Mycophenolate Mofetil in Primary Glomerular Diseases
The treatment of primary glomerular diseases is highly variable and is often complicated due to drug resistance, relapses and drug toxicity. Various immunosuppressive drugs have been tried, but there is as yet no superiority of any single drug. Mycophenolate mofetil is a relatively new drug which has shown some superiority in renal transplantation and lupus nephritis. It has an advantage of relatively less side effects with no nephrotoxicity. This article reviews the recent literature on the effect of this drug in managing primary glomerular diseases.
Glomerular diseases are of importance as they can not only have a protracted course but also are an important cause of end stage renal disease. The common primary glomerular diseases include minimal change glomerular disease(MCD), focal segmental glomerulosclerosis (FSGS), mesangioproliferative glomerulonephritis like IgA nephropathy(IgAN), membranous nephropathy(MN) and membranoproliferative glomerulonephritis(MPGN).
The pathogenesis of glomerular diseases is highly variable and often multifactorial with different mechanisms being postulated for various glomerular diseases. This can account for the lack of uniform treatment protocol for glomerular diseases. Treatment is thus highly variable with various immunosuppressive drugs used in varying combinations. Treatment is also hampered by the fact that resistance and relapses are common and drug toxicity often limits treatment options. This may explain why there is seldom a fixed treatment schedule for glomerular diseases and the entry of newer drugs with novel combinations.
Mycophenolate mofetil(MMF) is a relatively recent but widely used agent in renal transplantation and has immunosuppressive and antiproliferative actions.1 Purines can be synthesized by the de novo pathway and the salvage pathway. Proliferating lymphocytes are more dependent on the de novo pathway. Mycophenolic acid, the active metabolite of MMF reversibly and non-competitively inhibits inosine monophosphate dehydrogenase which is the rate limiting step in the de novo pathway of purine synthesis.2 Thus MMF preferentially inhibits lymphocyte production.3 It also inhibits antibody production by B lymphocytes4 and can block the glycosylation of adhesion molecules.5 As adhesion molecules are involved in the interaction between antigen presenting cells, lymphocytes and target cells, the immune response can be blunted. An antiproliferative effect on vascular smooth muscle cells and inhibition of intimal hypertrophy, smooth muscle hyperplasia and fibrosis are also described.6 As fibrosis, vascular lesions and microthrombi can occur in glomerular diseases, MMF may have benefits. Since in early glomerular disease inflammation is predominant while fibrosis occurs in later stages, MMF can show benefit in both early and late stages of glomerular diseases.
A proper understanding of the various pathogenetic mechanisms of the different primary glomerulopathies can throw light on the basis of medication choice in these diseases and whether MMF could have a role in their management.
1. Primary Nephrotic Syndrome in Children
The majority of childhood nephrotic syndrome (NS) is due to minimal change disease(MCD) and over 80% are steroid sensitive. A few cases are due to FSGS, mesangioproliferative glomerulonephritis and rarely MPGN. The majority of the steroid resistant nephrotics in childhood may have histology other than MCD.
The precise pathogenesis of MCD is unclear, but there is evidence of primary disorder of T cell function.7 This is supported by the fact that measles, which can suppress cell mediated immunity can induce a remission of nephrotic syndrome, occurrence with lymphomas and therapeutic response to steroids and cyclosporine (CsA). A role for a permeability factor probably produced by T cells is also implicated. A disorder of immune regulation involving T cells is also postulated.8 Antigen presentation to T lymphocytes can result in two types of immune response. Type 1 response is dominated by γ interferon and interleukin (IL) 2 while type 2 with IL 4, IL10,and IL13. Type 1 response is mainly seen with cell mediated immunity while Type 2 with humoral immunity. Type 2 is also involved in class switching of B cells to produce IgG 4 and IgE . The increased production of IgE in MCD suggests that there is mainly a Type 2 cytokine response. The association of nephrotic syndrome with atopy also favours this, as atopy is also associated with a Type 2 response. A defect in podocyte function has been described to explain steroid resistant and congenital nephrotic syndrome. 9 There is a possibility that immunotherapeutic agents may have direct action on podocytes.8
It is thus reasonable to assume that immunomodulatory medication would be useful in childhood nephrotic syndrome. In fact, more than 80% promptly respond to corticosteroids. However, tendency to relapse is common. Those who have more than 3 relapses per year (frequent relapsers) or those who are steroid dependent may need alternative agents. This may also need to be considered if steroid side effects occur. Addition of other agents can have a steroid sparing effect, and this is all the more important in children to prevent growth retardation. The preferred alternative drugs include cyclophosphamide, cyclosporine and levamisole.
MMF, though not a first line drug in this condition can be considered in those who i) fail to respond to the above drugs, ii) relapse while on the above drugs or iii)do not tolerate the above drugs.
Nineteen patients with steroid dependence and a mean age of 99.1 months who had received cyclophosphamide and levamisole earlier were given MMF in a mean dose of 29mg/kg/day in 2 divided doses with tapering dose of alternate day steroids. The mean relapse rate decreased from 6.6 to 2 episodes per year(p<0.0001). A significant reduction in prednisolone dose could be achieved. However 68.4% had recurrence of steroid dependence or frequent relapses after stopping the drug.10
MMF has also been tried in childhood steroid resistant cases along with ACE inhibitors with beneficial effects.11 In another study of 6 patients with childhood MCD who had features of cyclosporine(CsA) toxicity, MMF was found to be useful in producing prolonged remission with improvement in glomerular filtration rate.12 It appeared that MMF was more successful than CsA in this study. Similar observations were seen in a single centre study of 10 patients who were successfully shifted from CsA to MMF13 and in another study of 9 children with steroid dependence or steroid resistance where CsA nephrotoxicity was successfully tackled by switching to MMF without an increase in proteinuria.14 In another study of 12 children with steroid dependent nephrotic syndrome, 75% could be successfully weaned off CsA with a reduction in relapse rate.15
Though there are no firm guidelines on the duration of MMF therapy, six months to one year therapy has been tried. The danger of prolonged immunosuppression has to be considered if the duration exceeds one year, though the risk of nephrotoxicity is lesser than with CsA. If no response is seen by 4-6 months, further therapy may not be useful.11 Withdrawal can result in an immediate relapse in as many as 47% in a group of 26 children with steroid and CsA dependent or resistant nephrotic syndrome.16
2. Primary Nephrotic Syndrome in Adults
Unlike children, FSGS is the major cause of primary NS in adults and accounts for around 35% of nephrotics and is closely followed by membranous nephropathy(33%). MCD accounts for around 15% while the rest is mainly due to IgAN and MPGN.
a. Focal Segmental Glomerulosclerosis
There are five histological variants of this pattern which include collapsing variant, tip lesion, cellular variant and perihilar variant. It is the "not otherwise specified FSGS" which is the "classic FSGS". The pathogenesis of FSGS is unclear. An undefined circulating factor resembling lymphokines or cytokines is postulated. This can cause podocyte damage, alter glomerular permeability and cause sclerosis.17 The presence of a circulating factor can explain the immediate proteinuria following recurrence of FSGS following transplantation. It is believed that the final pathway lies in defects of the podocyte. Loss of podocytes lead to formation of tuft adhesions to the Bowman's capsule followed by misdirected filtration to the interstitium instead of the Bowmans space eventually resulting in damage to the nephron.
Adult FSGS seldom have spontaneous remissions and steroids alone are rarely effective with a failure rate of 30-65% .18 Attainment of remission and prevention of progression often requires the addition of cytotoxic drugs. Cyclophosphamide, cyclosporine A and tacrolimus have also been tried. It is postulated that besides the immunosuppressant action, there could be stabilization of the podocyte cytoskeleton, activation of podocyte antioxidant enzymes or antagonisation of permeability factors.19 Mycophenolate mofetil has been tried in FSGS with a view of decreasing steroid toxicity or in steroid dependent or frequent relapsers as well as in limiting the drawbacks of nephrotoxicity and hypertension with CsA. In a study of 18 adults with either steroid dependent or resistant FSGS,MMF when given along with steroids for a period of 4-22 months, produced complete remission in two and partial remission in six with a 48% reduction in proteinuria. 20 However, in a multicentre study of 18 steroid resistant FSGS, MMF given in a dose of 1.75gm/day for 6 months could not achieve initial complete remission in any patient though partial remission was seen in six. However relapses were common on discontinuing treatment though the drug was well tolerated.21 In two cases of steroid resistant FSGS, MMF could produce remission in one patient started early while the other who received MMF late in the course could not prevent progression.22 Thus though MMF may be effective in some who are resistant to other therapies and those at risk of CsA nephrotoxicity, more controlled randomized trials with or without steroids are needed to clarify its role in adult FSGS.
b. Minimal Change Nephropathy
Though most patients respond to corticosteroids, MMF can have a major steroid sparing effect with complete withdrawal possible in 5 out of 6 steroid dependent patients.20 When used in doses of 0.75 to 1gm twice a day either as monotherapy or in combination with steroids, MMF was effective in substantially reducing proteinuria and stabilizing serum creatinine. It has also been found to be useful in steroid dependent cases which have not responded to cyclophosphamide.23 Successful monotherapy with one year of MMF in a large cohort of 98 patients who were resistant to conventional therapy has also been reported with 54% achieving either partial or complete remission.24
c. IgA Nephropathy
IgAN is the most common form of primary glomerulonephritis world wide and is characterized by the predominant deposition of IgA in the glomerular mesangium. The increased deposition may be due to increased production of IgA trigered by infections, increased binding of IgA to certain receptors in the glomerulus or due to defective clearance of circulating IgA. It is believed that defective 'O' glycosylation at the hinge region of IgA can result in decreased clearance. The deposition of immune complexes in the glomerulus may involve involvement of cytokines, T cells and complement which can lead to eventual and progressive glomerular damage.
Therapeutic interventions have aimed at trying to slow the immune and inflammatory events thought to be responsible for progressive renal damage. Trials with corticosteroids and cyclophosphamide have been tried in patients at risk of progression like those with significant proteinuria , hypertension and reduced glomerular filtration rate at the time of diagnosis. Sixty two patients with proteinuria exceeding 2 gms/day were randomised to receive either MMF in a dose of 1-1.5 gm/day or prednisolone 30-40mg/day.Though proteinuria decreased in both, it was more for those on MMF. Serum creatinine levels were also more in those that received steroids. It is however not clear whether immunosuppressive medication has a clear role as use of corticosteroids and cytotoxics have shown benefit in only a few trials.25 In another study involving 24 patients comparing the effect of MMF vs placebo in those with proteinuria exceeding 1 gm / day, MMF showed a greater decrease in proteinuria and better preservation of renal functions.26 Similar results were seen among 3 patients who received MMF for more than a year with significant decrease in proteinuria and histological evidence of failure to progress. Infections with varicella zoster and pneumonia developed in 2 patients.27 Another study randomized forty IgAN patients with persistent proteinuria despite conventional treatment with renin-angiotensin system blockers to receive MMF for 24 weeks or continue conventional therapy, and followed up for 72 weeks. MMF was found to be effective in lowering proteinuria.28
However in a study where 40 patients with a mean creatinine of 2.3mg% were randomized to receive either MMF in a dose of 1gm twice daily or place, both groups did poorly with a high risk of progression.29 This suggests that once s. creatinine exceeds 2mg%, probably a point of no return is reached and immunosuppression may not make a difference. MMF was not found to be of benefit in a 2 year study comparing 33 patients with MMF and placebo.30 It is also noteworthy that MMF failed to prevent recurrence of IgA despite being used early in transplantation.31
d. Membranous Nephropathy
This disease is characterized by the deposits of immune complexes in the subepithelial part of the glomerular basement membrane. Since damage may be mediated by complement, cytokines or inflammatory cells, immunsupressants like prednisolone with cyclophosphamide or cyclosporine have been tried with success.32 Treatment is however recommended only for those who have risk factors for progression like nephrotic range proteinuria, older age and male sex etc. where achieving remission improves the long term survival.32
MMF in a dose of 500mg-1gm/day for a mean of 8 months was tried in 16 patients at high risk of progression who failed to respond to or relapsed following conventional therapy. Eleven of them had a s. creatinine exceeding 1.5mg%. Six had more than 50% reduction in proteinuria while 2 achieved complete remission One had to discontinue MMF due to gastrointestinal symptoms and one developed transient leucopenia.33 In another study involving 17 patients with steroid dependence or steroid resistance who did not respond to cyclosporine or cyclophosphamide, MMF produced a marked decrease in proteinuria, with two attaining complete remmission and 8 partial remission. None had worsening of s. creatinine and most were able to discontinue steroids.20
e. Membranoproliferative Glomerulonephritis
Treatment of MPGN is unsatisfactory and no definite benefit has been shown with conventional immunosuppression. Ten patients with MPGN resistant to steroids were given MMF. Two patients had improvement of renal functions. 34 However the numbers do not justify routine use of MMF in this condition.
MMF was tried in 10 patients with glomerulonephritis who were resistant to conventional treatment. This included 3 patients with MCD, 2FSGS, 2 with membranous nephropathy and 3 with lupus nephritis. MMF was given in a dose of for 6 months to 1 year. It was well tolerated. Five had a complete remission while 5 had partial remission. An improvement in creatinine clearance was also seen following MMF therapy. 35 It has also been successfully used in the pediatric age group in India10,11.
Summary and Conclusions
MMF is a promising drug which has shown superiority in enhancing graft survival following renal transplantation as well as in Class 1V lupus nephritis. Its use in primary glomerular diseases appears attractive as it does not produce growth retardation and thus has advantages over corticosteroids especially in childhood. It has advantages over cyclosporine in that it does not produce nephrotoxicity when used in the long term. It also does not have the risk of gonadal toxicity when compared to cyclophosphamide. Though studies are few, it can be recommended in patients with primary glomerulonephritis who relapse, are resistant to conventional therapy or develop side effects with conventional therapy. Its main disadvantage, especially in a developing country like India is its high cost (around Rupees 100 to 300/day) which makes it impractical for prolonged use. More data on the long term safety are also to be obtained before recommending its routine use.
- The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group: a blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. Transplantation 1996;61:1029-37.
- Sintchak M, Fleming MA, Futer O et al. Structure and mechanisms of inosine monophosphate dehydrogenase in complex with the immunosuppressant mycophenolic acid. Cell 1996;85:921-30.
- Allison AC, Eugui EM. Preferential suppression of lymphocytes proliferation by mycophenolic acid and predicted long term effects of mycophenolate mofetil in transplantation. Transplant Proc 1994;26:3205-10.
- Smith KGC,Isbel NM, Catton MG, Leydon JA Becker GJ, Walker RG. Supression of humoral immune response by mycophenolate mofetil. Nephrol Dial Transplant 1998;13:160-4.
- Allison AC, Kowalski WJ, Muller CJ, Waltes RV, Eugui EM. Mycophenolic acid and brequinar, inhibitors of purine and pyrimidine synthesis, block the glycosylation of adhesion molecules. Transplant Proc 1993;25:67-70.
- Gregory CR, Huang X, Pratt RE et al. Treatment with rapamycin and mycophenolic acid reduces arterial intimal thickening produced by mechanical injury and allows endothelial replacement. Transplantation 1995;59:655-61.
- Shalhoub RJ. Pathogenesis of lipoid nephrosis: a disease of T cell function. Lancet 1974;ii:556-60.
- Mathieson PW. Immune dysregulation in minimal change nephropathy. Nephrol Dial Transplant 2003;18( Suppl6):26-9.
- Antignac C. Molecular basis of steroid resistant nephrotic syndrome. Nefrologia 2005;25(suppl):25-8.
- Bagga A. Hari P, Moudgil A,Jordan SC. Mycophenolate mofetil and prednisolone therapy in children with steroid dependent nephrotic syndrome. Am J Kidney Dis 2003;42:1114-20.
- Moudgil A, Bagga A, Jordan SC. Mycophenolate mofetil therapy in frequently relapsing and steroid resistant nephrotic syndrome in childhood: current status and future directions. Pediatr Nephrol 2005;20:1376-81.
- Gellermann J, Querfeld U. Frequently relapsing nephrotic syndrome treated with mycophenolate mofetil. Pediatr Nephrol 2004;19:101-4.
- Barletta GM, Smoyer WE, Bunchmann JE, Flynn JT, Kershaw DB. Use of mycophenolate mofetil in steroid dependent and steroid resistant nephrotic syndrome. Pediatr Nephrol 2003;18:833-7.
- Ulinski T, Duborg L, Said MH, Parchoux B, Ranchin B, Cochat B. Switch from cyclosporine A to mycophenolate mofetil in nephrotic children. Pediatr Nephrol 2005;20:482-5.
- Fujinaga S, OhtomaY, Umino D, TakemotoM, ShimizuT,YamishiroY, KanekoK. A prospective study on the use of mycophenolate mofetil in children with cyclosporine dependent nephrotic syndrome. Pediatr Nephrol 2007;22:71-6.
- Mendizabal S, Zamora I, Berbel O, Sanahuja MJ, Fuentes J, Simon J. Mycophenolate mofetil in steroid/cyclosporine dependent/ resistant nephrotic syndrome. Pediatr Nephrol 2005;20:914-9.
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- Burgess E. Management of focal segmental glomerulosclerosis: evidence based recommendations. Kidnet Int 1999;70(suppl):s26-s32.
- Sharma R, Savin VJ. Cyclosporine prevents the increase in glomerular albumin permeability caused by serum from patients with focal segmental glomerulosclerosis.Transplantation 1996;61:381.
- Choi MJ, Eustace JA, Gimenez LF et al. Mycophenolate mofetil treatment for primary glomerular diseases. Kidney Int 2002;61:1098-1114.
- Cattran DC, Wang MM, Appel G et al. Mycophenolate mofetil treatment of focal segmental glomerulosclerosis. Clin Nephrol 2004;62:405.
- Tang S, Ho YW, Leung CY, Lai KN. Mycophenolate mofetil in the treatment of steroid resistant primary focal segmental glomerulosclerosis. J Nephrol 2005;18:429-32.
- Pesavento TE, Bay WH,Agarwal G, Hernandez RA, Hebert LA. Mycophenolate therapy in frequently relapsing minimal change disease that has failed cyclophosphamide therapy. Am J Kidney Dis 2004;43:e3-e6.
- Segarra A, Amoedo ML, Martinez Garcia JM, Pons S,Praga M, Garcia EI, Alonso JC, Gasco JM, Pou L, Piera L. Efficacy and safety of 'rescue therapy'with mycophenolate mofetil in resistant primary glomerulonephritis- a multicentre study. Nephrol Dial Transplant 2007;22:1351-60.
- Barratt J, Feehally J. IgA Nephropathy. J Am Soc Nephrol 2005;16:2088-97.
- Tang S, Leung JCK, Tang AWC, et al. for the Hong Kong IgA study Group . A prospective randomized case controlled study of MMF in IgA nephropathy with persistent proteinuria despite angiotensin blockade. [Abstract] J Am Soc Nephrol 2003;14:752A-3A.
- Bergner R, Hoffmann M,Brass H,Uppenkamp M. Therapy of IgA with mycophenolate mofetil . Report of 3 cases. Clin Nephrol 2004;61:207-12.
- Tang S, Leung JC, Chan LY et al. Mycophenolate mofetil alleviates persistent proteinuria in IgA nephropathy. Kidney Int 2005;68:802-12.
- Frish G, Lin J, Rosenstock J et al. Mycophenolate mofetil vs placebo in patients with moderately advanced IgA nephropathy: a double blind, randomized, controlled trial. Nephrol Dial Transpl 2005;20:2139-45.
- Maes BD,Oyen R claes K et al. Mycophenolate mofetil in IgA nephropathy: results of a 3 year placebo controlled randomized study. Kidney Int 2004;65:1842-49.
- Ratanapanichkich P, Barker CV, Cook WJ , Julian BA. Recurent IgA nephropathy despite mycophenolate mofetil immunosuppression. J Am Soc Nephrol 2000;704A (abstract A3705)
- Cattran DC. Membranous nephropathy:quo vadis? Kidney Int 2002;61:349-51.
- Miller G, Zimmermann R,Radhakrishnan J, Appel GB. Use of mycophenolate mofetil in resistant membranous nephropathy. Am J Kidney Dis 2000;36:250-53.
- Sahin GM, Sahin S, Kantarci G, Erqin H. Mycophenolate mofetil for therapy resistant glomerulopathies. Nephrology 2007;12:285-88.
- Saxena S, Virmani S, Singh K, Malhora KK. Mycophenolate mofetil in treatment of nephrotic syndrome. Ind J Nephrol 2004;14:15-17.