Membranous Glomerulonephritis Medication

Updated: Oct 09, 2019
  • Author: Abeera Mansur, MD; Chief Editor: Vecihi Batuman, MD, FASN  more...
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Medication

Medication Summary

Corticosteroids alone are ineffective in the treatment of membranous nephropathy. Alternating months of corticosteroid therapy and oral cytotoxic therapy with cyclophosphamide or chlorambucil has shown efficacy, but should be reserved for patients who exhibit clinical features such as severe or prolonged nephrosis, renal insufficiency, infections, thromboembolic events, or hypertension.

Alternating monthly treatment with a combination of chlorambucil and steroids for 6 months has been tried with some success, especially in patients with a creatinine level of less than 1.7 mg/dL. A 20-year follow-up of such cases showed complete remission in 9 of 15 patients and partial remission in 4 of 15 patients; 2 of 15 patients did not respond. The 10-year survival rate of the treated patients was 100%, whereas that of the untreated patients was 40%. [15]

Cyclophosphamide may be safer than chlorambucil in this setting, although data on this comparison are limited. [16] The Kidney Disease Improving Global Outcomes (KDIGO) guidelines suggest using cyclophosphamide rather than chlorambucil for initial therapy. As with chlorambucil, cyclophosphamide is given in alternating months with corticosteroids over 6 months, with adjustment of the cyclophosphamide dose according to the patient's age and estimated glomerular filtration rate. The goals are to achieve both total remission and preservation of renal function. [17]

Cyclical corticosteroid/alkylating agent therapy for idiopathic membranous nephropathy (IMN) (the Ponticelli regimen) is as follows:

  • Month 1: IV methylprednisolone (1 g) daily for 3 doses, then oral methylprednisolone (0.5 mg/kg/d) for 27 days
  • Month 2: Oral chlorambucil (0.15–0.2 mg/kg/d) or oral cyclophosphamide (2 mg/kg/d) for 30 days
  • Month 3: Repeat month 1
  • Month 4: Repeat month 2
  • Month 5: Repeat month 1
  • Month 6: Repeat month 2

Monitor every 2 weeks for 2 months, then every month for 6 months, with serum creatinine, urinary protein excretion, serum albumin, and white blood cell count. If the total leukocyte count falls to less than 3500/µL, hold chlorambucil or cyclophosphamide until recovery to 44000/µL.

KDIGO guidelines suggest conservative management for at least 6 months following the completion of this regimen before labelling the case as a treatment failure. [17]

Mycophenolate mofetil has been used with some success. A comparison of mycophenolate mofetil with cyclophosphamide showed decreased proteinuria and improved renal function in most patients, but mycophenolate mofetil did not appear as effective as or better tolerated than cyclophosphamide. [18] Although not recommended as initial therapy, it can be used in those patients who wish to avoid the toxicity of alkylating agents and for whom there is concern about the renal toxicity of calcineurin inhibitors.

Cyclosporine is indicated in those patients in whom the above cannot be used or in patients with a high risk of progression. In controlled trials, calcineurin inhibitors (CNIs), cyclosporine, and tacrolimus have also yielded increased remission rates of nephrotic syndrome and improved renal survival. These drugs can be used for at least 6 months in patients who meet the criteria for initial therapy but who choose not to or have contraindications to cyclical corticosteroid/alkylating agent regimen.

CNIs should be discontinued in patients who do not achieve complete or partial remission after 6 months of treatment. The dosage should be reduced at intervals of 4-8 weeks to a level of about 50% of the starting dosage once remission is maintained and continued for at least 12 months. Regimens are as follows:

  • Cyclosporine: 3.5–5.0 mg/kg/d given orally in 2 equally divided doses 12 hours apart, with prednisone 0.15 mg/kg/d, for 6 months

  • Tacrolimus: 0.05–0.075 mg/kg/d given orally in 2 divided doses 12 hours apart, without prednisone, for 6–12 months; levels should be monitored

It has been suggested that patients with IMN resistant to alkylating agent/steroid–based initial therapy be treated with a CNI and that patients with IMN resistant to CNI-based initial therapy be treated with an alkylating agent/steroid–based therapy. Relapses of nephrotic syndrome in IMN should be treated by reinstitution of the same therapy that resulted in the initial remission and should be repeated only once if a 6-month cyclical corticosteroid/alkylating agent regimen was used for initial therapy.

Despite these multiple therapeutic options, some patients with compelling indications for therapy fail to respond and need alternative therapy. Rituximab (a monoclonal antibody against CD20 antigen of B lymphocytes) and corticotropin have both been used in this situation, in the hope of improving the outcome of IMN and avoiding the adverse effects of steroids and immunosuppressants. [19]

Titration of rituximab to circulating CD20 B cell counts may improve safety by avoiding hypersensitivity; it also may limit the costs of treatment while achieving similar results. [20] However, it has not been possible to precisely predict which patients will respond to rituximab. [21] In a 2012 study, monthly rituximab was used in 100 patients, with varying results. In patients with long-standing membranous nephropathy resistant to immunosuppressants, rituximab did not produce sustained complete or partial remission. Thus, treating resistant membranous nephropathy may continue to be challenging. Using rituximab as first-line therapy may not be cost effective and may expose the patient to the risk of potential adverse effects. [22]

Some rituximab-treated patients show complete or partial remission of proteinuria and reduced levels of phospholipase A(2) receptor autoantibodies. In successful cases, rituximab therapy induces prolonged remission and enables discontinuation of other medications without substantially increasing the risk of infections and other serious adverse events. [23]

In the Membranous Nephropathy Trial of Rituximab (MENTOR) study, rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months. [24] In MENTOR,130 patients with proteinuria of more than 5 g, creatinine clearance of more than 40 ml/min, and renin-angiotensin system (RAS) blocker use for at least 3 months were randomized to rituximab or cyclosporine. At 12 months, rates of complete or partial remission were 60% in the rituximab group, compared with 52% in the cyclosporine group. The difference became more pronounced at 24 months, with 60% of patients treated with rituximab reaching the primary composite endpoint compared with 20% of those who received cyclosporine.

Corticotropin requires further study, as its mechanism of action remains unclear. It has some place in the treatment of those patients that have severe and resistant membranous nephropathy. [25]

In secondary membranous nephropathy associated with hepatitis B, in addition to int erferon, lamivudine monotherapy may induce and maintain complete remission. [26]

In patients with IMN, histology findings including interstitial fibrosis, tubular atrophy, and vascular sclerosis have been associated with the risk of renal failure, but it remains uncertain whether they are independent of the clinical variables at the time of biopsy, predict rate of progression, or should guide therapy. Although these histologic features were associated with a reduced renal survival rate, they did not predict this outcome independently of the baseline clinical variables, nor did they correlate with the rate of decline in function. [27]

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Diuretics

Class Summary

Used to control volume overload.

Furosemide (Lasix)

Has a potent diuretic effect because it blocks sodium reabsorption in the thick ascending loop of Henle.

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Hepatic 3-methylglutaryl coenzyme A reductase inhibitors

Class Summary

Decrease the increased cholesterol associated with nephrotic syndrome.

Simvastatin (Zocor)

Decreases intracellular cholesterol pools and increases LDL receptors, which causes a decrease in LDL-C.

Atorvastatin (Lipitor)

Inhibits 3-hydroxy-3-methylglutaryl coenzyme A, which, in turn, inhibits cholesterol synthesis and increases cholesterol metabolism.

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Corticosteroids

Class Summary

Induce remission of proteinuria.

Prednisone (Deltasone, Meticorten, Orasone, Sterapred)

Exerts an anti-inflammatory effect via the inhibition of inflammatory mediator gene transcription.

Methylprednisolone (Adlone, Medrol, Solu-Medrol)

Exerts an anti-inflammatory effect via inhibition of inflammatory mediator gene transcription.

Cyclophosphamide (Cytoxan, Neosar)

Used for remission of nephrotic syndrome. Interferes with normal function of DNA by alkylation and cross-linking the strands of DNA and by possible protein modification.

Chlorambucil (Leukeran)

For remission of proteinuria; given with prednisone (0.5 mg/kg/d) every other month. Steroids are given as 1 g methylprednisolone IV for 3 d. Interferes with DNA replication and RNA transcription by alkylation and cross-linking the strands of DNA

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Immunosuppressant agents

Class Summary

For remission of nephrotic syndrome.

Cyclosporine A (Sandimmune)

Inhibits production and release of IL-2, leading to inhibition of IL-2–mediated activation of T lymphocytes.

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Angiotensin-converting enzyme inhibitors

Class Summary

Control blood pressure and proteinuria.

Lisinopril (Zestril, Prinivil)

Inhibition of ACE leads to decreased plasma angiotensin II, which, in turn, leads to decreased vasopressor activity and decreased aldosterone secretion. ACE inhibitors minimize secondary intraglomerular hypertension and hypertrophy, leading to decreased proteinuria in idiopathic membranous nephropathy.

Enalapril (Vasotec)

Competitive inhibitor of ACE. Reduces angiotensin II levels, decreasing aldosterone secretion.

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Nonsteroidal anti-inflammatory drugs

Class Summary

Used to decrease proteinuria.

Ibuprofen (Motrin, Ibuprin)

Exerts its effects by inhibiting both constitutive and inducible isoforms of cyclooxygenase, which produces a mild-to-moderate anti-inflammatory and analgesic effect. NSAIDs decrease intraglomerular pressure and decrease proteinuria.

Naproxen (Anaprox, Naprelan, Naprosyn)

For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which is responsible for prostaglandin synthesis.

Ketoprofen (Actron, Orudis, Oruvail)

For relief of mild to moderate pain and inflammation.

Small doses are initially indicated in small and elderly patients and in those with renal or liver disease. Doses >75 mg do not increase therapeutic effects. Administer high doses with caution and closely observe patient for response.

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