Membranous Glomerulonephritis Medication
- Author: Abeera Mansur, MD; Chief Editor: Vecihi Batuman, MD, FASN more...
Corticosteroids alone are ineffective in the treatment of membranous nephropathy. Additionally, cyclophosphamide and chlorambucil 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 these patients 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%. Cyclophosphamide can be used as an alternative.
Within the class of alkylating agents, cyclophosphamide use supports its efficacy, as compared with chlorambucil. Cyclophosphamide had fewer adverse effects leading to patient withdrawal than did chlorambucil.
The Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend for initial therapy alternating months of corticosteroid therapy and oral cytotoxic therapy (cyclophosphamide suggested rather than chlorambucil, with adjustment of dose according to the age and estimated glomerular filtration rate of the patient) over 6 months, attempting to achieve both total remission and preservation of renal function. Cyclical corticosteroid/alkylating agent therapy for idiopathic membranous nephropathy (IMN) (the Ponticelli regimen) includes the following:
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 total leukocyte count falls to less than 3500/µL, hold chlorambucil or cyclophosphamide until recovery to 44000/µL.
They suggest conservative management for at least 6 months following the completion of this regimen before being labelled a treatment failure.
Recently, 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. 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. Calcineurin inhibitors (CNIs), cyclosporine, and tacrolimus have also yeilded increased remissions of the nephrotic syndrome and improved renal survival in controlled trials. 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. See the following:
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 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.
Monoclonal antibodies against the B-cell surface antigen CD20 have been used to explore whether specific inhibition of B cells may help improve the outcome of IMN and may avoid the adverse effects of steroids and immunosuppressants. Promising results have recently been obtained with rituximab, which is able to deplete B lymphocytes.
Titration of rituximab to circulating CD20 B cells may improve safety by avoiding hypersensitivity; it also may limit the costs of treatment while achieving similar results. However, it has not been possible to precisely predict which patients will respond to rituximab. 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 achieve 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.
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. These preliminary results need confirmation in prospective, randomized, controlled studies.
Corticotropin requires further study as the mechanism of action remains unclear. It has some place in the treatment of those patients that have severe and resistant membranous nephropathy.
In secondary membranous nephropathy associated with hepatitis B, in addition to interferon, lamivudine monotherapy may induce and maintain complete remission.
Histology findings of interstitial fibrosis, tubular atrophy, and vascular sclerosis, among other, IMN have been associated with the risk of renal failure, but whether they are independent of the clinical variables at the time of biopsy, predict rate of progression, or should guide therapy is uncertain. 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.
Used to control volume overload.
Has a potent diuretic effect because it blocks sodium reabsorption in the thick ascending loop of Henle.
Hepatic 3-methylglutaryl coenzyme A reductase inhibitors
Decrease the increased cholesterol associated with nephrotic syndrome.
Decreases intracellular cholesterol pools and increases LDL receptors, which causes a decrease in LDL-C.
Inhibits 3-hydroxy-3-methylglutaryl coenzyme A, which, in turn, inhibits cholesterol synthesis and increases cholesterol metabolism.
Induce remission of proteinuria.
Exerts an anti-inflammatory effect via the inhibition of inflammatory mediator gene transcription.
Exerts an anti-inflammatory effect via inhibition of inflammatory mediator gene transcription.
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.
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
For remission of nephrotic syndrome.
Inhibits production and release of IL-2, leading to inhibition of IL-2–mediated activation of T lymphocytes.
Angiotensin-converting enzyme inhibitors
Control blood pressure and proteinuria.
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.
Competitive inhibitor of ACE. Reduces angiotensin II levels, decreasing aldosterone secretion.
Nonsteroidal anti-inflammatory drugs
Used to decrease proteinuria.
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.
For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which is responsible for prostaglandin synthesis.
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.
Ronco P, Debiec H. New insights into the pathogenesis of membranous glomerulonephritis. Curr Opin Nephrol Hypertens. 2006 May. 15(3):258-63. [Medline].
Beck LH Jr, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009 Jul 2. 361(1):11-21. [Medline]. [Full Text].
Debiec H, Lefeu F, Kemper MJ, Niaudet P, Deschênes G, Remuzzi G, et al. Early-childhood membranous nephropathy due to cationic bovine serum albumin. N Engl J Med. 2011 Jun 2. 364(22):2101-10. [Medline].
Chen A, Frank R, Vento S, et al. Idiopathic membranous nephropathy in pediatric patients: presentation, response to therapy, and long-term outcome. BMC Nephrol. 2007 Aug 6. 8:11. [Medline].
El Kossi M, Harmer A, Goodwin J, et al. De novo membranous nephropathy associated with donor-specific alloantibody. Clin Transplant. 2008 Jan-Feb. 22(1):124-7. [Medline].
Lionaki S, Derebail VK, Hogan SL, Barbour S, Lee T, Hladunewich M, et al. Venous thromboembolism in patients with membranous nephropathy. Clin J Am Soc Nephrol. 2012 Jan. 7(1):43-51. [Medline]. [Full Text].
Polenakovic M, Grcevska L, Dzikova S. 20 years after methylprednisolone/chlorambucil treatment in idiopathic membranous nephropathy stage II-III with nephrotic syndrome. Prilozi. 2006 Dec. 27(2):5-12. [Medline].
[Guideline] Kidney Disease Improving Global Outcomes. KDIGO Clinical Practice Guidelines for Glomerulonephritis. Available at http://www.kdigo.org/clinical_practice_guidelines/pdf/KDIGO-GN-Guideline.pdf. Accessed: January 6, 2014.
Branten AJ, du Buf-Vereijken PW, Vervloet M, et al. Mycophenolate mofetil in idiopathic membranous nephropathy: a clinical trial with comparison to a historic control group treated with cyclophosphamide. Am J Kidney Dis. 2007 Aug. 50(2):248-56. [Medline].
Ruggenenti P, Cravedi P, Remuzzi G. Latest treatment strategies for membranous nephropathy. Expert Opin Pharmacother. 2007 Dec. 8(18):3159-71. [Medline].
Cravedi P, Ruggenenti P, Sghirlanzoni MC, et al. Titrating rituximab to circulating B cells to optimize lymphocytolytic therapy in idiopathic membranous nephropathy. Clin J Am Soc Nephrol. 2007 Sep. 2(5):932-7. [Medline].
Fervenza FC, Cosio FG, Erickson SB, et al. Rituximab treatment of idiopathic membranous nephropathy. Kidney Int. 2008 Jan. 73(1):117-25. [Medline].
Sinha A, Bagga A. Rituximab therapy in nephrotic syndrome: implications for patients' management. Nat Rev Nephrol. 2013 Mar. 9(3):154-69. [Medline].
Hogan J, Mohan P, Appel GB. Diagnostic Tests and Treatment Options in Glomerular Disease: 2014 Update. Am J Kidney Dis. 2013 Nov 14. [Medline].
Chuang TW, Hung CH, Huang SC, et al. Complete remission of nephrotic syndrome of hepatitis B virus-associated membranous glomerulopathy after lamivudine monotherapy. J Formos Med Assoc. 2007 Oct. 106(10):869-73. [Medline].
Troyanov S, Roasio L, Pandes M, et al. Renal pathology in idiopathic membranous nephropathy: a new perspective. Kidney Int. 2006 May. 69(9):1641-8. [Medline].
Cameron JS. The nephrotic syndrome and its complications. Am J Kidney Dis. 1987 Sep. 10(3):157-71. [Medline].
Choi MJ, Eustace JA, Gimenez LF, et al. Mycophenolate mofetil treatment for primary glomerular diseases. Kidney Int. 2002 Mar. 61(3):1098-114. [Medline].
Coupes B, Brenchley PE, Short CD, et al. Clinical aspects of C3dg and C5b-9 in human membranous nephropathy. Nephrol Dial Transplant. 1992. 7 Suppl 1:32-4. [Medline].
Cunningham PN, Quigg RJ. Contrasting roles of complement activation and its regulation in membranous nephropathy. J Am Soc Nephrol. 2005 May. 16(5):1214-22. [Medline].
Haas M, Meehan SM, Karrison TG, et al. Changing etiologies of unexplained adult nephrotic syndrome: a comparison of renal biopsy findings from 1976-1979 and 1995-1997. Am J Kidney Dis. 1997 Nov. 30(5):621-31. [Medline].
Hogan SL, Muller KE, Jennette JC, et al. A review of therapeutic studies of idiopathic membranous glomerulopathy. Am J Kidney Dis. 1995 Jun. 25(6):862-75. [Medline].
Honkanen E, Tornroth T, Gronhagen-Riska C. Natural history, clinical course and morphological evolution of membranous nephropathy. Nephrol Dial Transplant. 1992. 7 Suppl 1:35-41. [Medline].
Hunt LP. Statistical aspects of survival in membranous nephropathy. Nephrol Dial Transplant. 1992. 7 Suppl 1:53-9. [Medline].
Kuroki A, Iyoda M, Shibata T, et al. Th2 cytokines increase and stimulate B cells to produce IgG4 in idiopathic membranous nephropathy. Kidney Int. 2005 Jul. 68(1):302-10. [Medline].
Lin CY. Treatment of hepatitis B virus-associated membranous nephropathy with recombinant alpha-interferon. Kidney Int. 1995 Jan. 47(1):225-30. [Medline].
Muirhead N. Management of idiopathic membranous nephropathy: evidence-based recommendations. Kidney Int Suppl. 1999 Jun. 70:S47-55. [Medline].
Nangaku M, Shankland SJ, Couser WG. Cellular response to injury in membranous nephropathy. J Am Soc Nephrol. 2005 May. 16(5):1195-204. [Medline].
Ponticelli C, Zucchelli P, Passerini P, et al. A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney Int. 1995 Nov. 48(5):1600-4. [Medline].
Reichert LJ, Koene RA, Wetzels JF. Prognostic factors in idiopathic membranous nephropathy. Am J Kidney Dis. 1998 Jan. 31(1):1-11. [Medline].
Reichert LJ, Koene RA, Wetzels JF. Urinary excretion of beta 2-microglobulin predicts renal outcome in patients with idiopathic membranous nephropathy. J Am Soc Nephrol. 1995 Dec. 6(6):1666-9. [Medline].
Ruggenenti P, Chiurchiu C, Brusegan V, et al. Rituximab in idiopathic membranous nephropathy: a one-year prospective study. J Am Soc Nephrol. 2003 Jul. 14(7):1851-7. [Medline].
Schieppati A, Perna A, Zamora J, et al. Immunosuppressive treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome. Cochrane Database Syst Rev. 2004 Oct 18. CD004293. [Medline].
Yokoyama H, Yoshimoto K, Wada T. [Membranous nephropathy]. Nippon Rinsho. 2004 Oct. 62(10):1856-60. [Medline].