Receptor (MR) and PLA2R [45–47]. As with all the mannose receptor family, the transmembrane glycoprotein has an extracellular component, in the case of PLA2R, this is made up of an N-terminal ricin rich domain, a fibronectin type II domain and 8 C-type lectin domains (CTLDs) [48]. In the kidney, it is found almost exclusively on the podocytes, but it has also been found on neutrophils and in the lung [49, 50]. Its function in the kidney remains unknown, however, and how the anti-PLA2R antibodies alter its normal function leading to proteinuria, if indeed

The predominant antibody to PLA2R is IgG and in particular IgG4, which is the major component of immune complex deposition in primary MN [13, 14]. These immune complexes appear to form in the kidney with the IgG4 antibodies and the PLA2R antigen being co-localised, giving further evidence for the role of PLA2R in the disease process [52, 53]. The fact that the complexes form in situ in the kidney may explain why some patients with biopsy-proven MN and clinical evidence for the disease are serum anti-PLA2R negative. Debiec and Ronco showed in 2011 that there were a number of patients who were serum anti-PLA2R negative but had detectable PLA2R in glomerular deposits. They did also find a few patients with no PLA2R in the glomerular deposits but who were serologically positive [54]. We know that anti-PLA2R antibodies have a high affinity for PLA2R in the podocytes and it may be that a certain level of deposition is required to overload the system before the anti-PLA2R antibodies become serologically

Much of the excitement surrounding anti-PLA2R is due to its apparent pathogenicity with the resultant potential for use as a biomarker and as a treatment target. Several studies have provided evidence for its pathogenicity showing that a high titre correlates with disease activity. For patients who go into remission either spontaneously or through the use of immunosuppression, the anti-PLA2R level falls months before this becomes clinically apparent with a fall in proteinuria. If a patient

Outcomes can also be predicted with high titres predicting a worse outcome in regards to renal function and an improved outcome with low titres [55]. If treatment does not result in antibody negativity, then they are left with a high risk of relapse [51, 57]. Ruggenenti et al. have shown similar results with a reduction in anti-PLA2R levels strongly predicting remission and increasing titres following this,

With the increasingly strong evidence for the involvement of anti-PLA2R antibodies in the pathogenesis of primary MN, the focus has now shifted to trying to understand the antigen and its interaction with the autoantibody. Work carried out in Manchester has now determined the major epitope on the PLA2R antigen

condition was, as had been postulated, an autoimmune disease [15].

that is what is part of the process, also remains unknown [15, 51].

relapses, this again is predated by a rise in antibody titres [55–60].

**76**

detectable [48].

predicting relapse [59].

that is recognised by the anti-PLA2R antibodies. Four different sized fragments of extracellular PLA2R (full-length N-C8, N-terminus to C-type lectin domain (CTLD) 3 (N-C3), N-terminus to CTLD2 (N-C2) and a ricin rich domain) were used to investigate the reactivity of human anti-PLA2R autoantibodies. It was found that the major epitope was located in the N-C3 region of the receptor. The antibodies were also found to bind with an equal affinity to the four different fragments, confirming the existence of a single epitope. The epitope itself is a 31-mer peptide made up of the beta-1 and beta-3 strands and encompassing the beta-2 strand [48].

Leading on from this the Manchester team also constructed a 3D model of the structure of the immune complex incorporating the extracellular N-C8 PLA2R and the autoantibody with the binding site [48]. This work has been further confirmed by Kao et al. who found that the dominant epitope is in the N-terminal region as well, in particular in the region from the ricin rich domain through the fibronectinlike type to the CTLD1 [61].

#### **8. Thrombospondin type-1 domain-containing 7A**

The fact that anti-PLA2R antibodies are found in up to 80% of patients with primary MN raises a number of possibilities. It is known that some patients with secondary membranous can develop malignancies years after the diagnosis of MN and it may be that these patients fall into this category. Whether these patients represent a cohort who have two separate conditions and it is coincidental that one is known to cause the other is still up for debate. A second possibility is that there are more pathogenic antigens leading to the formation of autoantibodies than previously thought. In fact, for a small number of patients with primary MN, this seems to be the case.

Using western blotting, Thomas et al. discovered a glomerular protein of 250 kDa in patients with anti-PLA2R negative biopsy-proven membranous nephropathy. This corresponded to THSD7A, a protein found in the podocyte foot processes [44].

They went on to show that the predominant antibody to this antigen was IgG4 in keeping with a diagnosis of primary MN, and on histological staining, in a similar fashion to anti-PLA2R, the immune complexes were co-localised with the antigen. Levels of the antibody were shown to correlate with disease activity, being higher in active disease and lower as the clinical manifestations of the disease improved. Interestingly, there appeared to be no statistical significance in the clinical presentation or demographics between the anti-PLA2R positive and the anti-THSD7A positive patients, except for a slightly higher number of women in the anti-THSD7A group, although this is believed to be due to the small numbers involved.

This evidence suggests that for a minority of primary MN patients, approximately 2.5–5% in this study, a second unrelated and discrete antigen is involved with the pathogenesis of the disease [44]. Whether this all represents a separate disease and whether there are other minor antigens still to be discovered remains unknown as does the major epitope in THSD7A. However, for PLA2R, in addition to the major epitope in the CysR domain, evidence from the work of Fresquet et al. on the identification of the major epitope of PLA2R, showed that 10% of anti-PLA2R positive sera reacted with an epitope at CTLD4-8. This suggests that there may be a further, as yet unidentified, antibody to this minor epitope [48]. This idea of epitope spreading has been suggested by Lambeau et al. who have defined additional epitopes in CTLD1 and CTLD7 domains [62].

#### **9. The multi-hit hypothesis**

#### **9.1 Genetic association**

Why some patients develop an autoantibody to PLA2R is still an unknown, but it does appear to have a strong genetic component. The first clue to the genetic basis of the disease was the discovery of the association with Human Leucocyte Antigen (HLA)—DR3 followed closely by the identification of familial clustering in 1984 [30, 63, 64]. Following the discovery of the PLA2R antigen, researchers studying Korean and Chinese populations investigated the association of a number of single nucleotide polymorphisms (SNPs) known to be associated with PLA2R. They both found that a polymorphism at rs35771982 was significantly associated with primary MN. Interestingly, this polymorphism is located on CTLD1, in the region that was later found to contain an epitope in the antigen [48, 65, 66].

The major Genome-Wide Association Study (GWAS) in MN of 556 patients (French, Dutch and British) revealed two major loci of allelic association. The first is not unexpectedly on chromosome 6p21 within HLA-DQA1 gene, and the second is on chromosome 2q24 containing PLA2R1. For patients who were homozygous for these alleles, their odds ratio for having primary membranous nephropathy was 78.5 [67]. This work has recently been validated in a study using genotype and HLA imputation alongside a GWAS in 323 patients with primary MN. Here the association of HLA-DQA1 and PLA2R1 with primary MN was confirmed, without detecting any other novel signals [68].

How these genetic markers modulate the risk of developing MN is unknown. The idea that the genetically restricted class II presentation of PLA2R peptides to affect the class switch to high-affinity IgG anti-PLA2R is a theory that remains to be tested.

#### **9.2 Environmental trigger**

Indicative of the rapid pace of research into primary MN since the discovery of the PLA2R antigen, we now have not only the clinical correlation of the antibody with disease activity but also the major epitope on the antigen and evidence for the genetic polymorphism located in the antigen itself. This, however, does not completely explain the development of the disease. The polymorphisms described in these studies are actually variants that are common to the general population. It seems likely that, similar to other autoimmune diseases such as IgA nephropathy, primary MN is a multi-hit disease. A patient with the polymorphism has a genetic predisposition but to develop the disease needs an external trigger.

Fresquet et al. have shown that an amino acid sequence which is part of the dominant epitope in the CysR region of the PLA2R antigen is also found in the cell wall of some species of clostridia [48]. Further searches using the Basic Local Alignment Search Tool (BLAST) [69] has shown this peptide sequence is found in a number of other common pathogens such as Pseudomonas and *Saccharomyces cerevisiae*.

There is now also emerging evidence implicating air pollution in the development of autoimmune MN. A recent large study in China investigating the emerging trends of glomerulopathy based on renal biopsies in relation to air pollution noted a rise in the incidence of MN in all age ranges and in all regions, this is in contrast to other glomerular disease investigated which all remained the same. It was more prevalent in areas with the highest air pollution and the long-term average was found to be associated with a significantly increased risk of autoimmune MN.

**79**

*Primary Membranous Nephropathy as a Model of Autoimmune Disease*

What is not known at present is the risk of developing autoimmune MN if you have the genetic predisposition, only that you are more likely to have the risk alleles if you have autoimmune MN. What remains elusive is how a patient's immune system converts from an advantageous defence against common pathogens to a pathogenic entity in itself. A characteristic of autoimmune MN is the heterogeneity shown in prognosis and its waxing and waning nature over time. A proportion of patients will undergo a phenomenon of spontaneous remission, and in patients with a more severe phenotype, it is not unusual for them to follow a relapsing and remitting course. Many patients, when they first come to medical attention, will describe self-limiting episodes many months or years prior to their diagnosis that is likely to be nephrotic states and the first signs of the disease. This suggests that far from being a continuously progressive immunological process, particularly in light of the pathogenicity of the autoantibody, that there may be natural mechanisms at play attempting to maintain a balance. Work in other autoimmune diseases such as autoimmune thyroiditis has proven the existence of antigens capable of maintaining a population of natural T Regs and thereby keeping pathogenic antibodies sup-

As the technology evolves, flow cytometry is becoming an ever more powerful tool for the study of the immune system. A recent study using patients enrolled in the GEMRITUX trial showed that patients had lower proportions of IgD− and IgD+ memory B cells, T Regs and a higher proportion of naïve B cells at baseline compared to healthy donors [71]. In this study by Rosenzwajg et al., patients who responded to treatment were observed to have a lower proportion of T Regs at baseline compared to those who did not respond to treatment. They also noted that in patients with no response to treatment, there was no increase in T Regs following treatment, however in patients who went on to respond, there was a significantly

This is similar to work currently being undertaken in our lab (unpublished) in which flow cytometry was used to model the immune system following treatment with immunoadsorption [72]. In our cohort, we also found that there was a lower proportion of IgD+ memory B cells in the patient group but a similar level of IgD− memory B cells albeit with a much larger range. For the Naïve B cells and T Regs, the medians were very similar between the patients and control group but with a much larger range in the patient cohort. One of the striking differences between our patient group and the control group at baseline is that there does not seem to be any statistical difference in PLA2R positive B cells, with a number of volunteers in the control group showing a relatively high proportion of these cells. This seemingly counterintuitive result, in fact, appears to add weight to the importance of loss of

Given the shared sequence of amino acids (SVLTLENC), it could be expected during the development of normal natural immunity to a range of pathogens, developing IgM antibodies to this linear peptide sequence is common, entirely normal and beneficial to the host. The risk of developing an autoimmune pathology only arises then, if a patient has the genetic makeup (pathological alleles of DQA1 and PLA2R) required to present PLA2R T cell peptides to their immune system. Only with the permissive genetic background and continued exposure to the pathogen or environmental trigger, causing immune processing of PLA2R, will class switching occur from IgM to IgG, and therefore allowing the development of pathogenic high-affinity antibodies. In our PLA2R panel, the healthy control group showed a significant level of PLA2R positive B cells. A current on-going and unpublished project being carried out in our lab is the development of an IgM anti-PLA2R

higher proportion of T Regs at day 8 compared to baseline [71].

*DOI: http://dx.doi.org/10.5772/intechopen.88003*

**9.3 Loss of tolerance**

pressed [70].

tolerance in the disease process.

#### **9.3 Loss of tolerance**

*Glomerulonephritis and Nephrotic Syndrome*

Why some patients develop an autoantibody to PLA2R is still an unknown, but it does appear to have a strong genetic component. The first clue to the genetic basis of the disease was the discovery of the association with Human Leucocyte Antigen (HLA)—DR3 followed closely by the identification of familial clustering in 1984 [30, 63, 64]. Following the discovery of the PLA2R antigen, researchers studying Korean and Chinese populations investigated the association of a number of single nucleotide polymorphisms (SNPs) known to be associated with PLA2R. They both found that a polymorphism at rs35771982 was significantly associated with primary MN. Interestingly, this polymorphism is located on CTLD1, in the region that was

The major Genome-Wide Association Study (GWAS) in MN of 556 patients (French, Dutch and British) revealed two major loci of allelic association. The first is not unexpectedly on chromosome 6p21 within HLA-DQA1 gene, and the second is on chromosome 2q24 containing PLA2R1. For patients who were homozygous for these alleles, their odds ratio for having primary membranous nephropathy was 78.5 [67]. This work has recently been validated in a study using genotype and HLA imputation alongside a GWAS in 323 patients with primary MN. Here the association of HLA-DQA1 and PLA2R1 with primary MN was confirmed, without detect-

How these genetic markers modulate the risk of developing MN is unknown. The idea that the genetically restricted class II presentation of PLA2R peptides to affect the class switch to high-affinity IgG anti-PLA2R is a theory that remains to

Indicative of the rapid pace of research into primary MN since the discovery of the PLA2R antigen, we now have not only the clinical correlation of the antibody with disease activity but also the major epitope on the antigen and evidence for the genetic polymorphism located in the antigen itself. This, however, does not completely explain the development of the disease. The polymorphisms described in these studies are actually variants that are common to the general population. It seems likely that, similar to other autoimmune diseases such as IgA nephropathy, primary MN is a multi-hit disease. A patient with the polymorphism has a genetic

Fresquet et al. have shown that an amino acid sequence which is part of the dominant epitope in the CysR region of the PLA2R antigen is also found in the cell wall of some species of clostridia [48]. Further searches using the Basic Local Alignment Search Tool (BLAST) [69] has shown this peptide sequence is found in a number of other common pathogens such as Pseudomonas and *Saccharomyces* 

There is now also emerging evidence implicating air pollution in the development of autoimmune MN. A recent large study in China investigating the emerging trends of glomerulopathy based on renal biopsies in relation to air pollution noted a rise in the incidence of MN in all age ranges and in all regions, this is in contrast to other glomerular disease investigated which all remained the same. It was more prevalent in areas with the highest air pollution and the long-term average was found to be associated with a significantly increased risk of autoim-

predisposition but to develop the disease needs an external trigger.

later found to contain an epitope in the antigen [48, 65, 66].

**9. The multi-hit hypothesis**

ing any other novel signals [68].

**9.2 Environmental trigger**

be tested.

**9.1 Genetic association**

**78**

*cerevisiae*.

mune MN.

What is not known at present is the risk of developing autoimmune MN if you have the genetic predisposition, only that you are more likely to have the risk alleles if you have autoimmune MN. What remains elusive is how a patient's immune system converts from an advantageous defence against common pathogens to a pathogenic entity in itself. A characteristic of autoimmune MN is the heterogeneity shown in prognosis and its waxing and waning nature over time. A proportion of patients will undergo a phenomenon of spontaneous remission, and in patients with a more severe phenotype, it is not unusual for them to follow a relapsing and remitting course. Many patients, when they first come to medical attention, will describe self-limiting episodes many months or years prior to their diagnosis that is likely to be nephrotic states and the first signs of the disease. This suggests that far from being a continuously progressive immunological process, particularly in light of the pathogenicity of the autoantibody, that there may be natural mechanisms at play attempting to maintain a balance. Work in other autoimmune diseases such as autoimmune thyroiditis has proven the existence of antigens capable of maintaining a population of natural T Regs and thereby keeping pathogenic antibodies suppressed [70].

As the technology evolves, flow cytometry is becoming an ever more powerful tool for the study of the immune system. A recent study using patients enrolled in the GEMRITUX trial showed that patients had lower proportions of IgD− and IgD+ memory B cells, T Regs and a higher proportion of naïve B cells at baseline compared to healthy donors [71]. In this study by Rosenzwajg et al., patients who responded to treatment were observed to have a lower proportion of T Regs at baseline compared to those who did not respond to treatment. They also noted that in patients with no response to treatment, there was no increase in T Regs following treatment, however in patients who went on to respond, there was a significantly higher proportion of T Regs at day 8 compared to baseline [71].

This is similar to work currently being undertaken in our lab (unpublished) in which flow cytometry was used to model the immune system following treatment with immunoadsorption [72]. In our cohort, we also found that there was a lower proportion of IgD+ memory B cells in the patient group but a similar level of IgD− memory B cells albeit with a much larger range. For the Naïve B cells and T Regs, the medians were very similar between the patients and control group but with a much larger range in the patient cohort. One of the striking differences between our patient group and the control group at baseline is that there does not seem to be any statistical difference in PLA2R positive B cells, with a number of volunteers in the control group showing a relatively high proportion of these cells. This seemingly counterintuitive result, in fact, appears to add weight to the importance of loss of tolerance in the disease process.

Given the shared sequence of amino acids (SVLTLENC), it could be expected during the development of normal natural immunity to a range of pathogens, developing IgM antibodies to this linear peptide sequence is common, entirely normal and beneficial to the host. The risk of developing an autoimmune pathology only arises then, if a patient has the genetic makeup (pathological alleles of DQA1 and PLA2R) required to present PLA2R T cell peptides to their immune system. Only with the permissive genetic background and continued exposure to the pathogen or environmental trigger, causing immune processing of PLA2R, will class switching occur from IgM to IgG, and therefore allowing the development of pathogenic high-affinity antibodies. In our PLA2R panel, the healthy control group showed a significant level of PLA2R positive B cells. A current on-going and unpublished project being carried out in our lab is the development of an IgM anti-PLA2R

ELISA. Although it cannot be proven in the current flow cytometry experiment, it would appear to suggest that there is a high likelihood that the B cells seen in the healthy population may, in fact, be IgM positive B cells as opposed to being IgG positive.

A further interesting dimension to immune regulation and loss of tolerance that needs further study is the role that T reg cells play and how they are a potential mechanism for the suppression of pathogenic antibodies. The relapsing and remitting nature of autoimmune membranous nephropathy and the phenomenon of spontaneous remission indicates that at some level there must be an immune mechanism capable of suppressing the anti-PLA2R antibodies, much like that found in autoimmune thyroiditis. Another on-going study, again unpublished, in our lab has identified a number of healthy controls without the prerequisite HLA-DQA1 or PLA2R1 genes needed to develop autoimmune MN, who have a detectable level of circulating soluble PLA2R using mouse anti-PLA2R as the capture antibody. There is the potential that these circulating soluble-PLA2R antigens are active in maintaining a functioning level of T Regs to suppress class switching and downregulate the pathogenic antibody level. If natural T Regs did indeed have a role in keeping the pathogenic IgG anti-PLA2R antibodies suppressed, the expectation would be that in times of active disease the levels would be low. The opposite would also be true with high levels in times of remission or just before remission or response to treatment. The T cell panel used for the patient cohort does start to show a pattern of T Regs change over time, a pattern that appears to support the theory above, especially when taken in the context of antibody level. At week 4 follow up, the T Regs level has dropped to their lowest point, this is also at the same time point at which the anti-PLA2R is at its highest. The proportion of T Regs then show an increase at both week 10 and week 16 follow up, just as the antibody level is decreasing.

#### **10. Summary**

Autoimmune MN has experienced a step change in our understanding of the disease pathogenesis since the discovery of the anti-PLA2R autoantibody in 2009 [15], however, there is much that still remains unknown. Despite the advances seen over the last decade, the management of the disease remains an empirical treatment based on a regimen first introduced over two decades ago. There is as yet no disease-specific therapy or alternative to glucocorticoids and immunosuppression in mainstream use.

As with all autoimmune diseases, the eventual clinically apparent symptoms are the end result in a journey of multiple steps, the so-called multi-hit hypothesis. We know that there is a strong genetic component in the development of the disease, with patients homozygous for both the HLA-DQA1 and PLA2R1 genes are almost 80 times more likely to develop the disease than patients who do not [67]. What we still do not know is whether the possession of these genes in itself guarantees the development of the disease. It is likely that a further trigger (likely environmental) is required to progress to the disease state.

Development of the normal natural immunity requires the production of antibodies, including IgM, to linear peptides in a whole range of epitopes. With this beneficial protective immunity, circulating IgM antibodies to the PLA2R p28mer peptide can, in fact, be a normal occurrence. The presence of these antibodies in patients without the genetic predisposition to the disease would just be an expected variant of normal. It is in those patients who do have the genetic predisposition to developing the disease, that the presence of IgM antibodies with the ability to recognise the p28mer will have the potential to progress to the disease state to generate

**81**

*Primary Membranous Nephropathy as a Model of Autoimmune Disease*

first evidence for an antibody class switch in autoimmune MN.

a high-affinity IgG response. Once this occurs, and there is recognition of the podocyte PLA2R epitope there begins a positive reinforcement with ever-increasing affinity. The exact nature of how patients eventually develop a pathogenic IgG antibody remains elusive. However, there is now tentative emerging evidence showing that in a control group of healthy volunteers and a patient group with active disease there is a PLA2R antigen positive B cell population in both. This is coupled with an on-going unpublished study showing a level of circulating anti-PLA2R IgM antibodies in these normal healthy patients. This requires further work, but it is the

There is also data showing that as the anti-PLA2R antibody rises in the weeks following treatment, there is a reduction in the natural T Regs. Following this, as the level of T Regs starts to rise there is a corresponding fall in the antibody level. Taken in tandem with unpublished work that is on-going showing a measurable level of circulating soluble PLA2R in healthy controls, this would appear to show that a similar process to autoimmune thyroiditis is taking place in autoimmune MN. There do remain a number of important questions in relation to the disease pathogenesis though; how does the anti-PLA2R attaching to the epitope causes the damage we see? Despite strong circumstantial evidence suggesting its pathogenicity, direct evidence is currently lacking. Can the antibody titre supplant the need for a renal biopsy? How many patients who have the genetic predisposition eventually go on to develop the disease and is there a way to predict which patient does? And are there more autoantibodies associated with the development of autoimmune

Current understanding of the role anti-PLA2R plays in the pathogenesis has now led many to envisage a greater role for its use in clinical practice. Not only is it increasingly being used for disease monitoring and for prognosticating treatment response but it is also becoming a necessary tool for diagnosis. This has the distinct prospect of drastically altering the current diagnostic pathway and ultimately a patients quality of life. A number of groups are now actively investigating the feasibility of serum anti-PLA2R negating the need for a renal biopsy, not only reducing

The hope is that by understanding the pathway of disease in this and other autoimmune conditions, new safer and more efficacious treatment options will be available for patients in the future. This is particularly pertinent given the increasing incidence of autoimmune diseases worldwide and the increased burden on

time to diagnosis but also avoiding the need for an invasive procedure.

*DOI: http://dx.doi.org/10.5772/intechopen.88003*

membranous nephropathy.

patients and healthcare systems.

#### *Primary Membranous Nephropathy as a Model of Autoimmune Disease DOI: http://dx.doi.org/10.5772/intechopen.88003*

*Glomerulonephritis and Nephrotic Syndrome*

positive.

**10. Summary**

in mainstream use.

is required to progress to the disease state.

ELISA. Although it cannot be proven in the current flow cytometry experiment, it would appear to suggest that there is a high likelihood that the B cells seen in the healthy population may, in fact, be IgM positive B cells as opposed to being IgG

A further interesting dimension to immune regulation and loss of tolerance that needs further study is the role that T reg cells play and how they are a potential mechanism for the suppression of pathogenic antibodies. The relapsing and remitting nature of autoimmune membranous nephropathy and the phenomenon of spontaneous remission indicates that at some level there must be an immune mechanism capable of suppressing the anti-PLA2R antibodies, much like that found in autoimmune thyroiditis. Another on-going study, again unpublished, in our lab has identified a number of healthy controls without the prerequisite HLA-DQA1 or PLA2R1 genes needed to develop autoimmune MN, who have a detectable level of circulating soluble PLA2R using mouse anti-PLA2R as the capture antibody. There is the potential that these circulating soluble-PLA2R antigens are active in maintaining a functioning level of T Regs to suppress class switching and downregulate the pathogenic antibody level. If natural T Regs did indeed have a role in keeping the pathogenic IgG anti-PLA2R antibodies suppressed, the expectation would be that in times of active disease the levels would be low. The opposite would also be true with high levels in times of remission or just before remission or response to treatment. The T cell panel used for the patient cohort does start to show a pattern of T Regs change over time, a pattern that appears to support the theory above, especially when taken in the context of antibody level. At week 4 follow up, the T Regs level has dropped to their lowest point, this is also at the same time point at which the anti-PLA2R is at its highest. The proportion of T Regs then show an increase at both

week 10 and week 16 follow up, just as the antibody level is decreasing.

Autoimmune MN has experienced a step change in our understanding of the disease pathogenesis since the discovery of the anti-PLA2R autoantibody in 2009 [15], however, there is much that still remains unknown. Despite the advances seen over the last decade, the management of the disease remains an empirical treatment based on a regimen first introduced over two decades ago. There is as yet no disease-specific therapy or alternative to glucocorticoids and immunosuppression

As with all autoimmune diseases, the eventual clinically apparent symptoms are the end result in a journey of multiple steps, the so-called multi-hit hypothesis. We know that there is a strong genetic component in the development of the disease, with patients homozygous for both the HLA-DQA1 and PLA2R1 genes are almost 80 times more likely to develop the disease than patients who do not [67]. What we still do not know is whether the possession of these genes in itself guarantees the development of the disease. It is likely that a further trigger (likely environmental)

Development of the normal natural immunity requires the production of antibodies, including IgM, to linear peptides in a whole range of epitopes. With this beneficial protective immunity, circulating IgM antibodies to the PLA2R p28mer peptide can, in fact, be a normal occurrence. The presence of these antibodies in patients without the genetic predisposition to the disease would just be an expected variant of normal. It is in those patients who do have the genetic predisposition to developing the disease, that the presence of IgM antibodies with the ability to recognise the p28mer will have the potential to progress to the disease state to generate

**80**

a high-affinity IgG response. Once this occurs, and there is recognition of the podocyte PLA2R epitope there begins a positive reinforcement with ever-increasing affinity. The exact nature of how patients eventually develop a pathogenic IgG antibody remains elusive. However, there is now tentative emerging evidence showing that in a control group of healthy volunteers and a patient group with active disease there is a PLA2R antigen positive B cell population in both. This is coupled with an on-going unpublished study showing a level of circulating anti-PLA2R IgM antibodies in these normal healthy patients. This requires further work, but it is the first evidence for an antibody class switch in autoimmune MN.

There is also data showing that as the anti-PLA2R antibody rises in the weeks following treatment, there is a reduction in the natural T Regs. Following this, as the level of T Regs starts to rise there is a corresponding fall in the antibody level. Taken in tandem with unpublished work that is on-going showing a measurable level of circulating soluble PLA2R in healthy controls, this would appear to show that a similar process to autoimmune thyroiditis is taking place in autoimmune MN.

There do remain a number of important questions in relation to the disease pathogenesis though; how does the anti-PLA2R attaching to the epitope causes the damage we see? Despite strong circumstantial evidence suggesting its pathogenicity, direct evidence is currently lacking. Can the antibody titre supplant the need for a renal biopsy? How many patients who have the genetic predisposition eventually go on to develop the disease and is there a way to predict which patient does? And are there more autoantibodies associated with the development of autoimmune membranous nephropathy.

Current understanding of the role anti-PLA2R plays in the pathogenesis has now led many to envisage a greater role for its use in clinical practice. Not only is it increasingly being used for disease monitoring and for prognosticating treatment response but it is also becoming a necessary tool for diagnosis. This has the distinct prospect of drastically altering the current diagnostic pathway and ultimately a patients quality of life. A number of groups are now actively investigating the feasibility of serum anti-PLA2R negating the need for a renal biopsy, not only reducing time to diagnosis but also avoiding the need for an invasive procedure.

The hope is that by understanding the pathway of disease in this and other autoimmune conditions, new safer and more efficacious treatment options will be available for patients in the future. This is particularly pertinent given the increasing incidence of autoimmune diseases worldwide and the increased burden on patients and healthcare systems.

*Glomerulonephritis and Nephrotic Syndrome*

#### **Author details**

Patrick Hamilton1,2,3\*, Durga Kanigicherla1,2 and Paul Brenchley1,2,3

1 Manchester Institute of Nephrology and Transplantation, Manchester Royal Infirmary, Manchester, United Kingdom

2 Manchester Academic Health Science Centre (MAHSC), The University of Manchester, Manchester, United Kingdom

3 Lydia Becker Institute of Immunology & Inflammation, The University of Manchester, Manchester, United Kingdom

\*Address all correspondence to: patrick.hamilton@mft.nhs.uk

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**83**

*Primary Membranous Nephropathy as a Model of Autoimmune Disease*

utility-based quality of life in chronic kidney disease treatments. PLoS Medicine. 2012;**9**(9):e1001307-e1001310

[10] Overbeck I, Bartels M, Decker O, Harms J. Changes in quality of life after renal transplantation. Transplantation Proceedings. Apr 2005;**37**(3):1618-1621.

PubMed PMID: 15866689

1998;**9**(11):2135-2141

2010;**25**(10):3408-3415

Immunology. 1984;**58**(1):57

[14] Oliveira DB. Membranous nephropathy: An IgG4-mediated disease. Lancet. 1998;**351**(9103):670-671

membranous nephropathy. The New England Journal of Medicine.

2009;**361**(1):11-21

[15] Beck LH Jr, Bonegio RGB, Lambeau G, Beck DM, Powell DW, Cummins TD, et al. M-type phospholipase A 2receptor as target antigen in idiopathic

[16] Huang CC, Lehman A, Albawardi A, Satoskar A, Brodsky S, Nadasdy G, et al. IgG subclass staining in renal biopsies with membranous

[11] Schnuelle P, Lorenz D, Trede M, van der Woude FJ. Impact of renal cadaveric transplantation on survival in end-stage renal failure: Evidence for reduced mortality risk compared with hemodialysis during long-term follow-up. Journal of the American Society of Nephrology.

[12] Moroni G, Gallelli B, Quaglini S, Leoni A, Banfi G, Passerini P, et al. Long-term outcome of renal transplantation in patients with idiopathic membranous glomerulonephritis (MN).

Nephrology, Dialysis, Transplantation.

[13] Doi T, Mayumi M, Kanatsu K, Suehiro F, Hamashima Y. Distribution of IgG subclasses in membranous nephropathy. Clinical and Experimental

*DOI: http://dx.doi.org/10.5772/intechopen.88003*

[1] TADC Committee. Progress in autoimmune diseases research. National Institutes of Health. 2005;**1**(1):1-146

[2] Cooper GS, Bynum MLK, Somers EC. Recent insights in the epidemiology of autoimmune diseases: Improved prevalence estimates and understanding of clustering of diseases. Journal of Autoimmunity. 2009;**33**(3-4):197-207

[3] McGrogan A, Franssen CFM, de Vries CS. The incidence of primary glomerulonephritis worldwide: A systematic review of the literature. Nephrology, Dialysis, Transplantation.

[4] Barbour SJ, Greenwald A, Djurdjev O, Levin A, Hladunewich MA, Nachman PH, et al. Disease-specific risk of venous thromboembolic events is increased in idiopathic glomerulonephritis. Kidney International. 2011;**81**(2):190-195

[5] Llach F. Hypercoagulability, renal vein thrombosis, and other thrombotic complications of nephrotic syndrome. Kidney International.

KS. Thromboembolic complications

management. Thrombosis Research.

[7] Eknoyan G, Eckardt KU, Kasiske BL. KDIGO clinical practice guideline for glomerulonephritis. Kidney International. 2012;**2**:143

[8] Schieppati A, Mosconi L, Perna A. Prognosis of untreated patients with idiopathic membranous nephropathy. The New England Journal of Medicine.

[9] Wyld M, Morton RL, Hayen A, Howard K, Webster AC. A systematic

review and meta-analysis of

2011;**26**(2):414-430

1985;**28**(3):429-439

[6] Singhal R, Brimble

2006;**118**(3):397-407

8 Jul 1993;**329**(2):85-89

in the nephrotic syndrome: Pathophysiology and clinical

**References**

*Primary Membranous Nephropathy as a Model of Autoimmune Disease DOI: http://dx.doi.org/10.5772/intechopen.88003*

#### **References**

*Glomerulonephritis and Nephrotic Syndrome*

**82**

**Author details**

Infirmary, Manchester, United Kingdom

Manchester, Manchester, United Kingdom

Manchester, Manchester, United Kingdom

provided the original work is properly cited.

Patrick Hamilton1,2,3\*, Durga Kanigicherla1,2 and Paul Brenchley1,2,3

\*Address all correspondence to: patrick.hamilton@mft.nhs.uk

1 Manchester Institute of Nephrology and Transplantation, Manchester Royal

2 Manchester Academic Health Science Centre (MAHSC), The University of

3 Lydia Becker Institute of Immunology & Inflammation, The University of

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

[1] TADC Committee. Progress in autoimmune diseases research. National Institutes of Health. 2005;**1**(1):1-146

[2] Cooper GS, Bynum MLK, Somers EC. Recent insights in the epidemiology of autoimmune diseases: Improved prevalence estimates and understanding of clustering of diseases. Journal of Autoimmunity. 2009;**33**(3-4):197-207

[3] McGrogan A, Franssen CFM, de Vries CS. The incidence of primary glomerulonephritis worldwide: A systematic review of the literature. Nephrology, Dialysis, Transplantation. 2011;**26**(2):414-430

[4] Barbour SJ, Greenwald A, Djurdjev O, Levin A, Hladunewich MA, Nachman PH, et al. Disease-specific risk of venous thromboembolic events is increased in idiopathic glomerulonephritis. Kidney International. 2011;**81**(2):190-195

[5] Llach F. Hypercoagulability, renal vein thrombosis, and other thrombotic complications of nephrotic syndrome. Kidney International. 1985;**28**(3):429-439

[6] Singhal R, Brimble KS. Thromboembolic complications in the nephrotic syndrome: Pathophysiology and clinical management. Thrombosis Research. 2006;**118**(3):397-407

[7] Eknoyan G, Eckardt KU, Kasiske BL. KDIGO clinical practice guideline for glomerulonephritis. Kidney International. 2012;**2**:143

[8] Schieppati A, Mosconi L, Perna A. Prognosis of untreated patients with idiopathic membranous nephropathy. The New England Journal of Medicine. 8 Jul 1993;**329**(2):85-89

[9] Wyld M, Morton RL, Hayen A, Howard K, Webster AC. A systematic review and meta-analysis of

utility-based quality of life in chronic kidney disease treatments. PLoS Medicine. 2012;**9**(9):e1001307-e1001310

[10] Overbeck I, Bartels M, Decker O, Harms J. Changes in quality of life after renal transplantation. Transplantation Proceedings. Apr 2005;**37**(3):1618-1621. PubMed PMID: 15866689

[11] Schnuelle P, Lorenz D, Trede M, van der Woude FJ. Impact of renal cadaveric transplantation on survival in end-stage renal failure: Evidence for reduced mortality risk compared with hemodialysis during long-term follow-up. Journal of the American Society of Nephrology. 1998;**9**(11):2135-2141

[12] Moroni G, Gallelli B, Quaglini S, Leoni A, Banfi G, Passerini P, et al. Long-term outcome of renal transplantation in patients with idiopathic membranous glomerulonephritis (MN). Nephrology, Dialysis, Transplantation. 2010;**25**(10):3408-3415

[13] Doi T, Mayumi M, Kanatsu K, Suehiro F, Hamashima Y. Distribution of IgG subclasses in membranous nephropathy. Clinical and Experimental Immunology. 1984;**58**(1):57

[14] Oliveira DB. Membranous nephropathy: An IgG4-mediated disease. Lancet. 1998;**351**(9103):670-671

[15] Beck LH Jr, Bonegio RGB, Lambeau G, Beck DM, Powell DW, Cummins TD, et al. M-type phospholipase A 2receptor as target antigen in idiopathic membranous nephropathy. The New England Journal of Medicine. 2009;**361**(1):11-21

[16] Huang CC, Lehman A, Albawardi A, Satoskar A, Brodsky S, Nadasdy G, et al. IgG subclass staining in renal biopsies with membranous

glomerulonephritis indicates subclass switch during disease progression. Modern Pathology. 2013;**26**(6):799-805

[17] Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: from structure to effector functions. Frontiers in Immunology. 20 Oct 2014;**5**:520. DOI: 10.3389/fimmu.2014.00520

[18] Ponticelli C, Zucchelli P, Passerini P, Cesana B, Locatelli F, Pasquali S, et al. A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney International. 1995;**48**(5):1600-1604

[19] Ponticelli C, Altieri P, Scolari F, Passerini P, Roccatello D, Cesana B, et al. A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy. Journal of the American Society of Nephrology. 1998;**9**(3):444-450

[20] Jha V, Ganguli A, Saha TK, Kohli HS, Sud K, Gupta KL, et al. A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy. Journal of the American Society of Nephrology. 2007;**18**(6):1899-1904

[21] Cravedi P, Ruggenenti P, Remuzzi G. Circulating anti-PLA2R autoantibodies to monitor immunological activity in membranous nephropathy. Journal of the American Society of Nephrology. 2011;**22**(8):1400-1402

[22] Remuzzi G, Chiurchiu C, Abbate M, Brusegan V, Bontempelli M, Ruggenenti P. Rituximab for idiopathic membranous nephropathy. Lancet. 2002;**360**(9337):923-924

[23] Ruggenenti P, Cravedi P, Chianca A, Perna A, Ruggiero B, Gaspari F, et al. Rituximab in idiopathic

membranous nephropathy. Journal of the American Society of Nephrology. 2012;**23**(8):1416-1425

[24] Dahan K, Debiec H, Plaisier E, Cachanado M, Rousseau A, Wakselman L, et al. Rituximab for severe membranous nephropathy: A 6-month trial with extended follow-up. Journal of the American Society of Nephrology. Jan 2017;**28**(1):348-358

[25] Hamilton P, Kanigicherla D, Venning M, Brenchley P, Meads D. Rituximab versus the modified Ponticelli regimen in the treatment of primary membranous nephropathy: A health economic model. Nephrology, Dialysis, Transplantation. 1 Dec 2018;**33**(12):2145-2155

[26] Belak M, Borberg H, Jimenez C, Oette K. Technical and clinical experience with protein A immunoadsorption columns. Transfusion Science. 1994;**15**(4):419-422

[27] Schwenger V, Morath C. Immunoadsorption in nephrology and kidney transplantation. Nephrology, Dialysis, Transplantation. 2010;**25**(8):2407-2413

[28] Müller J, Wallukat G, Dandel M, Bieda H, Brandes K, Spiegelsberger S, et al. Immunoglobulin adsorption in patients with idiopathic dilated cardiomyopathy. Circulation. 2000;**101**(4):385-391

[29] Dandel M, Wallukat G, Englert A, Hetzer R. Immunoadsorption therapy for dilated cardiomyopathy and pulmonary arterial hypertension. Atherosclerosis. Supplements. 2013;**14**(1):203-211

[30] Short CD, Feehally J, Gokal R, Mallick NP. Familial membranous nephropathy. British Medical Journal (Clinical Research Ed.). 1984;**289**(6457):1500

**85**

*Primary Membranous Nephropathy as a Model of Autoimmune Disease*

et al. Prevention of hyperacute rejection by removal of antibodies to HLA immediately before renal transplantation. Lancet. 1996;**348**(9036):1208-1211

[39] Haas M, Böhmig GA, Mohr ZL, Exner M, Regele H, Derfler K, et al. Peri-operative immunoadsorption in sensitized renal transplant recipients. Nephrology, Dialysis, Transplantation.

[40] Böhmig GA, Regele H, Exner M, Derhartunian V, Kletzmayr J, Säemann MD, et al. C4d-positive acute humoral renal allograft rejection: Effective treatment by immunoadsorption. Journal of the American Society of Nephrology. 2001;**12**(11):2482-2489

[41] Farquhar MG, Saito A, Kerjaschki D, Orlando RA. The Heymann nephritis antigenic complex: Megalin (gp330) and RAP. Journal of the American Society of

[42] Kerjaschki D, Farquhar MG. The pathogenic antigen of Heymann

nephritis is a membrane glycoprotein of the renal proximal tubule brush border. Proceedings of the National Academy of Sciences of the United States of America. 1982;**79**(18):5557-5561

Nephrology. 1995;**6**(1):35-47

[43] Jefferson JA, Pippin JW,

2010;**7**(1-2):27-33

2014;**371**(24):2277-2287

[45] Beck LH Jr. The dominant humoral epitope in phospholipase A2 receptor-1: Presentation matters when serving up a slice of *π*. Journal of

Shankland SJ. Experimental models of membranous nephropathy. Drug Discovery Today: Disease Models.

[44] Tomas NM, Beck LH Jr, Meyer-Schwesinger C, Seitz-Polski B, Ma H, Zahner G, et al. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. The New England Journal of Medicine.

2002;**17**(8):1503-1508

*DOI: http://dx.doi.org/10.5772/intechopen.88003*

[31] Esnault VL, Besnier D, Testa A, Coville P, Simon P, Subra JF, et al. Effect of protein A immunoadsorption

[32] Haas M, Godfrin Y, Oberbauer R, Yilmaz N, Borchhardt K, Regele H, et al. Plasma immunadsorption treatment in patients with primary focal and segmental glomerulosclerosis. Nephrology, Dialysis, Transplantation. 1998;**13**(8):2013-2016

[33] Stummvoll GH. Immunoadsorption (IAS) for systemic lupus erythematosus.

[34] Gaubitz M, Seidel M, Kummer S, Schotte H, Perniok A, Domschke W, et al. Prospective randomized trial of two different immunoadsorbers in severe systemic lupus erythematosus.

[35] Koch M, Kohnle M, Trapp RA. Case report of successful long-term relapse control by protein-A immunoadsorption in an immunosuppressive-treated patient with end-stage renal disease due to Wegener's granulomatosis. Therapeutic Apheresis and Dialysis.

[36] Matic G, Michelsen A, Hofmann D, Winkler R, Tiess M, Schneidewind JM, et al. Three cases of C-ANCApositive vasculitis treated with

immunoadsorption: Possible benefit in early treatment. Therapeutic Apheresis

and Dialysis. 2001;**5**(1):68-72

PLoS One. 2014;**9**(7):e103568

[38] Higgins RM, Bevan DJ, Carey BS, Lea CK, Fallon M, Bühler R,

[37] Biesenbach P, Kain R, Derfler K, Perkmann T, Soleiman A, Benharkou A, et al. Long-term outcome of antiglomerular basement membrane antibody disease treated with immunoadsorption.

Lupus. 2011;**20**(2):115-119

Journal of Autoimmunity. 1998;**11**(5):495-501

2009;**13**(2):150-156

in nephrotic syndrome of various etiologies. Journal of the American Society of Nephrology.

1999;**10**(9):2014-2017

*Primary Membranous Nephropathy as a Model of Autoimmune Disease DOI: http://dx.doi.org/10.5772/intechopen.88003*

[31] Esnault VL, Besnier D, Testa A, Coville P, Simon P, Subra JF, et al. Effect of protein A immunoadsorption in nephrotic syndrome of various etiologies. Journal of the American Society of Nephrology. 1999;**10**(9):2014-2017

*Glomerulonephritis and Nephrotic Syndrome*

glomerulonephritis indicates subclass switch during disease progression. Modern Pathology. 2013;**26**(6):799-805 membranous nephropathy. Journal of the American Society of Nephrology.

[24] Dahan K, Debiec H, Plaisier E, Cachanado M, Rousseau A, Wakselman

membranous nephropathy: A 6-month trial with extended follow-up. Journal of the American Society of Nephrology. Jan

L, et al. Rituximab for severe

[25] Hamilton P, Kanigicherla D, Venning M, Brenchley P, Meads D. Rituximab versus the modified Ponticelli regimen in the treatment of primary membranous nephropathy: A health economic model. Nephrology, Dialysis, Transplantation. 1 Dec

2012;**23**(8):1416-1425

2017;**28**(1):348-358

2018;**33**(12):2145-2155

1994;**15**(4):419-422

2010;**25**(8):2407-2413

2000;**101**(4):385-391

2013;**14**(1):203-211

1984;**289**(6457):1500

[26] Belak M, Borberg H, Jimenez C, Oette K. Technical and clinical experience with protein A immunoadsorption columns. Transfusion Science.

[27] Schwenger V, Morath C. Immunoadsorption in nephrology and kidney transplantation.

Nephrology, Dialysis, Transplantation.

[28] Müller J, Wallukat G, Dandel M, Bieda H, Brandes K, Spiegelsberger S, et al. Immunoglobulin adsorption in patients with idiopathic dilated cardiomyopathy. Circulation.

[29] Dandel M, Wallukat G, Englert A, Hetzer R. Immunoadsorption therapy for dilated cardiomyopathy and pulmonary arterial hypertension.

Atherosclerosis. Supplements.

[30] Short CD, Feehally J, Gokal R, Mallick NP. Familial membranous nephropathy. British Medical Journal (Clinical Research Ed.).

[17] Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: from structure to effector functions. Frontiers in Immunology. 20 Oct 2014;**5**:520. DOI:

[18] Ponticelli C, Zucchelli P, Passerini P, Cesana B, Locatelli F, Pasquali S, et al. A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney International.

[19] Ponticelli C, Altieri P, Scolari F, Passerini P, Roccatello D, Cesana B, et al. A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy. Journal of the American Society of Nephrology.

10.3389/fimmu.2014.00520

1995;**48**(5):1600-1604

1998;**9**(3):444-450

2011;**22**(8):1400-1402

2002;**360**(9337):923-924

[20] Jha V, Ganguli A, Saha TK, Kohli HS, Sud K, Gupta KL, et al. A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy. Journal of the American Society of Nephrology. 2007;**18**(6):1899-1904

[21] Cravedi P, Ruggenenti P, Remuzzi G. Circulating anti-PLA2R autoantibodies to monitor immunological activity in membranous nephropathy. Journal of the American Society of Nephrology.

[22] Remuzzi G, Chiurchiu C, Abbate M, Brusegan V, Bontempelli M,

Ruggenenti P. Rituximab for idiopathic membranous nephropathy. Lancet.

[23] Ruggenenti P, Cravedi P, Chianca A, Perna A, Ruggiero B, Gaspari F, et al. Rituximab in idiopathic

**84**

[32] Haas M, Godfrin Y, Oberbauer R, Yilmaz N, Borchhardt K, Regele H, et al. Plasma immunadsorption treatment in patients with primary focal and segmental glomerulosclerosis. Nephrology, Dialysis, Transplantation. 1998;**13**(8):2013-2016

[33] Stummvoll GH. Immunoadsorption (IAS) for systemic lupus erythematosus. Lupus. 2011;**20**(2):115-119

[34] Gaubitz M, Seidel M, Kummer S, Schotte H, Perniok A, Domschke W, et al. Prospective randomized trial of two different immunoadsorbers in severe systemic lupus erythematosus. Journal of Autoimmunity. 1998;**11**(5):495-501

[35] Koch M, Kohnle M, Trapp RA. Case report of successful long-term relapse control by protein-A immunoadsorption in an immunosuppressive-treated patient with end-stage renal disease due to Wegener's granulomatosis. Therapeutic Apheresis and Dialysis. 2009;**13**(2):150-156

[36] Matic G, Michelsen A, Hofmann D, Winkler R, Tiess M, Schneidewind JM, et al. Three cases of C-ANCApositive vasculitis treated with immunoadsorption: Possible benefit in early treatment. Therapeutic Apheresis and Dialysis. 2001;**5**(1):68-72

[37] Biesenbach P, Kain R, Derfler K, Perkmann T, Soleiman A, Benharkou A, et al. Long-term outcome of antiglomerular basement membrane antibody disease treated with immunoadsorption. PLoS One. 2014;**9**(7):e103568

[38] Higgins RM, Bevan DJ, Carey BS, Lea CK, Fallon M, Bühler R,

et al. Prevention of hyperacute rejection by removal of antibodies to HLA immediately before renal transplantation. Lancet. 1996;**348**(9036):1208-1211

[39] Haas M, Böhmig GA, Mohr ZL, Exner M, Regele H, Derfler K, et al. Peri-operative immunoadsorption in sensitized renal transplant recipients. Nephrology, Dialysis, Transplantation. 2002;**17**(8):1503-1508

[40] Böhmig GA, Regele H, Exner M, Derhartunian V, Kletzmayr J, Säemann MD, et al. C4d-positive acute humoral renal allograft rejection: Effective treatment by immunoadsorption. Journal of the American Society of Nephrology. 2001;**12**(11):2482-2489

[41] Farquhar MG, Saito A, Kerjaschki D, Orlando RA. The Heymann nephritis antigenic complex: Megalin (gp330) and RAP. Journal of the American Society of Nephrology. 1995;**6**(1):35-47

[42] Kerjaschki D, Farquhar MG. The pathogenic antigen of Heymann nephritis is a membrane glycoprotein of the renal proximal tubule brush border. Proceedings of the National Academy of Sciences of the United States of America. 1982;**79**(18):5557-5561

[43] Jefferson JA, Pippin JW, Shankland SJ. Experimental models of membranous nephropathy. Drug Discovery Today: Disease Models. 2010;**7**(1-2):27-33

[44] Tomas NM, Beck LH Jr, Meyer-Schwesinger C, Seitz-Polski B, Ma H, Zahner G, et al. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. The New England Journal of Medicine. 2014;**371**(24):2277-2287

[45] Beck LH Jr. The dominant humoral epitope in phospholipase A2 receptor-1: Presentation matters when serving up a slice of *π*. Journal of the American Society of Nephrology. 2015;**26**(2):237-239

[46] East L. The mannose receptor family. Biochimica et Biophysica Acta (BBA). 2002;**1572**(2-3):364-386

[47] Llorca O. Extended and bent conformations of the mannose receptor family. Cellular and Molecular Life Sciences. 2008;**65**(9):1302-1310

[48] Fresquet M, Jowitt TA, Gummadova J, Collins R, O'Cualain R, McKenzie EA, et al. Identification of a major epitope recognized by PLA2R autoantibodies in primary membranous nephropathy. Journal of the American Society of Nephrology. Feb 2015;**26**(2):302-313

[49] Granata F, Petraroli A, Boilard E, Bezzine S, Bollinger J, Del Vecchio L, et al. Activation of cytokine production by secreted phospholipase A2 in human lung macrophages expressing the M-type receptor. Journal of Immunology. 2005;**174**(1):464-474

[50] Silliman CC, Moore EE, Zallen G, Gonzalez R, Johnson JL, Elzi DJ, et al. Presence of the M-type sPLA2 receptor on neutrophils and its role in elastase release and adhesion. American Journal of Physiology-Cell Physiology. 2002;**283**(4):C1102-C1113

[51] Herrmann SMS, Sethi S, Fervenza FC. Membranous nephropathy. Current Opinion in Nephrology and Hypertension. 2012;**21**(2):203-210

[52] Hoxha E, Kneißler U, Stege G, Zahner G, Thiele I, Panzer U, et al. Enhanced expression of the M-type phospholipase A2 receptor in glomeruli correlates with serum receptor antibodies in primary membranous nephropathy. Kidney International. 2012;**82**(7):797-804

[53] Kerjaschki D, Miettinen A, Farquhar MG. Initial events in the formation of immune deposits in passive Heymann nephritis. gp330-anti-gp330 immune complexes form in epithelial coated

pits and rapidly become attached to the glomerular basement membrane. The Journal of Experimental Medicine. 1987;**166**(1):109-128

[54] Debiec H, Ronco P. PLA2R autoantibodies and PLA2R glomerular deposits in membranous nephropathy. The New England Journal of Medicine. 2011;**364**(7):689-690

[55] Kanigicherla D, Gummadova J, McKenzie EA, Roberts SA, Harris S, Nikam M, et al. Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy. Kidney International. 2013;**83**(5):940-948

[56] Hofstra JM, Laurence H, Beck J, Beck DM, Wetzels JF, Salant DJ. Antiphospholipase A2 receptor antibodies correlate with clinical status in idiopathic membranous nephropathy. Clinical Journal of the American Society of Nephrology. 2011;**6**(6):1286-1291

[57] Bech AP, Hofstra JM, Brenchley PE, Wetzels JFM. Association of anti-PLA2R antibodies with outcomes after immunosuppressive therapy in idiopathic membranous nephropathy. Clinical Journal of the American Society of Nephrology. 2014;**9**(8):1386-1392

[58] Beck LH, Fervenza FC, Beck DM, Bonegio RGB, Malik FA, Erickson SB, et al. Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy. Journal of the American Society of Nephrology. 2011;**22**(8):1543-1550

[59] Ruggenenti P, Debiec H, Ruggiero B, Chianca A, Pellé T, Gaspari F, et al. Anti-phospholipase A2 receptor antibody titer predicts post-rituximab outcome of membranous nephropathy. Journal of the American Society of Nephrology. 2015;**26**(10):2545-2558

[60] Hoxha E, Thiele I, Zahner G, Panzer U, Harendza S, Stahl RAK. Phospholipase

**87**

*Primary Membranous Nephropathy as a Model of Autoimmune Disease*

[67] Stanescu HC, Arcos-Burgos M, Medlar A, Bockenhauer D, Köttgen A, Dragomirescu L, et al. Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy. The New England Journal of Medicine.

[68] Sekula P, Li Y, Stanescu HC, Wuttke M, Ekici AB, Bockenhauer D, et al. Genetic risk variants for membranous nephropathy: Extension

of and association with other chronic kidney disease aetiologies. Nephrology, Dialysis, Transplantation.

[69] Altschul SF, Madden TL, Schäffer AA, Zhang J, Zhang Z, Miller W, et al. Gapped BLAST and PSI-BLAST: A new generation of protein database search programs. Nucleic Acids Research. Oxford University Press.

[70] Kong Y, Brown N, Morris G, Flynn J. The essential role of circulating thyroglobulin in maintaining dominance of natural regulatory T cell function to prevent autoimmune thyroiditis. Hormone and Metabolic Research. 2015;**47**(10):711-720

[71] Rosenzwajg M, Languille E, Debiec H, Hygino J, Dahan K, Simon T, et al. B- and T-cell subpopulations in patients with severe idiopathic membranous nephropathy may predict an early response to rituximab. Kidney International. Jul 2017;**92**(1):227-237. DOI: 10.1016/j.kint.2017.01.012

[72] Hamilton P, Kanigicherla D, Hanumapura P, Walz L, Kramer D, Fischer M, et al. Peptide GAM immunoadsorption therapy in primary membranous nephropathy (PRISM): Phase II trial investigating the safety and feasibility of peptide GAM immunoadsorption in anti-PLA 2R positive primary membranous nephropathy. Journal of Clinical Apheresis. 2017;**17**(9):1594-1598

2011;**364**(7):616-626

2017;**32**(2):325-332

1997;**25**(17):3389-3402

*DOI: http://dx.doi.org/10.5772/intechopen.88003*

A2 receptor autoantibodies and clinical outcome in patients with primary membranous nephropathy. Journal of the American Society of Nephrology.

2014;**25**(6):1357-1366

2015;**26**(2):291-301

2016;**27**(5):1517-1533

[61] Kao L, Lam V, Waldman M, Glassock RJ, Zhu Q. Identification of the immunodominant epitope region in phospholipase A2 receptor-mediating autoantibody binding in idiopathic membranous nephropathy. Journal of the American Society of Nephrology.

[62] Seitz-Polski B, Dolla G, Payré C, Girard CA, Polidori J, Zorzi K, et al. Epitope spreading of autoantibody response to PLA2R associates with poor prognosis in membranous nephropathy. Journal of the American Society of Nephrology.

[63] Müller GA, Müller C, Liebau G, Kömpf J, Ising H, Wernet P. strong association of idiopathic membranous nephropathy (IMN) with HLA-DR 3 and MT-2 without involvement of HLA-B 18 and no Association to BfF1. Tissue Antigens. 1981;**17**(3):332-337

[64] Klouda PT, Manos J, Acheson EJ, Dyer PA, Goldby FS, Harris R, et al. Strong association between idiopathic membranous nephropathy and HLA-DRW3. Lancet. 1979;**2**(8146):770-771

[65] Kim S, Chin HJ, Na KY, Kim S, Oh J, Chung W, et al. Single nucleotide polymorphisms in the phospholipase A2 receptor gene are associated with genetic susceptibility to idiopathic membranous nephropathy. Nephron. Clinical Practice. 2011;**117**(3):c253-c258

[66] Liu Y-H, Chen C-H, Chen S-Y, Lin Y-J, Liao W-L, Tsai C-H, et al. Association of phospholipase A2 receptor 1 polymorphisms with

idiopathic membranous nephropathy in Chinese patients in Taiwan. Journal of Biomedical Science. 2010;**17**(1):81

*Primary Membranous Nephropathy as a Model of Autoimmune Disease DOI: http://dx.doi.org/10.5772/intechopen.88003*

A2 receptor autoantibodies and clinical outcome in patients with primary membranous nephropathy. Journal of the American Society of Nephrology. 2014;**25**(6):1357-1366

*Glomerulonephritis and Nephrotic Syndrome*

the American Society of Nephrology.

pits and rapidly become attached to the glomerular basement membrane. The Journal of Experimental Medicine.

[54] Debiec H, Ronco P. PLA2R

autoantibodies and PLA2R glomerular deposits in membranous nephropathy. The New England Journal of Medicine.

[55] Kanigicherla D, Gummadova J, McKenzie EA, Roberts SA, Harris S, Nikam M, et al. Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy. Kidney International.

[56] Hofstra JM, Laurence H, Beck J, Beck DM, Wetzels JF, Salant DJ. Antiphospholipase A2 receptor antibodies correlate with clinical status in idiopathic membranous nephropathy. Clinical Journal of the American Society of Nephrology. 2011;**6**(6):1286-1291

[57] Bech AP, Hofstra JM, Brenchley PE, Wetzels JFM. Association of anti-PLA2R antibodies with outcomes after immunosuppressive therapy in idiopathic membranous nephropathy. Clinical Journal of the American Society of Nephrology. 2014;**9**(8):1386-1392

[58] Beck LH, Fervenza FC, Beck DM, Bonegio RGB, Malik FA, Erickson SB, et al. Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy. Journal of the American Society of Nephrology. 2011;**22**(8):1543-1550

[59] Ruggenenti P, Debiec H, Ruggiero B, Chianca A, Pellé T, Gaspari F, et al. Anti-phospholipase A2 receptor antibody titer predicts post-rituximab outcome of membranous nephropathy. Journal of the American Society of Nephrology. 2015;**26**(10):2545-2558

[60] Hoxha E, Thiele I, Zahner G, Panzer U, Harendza S, Stahl RAK. Phospholipase

1987;**166**(1):109-128

2011;**364**(7):689-690

2013;**83**(5):940-948

[46] East L. The mannose receptor family. Biochimica et Biophysica Acta (BBA). 2002;**1572**(2-3):364-386

[47] Llorca O. Extended and bent conformations of the mannose receptor family. Cellular and Molecular Life Sciences. 2008;**65**(9):1302-1310

[48] Fresquet M, Jowitt TA, Gummadova J, Collins R, O'Cualain R, McKenzie EA, et al. Identification of a major epitope recognized by PLA2R autoantibodies in primary membranous nephropathy. Journal of the American Society of Nephrology. Feb 2015;**26**(2):302-313

[49] Granata F, Petraroli A, Boilard E, Bezzine S, Bollinger J, Del Vecchio L, et al. Activation of cytokine production

by secreted phospholipase A2 in human lung macrophages expressing the M-type receptor. Journal of Immunology. 2005;**174**(1):464-474

[50] Silliman CC, Moore EE, Zallen G, Gonzalez R, Johnson JL, Elzi DJ, et al. Presence of the M-type sPLA2 receptor on neutrophils and its role in elastase release and adhesion. American Journal of Physiology-Cell Physiology.

[51] Herrmann SMS, Sethi S, Fervenza FC. Membranous nephropathy. Current Opinion in Nephrology and Hypertension. 2012;**21**(2):203-210

[52] Hoxha E, Kneißler U, Stege G, Zahner G, Thiele I, Panzer U, et al. Enhanced expression of the M-type phospholipase A2 receptor in glomeruli correlates with serum receptor antibodies in primary membranous nephropathy. Kidney International. 2012;**82**(7):797-804

[53] Kerjaschki D, Miettinen A, Farquhar MG. Initial events in the formation of immune deposits in passive Heymann nephritis. gp330-anti-gp330 immune complexes form in epithelial coated

2002;**283**(4):C1102-C1113

2015;**26**(2):237-239

**86**

[61] Kao L, Lam V, Waldman M, Glassock RJ, Zhu Q. Identification of the immunodominant epitope region in phospholipase A2 receptor-mediating autoantibody binding in idiopathic membranous nephropathy. Journal of the American Society of Nephrology. 2015;**26**(2):291-301

[62] Seitz-Polski B, Dolla G, Payré C, Girard CA, Polidori J, Zorzi K, et al. Epitope spreading of autoantibody response to PLA2R associates with poor prognosis in membranous nephropathy. Journal of the American Society of Nephrology. 2016;**27**(5):1517-1533

[63] Müller GA, Müller C, Liebau G, Kömpf J, Ising H, Wernet P. strong association of idiopathic membranous nephropathy (IMN) with HLA-DR 3 and MT-2 without involvement of HLA-B 18 and no Association to BfF1. Tissue Antigens. 1981;**17**(3):332-337

[64] Klouda PT, Manos J, Acheson EJ, Dyer PA, Goldby FS, Harris R, et al. Strong association between idiopathic membranous nephropathy and HLA-DRW3. Lancet. 1979;**2**(8146):770-771

[65] Kim S, Chin HJ, Na KY, Kim S, Oh J, Chung W, et al. Single nucleotide polymorphisms in the phospholipase A2 receptor gene are associated with genetic susceptibility to idiopathic membranous nephropathy. Nephron. Clinical Practice. 2011;**117**(3):c253-c258

[66] Liu Y-H, Chen C-H, Chen S-Y, Lin Y-J, Liao W-L, Tsai C-H, et al. Association of phospholipase A2 receptor 1 polymorphisms with idiopathic membranous nephropathy in Chinese patients in Taiwan. Journal of Biomedical Science. 2010;**17**(1):81

[67] Stanescu HC, Arcos-Burgos M, Medlar A, Bockenhauer D, Köttgen A, Dragomirescu L, et al. Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy. The New England Journal of Medicine. 2011;**364**(7):616-626

[68] Sekula P, Li Y, Stanescu HC, Wuttke M, Ekici AB, Bockenhauer D, et al. Genetic risk variants for membranous nephropathy: Extension of and association with other chronic kidney disease aetiologies. Nephrology, Dialysis, Transplantation. 2017;**32**(2):325-332

[69] Altschul SF, Madden TL, Schäffer AA, Zhang J, Zhang Z, Miller W, et al. Gapped BLAST and PSI-BLAST: A new generation of protein database search programs. Nucleic Acids Research. Oxford University Press. 1997;**25**(17):3389-3402

[70] Kong Y, Brown N, Morris G, Flynn J. The essential role of circulating thyroglobulin in maintaining dominance of natural regulatory T cell function to prevent autoimmune thyroiditis. Hormone and Metabolic Research. 2015;**47**(10):711-720

[71] Rosenzwajg M, Languille E, Debiec H, Hygino J, Dahan K, Simon T, et al. B- and T-cell subpopulations in patients with severe idiopathic membranous nephropathy may predict an early response to rituximab. Kidney International. Jul 2017;**92**(1):227-237. DOI: 10.1016/j.kint.2017.01.012

[72] Hamilton P, Kanigicherla D, Hanumapura P, Walz L, Kramer D, Fischer M, et al. Peptide GAM immunoadsorption therapy in primary membranous nephropathy (PRISM): Phase II trial investigating the safety and feasibility of peptide GAM immunoadsorption in anti-PLA 2R positive primary membranous nephropathy. Journal of Clinical Apheresis. 2017;**17**(9):1594-1598

**89**

**Chapter 6**

**Abstract**

**1. Introduction**

cause of NS in the Caucasian adult [1].

Treatment of Idiopathic

Membranous Nephropathy (IMN)

*María Carmen Prados Soler, María Dolores Del Pino y Pino,* 

We present a 59-year-old patient with type 2 diabetes mellitus and massive nephrotic syndrome (anasarca) and biochemical syndrome. The renal biopsy showed a membranous nephropathy (MN). In the blood analysis the patient presented antibodies against M-type phospholipase A2 receptor (anti-PLA2R) positive at a very high titer. Given the existence of idiopathic membranous nephropathy (IMN), treatment was started with a modified Ponticelli regimen, with no response, requiring periodic ultrafiltration sessions. Rituximab induces nephrotic syndrome (NS) remission in two-thirds of patients with IMN, even after other treatments have failed. We proposed treatment with rituximab based on published evidence. In IMN, the presence of M-type anti-receptor antibodies of A2 phospholipase is considered highly specific to idiopathic forms, but the presence of such antibodies has not been shown to be associated with a particular clinical profile. Assessing circulating anti-PLA2R autoantibodies and proteinuria may help in monitoring disease activity and

guiding personalized rituximab therapy in nephrotic patients with IMN.

**Keywords:** idiopathic membranous nephropathy, nephrotic syndrome, antibodies against M-type phospholipase A2 receptor (anti-PLA2R), rituximab

MN is a disease characterized by the deposition of immune complexes at subepithelial level. Its most frequent clinical presentation is NS, and it is today the first

In recent years, it has been discovered that IMN has an immunological basis. The data in favour of this alteration of the immune system are the findings found in the electron microscopy of renal biopsies, the granular deposits of immunoglobulin G (mainly IgG4) and C3 along the glomerular basement membrane, and the deposit of electrodense immunocomplexes in the subepithelium that entails an activation of the complement products. MN may also be secondary to infections, tumors, autoimmune diseases, and use of different drugs [1]. PLA2R has been found to be the target antigen of autoantibodies in IMN patients, and is known as anti-PLA2R. PLA2R is a type I transmembrane glycoprotein related to the animal family of type C lectin. More recently, anti-PLA2Rs have been found to be immunoglobulins of the IgG4 type [2]. Currently, these antibodies are present in 60–80%

*Álvaro Pérez Fernández, Llenalia Gordillo García,* 

*María José López Ruiz and César Luis Ramírez-Tortosa*

#### **Chapter 6**

## Treatment of Idiopathic Membranous Nephropathy (IMN)

*María Carmen Prados Soler, María Dolores Del Pino y Pino, Álvaro Pérez Fernández, Llenalia Gordillo García, María José López Ruiz and César Luis Ramírez-Tortosa*

#### **Abstract**

We present a 59-year-old patient with type 2 diabetes mellitus and massive nephrotic syndrome (anasarca) and biochemical syndrome. The renal biopsy showed a membranous nephropathy (MN). In the blood analysis the patient presented antibodies against M-type phospholipase A2 receptor (anti-PLA2R) positive at a very high titer. Given the existence of idiopathic membranous nephropathy (IMN), treatment was started with a modified Ponticelli regimen, with no response, requiring periodic ultrafiltration sessions. Rituximab induces nephrotic syndrome (NS) remission in two-thirds of patients with IMN, even after other treatments have failed. We proposed treatment with rituximab based on published evidence. In IMN, the presence of M-type anti-receptor antibodies of A2 phospholipase is considered highly specific to idiopathic forms, but the presence of such antibodies has not been shown to be associated with a particular clinical profile. Assessing circulating anti-PLA2R autoantibodies and proteinuria may help in monitoring disease activity and guiding personalized rituximab therapy in nephrotic patients with IMN.

**Keywords:** idiopathic membranous nephropathy, nephrotic syndrome, antibodies against M-type phospholipase A2 receptor (anti-PLA2R), rituximab

#### **1. Introduction**

MN is a disease characterized by the deposition of immune complexes at subepithelial level. Its most frequent clinical presentation is NS, and it is today the first cause of NS in the Caucasian adult [1].

In recent years, it has been discovered that IMN has an immunological basis. The data in favour of this alteration of the immune system are the findings found in the electron microscopy of renal biopsies, the granular deposits of immunoglobulin G (mainly IgG4) and C3 along the glomerular basement membrane, and the deposit of electrodense immunocomplexes in the subepithelium that entails an activation of the complement products. MN may also be secondary to infections, tumors, autoimmune diseases, and use of different drugs [1]. PLA2R has been found to be the target antigen of autoantibodies in IMN patients, and is known as anti-PLA2R. PLA2R is a type I transmembrane glycoprotein related to the animal family of type C lectin. More recently, anti-PLA2Rs have been found to be immunoglobulins of the IgG4 type [2]. Currently, these antibodies are present in 60–80% of IMN patients prior to immunosuppressive therapy. However, in secondary MN forms these antibodies are much less prevalent. No anti-PLA2R has been observed in other pathological conditions or in healthy individuals. In recent years, articles have been published in which several researchers have addressed the appearance of anti-PLA2R antibodies in patients with secondary MN, so more data are needed to conclude with certainty that when these antibodies are found, there is no need to investigate an underlying cause to guide a secondary MN [2, 3].

Recently, various studies have described that about 70% of MNI cases are associated with the presence of anti-PLA2R. Antibody titer at diagnosis is related to the likelihood of spontaneous remission (SR) and response to treatment. However, it has not been demonstrated that in patients with MNI, the presence of anti-PLA2R antibodies is associated with a certain clinical profile of disease presentation or implies differences in clinical course, response to treatment or long-term prognosis. On the other hand, although most studies agree that the presence of anti-PLA2R antibodies is highly specific to IMN, there are cases described in which the presence of these antibodies coincides with other possible etiologies and about 30% of patients with IMN are anti-PLA2R negative. In this last group of patients, antibodies have been described against other podocyte antigens whose clinical correlation is still being investigated and, therefore, there is greater uncertainty about the possible identification of secondary etiologies over time. However, since most studies have been cross-sectional, little information is available about the diagnosis of possible etiologies responsible for MN over time in both positive and negative anti-PLA2R patients [4].

In IMN the disease appears to develop by the binding of an autoantibody directed against an antigen. A podocyte that is located on the subepithelial slope of the podocyte. For this motive there are currently various immunosuppressive treatments available [2].

A very high percentage of patients (more than 40% in many series) develop spontaneous remission of the disease without any type of treatment, while another considerable percentage (around 30–40%) develops progressive renal failure accompanied by nephrotic proteinuria [2].

Ponticelli in 1989 showed that combined treatment with cytotoxics produced partial or complete remission of proteinuria in a significant proportion of patients with membranous nephropathy [5]. However, the literature is controversial regarding the effectiveness of the scheme described by Ponticelli et al. [6].

The most important predictors of risk for a progressive decline in renal function are persistent severe proteinuria for at least 3 months, a reduced creatinine clearance at presentation, and a decline in creatinine clearance over the assessed proteinuria period [7].

Resistant patients are defined as those with moderate or high risk disease who fail an adequate trial of treatment with both cyclophosphamide-based and calcineurin inhibitor-based regimens [8].

A trial of rituximab can be considered after a careful evaluation of the potential risks and benefits of further immunosuppression. Weak evidence suggests that a clinically relevant response to rituximab may be less likely in patients with a creatinine clearance below 75 mL/min per 1.73 m2 [9].

In this case, we present a 59-year-old patient with type 2 diabetes mellitus and massive nephrotic syndrome (anasarca) and biochemical syndrome. The renal biopsy showed a membranous nephropathy (MN). Anti-PLA2 positive antibodies at a very high titer (366 RU/mL). Given the existence of IMN, treatment was started with a modified Ponticelli regimen, with no response, requiring periodic ultrafiltration sessions. We proposed treatment with rituximab based on published evidence.

**91**

**Figure 1.**

*capsule (blue arrow).*

*Treatment of Idiopathic Membranous Nephropathy (IMN)*

A 59-year-old male with a history of long-standing type 2 DM with retinopathy and diabetic neuropathy, OSAS and intrinsic asthma. Blood pressure and normal renal function. One month prior to your entry into our Service (October 2018) refers pretibial edemas—malleolar and scrotal edema of morning onset, with worsening throughout the day and dyspnea of moderate efforts. Initially consult with your Primary Care doctor, being treated with furosemide. In the absence of a

Upon admission, the patient is afebrile, dyspnoeic, conscious and oriented and presents a slight cutaneous-mucosal pallor. Blood pressure: 100/70 mmHg. Heart rate: 72 bpm. Normal head, neck without jugular vein. Rhythmic cardiac auscultation, without murmurs. Respiratory auscultation with bilateral diffuse crackles. Abdomen, without pathological findings and lower extremities with edemas ++++/++++ to English that leave fovea. Scrotal edema. No signs of deep vein thrombosis. Peripheral pulses preserved. Analytical on admission: leukocytes 7.30 × 10. e3/μL with normal formula, hemoglobin 11 g/dl, hematocrit 32.5%, platelets 164 × 10.3/μL ESR 19 mm/h, sodium 138 mM/L, potassium 3.9 mM/L, urea 110 mg/ dl, creatinine 2.08 mg/dl, total cholesterol 282 mg/dl, cholesterol-HDL 88 mg/ ml cholesterol-LDL 158 mg/ml, triglycerides 171 mg/dl, albumin 2.4 g/dl, total protein 4.9 g/dl. GOT, GPT, LDH, GGT, alkaline phosphatase, glucose, calcium, phosphorus and bilirubin within normal limits. Protein level in blood: albumin 44.2%, alpha-1 9.4%, alpha-2 17.4%, beta 18.2%, gamma 10.7%. In urine: proteinuria 14 g/24 h. Coagulation: normal, fibrinogen 676. Tumor markers: carcinoembryonic antigen, alpha-fetoprotein, PSA ng/ml and Ca 19.9: normal. ANA, ANCA, rheumatoid factor and negative glomerular baseline anti-membrane antibodies.

Kidney ultrasound showed normal-sized kidneys, with good cortico-medullary differentiation, without dilation of the urinary tract. A percutaneous renal biopsy was performed observing a renal parenchyma corresponding to the cortical zone that included 28 glomeruli. Diffuse and global thickening of the glomerular basement membranes by subepithelial deposit ("comb peaks") with mesangial focal extension not associated with mesangial cell proliferation but with floccularcapsular adhesions, no endocapillary proliferation or glomerulitis, absence of

*Staining with Hematoxylin and Eosin. 40X, Global Thickening of the capillary membranes (black arrows) of the glomerulus not accompanied by mesangial or endocapillary proliferation. Discreet thickening of Bowman's* 

NT-ProBNP: 200 pg/ml. Ac anti-PLA2: positive (366 RU/mL).

*DOI: http://dx.doi.org/10.5772/intechopen.86741*

response, he is referred to the hospital.

**2. Clinical case**

#### **2. Clinical case**

*Glomerulonephritis and Nephrotic Syndrome*

anti-PLA2R patients [4].

treatments available [2].

proteinuria period [7].

neurin inhibitor-based regimens [8].

creatinine clearance below 75 mL/min per 1.73 m2

accompanied by nephrotic proteinuria [2].

of IMN patients prior to immunosuppressive therapy. However, in secondary MN forms these antibodies are much less prevalent. No anti-PLA2R has been observed in other pathological conditions or in healthy individuals. In recent years, articles have been published in which several researchers have addressed the appearance of anti-PLA2R antibodies in patients with secondary MN, so more data are needed to conclude with certainty that when these antibodies are found, there is no need to

Recently, various studies have described that about 70% of MNI cases are associated with the presence of anti-PLA2R. Antibody titer at diagnosis is related to the likelihood of spontaneous remission (SR) and response to treatment. However, it has not been demonstrated that in patients with MNI, the presence of anti-PLA2R antibodies is associated with a certain clinical profile of disease presentation or implies differences in clinical course, response to treatment or long-term prognosis. On the other hand, although most studies agree that the presence of anti-PLA2R antibodies is highly specific to IMN, there are cases described in which the presence of these antibodies coincides with other possible etiologies and about 30% of patients with IMN are anti-PLA2R negative. In this last group of patients, antibodies have been described against other podocyte antigens whose clinical correlation is still being investigated and, therefore, there is greater uncertainty about the possible identification of secondary etiologies over time. However, since most studies have been cross-sectional, little information is available about the diagnosis of possible etiologies responsible for MN over time in both positive and negative

In IMN the disease appears to develop by the binding of an autoantibody directed against an antigen. A podocyte that is located on the subepithelial slope of the podocyte. For this motive there are currently various immunosuppressive

A very high percentage of patients (more than 40% in many series) develop spontaneous remission of the disease without any type of treatment, while another considerable percentage (around 30–40%) develops progressive renal failure

Ponticelli in 1989 showed that combined treatment with cytotoxics produced partial or complete remission of proteinuria in a significant proportion of patients with membranous nephropathy [5]. However, the literature is controversial regard-

The most important predictors of risk for a progressive decline in renal function are persistent severe proteinuria for at least 3 months, a reduced creatinine clearance at presentation, and a decline in creatinine clearance over the assessed

Resistant patients are defined as those with moderate or high risk disease who fail an adequate trial of treatment with both cyclophosphamide-based and calci-

A trial of rituximab can be considered after a careful evaluation of the potential risks and benefits of further immunosuppression. Weak evidence suggests that a clinically relevant response to rituximab may be less likely in patients with a

In this case, we present a 59-year-old patient with type 2 diabetes mellitus and massive nephrotic syndrome (anasarca) and biochemical syndrome. The renal biopsy showed a membranous nephropathy (MN). Anti-PLA2 positive antibodies at a very high titer (366 RU/mL). Given the existence of IMN, treatment was started with a modified Ponticelli regimen, with no response, requiring periodic ultrafiltration sessions. We proposed treatment with rituximab based on pub-

[9].

ing the effectiveness of the scheme described by Ponticelli et al. [6].

investigate an underlying cause to guide a secondary MN [2, 3].

**90**

lished evidence.

A 59-year-old male with a history of long-standing type 2 DM with retinopathy and diabetic neuropathy, OSAS and intrinsic asthma. Blood pressure and normal renal function. One month prior to your entry into our Service (October 2018) refers pretibial edemas—malleolar and scrotal edema of morning onset, with worsening throughout the day and dyspnea of moderate efforts. Initially consult with your Primary Care doctor, being treated with furosemide. In the absence of a response, he is referred to the hospital.

Upon admission, the patient is afebrile, dyspnoeic, conscious and oriented and presents a slight cutaneous-mucosal pallor. Blood pressure: 100/70 mmHg. Heart rate: 72 bpm. Normal head, neck without jugular vein. Rhythmic cardiac auscultation, without murmurs. Respiratory auscultation with bilateral diffuse crackles. Abdomen, without pathological findings and lower extremities with edemas ++++/++++ to English that leave fovea. Scrotal edema. No signs of deep vein thrombosis. Peripheral pulses preserved. Analytical on admission: leukocytes 7.30 × 10. e3/μL with normal formula, hemoglobin 11 g/dl, hematocrit 32.5%, platelets 164 × 10.3/μL ESR 19 mm/h, sodium 138 mM/L, potassium 3.9 mM/L, urea 110 mg/ dl, creatinine 2.08 mg/dl, total cholesterol 282 mg/dl, cholesterol-HDL 88 mg/ ml cholesterol-LDL 158 mg/ml, triglycerides 171 mg/dl, albumin 2.4 g/dl, total protein 4.9 g/dl. GOT, GPT, LDH, GGT, alkaline phosphatase, glucose, calcium, phosphorus and bilirubin within normal limits. Protein level in blood: albumin 44.2%, alpha-1 9.4%, alpha-2 17.4%, beta 18.2%, gamma 10.7%. In urine: proteinuria 14 g/24 h. Coagulation: normal, fibrinogen 676. Tumor markers: carcinoembryonic antigen, alpha-fetoprotein, PSA ng/ml and Ca 19.9: normal. ANA, ANCA, rheumatoid factor and negative glomerular baseline anti-membrane antibodies. NT-ProBNP: 200 pg/ml. Ac anti-PLA2: positive (366 RU/mL).

Kidney ultrasound showed normal-sized kidneys, with good cortico-medullary differentiation, without dilation of the urinary tract. A percutaneous renal biopsy was performed observing a renal parenchyma corresponding to the cortical zone that included 28 glomeruli. Diffuse and global thickening of the glomerular basement membranes by subepithelial deposit ("comb peaks") with mesangial focal extension not associated with mesangial cell proliferation but with floccularcapsular adhesions, no endocapillary proliferation or glomerulitis, absence of

#### **Figure 1.**

*Staining with Hematoxylin and Eosin. 40X, Global Thickening of the capillary membranes (black arrows) of the glomerulus not accompanied by mesangial or endocapillary proliferation. Discreet thickening of Bowman's capsule (blue arrow).*

karyorrhexis, irregular thickening of Bowman's capsule, immunocomplex subepithelial deposits (IgG), Glomerular sclerosis (10%); tubular atrophy and interstitial fibrosis (moderate), arteriosclerosis (moderate), hyaline arteriolosclerosis, and vascular changes associated with hypertension (**Figures 1–6**). Depletive treatment

#### **Figure 2.**

*PAS 40X. The technique of PAS also shows the thickening of glomerular capillary membranes (black arrows).*

#### **Figure 3.**

*Jones' Silver. 40X. subepithelial Depsoits in the basal membranes of the glomerular capillaries showing an image in "Spikes de peine" (blue Arrow). This technique stains the basal membrane black. Immuncomplements deposits are not stained.*

#### **Figure 4.**

*IF. IgG. Subepithelial granular Deposits in capillary basal membrane with global and diffuse pattern and staining intensity 3 +/3.*

**93**

**3. Discussion**

**Figure 5.**

**Figure 6.**

*pattern and staining intensity 3 +/3.*

*Treatment of Idiopathic Membranous Nephropathy (IMN)*

was started with IV furosemide at high doses and IV albumin, with poor response, requiring periodic ultrafiltration sessions. Treatment was started with a modified Ponticelli regimen: prednisone at a dose of 0.5 mg/kg/day and cyclophosphamide 125 mg/day initially and then 100 mg/day, adjusted for renal function. An inhibitor of the angiotensin conversion enzyme was associated. Two months later, proteinuria has not changed. Kidney function remains normal. After 2 months of treatment, we have not shown changes in proteinuria. Continue to specify ultrafiltration sessions. We have decided to administer Rituximab. We will continue to monitor

*IF. Kappa Light Chains. Subepithelial granular Deposits in capillary basal membrane with global and diffuse* 

*IF. Lambda Light Chains. Subepithelial granular Deposits in capillary basal membrane with global and* 

MN is the first cause of NS in the adult [1]. From A clinical perspective, it is classified in idiopathic (IMN) or secondary depending on whether or not it is possible to identify a responsible etiology. In the absence of clinical or biochemical data indicating a specific etiology, distinguishing between the two forms can be difficult

MN in adults is most often idiopathic (approximately 75% of cases) but can be caused by a variety of drugs, infections, and underlying diseases. These include

renal function, proteinuria and anti-PLA2 Ac.

only through the data provided by the renal biopsy [2].

*DOI: http://dx.doi.org/10.5772/intechopen.86741*

*diffuse pattern and staining intensity 1-2 +/3.*

*Treatment of Idiopathic Membranous Nephropathy (IMN) DOI: http://dx.doi.org/10.5772/intechopen.86741*

#### **Figure 5.**

*Glomerulonephritis and Nephrotic Syndrome*

karyorrhexis, irregular thickening of Bowman's capsule, immunocomplex subepithelial deposits (IgG), Glomerular sclerosis (10%); tubular atrophy and interstitial fibrosis (moderate), arteriosclerosis (moderate), hyaline arteriolosclerosis, and vascular changes associated with hypertension (**Figures 1–6**). Depletive treatment

*Jones' Silver. 40X. subepithelial Depsoits in the basal membranes of the glomerular capillaries showing an image in "Spikes de peine" (blue Arrow). This technique stains the basal membrane black. Immuncomplements* 

*PAS 40X. The technique of PAS also shows the thickening of glomerular capillary membranes (black arrows).*

*IF. IgG. Subepithelial granular Deposits in capillary basal membrane with global and diffuse pattern and* 

**92**

**Figure 4.**

*staining intensity 3 +/3.*

**Figure 3.**

**Figure 2.**

*deposits are not stained.*

*IF. Lambda Light Chains. Subepithelial granular Deposits in capillary basal membrane with global and diffuse pattern and staining intensity 1-2 +/3.*

#### **Figure 6.**

*IF. Kappa Light Chains. Subepithelial granular Deposits in capillary basal membrane with global and diffuse pattern and staining intensity 3 +/3.*

was started with IV furosemide at high doses and IV albumin, with poor response, requiring periodic ultrafiltration sessions. Treatment was started with a modified Ponticelli regimen: prednisone at a dose of 0.5 mg/kg/day and cyclophosphamide 125 mg/day initially and then 100 mg/day, adjusted for renal function. An inhibitor of the angiotensin conversion enzyme was associated. Two months later, proteinuria has not changed. Kidney function remains normal. After 2 months of treatment, we have not shown changes in proteinuria. Continue to specify ultrafiltration sessions. We have decided to administer Rituximab. We will continue to monitor renal function, proteinuria and anti-PLA2 Ac.

#### **3. Discussion**

MN is the first cause of NS in the adult [1]. From A clinical perspective, it is classified in idiopathic (IMN) or secondary depending on whether or not it is possible to identify a responsible etiology. In the absence of clinical or biochemical data indicating a specific etiology, distinguishing between the two forms can be difficult only through the data provided by the renal biopsy [2].

MN in adults is most often idiopathic (approximately 75% of cases) but can be caused by a variety of drugs, infections, and underlying diseases. These include

gold, penicillamine, systemic lupus erythematosus, malignancy, and hepatitis B and C virus infection [2].

It is often not possible to distinguish idiopathic from secondary MN on clinical grounds alone, even though serologic studies (e.g., antinuclear antibodies, hepatitis B serology) and a history of drug exposure or cancer may be revealing of a potential cause. However, there are certain findings on electron microscopy and immunofluorescence that suggest secondary disease. In patients with secondary MN, cessation of the offending drug or effective treatment of the underlying disease is usually associated with improvement in the nephrotic syndrome [10].

In view of the potential toxicity of the drugs used to treat IMN, with or without the nephrotic syndrome, the decision to initiate therapy is based, in part, upon an understanding of the natural history of untreated patients, with and without features of the nephrotic syndrome at presentation [11]:


Risk factors for progressive idiopathic MN—in view of the often benign clinical course, immunosuppressive agents should be considered only in those with idiopathic MN who are most at risk for progressive disease or who have severe symptomatic nephrotic syndrome. Both histologic and clinical findings may be important in risk assessment.

• Clinical findings associated with a higher risk of developing end-stage renal disease include older age at onset (particularly greater than 50 years), male sex, nephrotic-range proteinuria (particularly if protein excretion exceeds 8–10 g/day), and an increased serum creatinine at presentation [12].

In contrast to these adverse risk factors, women, children, and young adults, non-nephrotic-range proteinuria, a progressive decline in protein excretion, and presentation with normal renal function have been associated with a relatively benign course [7]. In addition, patients of Asian ancestry seem to have a better long-term prognosis than other ancestries.

• Histologic findings are frequently regarded as important predictors of outcome, as the risk of progression is increased in patients with glomerular scarring (segmental sclerosis) and correlates more closely with the severity of the tubulointerstitial disease than with the degree of glomerular injury [12, 13]. This observation is typical of most glomerular diseases.

Importance of attaining remission—attainment of a complete remission (whether spontaneous or not) is associated with good long-term outcomes. In contrast, little is known about the prognosis in patients with a partial remission [14].

A complete remission was defined as protein excretion below 0.3 g/day, while a partial remission was defined as protein excretion below 3.5 g/day plus a 50% or greater reduction in protein excretion from the peak value. Renal failure was defined as a creatinine clearance ≤15 mL/min, initiation of dialysis, or renal transplantation.

**95**

*Treatment of Idiopathic Membranous Nephropathy (IMN)*

ate analysis that took into account clinical and laboratory data:

The following findings were associated with a better renal survival on multivari-

• higher initial creatinine clearance and lower proteinuria at presentation,

Based upon this model, is defined as low-, moderate-, and high-risk patient subsets with varying degrees of risk for progression to more advanced kidney insuf-

• Low risk—proteinuria remains less than 4 g/day and creatinine clearance remains normal for a 6-month follow-up period. Such patients have a less than

• Moderate risk—proteinuria is between 4 and 8 g/day and persists for more than 6 months. Creatinine clearance is normal or near normal and remains stable over 6 months of observation. Chronic renal insufficiency develops over

• High risk—proteinuria is greater than 8 g/day and persists for 3 months and/ or renal function that is either below normal (and considered due to MN) or decreases during the observation period. Approximately 75% of such patients

are at risk of progression to chronic renal insufficiency over 5 years.

Given the high rate of gradual spontaneous improvement in patients with IMN, only selected patients with more severe or progressive disease should receive

In contrast, almost all patients are candidates for more general therapies for nephrotic syndrome, such as angiotensin inhibition, lipid lowering, and, in selected patients, anticoagulation. Other aspects of therapy include diuretics to control

Proteinuria goal—the optimal proteinuria goal in patients with chronic kidney

Goal blood pressure—the goal blood pressure in patients with MN is the same as it is in other patients with proteinuric chronic kidney disease (125/75 mmHg). Attainment of this goal can slow the progression of proteinuric chronic kidney disease and can provide cardiovascular protection since chronic kidney disease is associated with a marked increase in cardiovascular risk. The data supporting these

Attainment of the blood pressure goal in patients with MN usually requires more than angiotensin inhibition alone. Correction of volume overload is of particular importance and usually requires loop diuretics. Diuretics should be pushed until the blood pressure goal is reached or the patient has attained "dry weight" which, in the presence of persistent hypertension, is defined as the weight at which further fluid removal leads to symptoms (fatigue, orthostatic hypotension) or to decreased tissue perfusion as evidenced by an otherwise unexplained elevation in the blood urea

disease is less than 1000 mg/day. However, this goal is often not attainable in

) over 5 years:

• lower mean arterial blood pressure over the observation period,

• attainment of complete or partial remission in proteinuria.

ficiency (defined as a creatinine clearance ≤60 mL/min per 1.73 m2

5 years in approximately 50% of these patients.

**4. Nonimmunosuppressive therapies**

edema and maintenance of adequate nutrition.

recommendations are presented separately.

nitrogen and/or serum creatinine concentration.

immunosuppressive therapy [1].

patients with IMN.

8% risk of developing chronic renal insufficiency over 5 years.

*DOI: http://dx.doi.org/10.5772/intechopen.86741*

*Glomerulonephritis and Nephrotic Syndrome*

C virus infection [2].

at 5 years.

in risk assessment.

gold, penicillamine, systemic lupus erythematosus, malignancy, and hepatitis B and

It is often not possible to distinguish idiopathic from secondary MN on clinical grounds alone, even though serologic studies (e.g., antinuclear antibodies, hepatitis B serology) and a history of drug exposure or cancer may be revealing of a potential cause. However, there are certain findings on electron microscopy and immunofluorescence that suggest secondary disease. In patients with secondary MN, cessation of the offending drug or effective treatment of the underlying disease is usually

In view of the potential toxicity of the drugs used to treat IMN, with or without the nephrotic syndrome, the decision to initiate therapy is based, in part, upon an understanding of the natural history of untreated patients, with and without

• Spontaneous complete remission of proteinuria occurs in 5–30% at 5 years.

• The occurrence of end-stage renal disease in untreated patients is approxi-

• Clinical findings associated with a higher risk of developing end-stage renal disease include older age at onset (particularly greater than 50 years), male sex, nephrotic-range proteinuria (particularly if protein excretion exceeds 8–10 g/day),

In contrast to these adverse risk factors, women, children, and young adults, non-nephrotic-range proteinuria, a progressive decline in protein excretion, and presentation with normal renal function have been associated with a relatively benign course [7]. In addition, patients of Asian ancestry seem to have a better

• Histologic findings are frequently regarded as important predictors of outcome, as the risk of progression is increased in patients with glomerular scarring (segmental sclerosis) and correlates more closely with the severity of the tubulointerstitial disease than with the degree of glomerular injury [12, 13].

Importance of attaining remission—attainment of a complete remission (whether spontaneous or not) is associated with good long-term outcomes. In contrast, little is known about the prognosis in patients with a partial remission [14]. A complete remission was defined as protein excretion below 0.3 g/day, while a partial remission was defined as protein excretion below 3.5 g/day plus a 50% or greater reduction in protein excretion from the peak value. Renal failure was defined as a creatinine clearance ≤15 mL/min, initiation of dialysis, or renal

mately 14% at 5 years, 35% at 10 years, and 41% at 15 years.

and an increased serum creatinine at presentation [12].

This observation is typical of most glomerular diseases.

long-term prognosis than other ancestries.

• Spontaneous partial remission (≤2 g of proteinuria per day) occurs in 25–40%

Risk factors for progressive idiopathic MN—in view of the often benign clinical course, immunosuppressive agents should be considered only in those with idiopathic MN who are most at risk for progressive disease or who have severe symptomatic nephrotic syndrome. Both histologic and clinical findings may be important

associated with improvement in the nephrotic syndrome [10].

features of the nephrotic syndrome at presentation [11]:

**94**

transplantation.

The following findings were associated with a better renal survival on multivariate analysis that took into account clinical and laboratory data:


Based upon this model, is defined as low-, moderate-, and high-risk patient subsets with varying degrees of risk for progression to more advanced kidney insufficiency (defined as a creatinine clearance ≤60 mL/min per 1.73 m2 ) over 5 years:


#### **4. Nonimmunosuppressive therapies**

Given the high rate of gradual spontaneous improvement in patients with IMN, only selected patients with more severe or progressive disease should receive immunosuppressive therapy [1].

In contrast, almost all patients are candidates for more general therapies for nephrotic syndrome, such as angiotensin inhibition, lipid lowering, and, in selected patients, anticoagulation. Other aspects of therapy include diuretics to control edema and maintenance of adequate nutrition.

Proteinuria goal—the optimal proteinuria goal in patients with chronic kidney disease is less than 1000 mg/day. However, this goal is often not attainable in patients with IMN.

Goal blood pressure—the goal blood pressure in patients with MN is the same as it is in other patients with proteinuric chronic kidney disease (125/75 mmHg). Attainment of this goal can slow the progression of proteinuric chronic kidney disease and can provide cardiovascular protection since chronic kidney disease is associated with a marked increase in cardiovascular risk. The data supporting these recommendations are presented separately.

Attainment of the blood pressure goal in patients with MN usually requires more than angiotensin inhibition alone. Correction of volume overload is of particular importance and usually requires loop diuretics. Diuretics should be pushed until the blood pressure goal is reached or the patient has attained "dry weight" which, in the presence of persistent hypertension, is defined as the weight at which further fluid removal leads to symptoms (fatigue, orthostatic hypotension) or to decreased tissue perfusion as evidenced by an otherwise unexplained elevation in the blood urea nitrogen and/or serum creatinine concentration.

A low-salt diet is an important component of antihypertensive therapy (especially when using angiotensin inhibitors) and edema control in patients with MN. In addition, a high-salt diet can increase proteinuria, and in some individuals, a high-salt diet rather than increased immunologic activity should be considered as an underlying cause of worsening proteinuria.

Lipid lowering—hyperlipidemia, with often dramatic elevations in the serum cholesterol concentration, is commonly present in patients with nephrotic syndrome. The mainstay of therapy for such hypercholesterolemia is statins.

#### **5. Immunosuppressive therapies**

Indications for and choice of therapy—since many patients with mild to moderate disease undergo spontaneous remission and immunosuppressive agents have appreciable toxicity, the decision to treat must be based upon the probability that the patient will have progressive disease (defined as an otherwise unexplained elevation in serum creatinine or persistent high-grade or increasing proteinuria in patients at moderate to high risk for progression) [15].

The treatment regimen must be based upon the risk of progressive disease. First-line immunosuppressive therapy consists of cytotoxic drugs (usually cyclophosphamide) plus glucocorticoids or a calcineurin inhibitor with low-dose or no glucocorticoids (a regimen based upon cytotoxic drugs is preferred in some high-risk patients with declining glomerular filtration rate due to MN and an estimated glomerular filtration rate above 30 mL/min/1.73 m2 ). Patients who do not respond to one regimen are usually treated with the other, and those with resistant disease may be treated with rituximab.

In our case, it is a patient with a high risk of progression.

High risk for progression—high-risk patients with idiopathic MN are defined as those with protein excretion exceeding 8 g/day that persists for more than 3 months and/or renal function that is either below normal (and considered due to MN) or decreases during the observation period, despite maximum nonimmunosuppressive therapy. These patients are also likely to have prominent nephrotic symptoms or signs, such as marked hypoalbuminemia and edema. Approximately 75% of such patients progress to worsened renal insufficiency over 5 years.

Rituximab has been used in patients with idiopathic membranous nephropathy who have failed previous treatment with other immunosuppressive regimens.

Rituximab may have benefit among patients with a moderate risk of progression who have not previously received immunosuppressive therapy [8, 16]. In one unblinded trial for 12 months, the rate of complete or partial remission was higher among patients treated with rituximab (65 versus 34%). These findings are consistent with observational studies that demonstrate a maximal reduction in proteinuria at 18–24 months after treatment with rituximab. Anti-PLA2R antibodies, which were present in 73% of patients at baseline, disappeared in a greater proportion of patients receiving rituximab (50 versus 12%). Serious adverse events were similar between the two groups.

Resistant disease—the optimal approach to moderate- or high-risk patients with stable renal function who fail treatment with both cyclophosphamide and calcineurin inhibitor-based regimens is not known. We prefer a trial of rituximab in such patients, although limited data are available suggesting efficacy.

Several observational (nonrandomized) studies in patients with idiopathic resistant MN have reported outcomes following the administration of rituximab:

Rituximab therapy is generally well tolerated, adverse effects are minor and primarily consisted of infusion reactions.

**97**

*Treatment of Idiopathic Membranous Nephropathy (IMN)*

sion rates compared with patients who had higher titers.

proteinuria may have this dose repeated at 6 months.

clinical response to rituximab treatment [17, 18].

than is provided by measurement of proteinuria alone [17, 18].

betic adults, accounting for up to one-third of biopsy diagnoses.

neous or treatment-induced remission.

progressive chronic kidney disease.

among patients treated with Rituximab.

**6. Conclusions**

Anti-PLA2R-positive patients with lower titers had significantly greater remis-

Rituximab may provide benefit to patients who failed prior immunosuppressive therapy, especially those with relatively preserved renal function. Four weekly

It is suggested the somewhat simpler and cheaper regimen of a dose of 1 g given intravenously and repeated in 2 weeks. Patients who continue to have significant

A decline in antiphospholipase A2 receptor (PLA2R) antibodies may predict the

The anti-PLA2R autoantibody-negative patients may be in the midst of a sponta-

The monitoring serum anti-PLA2R antibodies may allow a more accurate assessment of the immunological response to rituximab (and possibly other therapies)

MN is among the most common causes of the nephrotic syndrome in nondia-

Rituximab induces NS remission in two-thirds of patients with IMN, even after other treatments have failed. The rate of complete or partial remission was higher

Therefore, assessing circulating anti-PLA2R autoantibodies and proteinuria may help in monitoring disease activity and guiding personalized rituximab therapy in nephrotic patients with IMN. The monitoring serum anti-PLA2R antibodies may allow a more accurate assessment of the immunological response to rituximab (and possibly other therapies) than is provided by measurement of proteinuria alone.

A significant percentage (15–50% of cases) of patients with IMN develop

PLA2R is a transmembrane receptor that is highly expressed in glomerular podocytes and has been identified as a major antigen in human idiopathic MN.

) appear to have the same effect on proteinuria

*DOI: http://dx.doi.org/10.5772/intechopen.86741*

reduction as a regimen of 1 g every 2 weeks.

doses of rituximab (375 mg/m2

*Treatment of Idiopathic Membranous Nephropathy (IMN) DOI: http://dx.doi.org/10.5772/intechopen.86741*

Anti-PLA2R-positive patients with lower titers had significantly greater remission rates compared with patients who had higher titers.

Rituximab may provide benefit to patients who failed prior immunosuppressive therapy, especially those with relatively preserved renal function. Four weekly doses of rituximab (375 mg/m2 ) appear to have the same effect on proteinuria reduction as a regimen of 1 g every 2 weeks.

It is suggested the somewhat simpler and cheaper regimen of a dose of 1 g given intravenously and repeated in 2 weeks. Patients who continue to have significant proteinuria may have this dose repeated at 6 months.

PLA2R is a transmembrane receptor that is highly expressed in glomerular podocytes and has been identified as a major antigen in human idiopathic MN.

A decline in antiphospholipase A2 receptor (PLA2R) antibodies may predict the clinical response to rituximab treatment [17, 18].

The anti-PLA2R autoantibody-negative patients may be in the midst of a spontaneous or treatment-induced remission.

The monitoring serum anti-PLA2R antibodies may allow a more accurate assessment of the immunological response to rituximab (and possibly other therapies) than is provided by measurement of proteinuria alone [17, 18].

#### **6. Conclusions**

*Glomerulonephritis and Nephrotic Syndrome*

**5. Immunosuppressive therapies**

above 30 mL/min/1.73 m2

were similar between the two groups.

primarily consisted of infusion reactions.

an underlying cause of worsening proteinuria.

patients at moderate to high risk for progression) [15].

In our case, it is a patient with a high risk of progression.

patients progress to worsened renal insufficiency over 5 years.

patients, although limited data are available suggesting efficacy.

A low-salt diet is an important component of antihypertensive therapy (especially when using angiotensin inhibitors) and edema control in patients with MN. In addition, a high-salt diet can increase proteinuria, and in some individuals, a high-salt diet rather than increased immunologic activity should be considered as

Lipid lowering—hyperlipidemia, with often dramatic elevations in the serum cholesterol concentration, is commonly present in patients with nephrotic syndrome. The mainstay of therapy for such hypercholesterolemia is statins.

Indications for and choice of therapy—since many patients with mild to moderate disease undergo spontaneous remission and immunosuppressive agents have appreciable toxicity, the decision to treat must be based upon the probability that the patient will have progressive disease (defined as an otherwise unexplained elevation in serum creatinine or persistent high-grade or increasing proteinuria in

The treatment regimen must be based upon the risk of progressive disease. First-line immunosuppressive therapy consists of cytotoxic drugs (usually cyclophosphamide) plus glucocorticoids or a calcineurin inhibitor with low-dose or no glucocorticoids (a regimen based upon cytotoxic drugs is preferred in some high-risk patients with declining glomerular filtration rate due to MN and an estimated glomerular filtration rate

treated with the other, and those with resistant disease may be treated with rituximab.

High risk for progression—high-risk patients with idiopathic MN are defined as those with protein excretion exceeding 8 g/day that persists for more than 3 months and/or renal function that is either below normal (and considered due to MN) or decreases during the observation period, despite maximum nonimmunosuppressive therapy. These patients are also likely to have prominent nephrotic symptoms or signs, such as marked hypoalbuminemia and edema. Approximately 75% of such

Rituximab has been used in patients with idiopathic membranous nephropathy

Resistant disease—the optimal approach to moderate- or high-risk patients with stable renal function who fail treatment with both cyclophosphamide and calcineurin inhibitor-based regimens is not known. We prefer a trial of rituximab in such

Several observational (nonrandomized) studies in patients with idiopathic resistant MN have reported outcomes following the administration of rituximab: Rituximab therapy is generally well tolerated, adverse effects are minor and

who have failed previous treatment with other immunosuppressive regimens. Rituximab may have benefit among patients with a moderate risk of progression who have not previously received immunosuppressive therapy [8, 16]. In one unblinded trial for 12 months, the rate of complete or partial remission was higher among patients treated with rituximab (65 versus 34%). These findings are consistent with observational studies that demonstrate a maximal reduction in proteinuria at 18–24 months after treatment with rituximab. Anti-PLA2R antibodies, which were present in 73% of patients at baseline, disappeared in a greater proportion of patients receiving rituximab (50 versus 12%). Serious adverse events

). Patients who do not respond to one regimen are usually

**96**

MN is among the most common causes of the nephrotic syndrome in nondiabetic adults, accounting for up to one-third of biopsy diagnoses.

A significant percentage (15–50% of cases) of patients with IMN develop progressive chronic kidney disease.

Rituximab induces NS remission in two-thirds of patients with IMN, even after other treatments have failed. The rate of complete or partial remission was higher among patients treated with Rituximab.

Therefore, assessing circulating anti-PLA2R autoantibodies and proteinuria may help in monitoring disease activity and guiding personalized rituximab therapy in nephrotic patients with IMN. The monitoring serum anti-PLA2R antibodies may allow a more accurate assessment of the immunological response to rituximab (and possibly other therapies) than is provided by measurement of proteinuria alone.

*Glomerulonephritis and Nephrotic Syndrome*

### **Author details**

María Carmen Prados Soler1 \*, María Dolores Del Pino y Pino1 , Álvaro Pérez Fernández1 , Llenalia Gordillo García1 , María José López Ruiz1 and César Luis Ramírez-Tortosa2

1 Nephrology Service, Complejo Hospitalario Torrecárdenas, Almería, Spain

2 Pathological Anatomy Service, Hospital Virgen de las Nieves, Granada, Spain

\*Address all correspondence to: lensasu@yahoo.es

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**99**

2017;**28**:348

1998;**9**:444

*Treatment of Idiopathic Membranous Nephropathy (IMN)*

[9] Ruggenenti P, Cravedi P, Chianca A, et al. Rituximab in idiopathic membranous nephropathy. Journal of the American Society of Nephrology.

[10] Troyanov S, Roasio L, Pandes M, et al. Renal pathology in idiopathic membranous nephropathy: A new perspective. Kidney International.

[11] Jha V, Ganguli A, Saha TK, et al. A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy. Journal of the American Society of

[12] Shiiki H, Saito T, Nishitani Y, et al. Prognosis and risk factors for idiopathic

[13] Wu Q, Jinde K, Nishina M, et al. Analysis of prognostic predictors in idiopathic membranous nephropathy. American Journal of Kidney Diseases.

[14] Troyanov S, Wall CA, Miller JA, et al. Idiopathic membranous nephropathy: Definition and relevance

of a partial remission. Kidney International. 2004;**66**:1199

of proteinuria in primary

Nephrology. 2015;**26**:2545

[15] Philibert D, Cattran D. Remission

[16] Ruggenenti P, Debiec H, Ruggiero B, et al. Anti-phospholipase A2 receptor antibody titer predicts post-rituximab outcome of membranous nephropathy. Journal of the American Society of

glomerulonephritis: We know the goal but do we know the price? Nature Clinical Practice. Nephrology.

membranous nephropathy with nephrotic syndrome in Japan. Kidney

International. 2004;**65**:1400

2001;**37**:380

2008;**4**:550

Nephrology. 2007;**18**:1899

2012;**23**:1416

2006;**69**:1641

*DOI: http://dx.doi.org/10.5772/intechopen.86741*

[1] Fervenza FC, Sethi S, Specks U. Idiopathic membranous nephropathy: Diagnosis and treatment. Clinical Journal of the American Society of

Nephrology. 2008;**3**:905

Nephrology. 2011;**22**:1137

of Nephrology. 2011;**6**:1286

P, et al. A 10-year follow-up of a randomized study with

International. 1995;**48**:1600

[2] Debiec H, Ronco P. PLA2R

autoantibodies and PLA2R glomerular deposits in membranous nephropathy. The New England Journal of Medicine.

[3] Qin W, Beck LH Jr, Zeng C, et al. Anti-phospholipase A2 receptor antibody in membranous nephropathy. Journal of the American Society of

[4] Hofstra JM, Beck LH Jr, Beck DM, et al. Anti-phospholipase A₂ receptor antibodies correlate with clinical status in idiopathic membranous nephropathy. Clinical Journal of the American Society

[5] Ponticelli C, Zucchelli P, Passerini

methylprednisolone and chlorambucil in membranous nephropathy. Kidney

[6] Ponticelli C, Altieri P, Scolari F, et al. A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy. Journal of the American Society of Nephrology.

[7] Reichert LJ, Koene RA, Wetzels JF. Prognostic factors in idiopathic membranous nephropathy. American Journal of Kidney Diseases. 1998;**31**:1

[8] Dahan K, Debiec H, Plaisier E, et al. Rituximab for severe membranous nephropathy: A 6-month trial with extended follow-up. Journal of the American Society of Nephrology.

**References**

2011;**364**:689

*Treatment of Idiopathic Membranous Nephropathy (IMN) DOI: http://dx.doi.org/10.5772/intechopen.86741*

#### **References**

*Glomerulonephritis and Nephrotic Syndrome*

**98**

**Author details**

María Carmen Prados Soler1

and César Luis Ramírez-Tortosa2

\*Address all correspondence to: lensasu@yahoo.es

provided the original work is properly cited.

Álvaro Pérez Fernández1

\*, María Dolores Del Pino y Pino1

, Llenalia Gordillo García1

1 Nephrology Service, Complejo Hospitalario Torrecárdenas, Almería, Spain

2 Pathological Anatomy Service, Hospital Virgen de las Nieves, Granada, Spain

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

,

, María José López Ruiz1

[1] Fervenza FC, Sethi S, Specks U. Idiopathic membranous nephropathy: Diagnosis and treatment. Clinical Journal of the American Society of Nephrology. 2008;**3**:905

[2] Debiec H, Ronco P. PLA2R autoantibodies and PLA2R glomerular deposits in membranous nephropathy. The New England Journal of Medicine. 2011;**364**:689

[3] Qin W, Beck LH Jr, Zeng C, et al. Anti-phospholipase A2 receptor antibody in membranous nephropathy. Journal of the American Society of Nephrology. 2011;**22**:1137

[4] Hofstra JM, Beck LH Jr, Beck DM, et al. Anti-phospholipase A₂ receptor antibodies correlate with clinical status in idiopathic membranous nephropathy. Clinical Journal of the American Society of Nephrology. 2011;**6**:1286

[5] Ponticelli C, Zucchelli P, Passerini P, et al. A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney International. 1995;**48**:1600

[6] Ponticelli C, Altieri P, Scolari F, et al. A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy. Journal of the American Society of Nephrology. 1998;**9**:444

[7] Reichert LJ, Koene RA, Wetzels JF. Prognostic factors in idiopathic membranous nephropathy. American Journal of Kidney Diseases. 1998;**31**:1

[8] Dahan K, Debiec H, Plaisier E, et al. Rituximab for severe membranous nephropathy: A 6-month trial with extended follow-up. Journal of the American Society of Nephrology. 2017;**28**:348

[9] Ruggenenti P, Cravedi P, Chianca A, et al. Rituximab in idiopathic membranous nephropathy. Journal of the American Society of Nephrology. 2012;**23**:1416

[10] Troyanov S, Roasio L, Pandes M, et al. Renal pathology in idiopathic membranous nephropathy: A new perspective. Kidney International. 2006;**69**:1641

[11] Jha V, Ganguli A, Saha TK, et al. A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy. Journal of the American Society of Nephrology. 2007;**18**:1899

[12] Shiiki H, Saito T, Nishitani Y, et al. Prognosis and risk factors for idiopathic membranous nephropathy with nephrotic syndrome in Japan. Kidney International. 2004;**65**:1400

[13] Wu Q, Jinde K, Nishina M, et al. Analysis of prognostic predictors in idiopathic membranous nephropathy. American Journal of Kidney Diseases. 2001;**37**:380

[14] Troyanov S, Wall CA, Miller JA, et al. Idiopathic membranous nephropathy: Definition and relevance of a partial remission. Kidney International. 2004;**66**:1199

[15] Philibert D, Cattran D. Remission of proteinuria in primary glomerulonephritis: We know the goal but do we know the price? Nature Clinical Practice. Nephrology. 2008;**4**:550

[16] Ruggenenti P, Debiec H, Ruggiero B, et al. Anti-phospholipase A2 receptor antibody titer predicts post-rituximab outcome of membranous nephropathy. Journal of the American Society of Nephrology. 2015;**26**:2545

[17] Cattran DC, Kim ED, Reich H, et al. Membranous nephropathy: Quantifying remission duration on outcome. Journal of the American Society of Nephrology. 2017;**28**:995

[18] Cravedi P, Ruggenenti P, Remuzzi G. Circulating anti-PLA2R autoantibodies to monitor immunological activity in membranous nephropathy. Journal of the American Society of Nephrology. 2011;**22**:1400

**101**

Section 4

Renal Rehabilitation

Section 4
