Glomerular diseases

The nephrotic syndrome is characterized by a urine protein-creatinine ratio above 3.5 mg/mg, hypoalbuminemia, hyperlipidemia, lipiduria, edema, and hypercoagulability.

Minimal change disease is characterized by the sudden onset of proteinuria that may be significant, the effacement or flattening of the podocytes seen on electron microscopy, and normal findings on light and immunofluorescence microscopy.

Daily or alternate-day therapy with prednisone, 60 mg for 4 weeks followed by 40 mg/m2 every other day for 4 weeks, is indicated to initially treat minimal change disease.

The nephritic syndrome is characterized by hematuria, oliguria, hypertension, kidney insufficiency, and proteinuria caused by glomerular inflammation.

Features of the nephrotic and nephritic syndrome often overlap, and kidney biopsy is used to distinguish between these conditions.

Nonnephrotic patients with focal segmental glomerulosclerosis should undergo treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers; those with persistent nephrotic syndrome are also treated with prednisone, cyclosporine, or mycophenolate mofetil.

Membranous nephropathy commonly manifests as the nephrotic syndrome and microscopic hematuria, but some patients may have asymptomatic proteinuria.

In addition to age- and sex-appropriate screening, screening for other malignancies based on the patient’s clinical presentation is warranted in patients with membranous nephropathy.

Common manifestations of fibrillary and immunotactoid glomerulonephritis include kidney dysfunction, proteinuria that may be nephrotic range, microscopic hematuria, and hypertension.

Plasmapheresis, prednisone, cytotoxic agents, NSAIDs, and colchicine have been used to manage fibrillary and immunotactoid glomerulonephritis.

Manifestations of diabetic nephropathy include proteinuria, a decline in kidney function, and hypertension that develops in patients with a 10- to 20-year history of type 1 diabetes or a 5- to 10-year history of type 2 diabetes.

Renin-angiotensin system inhibitors should be used to decrease the blood pressure to below 130/80 mm Hg in all patients with diabetes and to less than 125/75 mm Hg in patients with diabetes who have a urine protein-creatinine ratio above 1 mg/mg.

Patients with kidney amyloidosis typically have severe proteinuria and kidney dysfunction.

HIV-associated nephropathy manifests as the nephrotic syndrome; large, highly echogenic kidneys seen on ultrasonography; kidney insufficiency; and rapid progression to end-stage kidney disease.

Management of HIV-associated nephropathy may include highly active antiretroviral therapy, renin-angiotensin-aldosterone system inhibition, and kidney transplantation.

Lamivudine therapy results in improved kidney outcome in patients with hepatitis B virus infection–induced membranous nephropathy who have a urine protein-creatinine ratio greater than 3mg/mg.

IgA nephropathy may only involve the kidney or occur as part of a syndrome that includes skin or liver disease and other disorders such as inflammatory bowel disease, celiac disease, ankylosing spondylitis, and infections.

Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy is indicated for patients with IgA nephropathy who have normal kidney function, normal blood pressure, and urine protein-creatinine ratio less than 1 mg/mg.

Patients with progressive IgA nephropathy or a urine protein-creatinine ratio above 1 mg/mg should receive pulse corticosteroid therapy or, if kidney insufficiency is present, corticosteroids and an alkylating agent.

Membranoproliferative glomerulonephritis is most often associated with autoimmune diseases such as systemic lupus erythematosus or Sjögren syndrome, infections such as hepatitis C virus or infective endocarditis, or certain malignancies.

Membranoproliferative glomerulonephritis frequently manifests as glomerular hematuria and a low C3 level.

Combination therapy with prednisolone, interferon alfa, and lamivudine is effective in 70% to 100% of patients with hepatitis B virus–associated polyarteritis nodosa.

Poststreptococcal glomerulonephritis initially manifests as sudden-onset edema, hematuria, and kidney insufficiency that develop 2 or 3 weeks after the onset of streptococcal pharyngitis or cellulitis.

Testing for antistreptolysin O and anti-DNAse B antibodies is the most effective method of diagnosing poststreptococcal glomerulonephritis.

In patients with class III or IV lupus nephritis, 6 consecutive months of once-monthly intravenous cyclophosphamide therapy with additional cyclophosphamide therapy administered every 3 months for up to 2 years has been shown to provide long-term improvement in kidney function.

In patients with diffuse proliferative glomerulonephritis, mycophenolate mofetil as induction therapy appears equivalent to intravenous cyclophosphamide and is superior to intravenous cyclophosphamide in maintaining disease remission for up to 48 months.

The pulmonary-kidney presentation of anti–glomerular basement membrane antibody disease is known as Goodpasture syndrome and typically affects young men, whereas older women typically have involvement of only the kidneys.

Corticosteroids and cyclophosphamide are indicated to induce disease remission in patients with anti–glomerular basement antibodies.

Kidney disease in patients with systemic vasculitis frequently manifests as a rapidly progressive glomerulonephritis.

Most patients with polyarteritis and microscopic polyangiitis are ANCA positive; antiproteinase-3 (anti-PR3) antibodies are usually detected in patients with Wegener granulomatosis, whereas antimyeloperoxidase (anti-MPO) antibodies are usually found in those with microscopic polyangiitis.

In patients with severe Wegener granulomatosis, plasma exchange in addition to immunosuppressive therapy has a 24% risk reduction for progression to end-stage kidney disease compared with those who received immunosuppressive therapy alone.

Plasma exchange may delay or eliminate the need for dialysis in patients with microscopic polyangiitis–related kidney disease who have undergone induction therapy and are receiving maintenance therapy.

Thrombotic microangiopathy is a clinical syndrome characterized by multiple organ involvement, thrombocytopenia, and microangiopathic hemolytic anemia.

Empiric plasma exchange therapy is indicated for patients with a clinical presentation compatible with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.

Urinalysis usually reveals dysmorphic erythrocytes, acanthocytes, and erythrocyte casts. Proteinuria, sometimes in the nephrotic range, is usually present, but can be in the normal range.

This condition is usually idiopathic but may develop secondary to use of NSAIDs or lithium. Hodgkin lymphoma and other less-common lymphomas or leukemias; thymoma; and malignancies of the kidney cells, duodenum, and pancreas also may be associated with minimal change disease.

A diagnosis of minimal change disease can be established in patients with effacement or flattening of the podocytes seen on electron microscopy and normal findings on light and immunofluorescence microscopy.

FSGS is a more indolent form of the nephrotic syndrome than minimal change disease. Patients with primary FSGS usually present with microscopic hematuria, hypertension, and kidney insufficiency. Patients with secondary FSGS have minimal edema and rarely have the full spectrum of the nephrotic syndrome, such as nephrotic-range proteinuria.

This condition is caused by immune complex deposition in the glomeruli; mesangial and endothelial cell proliferation; expansion of the mesangial matrix; thickening of the peripheral capillary walls by subendothelial immune and/or intramembranous dense deposits; and mesangial cell interposition into the capillary wall, which causes thickening of the GBM on light microscopy.

Membranous nephropathy is usually idiopathic but may occur secondary to conditions such as hepatitis B or C virus infection, malaria, syphilis, systemic lupus erythematosus, diabetes, and rheumatoid arthritis; use of drugs such as NSAIDs, captopril, and penicillamine; and malignancies of the breast, colon, stomach, kidney, and lung. Obtaining an antinuclear antibody assay to screen for lupus and serologic testing for hepatitis B and C virus infections are useful to exclude these potential secondary causes. In addition to age- and sex-appropriate screening, screening for other malignancies based on the patient’s clinical presentation also is warranted.

Factors such as the baseline serum creatinine level and degree of proteinuria determine the rate of disease progression.

Factors associated with a poor prognosis include male sex, older age, abnormal kidney function, a urine protein-creatinine ratio greater than 6 mg/mg sustained over 6 months, lack of complete remission with treatment, and the presence of tubulointerstitial lesions on kidney biopsy.

• Fibrillary and immunotactoid glomerulonephritis are relatively rare conditions caused by the deposition of randomly arranged fibrils derived from immunoglobulins that accumulate in the glomeruli. These deposited fibrils are larger than those associated with amyloidosis and do not react with Congo red staining or other agents used to diagnose amyloidosis. Fibrillary glomerulonephritis accounts for 85% to 90% of these conditions.
• Fibrillary and immunotactoid glomerulonephritis are usually idiopathic, but immunotactoid glomerulonephritis can occur secondary to lymphocytic leukemia or B-cell lymphomas. This condition also may be associated with hepatitis C virus infection, cryoglobulinemia, and SLE.

The mean age of presentation in patients with fibrillary and immunotactoid glomerulonephritis is 55 to 60 years. Common manifestations of these conditions include kidney dysfunction, proteinuria that is usually in the nephrotic range, microscopic hematuria, and hypertension. Nearly 50% of affected patients progress to ESKD within 10 years of diagnosis. Fibrillary and immunotactoid glomerulonephritis can recur in kidney transplantation recipients.

Screening for microalbuminuria is strongly recommended for all patients with diabetes. The American Diabetes Association 2009 guidelines specifically recommend annual measurement of the urine albumin excretion for patients who have had type 1 diabetes for 5 years or more and for all patients with type 2 diabetes beginning at the time of diagnosis.

Screening for microalbuminuria usually involves obtaining an albumin-creatinine ratio on a first morning void urine sample, a random sample, or a timed urine collection. Microalbuminuria is confirmed when two of three samples obtained within a 6-month period reveal a urine albumin-creatinine ratio between 30 and 300 mg/g.

Affected tissues stained with Congo red should reveal characteristic apple-green birefringence under polarized microscopy

AL amyloidosis is the most common type of systemic amyloidosis in the United States. This condition is a primary disorder associated with deposition of an immunoglobulin light chain or a fragment of a light chain. Heavy chain deposition is rare and is associated with multiple myeloma, plasma cell disorders, and lymphomas. Detection of monoclonal immunoglobulin in serum, blood, or tissues differentiates AL amyloidosis from other forms of amyloidosis.

AA amyloidosis accounts for 45% of cases of systemic amyloidosis worldwide and is more common in developing countries. This condition is caused by deposition of the amyloid A protein that is a fragment of serum amyloid A, which is an acute phase reactant produced by the liver. AA amyloidosis develops secondary to chronic inflammatory states and is associated with numerous disorders as well as injection drug use (Table 23 ). The diagnosis of amyloidosis should be considered in patients with long-standing, chronic inflammatory disease who develop a pattern of multiorgan dysfunction, especially if the kidneys, liver, or bowel is involved.

Familial (AF) amyloidosis is an autosomal-dominant disorder that may be caused by deformities of transthyretin. Disorders of the fibrinogen A alpha chain also can cause hereditary amyloidosis. AF amyloidosis should be considered in patients with signs and symptoms of AL or AA amyloidosis with a clear-cut inheritance pattern.

AL amyloidosis can be treated with chemotherapeutic regimens such as high-dose melphalan and autologous peripheral stem-cell transplantation.

In patients with cast nephropathy, volume expansion, alkalinization of the urine, discontinuation of nephrotoxic agents, and avoidance of radiocontrast agents is important. In addition, treatment of concomitant hypercalcemia is indicated to decrease the risk for intratubular cast formation and progressive kidney failure. Plasmapheresis is no longer recommended in patients with multiple myeloma who have kidney failure.

Biopsy of abdominal fat or rectal or duodenal mucosa is indicated if there is suspicion for systemic amyloidosis.

Control of the underlying infection is usually indicated for patients with AA amyloidosis; eprodisate (low-molecular-weight anionic sulfonate) also appears to slow kidney disease progression in patients with AA amyloidosis but has not yet been approved for clinical use by the U.S. Food and Drug Administration.

Colchicine may be effective for amyloidosis secondary to familial Mediterranean fever.

Liver transplantation is used for patients with ATTR amyloidosis.

Patients with myeloma-related kidney disease may have tubular dysfunction, including acid-base and concentration abnormalities and the Fanconi syndrome. Less than 15% to 25% of those with multiple myeloma have the nephrotic syndrome. Kidney disorders associated with multiple myeloma include acute kidney injury, light chain or AL amyloidosis, monoclonal immunoglobulin deposition, cast nephropathy (also known as myeloma kidney), cryoglobulinemic glomerulonephritis, and proliferative glomerulonephritis. Rarely, treatment with bisphosphonates for skeletal complications of multiple myeloma causes FSGS and acute tubular necrosis.

Urine dipstick does not reveal albuminuria in patients with myeloma-related kidney disorders, but the addition of sulfosalicylic acid to the urine will precipitate all nonalbumin proteins, including light chains. Kidney biopsy is recommended to confirm multiple myeloma in the absence of other tissue diagnoses and to exclude other kidney disorders.

Patients with multiple myeloma and ESKD are as responsive to chemotherapy as other patients, and management of myeloma-related kidney disorders should include systemic chemotherapy and autologous stem-cell transplantation to resolve the underlying disorder.

Melphalan and prednisone should be used in patients who are not eligible for autologous stem-cell transplantation.

In patients with cast nephropathy, volume expansion, alkalinization of the urine, discontinuation of nephrotoxic agents, and avoidance of radiocontrast agents is important. In addition, treatment of concomitant hypercalcemia is indicated to decrease the risk for intratubular cast formation and progressive kidney failure. Plasmapheresis is no longer recommended in patients with multiple myeloma who have kidney failure.

Kidney function is one of the most important determinants of survival in patients with multiple myeloma.

Patients who attain remission with autologous stem-cell transplantation have a median survival of 40 months to 89 months compared with 26 months in those who are unresponsive to this therapy. Approximately 24% of patients with multiple myeloma new to dialysis who have undergone successful autologous stem-cell transplantation regain sufficient kidney function to discontinue dialysis.

- is a disease of the proximal renal tubules of the kidney in which glucose, amino acids, uric acid, phosphate and bicarbonate are passed into the urine, instead of being reabsorbed. Fanconi syndrome affects the proximal tubule, which is the first part of the tubule to process fluid after it is filtered through the glomerulus. It may be inherited, or caused by drugs or heavy metals.

Patients who attain remission with autologous stem-cell transplantation have a median survival of 40 months to 89 months compared with 26 months in those who are unresponsive to this therapy. Approximately 24% of patients with multiple myeloma new to dialysis who have undergone successful autologous stem-cell transplantation regain sufficient kidney function to discontinue dialysis.

HIVAN is characterized by the nephrotic syndrome, kidney insufficiency, and rapid progression to ESKD. Patients with HIVAN usually do not have edema or hypertension due to sodium wasting caused by proximal tubular lesions. On ultrasonography, the kidneys are typically large and highly echogenic. Kidney biopsy in patients with HIVAN may reveal segmental glomerulosclerosis, but tubular cystic lesions are pathognomonic of this condition. The presence of tubular reticular bodies seen on electron microscopy of a biopsy specimen further supports the diagnosis.

Therapies that attempt to slow the progression of HIVAN include antiretroviral therapy and renin-angiotensin-aldosterone system inhibition with ACE inhibitors and ARBs. Limited evidence suggests a possible benefit of high-dose corticosteroids; however, the benefit of these interventions should be weighed against the risks of infection. HAART is typically used in this setting and helps to delay kidney disease progression. Patients with HIV infection also are eligible for kidney transplantation.

Lamivudine therapy results in improved kidney outcome in patients with hepatitis B virus infection–induced membranous nephropathy who have a urine protein-creatinine ratio greater than 3 mg/mg. This therapy helps to decrease proteinuria and stop progression to ESKD independent of blood pressure control. Potential resistance to lamivudine therapy because of YMDD mutations of hepatitis B virus may require use of other, potentially nephrotoxic, agents such as adefovir. Patients with hepatitis B virus infection–induced membranous nephropathy have a worse kidney prognosis than those with idiopathic membranous nephropathy.

IgA nephropathy is caused by defective mucosal immunity in which IgA molecules react to as-yet unidentified antigens. These IgA antibodies are abnormally glycosylated and are therefore not effectively removed by the reticuloendothelial system. Once deposited, these immune complexes incite an inflammatory response that stimulates circulating factors such as platelet-derived growth factor that results in mesangial cell proliferation and mesangial matrix expansion. IgA nephropathy may have a genetic propensity, but most cases are sporadic.

• IgA nephropathy may only involve the kidney or occur as part of a syndrome that includes skin or liver disease as well as other disorders such as inflammatory bowel disease; celiac disease; ankylosing spondylitis; and infections. IgA nephropathy also may develop in patients with Henoch-Schönlein purpura.
• Approximately 30% to 40% of patients with IgA nephropathy present with an episode of macroscopic or gross hematuria that is usually associated with a concomitant pharyngitic or gastrointestinal infection. Complete resolution of hematuria in these patients is usually associated with infrequent disease recurrence, prolonged periods of disease quiescence, and excellent long-term prognosis.Approximately 40% of patients with IgA nephropathy have persistent asymptomatic microscopic hematuria and proteinuria. In this setting, hypertension is much more common, kidney function impairment develops over time, and remission is rare. Some patients with IgA nephropathy present with the nephrotic syndrome caused by either diffuse proliferative glomerulonephritis or, rarely, the presence of a concomitant unrelated glomerulopathy such as minimal change disease.

Conservative management with an ACE inhibitor or an ARB is indicated for patients with IgA nephropathy who have good prognostic indicators such as normal kidney function, normal blood pressure, and a urine protein-creatinine ratio less than 1 mg/mg. Those with more progressive disease who have elevated serum creatinine levels should receive pulse corticosteroid therapy or, if kidney insufficiency is present, corticosteroids and an alkylating agent.

This condition is caused by immune complex deposition in the glomeruli; mesangial and endothelial cell proliferation; expansion of the mesangial matrix; thickening of the peripheral capillary walls by subendothelial immune and/or intramembranous dense deposits; and mesangial cell interposition into the capillary wall, which causes thickening of the GBM on light microscopy.

- most often associated with autoimmune diseases such as SLE or Sjögren syndrome, infections such as hepatitis C virus or poststreptococcal or infective endocarditis, or certain malignancies.

• Membranoproliferative glomerulonephritis frequently manifests as glomerular hematuria, which is suggested by dysmorphic erythrocytes and erythrocyte casts seen on urinalysis.
• Additional findings include a low C3 level with a normal C4 level.

• Idiopathic membranoproliferative glomerulonephritis regardless of type has been treated with corticosteroids and other immunosuppressive agents, antiplatelet agents, anticoagulants, antithrombolytic agents, plasmapheresis, and plasma exchange. The two main treatment approaches have been corticosteroids and antiplatelet agents, but the efficacy of these approaches has not been adequately evaluated.
• Treatment of the underlying disorder is an effective means of managing patients with secondary membranoproliferative disease. When membranoproliferative glomerulonephritis is associated with hepatitis C virus infection, pegylated interferon-alfa 2a and ribavirin therapy may decrease proteinuria and improve kidney function.

• Hepatitis C virus–associated kidney disease most often manifests as membranoproliferative glomerulonephritis and mixed cryoglobulinemia.
• Mesangioproliferative glomerulonephritis also may be associated with cryoglobulinemia in patients with hepatitis C virus infection.
• In the absence of cryoglobulins, patients with hepatitis C virus infection may develop membranous glomerulonephropathy and polyarteritis nodosa that may be associated with hypocomplementemia. Hypertension is present in 25% to 75% of patients with membranoproliferative glomerulonephritis and cryoglobulinemia, and edema is present in most patients. Nephritic sediment is common in these patients, whereas nephrotic-range proteinuria occurs in approximately 20% of patients.
• Rapidly progressive glomerulonephritis develops in 20% of patients with membranoproliferative glomerulonephritis and cryoglobulinemia, but terminal kidney disease is rare. Patients with active hepatitis C virus infection and cardiovascular disease tend to have a poor prognosis.

Treatment of hepatitis C virus infection includes antiviral therapy with interferon alfa or pegylated interferon. The addition of ribavirin to these agents has been shown to improve kidney outcome in patients with membranoproliferative glomerulonephritis associated with hepatitis C virus infection and mixed cryoglobulinemia, but treatment response is decreased in those with advanced kidney failure. In addition, ribavirin-induced hemolytic anemia may develop in patients with poor kidney function and requires treatment with iron and erythropoietin.

- ribavirin-induced hemolytic anemia may develop in patients with poor kidney function and requires treatment with iron and erythropoietin.

Patients with hepatitis B virus infection and polyarteritis nodosa usually demonstrate complement activation. Clinical features include hypertension, variable kidney insufficiency, and occasionally kidney infarction bleeding caused by renal artery microaneurysm rupture. Urinalysis may show hematuria and subnephrotic proteinuria.

• Approximately 50% of patients treated with interferon alfa and plasma exchange experience eradication of hepatitis B virus and resolution of polyarteritis nodosa.
• Combination therapy with prednisolone, interferon alfa, and lamivudine is effective in 70% to 100% of patients with hepatitis B virus–associated polyarteritis nodosa.

Poststreptococcal glomerulonephritis initially manifests as sudden-onset edema, hematuria, and kidney insufficiency that develop 2 or 3 weeks after the onset of streptococcal pharyngitis or cellulitis. Hypertension and acute kidney insufficiency also may develop but rapidly resolve. Diuresis begins within 1 week, and kidney function returns to baseline after 3 or 4 weeks. Most patients, particularly children, achieve complete clinical resolution after an initial episode.

Approximately 70% of patients with poststreptococcal glomerulonephritis have elevated antistreptolysin O antibody titers, and 90% of patients with this condition have anti-DNAse B antibodies. Testing for both of these antibodies is the most effective method of diagnosing poststreptococcal glomerulonephritis.

Therapy is supportive, and these patients usually do not require immunosuppressive therapy.

Kidney biopsy results in patients with World Health Organization (WHO) class I or II lupus nephritis may be normal or reveal minimal mesangial deposits or a mesangioproliferative glomerulonephritis. These patients typically have hematuria and/or proteinuria and usually do not have kidney insufficiency. Class III or IV disease is associated with focal or diffuse nephritis and manifests as acute nephritis with hematuria and proteinuria. Typically, erythrocyte casts are seen on urinalysis. Depending on the number of glomeruli involved, these patients also may have kidney insufficiency. Patients with membranous lupus nephritis (class V) typically have proteinuria that is within the nephrotic range.

• Disease severity should determine treatment in lupus nephritis. Class I and II disease is generally associated with an excellent prognosis, and immunosuppressive therapy in these patients is not indicated unless the disease progresses.
• Six consecutive months of once-monthly intravenous cyclophosphamide therapy with additional cyclophosphamide therapy administered every 3 months for up to 2 years has been shown to provide long-term improvement in kidney function in patients with class III and IV disease. Prednisone alone does not provide equivalent kidney protection over a 10-year period.

Corticosteroids and cyclophosphamide are indicated to induce disease remission in patients with anti-GBM antibody disease. Because relapse rarely occurs, cyclophosphamide may be discontinued after 3 to 6 months. In addition, pulmonary hemorrhage is a medical emergency requiring immediate plasmapheresis to remove the causative antibody.

• Diagnosis of Wegener granulomatosis or microscopic polyangiitis involves antibody assays and kidney biopsy. Most patients are ANCA positive. Antiproteinase-3 (anti-PR3) antibodies are usually detected in patients with Wegener granulomatosis, whereas antimyeloperoxidase (anti-MPO) antibodies are usually found in those with microscopic polyangiitis. Serial ANCA testing should not be used to monitor disease activity or to guide treatment decisions in patients with Wegener granulomatosis.
• To establish a diagnosis of Wegener granulomatosis, microscopic polyangiitis, polyarteritis nodosa, or Churg-Strauss syndrome with kidney involvement, kidney biopsy must reveal the presence of a necrotizing crescentic glomerulonephritis or necrotizing vasculitis of microscopic vessels such as the small arteries, arterioles, capillaries, or venules.

A study performed by the European Vasculitis Study Group showed that patients with severe Wegener granulomatosis who underwent plasma exchange in addition to immunosuppressive therapy with daily cyclophosphamide and high-dose oral methylprednisolone had a 24% risk reduction for progression to ESKD compared with those who received immunosuppressive therapy alone.

• Combination therapy with cyclophosphamide and high-dose corticosteroids results in remission in 75% to 90% of patients with microscopic polyangiitis–related kidney disease at 6 months.
• Indefinite follow-up is recommended for patients with microscopic polyangiitis, with continued ANCA positivity a predictor of relapse. Furthermore, plasma exchange may delay or eliminate the need for dialysis in patients with microscopic polyangiitis–related kidney disease who have undergone induction therapy and are now on maintenance therapy.

More than 80% of patients with Churg-Strauss syndrome or polyarteritis nodosa achieve remission with appropriate therapy. Immunosuppressive therapy benefits these patients. Corticosteroids alone can be used in patients without poor prognostic factors with immunosuppressive agents added in case of treatment failure. However, most patients require combination therapy with corticosteroids and immunosuppressive agents, particularly pulse cyclophosphamide. Adjuvant therapy with plasma exchange also is indicated for patients with severe kidney involvement. Once remission is achieved, maintenance therapy with at least 18 months of azathioprine or methotrexate can replace cyclophosphamide.