Membranoproliferative Glomerulonephritis Treatment & Management

Membranoproliferative glomerulonephritis (MPGN) is a rare glomerulonephritis with a protracted natural history, which makes studies on treatment logistically difficult to conduct. No serologic markers are available to assess disease activity. Most studies are confined to MPGN type I and have a relatively short-term follow-up period; furthermore, hepatitis C virus (HCV) is now known to be an important cause of many cases that were previously thought to be idiopathic MPGN, ^{[27, 28, 31, 32, 33, 34]} making older treatment results difficult to interpret.

Only a handful of randomized controlled trials have been published with sufficient power to determine the benefits of therapy for MPGN. The use of variable end points (eg, reduction in proteinuria, renal function measured using variable techniques) further confounds the data.

Thus, the optimal treatment of idiopathic MPGN is not clearly defined. Specific therapies should be reserved for patients with MPGN who have one or more of the following indications:

• Proteinuria exceeding 3 g/d
• Active interstitial or glomerular disease (crescents) on biopsy
• Impaired renal function at presentation
• A progressive decline in renal function

Consultations with nephrology, hepatology (if hepatitis virus B– or HCV-associated MPGN), and nutrition specialists may be helpful in managing patients with this rare disease.

General measures

The Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines recommend when the cause of ICGN is determined, the initial approach to treatment should focus on the underlying pathologic process. For most patients with idiopathic ICGN presenting with an eGFR < 30 ml/min per 1.73 m2, treat with supportive care alone. ^[3]

For patients with idiopathic ICGN and proteinuria < 3.5 g/d, the absence of the nephrotic syndrome, and a normal eGFR, supportive therapy with renin-angiotensin system (RAS) inhibition alone is recommended. For patients with a nephrotic syndrome, and normal or near-normal SCr, a limited treatment course of glucocorticoids should be tried. For patients with abnormal kidney function (but without crescentic involvements), active urine sediment, with or without nephrotic-range proteinuria, glucocorticoids and immunosuppressive therapy should be added to supportive care. High-dose glucocorticoids and cyclophosphamide are recommended for rapidly progressive crescentic disease. ^[3]

Moderate-to-severe C3 glomerulonephritis without monoclonal gammopathy should be treated initially with mycophenolate mofetil (MMF) plus glucocorticoids, and if this fails, eculizumab should be considered. ^[3]   

Nondihydropyridine calcium channel blockers such as verapamil and diltiazem may also have antiproteinuric effects.

Diuretics are usually needed to control hypertension and manage edema. Thiazide diuretics suffice for many patients. Loop diuretics are indicated for more refractory edema with renal insufficiency. A combination of diuretics acting at different sites in the tubule may be needed in some patients. Potassium-sparing diuretics may be used concomitantly to prevent hypokalemia. Patients with severe and refractory edema and those with hypovolemia and orthostatic hypotension may respond to salt-free albumin infusions.

Lipids must be controlled according to the National Cholesterol Education Program (NCEP) guidelines, although several nephrologists recommend low-density lipoprotein (LDL) cholesterol levels to be maintained below 70 mg/dL.

Patients should be given the pneumococcal vaccine and yearly influenza vaccine.

Specific measures

Approaches to treatment of idiopathic membranoproliferative glomerulonephritis (MPGN) have included immunosuppression, inhibiting platelet-induced injury with aspirin and dipyridamole, minimizing glomerular fibrin deposition with anticoagulants, and use of steroidal and nonsteroidal anti-inflammatory agents. Anticoagulant and nonsteroidal therapies have been found to have minimal beneficial effects and are associated with severe adverse effects.

Immunosuppression may be indicated for patients with nephrotic syndrome, progressive decline in kidney function, or very active inflammation (crescents) on the biopsy. Patients with normal GFR and non-nephrotic proteinuria should be managed conservatively and followed closely.

Corticosteroids

Children with idiopathic MPGN type I who have nephrotic-range proteinuria, interstitial disease, or renal insufficiency may benefit from corticosteroid therapy. No systemic evaluation of corticosteroid therapy has occurred in adults.

Benefits in children include stabilization of the renal function, slowing of the decline in GFR, and a decrease in proteinuria. These therapies are associated with multiple complications, including hypertension and seizures in children. Because active inflammation is more likely to be present early in the disease, prompt initiation of therapy may provide better outcomes.

In the International Study of Kidney Disease in Children, investigators suggested the outcome of children with MPGN may be improved with long-term use of prednisone. ^[35] Alternate-day prednisone was administered for a mean of 130 months; at the end of the study period, approximately 61% of the treatment group had stable renal function relative to 12% of the control group. ^[35]

The group at Cincinnati has also shown benefit of prolonged alternate-day steroid regimens. ^[36] Renal survival rates improved, and findings on repeat kidney biopsy at 2 years demonstrated an increase in capillaries with open lumina and a decrease in mesangial matrix and cellularity; however, an increase in glomerular sclerosis and tubular atrophy occurred. ^[36] The same group reported that patients with MPGN type III respond poorly to steroids. ^[24] Several other studies also documented the benefit of steroid therapy in types I and II MPGN. ^[37]

Antiplatelet therapy

Antiplatelet therapies benefit adults with MPGN. Probable mechanisms that underlie the therapeutic benefits of aspirin include inhibition of platelet aggregation, mesangial proliferation, and alteration of renal hemodynamics. Dipyridamole may enhance the effects of aspirin.

In one randomized controlled study, the use of antiplatelet agents administered over 1 year reduced the incidence of renal failure at 3-5 years, but the renal survival rate was no different at 10 years. ^[38] In another study of 18 patients with biopsy-proven MPGN (15 type I, 3 type II) and nephrotic syndrome and moderately reduced kidney function, dipyridamole and aspirin caused a significant reduction in proteinuria at 3 years, with no impact on renal function. ^[39] Reduction in proteinuria to a non-nephrotic range was documented in a group of 14 patients treated with this combination for 2 years by Harmakayaet al. ^[40] One small uncontrolled study of MPGN type I in children found improved outcome and attenuated inflammation on biopsy with the administration of a combination of prednisolone and dipyridamole. ^[37]

Cyclophosphamide

Cyclophosphamide therapy is generally recommended for rapidly progressive kidney failure (crescentic glomerulonephritis) in conjunction with intravenous steroids.

In a 10-month study of 19 pediatric and adult patients with MPGN, therapy was induced with pulse methylprednisone and cyclophosphamide and maintained with cyclophosphamide and every-other-day prednisone. Steroids were tapered in the third phase of the study. Lastly, cyclophosphamide was stopped and prednisone gradually withdrawn. Fifteen patients remitted, 3 improved, and 1 progressed. There were 8 relapses in 6 patients: 4 in 3 patients were treated with repeat cycles and remitted completely. Four patients who had relapsed after 4, 8, 11, and 13 years of remission refused retreatment and progressed rapidly to ESRD. ^[41]

A study by Cattran et al found no benefit with a treatment regimen of cyclophosphamide, warfarin, and dipyridamole in MPGN types I and II with a GFR of less than 80 mL/min and/or proteinuria greater than 2 g/day. ^[42]

Mycophenolate mofetil

Data on the use of mycophenolate in MPGN are very limited. An observational study reported that 5 patients with idiopathic MPGN had significant reduction in proteinuria over an 18-month period when they were treated with oral prednisolone and mycophenolate mofetil relative to a control group of 6 patients who did not receive immunosuppression. ^[43] No significant change occurred in serum creatinine or creatinine clearance in the treatment group; however, in the control group, serum creatinine and creatinine clearance deteriorated significantly. ^[43]

Calcineurin inhibitors

A small case series demonstrated that cyclosporine was effective in the treatment of MPGN that had failed alternative treatments. Eighteen patients were treated with cyclosporine plus low-dose prednisone and were followed for an average 108 weeks. Partial or complete remission of proteinuria occurred in 94% of the patients (P< 0.01). Relapse occurred in one (14.2%) of the remitters after discontinuation of the drug. ^[44]

Rituximab

Anecdotal reports have demonstrated the efficacy or rituximab in treating MPGN secondary to chronic lymphocytic leukemia. ^{[45, 46]} Rituximab has also been shown to be effective in patients with MPGN related to a monoclonal gammopathy. ^[47]

In an open label trial with rituximab, six patients with MPGN type I were treated with rituximab 1000 mg on days 1 and 15 and followed for 1 year. Proteinuria fell in all patients, at all time points, after rituximab administration. Renal function did not change. ^[48]

Other treatment options

New treatments on the horizon include eculizumab, an anti-C5 antibody, to decrease C5-mediated glomerular damage. Case reports have supported the use of eculizumab in refractory MPGN secondary to complement dysregulation. In a single-arm trial in 10 patients, eculizumab blunted terminal complement activation in all patients with immune complex–mediated MPGN or C3 glomerulonephritis and nephrotic syndrome, but persistently reduced proteinuria in only a subgroup. ^[49] Other clinical trials are still under way to establish the role of eculizumab in MPGN and C3 glomerulonephritis.

Other potential treatments of MPGN type II include plasma infusion/plasmapheresis and reducing C3NeF (nephritic factor of the amplification loop). Plasma infusion or plasmapheresis with plasma exchange may provide functionally intact factor H in patients with defined pathologic mutation of the factor H gene.

Every patient with membranoproliferative glomerulonephritis (MPGN) must be carefully evaluated for a secondary cause of the disease. An excellent history, histopathologic findings, and serologies may help identify the underlying cause.

Appropriate treatment of infections such as endocarditis or infected ventriculoatrial shunts may induce remissions. Antiviral therapy is indicated for hepatitis B and C. Aggressive immunosuppression and plasmapheresis should be reserved for patients with severe acute MPGN and/or vasculitis with hepatitis C. For patients with lupus and other rheumatologic conditions, offer treatment based on principles of care for those diseases.

Dietary considerations include sodium, protein, and lipid intake.

Dietary sodium needs to be restricted to 3 to 4g/d. These measures, along with the judicious use of diuretics, can be very useful in managing hypertension and edema.

Ensure that patients with normal renal function receive a protein intake of approximately 1 g/kg/d, plus the amount lost in urine. Confirm that the protein is of high biologic value. Higher protein intake does not improve nutrition, because protein catabolism increases proportionally; however, once renal insufficiency develops, recommend moderate protein restriction (eg, 0.65-0.80 g/kg/d, plus urinary losses).

Recommend a low-cholesterol healthy-heart diet to patients, because hyperlipidemia is common with nephrotic proteinuria.

No restriction of activity is recommended, unless the patient has uncontrolled severe hypertension. Note that diuretics are most effective when the patient is supine. In patients with resistant edema, lying down after taking diuretics may increase their efficacy.

Underlying renal diseases, including membranoproliferative glomerulonephritis (MPGN), increase the risk of fetal loss, intrauterine growth restriction, and prematurity. Patients with hypertension, renal insufficiency, and nephrotic syndrome have increased risks for a more unfavorable fetal outcome. Preeclampsia develops in 20-40% of patients with underlying renal disease. The development of preeclampsia increases the risks of fetal wastage.

Patients with MPGN are more likely than those with most other glomerular diseases to develop deterioration of renal function, increasing proteinuria, or worsening of hypertension during pregnancy. The risk for adverse outcomes depends on the patient's severity of hypertension, 24-hour proteinuria, and the level of renal function before pregnancy.

Better fetal outcome is reported in patients with MPGN type II (dense deposit disease) who have normal renal function, as compared with patients with MPGN type I. ^[50]

Close monitoring of the patient by a high-risk obstetrician and a nephrologist is essential during pregnancy.

Patients should be followed at regular intervals. The frequency of visits should be dictated by the level of kidney function, level of proteinuria, and nature of intervention prescribed. Kidney function, proteinuria and clearances, lipid profiles, and serum albumin should be followed during these visits. The urine albumin–to–creatinine ratio may be used as a rough guide to 24-hour urinary albumin excretion. The nutritional status should be assessed using the subjective global assessment (SGA) scale.

Ensure that patients with progressive azotemia receive timely education regarding renal replacement options. ^[51] In addition, recommend that patients have frequent follow-up visits with a dietitian, which are essential to ensuring patient diet compliance.

For patient information, see Chronic Kidney Disease, and Kidney Transplant. Further information is available at the Mayo Clinic's Kidney Transplant Web pages.