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,^{[19, 20, 21, 22, 23, 24]} making older treatment results difficult to interpret. Only a handful of randomized control 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 proteinuria exceeding 3 g/d, interstitial disease on biopsy, or impaired renal function.

Treat the underlying cause of secondary forms of MPGN, and administer appropriate antimicrobial therapy for patients with infective endocarditis or infected atrioventricular shunts. For patients with lupus and other rheumatologic conditions, offer treatment based on principles of care for those diseases.

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

Various small reports discuss the benefit of antiviral therapy for patients with hepatitis C virus (HCV)–induced renal disease and cryoglobulinemia. Patients with hepatitis B virus–associated MPGN often go into spontaneous remission but may benefit from antiviral agents.^{[25, 26]} Little role exists for immunosuppression in these patients.

Interferon alfa

In a small trial that randomized patients with HCV-associated type II cryoglobulinemia to interferon alfa-2a or conventional therapy, HCV RNA fell to undetectable levels in 60% of patients in the interferon alfa group.^[27] These patients showed improvement in cutaneous vasculitis, in cryoglobulin titers, and in plasma creatinine concentration. After treatment with interferon alfa-2a was discontinued, viremia and cryoglobulinemia recurred in all 15 HCV RNA–negative patients.^[27] On resumption of treatment, 3 of 4 patients had virologic, clinical, and biochemical responses. In comparison, no clinical or serologic improvement was noted in the patients receiving conventional therapy or in those given interferon alfa in whom there was no fall in HCV RNA in the plasma.^[27]

The appropriate dose and length of interferon alfa-2a therapy have not been established. A short course of a much higher dose of interferon alfa may be effective in patients in whom lower dose therapy fails. Relapses are common after stopping therapy. Furthermore, in some patients, interferon therapy may cause worsening renal function.

Interferon alfa-2a plus ribavirin

Combination therapies for interferon alfa-2a and ribavirin have also been studied in a small number of patients and have shown moderate success. The use of ribavirin in patients with creatinine clearances of less than 50 mL/min is contraindicated. Ribavirin can cause a dose-related hemolysis that can be severe and even life-threatening in patients with renal disease. There are anecdotal reports of patients with moderate renal insufficiency doing well with a proportionate reduction in the ribavirin dose and close monitoring, including measurement of plasma ribavirin levels. The use of ribavirin in patients with decreased glomerular filtration rate (GFR) at the present time cannot be recommended.^[28]

Aggressive immunosuppression and plasmapheresis should be reserved for patients with severe acute membranoproliferative glomerulonephritis (MPGN) and/or vasculitis. The immunosuppression protocols usually include pulse dose methylprednisone (0.5-1 g/d for 3-5 d) followed by 0.5-1.0 mg/kg/d of prednisone and cytotoxic agents (usually oral cyclophosphamide at 2 mg/kg/d) for 8-12 weeks.

Plasmapheresis (exchanges of 3 L of plasma 3-4 times/wk for 2-3 wk) helps remove cryoglobulins and inflammatory mediators. Rituximab, a monoclonal antibody to B cells may be helpful in refractory cases.^[29] There is concern that such intensive therapy may increase virus replication and viremia, but, fortunately, there are no consistent reports of acute liver damage with short-term aggressive therapy. Antiviral therapy, although capable of suppressing viremia and cryoglobulinemia, is more often than not ineffective in controlling inflammation in such patients and can be associated with worsening renal disease.

Patients with membranoproliferative glomerulonephritis (MPGN) receiving liver transplants may go into remission; however, proteinuria reappears with a relapse of hepatitis C in the liver allograft.

In a study of 11 patients with MPGN type I, Arikan et al suggested that patient remission was associated with reductions in mesangial cellularity and tubulointerstitial cell infiltration and with increases in mesangial matrix expansion, as well as with increases in glomerular and tubulointerstitial transforming growth factor (TGF)-beta1 and tenascin expression.^[30] The investigators also found that the mesangial cell proliferation and glomerular tenascin scores were higher in patients who relapsed than in those who were still in remission at the end of the study.^[30] Patients in the study were biopsied after having been in remission for at least 1 year following the cessation of immunosuppressive drugs; by the end of a mean 51.5-month follow-up period, 8 patients had relapsed.

Dietary considerations include sodium, protein, and lipid intake.

Restrict salt intake to 4-6 g/d to help control edema and hypertension. In addition, the judicious use of diuretics is helpful in managing edema. Thiazide diuretics suffice for many patients. Loop diuretics may be 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.

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 retardation, 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 to patients with MPGN type I.^[31]

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

Offer the pneumococcal vaccine and yearly influenza vaccine to all patients, monitor patients for medication adverse effects, and monitor patient nutritional status by using the subjective global assessment (SGA) scale. At regular intervals, evaluate kidney function, proteinuria and clearances, lipid profiles, and serum albumin. The urine protein–to–creatinine ratio may be used as a rough guide to 24-hour urinary protein excretion.

Aggressively control blood pressure in patients with membranoproliferative glomerulonephritis (MPGN). The target blood pressure for adults with proteinuria exceeding 1 g/d is less than 125/75 mm Hg.

Administer angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) to decrease proteinuria and to retard the progression of glomerular disease. No direct evidence suggests that these agents are beneficial in MPGN, although their efficacy is demonstrated in other renal diseases.

Nondihydropyridine calcium channel blockers such as verapamil and diltiazem may also have antiproteinuric effects. Combination therapy with ACEIs and/or ARBs may provide additional benefit.

Prescribe salt restriction and administer diuretics to treat patients with edema.

Control lipids 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.