**3. Renal amyloidosis**

Renal amyloidosis is often the major cause of death for individuals with AL, AA, and hereditary amyloidosis; untreated, it usually progresses to end-stage renal disease. Understanding how amyloid fibrils form, and how the renal amyloidosis manifests are crucial in determining treatment approaches specific to each type of amyloidosis.

While amyloid can be found anywhere in the kidney, it often predominates in the glomerulus, forming nodules composed of amyloid protein that disrupt glomerular function. Consequently, patients with renal amyloidosis present with the components of nephrotic syndrome: severe proteinuria, hypoalbuminemia, edema, decreased GFR. When the amyloid protein is in the tubulointerstitium or vasculature, the patient will instead demonstrate minimal proteinuria with a decrease in GFR. (Vascular involvement may also come with HTN.) Generally, renal impairment progresses more rapidly with glomerular involvement. Patients mostly present with normal-sized kidneys but amyloidosis can cause enlargement of the kidneys.

Of the three main categories of renal amyloidoses, AL remains the most common, accounting for 81 and 68% of amyloidosis cases in two recent studies from the U.S. and Italy [15, 16]. In 50% of patients with systemic Ig-related amyloidosis, kidney disease presents as the most common manifestation [17].

#### **3.1 Renal AL amyloidosis**

Because AL amyloidosis is commonly associated with an underlying plasma cell dyscrasia, the purpose of treatment is to destroy amyloid-producing plasma cells. Therefore, treating AL amyloidosis is based on anti-myeloma therapy, which must be tailored to each patient's age, comorbidities, extent of organ involvement, and patient's wishes. The standard treatment was repeated cycles of oral melphalan and prednisone with an increase in median survival to 1.5 years [18]; however, this has changed in the past decade. In an 8 year longitudinal study by [19], 25–50% of patients who underwent high-dose intravenous melphalan followed by autologous stem cell transplantation(HDM/SCT to support bone marrow recovery demonstrated

**25**

*Amyloidosis: Systems-Based Therapies*

*DOI: http://dx.doi.org/10.5772/intechopen.85201*

recurrent amyloid related pleural effusions [22].

**3.2 Renal AA amyloidosis**

mediators of cellular toxicity [26].

**3.3 Dialysis and kidney transplantation**

complete hematologic responses. In 2006, Seldin et al. followed 43 patients who received HDM/SCT between 1994 and 1996, and found that median survival rate of 10 years for patients with a complete hematologic response [20]. In 2011, Sanchorawala et al. followed the long-term outcome of 421 patients and reported a long-term survival of up to 20 years [19]. More research is being done on the effectiveness of repeated HDM/SCT treatments, some of them reporting favorable outcomes in patients who did not achieve a complete hematologic response the first time. Despite the success of HDM/SCT, treatment-associated mortality is 12–14% with a higher prevalence in those with cardiac amyloidosis. Because stem cell mobilization requires high doses of growth factors, this can be complicated in patients with nephrotic syndrome or heart failure due to fluid retention. In addition to increased risks for splenic rupture (especially in patients with splenic amyloid), thrombocytopenia, and neutropenia, patients may also be subject to acute renal failure as reported by two different studies [21]. The British Journal of Hematology published guidelines in 2014 for HDM/SCT as first line treatment for selected patients up to 60–75 years of age with eGFR >50 ml/min, low cardiac biomarkers, low level plasma cell infiltration in the bone marrow, and lacking the following contraindications: cardiac amyloidosis, severe autonomic neuropathy, significant GI bleeding due to amyloid, advanced renal failure, age over 7 years, symptomatic

As an alternative to HDM/SCT, a combination of oral melphalan and high dose dexamethasone was shown by Pallidini et al. to have a 33% complete hematologic response in patients who are ineligible for HDM/SCT [23]. In addition to the oral melphalan and dexamethasone, patients can use proteasome inhibitor-based regimens and a bortezomib-alkylator-steroid combination for a rapid response [22].

Because AA amyloidosis is often associated with the production of serum amyloid A (SAA), an acute phase reactant protein from an underlying inflammatory disease, the goal of treatment is to treat the cause. Stopping the inflammatory processes of familial Mediterranean fever (FMF), rheumatoid arthritis (RA), and other causes of AA has been shown by several studies to prevent amyloidosis. For example, colchicine is used to inhibit Familial Mediterranean Fever-associated inflammation, which prevented amyloidosis production [24]. In a 2002 study, Elkyam et al. treated a patient with infliximab for rheumatoid arthritis, whose proteinuria resolved [25]. It is thought that these agents have additional anti-amyloid effects by suppressing cytokine production or by altering expression of specific

A new treatment approach involving fibrillogenic inhibition is currently underway, involving eprosidate, a sulfonated, negatively charged molecule like heparan sulfate. The molecule competitively binds to glycosaminoglycan-binding sites on SAA, and inhibits fibril polymerization and amyloid deposition. In a multicenter, randomized, double-blind, placebo controlled trial, Dember et al. demonstrated that eprodisate slowed the decline of renal function in AA amyloidosis patients [27]. The results from the second Phase III study will help determine whether eprosidate will become one of the new treatment approaches in fighting renal AA amyloidosis [28].

For patients with renal amyloidosis who are in ESRD, dialysis or kidney transplantation is other options. Currently, the literature for dialysis differs for AL amyloidosis patients and AA amyloidosis patients, but the consensus is a poor prognosis

#### *Amyloidosis: Systems-Based Therapies DOI: http://dx.doi.org/10.5772/intechopen.85201*

*Amyloid Diseases*

**2.3 Sexual dysfunction**

**3. Renal amyloidosis**

**3.1 Renal AL amyloidosis**

amyloidosis.

significant associations between geriatric depression and β-amyloid peptide deposits in the insula, hippocampus, and amygdale [12]. Another recent study showed the link between hereditary gelsolin amyloidosis (AGel) and neuropsychiatric changes. The gelsolin mutation is associated with cerebrovascular fragility, and is an autosomal dominant form of systemic amyloidosis. The study found visuoconstructional difficulties in the AGel group in both the block design and drawing tasks. While overall processing speed was similar in both groups, the AGel group produced more errors [13]. The behavioral and psychological symptoms of people with dementia result in greater cognitive and functional impairment, and are associated with greater amyloid deposition in the neurodegenerative process leading to Alzheimer's disease [14].

The pathophysiology of sexual dysfunction in amyloidosis can range from medication side effects (corticosteroids, opioids), to primary hypogonadism (amyloid deposition in the testes), and depression. Determining the etiology of sexual dysfunction is key in selecting the proper treatment. For erectile dysfunction, sildenafil has been shown to be effective. Testosterone replacement may help in cases of hypogonadism, but has not been studied in patients with amyloidosis.

Renal amyloidosis is often the major cause of death for individuals with AL, AA,

While amyloid can be found anywhere in the kidney, it often predominates in the glomerulus, forming nodules composed of amyloid protein that disrupt glomerular function. Consequently, patients with renal amyloidosis present with the components of nephrotic syndrome: severe proteinuria, hypoalbuminemia, edema, decreased GFR. When the amyloid protein is in the tubulointerstitium or vasculature, the patient will instead demonstrate minimal proteinuria with a decrease in GFR. (Vascular involvement may also come with HTN.) Generally, renal impairment progresses more rapidly with glomerular involvement. Patients mostly present with normal-sized kidneys but amyloidosis can cause enlargement of the kidneys. Of the three main categories of renal amyloidoses, AL remains the most common, accounting for 81 and 68% of amyloidosis cases in two recent studies from the U.S. and Italy [15, 16]. In 50% of patients with systemic Ig-related amyloidosis,

Because AL amyloidosis is commonly associated with an underlying plasma cell dyscrasia, the purpose of treatment is to destroy amyloid-producing plasma cells. Therefore, treating AL amyloidosis is based on anti-myeloma therapy, which must be tailored to each patient's age, comorbidities, extent of organ involvement, and patient's wishes. The standard treatment was repeated cycles of oral melphalan and prednisone with an increase in median survival to 1.5 years [18]; however, this has changed in the past decade. In an 8 year longitudinal study by [19], 25–50% of patients who underwent high-dose intravenous melphalan followed by autologous stem cell transplantation(HDM/SCT to support bone marrow recovery demonstrated

and hereditary amyloidosis; untreated, it usually progresses to end-stage renal disease. Understanding how amyloid fibrils form, and how the renal amyloidosis manifests are crucial in determining treatment approaches specific to each type of

kidney disease presents as the most common manifestation [17].

**24**

complete hematologic responses. In 2006, Seldin et al. followed 43 patients who received HDM/SCT between 1994 and 1996, and found that median survival rate of 10 years for patients with a complete hematologic response [20]. In 2011, Sanchorawala et al. followed the long-term outcome of 421 patients and reported a long-term survival of up to 20 years [19]. More research is being done on the effectiveness of repeated HDM/SCT treatments, some of them reporting favorable outcomes in patients who did not achieve a complete hematologic response the first time.

Despite the success of HDM/SCT, treatment-associated mortality is 12–14% with a higher prevalence in those with cardiac amyloidosis. Because stem cell mobilization requires high doses of growth factors, this can be complicated in patients with nephrotic syndrome or heart failure due to fluid retention. In addition to increased risks for splenic rupture (especially in patients with splenic amyloid), thrombocytopenia, and neutropenia, patients may also be subject to acute renal failure as reported by two different studies [21]. The British Journal of Hematology published guidelines in 2014 for HDM/SCT as first line treatment for selected patients up to 60–75 years of age with eGFR >50 ml/min, low cardiac biomarkers, low level plasma cell infiltration in the bone marrow, and lacking the following contraindications: cardiac amyloidosis, severe autonomic neuropathy, significant GI bleeding due to amyloid, advanced renal failure, age over 7 years, symptomatic recurrent amyloid related pleural effusions [22].

As an alternative to HDM/SCT, a combination of oral melphalan and high dose dexamethasone was shown by Pallidini et al. to have a 33% complete hematologic response in patients who are ineligible for HDM/SCT [23]. In addition to the oral melphalan and dexamethasone, patients can use proteasome inhibitor-based regimens and a bortezomib-alkylator-steroid combination for a rapid response [22].

#### **3.2 Renal AA amyloidosis**

Because AA amyloidosis is often associated with the production of serum amyloid A (SAA), an acute phase reactant protein from an underlying inflammatory disease, the goal of treatment is to treat the cause. Stopping the inflammatory processes of familial Mediterranean fever (FMF), rheumatoid arthritis (RA), and other causes of AA has been shown by several studies to prevent amyloidosis. For example, colchicine is used to inhibit Familial Mediterranean Fever-associated inflammation, which prevented amyloidosis production [24]. In a 2002 study, Elkyam et al. treated a patient with infliximab for rheumatoid arthritis, whose proteinuria resolved [25]. It is thought that these agents have additional anti-amyloid effects by suppressing cytokine production or by altering expression of specific mediators of cellular toxicity [26].

A new treatment approach involving fibrillogenic inhibition is currently underway, involving eprosidate, a sulfonated, negatively charged molecule like heparan sulfate. The molecule competitively binds to glycosaminoglycan-binding sites on SAA, and inhibits fibril polymerization and amyloid deposition. In a multicenter, randomized, double-blind, placebo controlled trial, Dember et al. demonstrated that eprodisate slowed the decline of renal function in AA amyloidosis patients [27]. The results from the second Phase III study will help determine whether eprosidate will become one of the new treatment approaches in fighting renal AA amyloidosis [28].

#### **3.3 Dialysis and kidney transplantation**

For patients with renal amyloidosis who are in ESRD, dialysis or kidney transplantation is other options. Currently, the literature for dialysis differs for AL amyloidosis patients and AA amyloidosis patients, but the consensus is a poor prognosis for AL amyloidosis patients on dialysis, especially those with cardiac involvement. For AA amyloidosis patients on dialysis, Guillaume et al. reported a 15% mortality rate, a better prognosis overall [29]. Treating patients who are on dialysis with HDM/SCT has shown no difference between the hematologic response rate and treatment -associated mortality are similar in dialysis-dependent patients compared with the overall population of patients who undergo this treatment [27].

Kidney transplantation is a good option for patients who have a complete hematologic response in AL amyloidosis and do not have significant extrarenal disease. In 2012, Gurusu et al. examined survival rates of 44 patients with amyloidosis who had undergone kidney transplantation and found the same outcomes with patients with other kidney diseases [30]. This indicates that amyloidosis patients should be accepted as transplant candidates.
