**3. Glomerular, tubulointerstitial and vascular lesions**

The glomeruli are the most affected compartment in the LN. The initial injury is related to immune deposits in the mesangium and/or capillary loops. Large subendothelial deposits can be easily seen by LM. The distribution of deposits in the mesangium and/or glomerular capillaries defines the morphological pattern of the disease and consequently clinical manifestations. Some cases have only mesangial deposits, and others have deposits in the mesangium and in the capillary loops. Deposits in the capillary loops can be intramembranous, subendothelial (between endothelial cells and glomerular basement membrane) or subepithelial (between podocytes and glomerular basement membrane). Large subendothelial deposits characterize the wire loops and determine intense thickening of the glomerular basement membrane with occlusion of capillary loops (**Figure 1**). Immune deposits with complement activation determines an inflammatory reaction with proliferation of resident cells and exudation of mononuclear cells and polymorphonuclear neutrophils. Mesangial deposits stimulate proliferation of mesangial cells and deposition of mesangial matrix. Subendothelial deposits in capillary loops stimulate endothelial proliferation, and subepithelial deposits determines thickening of the GBM without significant cellular proliferation. Capillary involvement by the inflammatory response may result in segmental glomerular necrosis and adjacent cellular crescents. Prolonged glomerular injury result in segmental and/or global

**23**

**Figure 2.**

*Granular deposits of IgG in the mesangium and capillary loops. IF-400x.*

**Figure 1.**

*loops (wire loops). Masson thricrome 400x.*

*Lupus Nephritis: Renal Biopsy Guiding the Clinician DOI: http://dx.doi.org/10.5772/intechopen.97169*

scarring. The IF staining is variable. IgG is the most frequent immunoglobulin (**Figure 2**), usually associated with deposits of C1q and C3. IgM and IgA deposits may also be present. Fibrin deposits are frequent in areas of necrosis and in association with active crescents. The IF staining is called the full house when there is deposition of the three immunoglobulins, C1q and C3. This staining pattern is very useful for diagnosing LN. The EM confirms the IF findings showing since small mesangial electron dense deposits to large and abundant deposits in the mesangium with extension to capillary loops. Immune deposits limited to the mesangium are associated with mild clinical signs and symptoms. The presence of deposits in the capillary loops, especially in the subendothelial space, is related to more harmful forms of the disease. Anti-dsDNA and anti-C1q antibodies correlate with

*Glomerulus with intense global hypercellularity and subendothelial hyaline deposits in peripheral capillary* 

*Lupus Nephritis: Renal Biopsy Guiding the Clinician DOI: http://dx.doi.org/10.5772/intechopen.97169*

#### **Figure 1.**

*Lupus - Need to Know*

**2. Renal biopsy**

progressive renal failure [7].

and electron microscopy (EM) findings [11].

**3. Glomerular, tubulointerstitial and vascular lesions**

The glomeruli are the most affected compartment in the LN. The initial injury

is related to immune deposits in the mesangium and/or capillary loops. Large subendothelial deposits can be easily seen by LM. The distribution of deposits in the mesangium and/or glomerular capillaries defines the morphological pattern of the disease and consequently clinical manifestations. Some cases have only mesangial deposits, and others have deposits in the mesangium and in the capillary loops. Deposits in the capillary loops can be intramembranous, subendothelial (between endothelial cells and glomerular basement membrane) or subepithelial (between podocytes and glomerular basement membrane). Large subendothelial deposits characterize the wire loops and determine intense thickening of the glomerular basement membrane with occlusion of capillary loops (**Figure 1**). Immune deposits with complement activation determines an inflammatory reaction with proliferation of resident cells and exudation of mononuclear cells and polymorphonuclear neutrophils. Mesangial deposits stimulate proliferation of mesangial cells and deposition of mesangial matrix. Subendothelial deposits in capillary loops stimulate endothelial proliferation, and subepithelial deposits determines thickening of the GBM without significant cellular proliferation. Capillary involvement by the inflammatory response may result in segmental glomerular necrosis and adjacent cellular crescents. Prolonged glomerular injury result in segmental and/or global

of corticosteroids is a risk factor for coronary atherosclerosis and cardiovascular disease [1, 6]. Glomerular immune complexes can activate complement and engage leukocyte Fc receptors to initiate renal inflammation and injury [1]. LN has very pleomorphic clinical and morphologic expressions. Clinical findings range from asymptomatic hematuria and proteinuria to nephrotic syndrome or rapidly

The renal biopsy is the gold standard for the diagnosis of LN, providing important information to the clinician for the management of the patients [7–9]. A diagnosis of SLE is based on clinical systemic features and serologic tests attending the American College of Rheumatology (ACR) criteria for SLE [10]. However, it is not uncommon that the renal biopsy shows morphologic expressions that is very suspicious or conclusive of LN before extrarenal manifestations are evident [11]. The renal biopsy provides an important information about the morphology and severity of the lesions, their classification, grades of activity and chronicity of the disease. With the appearance of any signs or symptoms of kidney disease such as hematuria, proteinuria, nephrotic syndrome or renal insufficiency the renal biopsy should be performed. Repeat kidney biopsies should also be done for clinical indications due to SLE flare, persistent proteinuria or declining renal function. The role of the renal biopsy in diagnosis, treatment, management, and follow-up of LN is critical, although to predict the outcome has been a matter of controversy [1, 7, 8]. Considering the importance of the biopsy making the treatment decision and determining the prognosis, it is essential to assess renal histopathology with high accuracy [9, 12, 13]. LN can affect all compartments of the kidney including glomeruli, tubules, interstitium and blood vessels. The analysis of the renal lesions is based on light microscopy (LM) associated with the immunofluorescence (IF)

**22**

*Glomerulus with intense global hypercellularity and subendothelial hyaline deposits in peripheral capillary loops (wire loops). Masson thricrome 400x.*

scarring. The IF staining is variable. IgG is the most frequent immunoglobulin (**Figure 2**), usually associated with deposits of C1q and C3. IgM and IgA deposits may also be present. Fibrin deposits are frequent in areas of necrosis and in association with active crescents. The IF staining is called the full house when there is deposition of the three immunoglobulins, C1q and C3. This staining pattern is very useful for diagnosing LN. The EM confirms the IF findings showing since small mesangial electron dense deposits to large and abundant deposits in the mesangium with extension to capillary loops. Immune deposits limited to the mesangium are associated with mild clinical signs and symptoms. The presence of deposits in the capillary loops, especially in the subendothelial space, is related to more harmful forms of the disease. Anti-dsDNA and anti-C1q antibodies correlate with

**Figure 2.** *Granular deposits of IgG in the mesangium and capillary loops. IF-400x.*

subendothelial deposits that stimulate endothelial proliferation and glomerular necrosis. The most severe form of LN are cases of diffuse proliferative nephritis that show voluminous subendothelial deposits with high correlation with disease activity. Furthermore, during the course of the disease, LN can undergo transformations. Purely mesangial injuries can evolve to more severe mesangioendothelial proliferative disease with damage of capillary loops. After treatment, severe LN with endothelial proliferation can turn into mesangial proliferative lesion [7, 11].

Tubulointerstitial lesions are found in all types of glomerular lesions, although is more frequent in the most severe forms of proliferative LN. The lesions result from the autoimmune inflammatory activity of the disease and/or prolonged periods of proteinuria [11]. The acute phase is characterized by edema and inflammatory infiltrate with a predominance of mononuclear cells. Immune deposits are detected by IF and EM mainly in the tubular basement membrane and peritubular capillaries in 50% of the patients (**Figure 3**). Immunoglobulins are associated with complement components C1q and C3 in most cases. There was no correlation between prevalence of deposits and the severity of interstitial inflammation, suggesting that the immune complexes are not involved in the pathogenesis of interstitial nephritis in SLE [11, 14]. The predominance of T lymphocytes, CD4 or CD8, with frequent presence of monocytes and NK cells suggests cellular immunity. While several mechanisms may play an initial role, interstitial T cells and monocytes may be important determinants of pathogenesis of interstitial nephritis, and monocytes may be the major factor in the chronic injury and progression of LN [15]. On the other hand, nephrotic proteinuria also induces changes in the tubular cells due to active and excessive resorption of filtered proteins and lipoproteins by the proximal tubules [11]. After a prolonged period of damage, tubular atrophy and interstitial fibrosis characterize the chronic phase of the disease. Active and severe tubulointerstitial injury is most common in severe diffuse proliferative LN. The severity of interstitial inflammation correlated with the degree of renal insufficiency and was an accurate prognostic indicator of progressive deterioration of renal function. Many studies have shown an association between tubulointerstitial damage and a poor renal outcome in LN and in order to avoid progression to end

**25**

failure.

**Classification (2003)**

*Lupus Nephritis: Renal Biopsy Guiding the Clinician DOI: http://dx.doi.org/10.5772/intechopen.97169*

85.9% in patients without vascular lesion, respectively [20].

**4. International Society of Nephrology and Renal Pathology Society** 

The classifications of LN are based on glomerular morphologic lesions in different classes of LN and aim to identify patients at risk of progressing to chronic renal

ment of interstitial fibrosis [15–18].

stage renal disease some studies suggest an early intervention before the develop-

A variety of vascular lesions are encountered in renal biopsies of patients with SLE: uncomplicated vascular immune deposits, noninflammatory necrotizing vasculopathy, true renal vasculitis, thrombotic microangiopathy and arteriosclerosis. The interlobular arteries and arterioles are the most involved vessels [11, 19–21]. Large study with 285 patients with LN found vascular lesion in 79 (27.7%): 9.47% with noninflammatory necrotizing vasculopathy, 8.42% with thrombotic microangiopathy, 7.02% with arteriosclerosis and 2.81% with true vasculitis [20]. Wu *et al* [21] studying 341 patients with LN found 81.8% of vascular injury, including 74.19% of uncomplicated vascular immune deposits, 24.5% of arteriosclerosis, 17.59% of thrombotic microangiopathy, 3.81% of noninflammatory necrotizing vasculopathy and 0.59% of true vasculitis. The inclusion of cases of uncomplicated vascular immune deposits explains the higher incidence of vascular lesions in this study. Uncomplicated vascular immune deposits are the most common lesion and do not significantly affect prognosis. This type of injury shows deposits of immunoglobulins and complement in the small arteries and arterioles, without any inflammatory process and impairment of vascular lumen. The noninflammatory necrotizing vasculopathy determines severe vascular narrowing by abundant eosinophilic material constituted by immune deposits, plasma proteins and fibrin insudation in the vessel wall. There are also degenerative changes and loss of endothelial cells and myocytes. This is a form of vascular lesion associated to more severe forms of glomerular lesion, and is less common than uncomplicated vascular immune deposits. The necrotizing vasculopathy has a poor prognosis with a high degree of disease progression. A true renal vasculitis, with inflammatory infiltrate and necrosis of the vascular wall, is the least common vascular lesion in the LN. This kind of lesion is very severe with an ominous prognosis and need an aggressive immunosuppressive therapy. The thrombotic microangiopathy is characterized by myointimal proliferation of the small vessels, with a pattern of "onion skin", that complicates with thrombosis. In patients with SLE this vascular lesion occurs in association with hemolytic-uremic syndrome, antiphospholipid syndrome and malignant hypertension. Arteriosclerosis is a degenerative non-immunological vascular lesion characterized by fibrous thickening of the intima of the arteries without necrosis, proliferation or thrombosis. This lesion is common in LN due to the high prevalence of risk factors for arteriosclerosis in lupus patients such as hypertension, hyperlipidemia and prolonged use of corticosteroids. Vascular lesion can occur in any type of glomerular injury, but they are more frequent in the more active glomerulitis with mesangial and glomerular capillaries involvement [11, 19, 21]. Renal vascular lesions, specially of the necrotizing, vasculitic or thrombotic type adversely affects renal outcome with a higher rate of progression to renal failure [11, 19–21]. At the time of renal biopsy, patients with vascular lesion had higher levels of serum creatinine than patients without vascular lesion (2.2 mg/dl vs. 1.2 mg/dl). The probability of a kidney survival at 5 and 10 years was 74.3% and 58.0% in patients with vascular lesion, compared with 89.6% and

#### *Lupus Nephritis: Renal Biopsy Guiding the Clinician DOI: http://dx.doi.org/10.5772/intechopen.97169*

*Lupus - Need to Know*

subendothelial deposits that stimulate endothelial proliferation and glomerular necrosis. The most severe form of LN are cases of diffuse proliferative nephritis that show voluminous subendothelial deposits with high correlation with disease activity. Furthermore, during the course of the disease, LN can undergo transformations. Purely mesangial injuries can evolve to more severe mesangioendothelial proliferative disease with damage of capillary loops. After treatment, severe LN with endothelial proliferation can turn into mesangial proliferative lesion [7, 11]. Tubulointerstitial lesions are found in all types of glomerular lesions, although is more frequent in the most severe forms of proliferative LN. The lesions result from the autoimmune inflammatory activity of the disease and/or prolonged periods of proteinuria [11]. The acute phase is characterized by edema and inflammatory infiltrate with a predominance of mononuclear cells. Immune deposits are detected by IF and EM mainly in the tubular basement membrane and peritubular capillaries in 50% of the patients (**Figure 3**). Immunoglobulins are associated with complement components C1q and C3 in most cases. There was no correlation between prevalence of deposits and the severity of interstitial inflammation, suggesting that the immune complexes are not involved in the pathogenesis of interstitial nephritis in SLE [11, 14]. The predominance of T lymphocytes, CD4 or CD8, with frequent presence of monocytes and NK cells suggests cellular immunity. While several mechanisms may play an initial role, interstitial T cells and monocytes may be important determinants of pathogenesis of interstitial nephritis, and monocytes may be the major factor in the chronic injury and progression of LN [15]. On the other hand, nephrotic proteinuria also induces changes in the tubular cells due to active and excessive resorption of filtered proteins and lipoproteins by the proximal tubules [11]. After a prolonged period of damage, tubular atrophy and interstitial fibrosis characterize the chronic phase of the disease. Active and severe tubulointerstitial injury is most common in severe diffuse proliferative LN. The severity of interstitial inflammation correlated with the degree of renal insufficiency and was an accurate prognostic indicator of progressive deterioration of renal function. Many studies have shown an association between tubulointerstitial damage and a poor renal outcome in LN and in order to avoid progression to end

**24**

**Figure 3.**

*Granular deposits of C1q in tubular basement membrane and peritubular spaces. IF-400x.*

stage renal disease some studies suggest an early intervention before the development of interstitial fibrosis [15–18].

A variety of vascular lesions are encountered in renal biopsies of patients with SLE: uncomplicated vascular immune deposits, noninflammatory necrotizing vasculopathy, true renal vasculitis, thrombotic microangiopathy and arteriosclerosis. The interlobular arteries and arterioles are the most involved vessels [11, 19–21]. Large study with 285 patients with LN found vascular lesion in 79 (27.7%): 9.47% with noninflammatory necrotizing vasculopathy, 8.42% with thrombotic microangiopathy, 7.02% with arteriosclerosis and 2.81% with true vasculitis [20]. Wu *et al* [21] studying 341 patients with LN found 81.8% of vascular injury, including 74.19% of uncomplicated vascular immune deposits, 24.5% of arteriosclerosis, 17.59% of thrombotic microangiopathy, 3.81% of noninflammatory necrotizing vasculopathy and 0.59% of true vasculitis. The inclusion of cases of uncomplicated vascular immune deposits explains the higher incidence of vascular lesions in this study. Uncomplicated vascular immune deposits are the most common lesion and do not significantly affect prognosis. This type of injury shows deposits of immunoglobulins and complement in the small arteries and arterioles, without any inflammatory process and impairment of vascular lumen. The noninflammatory necrotizing vasculopathy determines severe vascular narrowing by abundant eosinophilic material constituted by immune deposits, plasma proteins and fibrin insudation in the vessel wall. There are also degenerative changes and loss of endothelial cells and myocytes. This is a form of vascular lesion associated to more severe forms of glomerular lesion, and is less common than uncomplicated vascular immune deposits. The necrotizing vasculopathy has a poor prognosis with a high degree of disease progression. A true renal vasculitis, with inflammatory infiltrate and necrosis of the vascular wall, is the least common vascular lesion in the LN. This kind of lesion is very severe with an ominous prognosis and need an aggressive immunosuppressive therapy. The thrombotic microangiopathy is characterized by myointimal proliferation of the small vessels, with a pattern of "onion skin", that complicates with thrombosis. In patients with SLE this vascular lesion occurs in association with hemolytic-uremic syndrome, antiphospholipid syndrome and malignant hypertension. Arteriosclerosis is a degenerative non-immunological vascular lesion characterized by fibrous thickening of the intima of the arteries without necrosis, proliferation or thrombosis. This lesion is common in LN due to the high prevalence of risk factors for arteriosclerosis in lupus patients such as hypertension, hyperlipidemia and prolonged use of corticosteroids. Vascular lesion can occur in any type of glomerular injury, but they are more frequent in the more active glomerulitis with mesangial and glomerular capillaries involvement [11, 19, 21]. Renal vascular lesions, specially of the necrotizing, vasculitic or thrombotic type adversely affects renal outcome with a higher rate of progression to renal failure [11, 19–21]. At the time of renal biopsy, patients with vascular lesion had higher levels of serum creatinine than patients without vascular lesion (2.2 mg/dl vs. 1.2 mg/dl). The probability of a kidney survival at 5 and 10 years was 74.3% and 58.0% in patients with vascular lesion, compared with 89.6% and 85.9% in patients without vascular lesion, respectively [20].
