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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2005  |  Volume : 16  |  Issue : 1  |  Page : 23-28
Mycophenolate Mofetil (MMF) Efficacy in Glomerulonephritis (GN), a Retrospective Analysis


King Fahad National Guard Hospital, Riyadh, Saudi Arabia

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   Abstract 

Mycophenolate Mofetil MMF has been widely used in post-transplant immunosuppression. Its role is emerging in GN. MMF demonstrated promising results compared with cyclosphosphamide in stage IV lupus nephritis, in a recently published trial. It has been found to have a wide safety profile, with mostly gastroinetestinal side effects, which can be avoided through titration. Its action is through inhibition of the enzyme IMDPH (ionosine monophosphate dehydrogenase), leading to purine antagonism and inhibition of lymphocytes. We were aiming to demonstrate the efficacy of MMF in our GN population. In this study, we reviewed 17 patients who received MMF (dose - 1 gm po bid) for the past year. They were only included if it was given for the management of resistant primary glomerulonephritis. Complete remission has been defined as proteinuria of less than 0.5 g/day and partial remission as a reduction of proteinuria < 50% of starting MMF therapy; all 17 MMF therapy patients uniformly achieved good BP (< 140/80) control. MMF was used for a minimum of 1 year and a maximum of 2 years. The results indicate that 7 patients (41%) had a partial remission to MMF. This group was composed of 2 membranous GN, 2 lupus GN (stage IV and stage V) and two with FSGS (1 with single kidney not biopsied) and one with MPGN. Five of 17 (29%) achieved complete remission and this group consisted of 1 membranous GN, 2 lupus GN (type IV and membranous), one FSGS and one with MPGN. Four of 17 (23%) were non-responders to therapy. This group articles.aspx? id=41 to side effects. We conclude that the MMF appears to be an effective alternate treatment modality in resistant membranous GN, lupus nephritis (type IV and V) and possibly MPGN, and to a lesser extent in resistant FSGS. Further prospective data may demonstrate the efficacy of MMF in GN.

Keywords: Resistant glomerulonephritis, Mycophenolate mofetil.

How to cite this article:
Huraib SO, Qureshi JI, Quadri KH, Al Flaiw A, Al Ghamdi G, Jumani A, Al Hejaili F, Raza H, Al Johani A, Al-Katheri A, Al-Khader AA. Mycophenolate Mofetil (MMF) Efficacy in Glomerulonephritis (GN), a Retrospective Analysis. Saudi J Kidney Dis Transpl 2005;16:23-8

How to cite this URL:
Huraib SO, Qureshi JI, Quadri KH, Al Flaiw A, Al Ghamdi G, Jumani A, Al Hejaili F, Raza H, Al Johani A, Al-Katheri A, Al-Khader AA. Mycophenolate Mofetil (MMF) Efficacy in Glomerulonephritis (GN), a Retrospective Analysis. Saudi J Kidney Dis Transpl [serial online] 2005 [cited 2019 Sep 21];16:23-8. Available from: http://www.sjkdt.org/text.asp?2005/16/1/23/32947

   Introduction Top
Mycophenolate Mofetil (MMF) has been widely used in post-transplant immunosuppression. Its role is emerging in the management of glomerulonephritis (GN). MMF demonstrated promising results compared with cyclophos計hamide in stage IV lupus nephritis, in a recently published trial. [1] It has been found to have a wide safety profile, with predomi要antly gastrointestinal side effects, which can be avoided through dose titration. Its mode of action is through inhibition of the enzyme inosine monophosphate dehydrogenase (IMDPH), leading to purine antagonism and inhibition of activation of lymphocytes. It has also shown to have antiproliferative effects. We were aiming to review the efficacy of MMF in our resistant GN population.

In our clinical practice, we frequently encounter patients with resistant GN. This subset of patients although small, has frequently exhausted all therapeutic options in our armamentarium against GN. In these patients, instead of condemning them to progressive decline and early progression to ESRD, we have attempted to study the efficacy of the immunosuppressant MMF.


   Mode of Action Top


MMF is a prodrug of mycophenotic acid (MPA), an inhibitor of ionisine monopho計hosphate dehydrogenase (IMPDH). This is the rate-limiting enzyme in de novo synthesis of guanosine nucleotides. T- and B-lympho苞ytes are more dependent on this pathway than other cell types.

MPA has a potent cytostatic effect predomi要antly on lymphocytes than other cell types. This mechanism is the principal mechanism by which MPA exerts immunosuppressive effects. [2]

MMF has shown, in the rat model, to signi苯icantly improve glomerular histology. Treat衫ent of nephrotic rats by MMF resulted in less basement membrane deposition and reduction in mesangial expansion. Proteinuria showed a clear tendency towards improvement with therapy. This study showed that mesangial cell proliferation can be inhibited by MPA in vitro and in vivo. [3]

Data from other experimental models of GN, especially in lupus nephritis, have demonstrated ability of MMF to reverse both autoimmune and inflammatory aspects of disease and therefore influence outcome. [4]


   Hypothesis Top


Past research has shown antiproliferative effects of MMF and its active metabolite MPA; [3] we therefore hypothesized that the proliferative changes, seen in various GN in the mesangium as well as glomerular basement membrane (GBM) expansion, could be inhi苑ited by MMF.

Similarly, limiting mesangial expansion through its antiproliferative effects will also serve to preserve the architecture of the glo衫eruli. In the rat model, MMF therapy resulted in significant improvement in glomerular hypertrophy through decreased synthesis of alpha-smooth muscle actin, less extracellular matrix deposition and reduced glomerular cellularity. [5]


   Methods Top


In this retrospective study, we reviewed all patients who received MMF for the past year. They were only included if it was given for the management of resistant GN. The date of the biopsy was recorded as well as the age and sex of the patients. Other medications, especially antiproteinuric, antihypertensive or other immunomodulating agents were recorded. The 24-hour urinary protein and creatinine were recorded. Blood pressure was also docu--mented to ensure adequate (<140/80 mm Hg) control. The type of GN was also recorded through a renal biopsy (except one; single kidney). The serum At the beginning of therapy and at the date of last review.

The patients were started on MMF therapy after being off other chemotherapeutic agents (except prednisone) for at least three months. If proteinuria persisted, was ≥ 1 gm/24 hrs, with or without nephrotic syndrome, or worsening renal insufficiency, therapy with MMF was begun. Therapy was initiated with a dose of 500 mg po BID and titrated upwards to a maximum of 1 gm po BID. Therapy was generally well tolerated. Prednisone therapy was decreased gradually to < 10 mg, if at all employed. The patients were followed-up every 2-3 months in the out-patient clinic with a complete blood count, serum chemistry, serum creatinine and blood urea nitrogen, liver function tests and 24-hour urine for protein and creatinine (to determine accuracy of the specimen).


   Definitions Top


Complete remission (CR) was defined as a normalization of the serum albumin along with a drop of the 24 hour urinary protein < 0.5 g. Partial remission (PR) was defined as

at least a 50% reduction in proteinuria level from the date of start of MMF therapy. MMF, if tolerated, was used for a minimum of one year and a maximum of two years duration.

Resistant GN was defined as failure to achieve or maintain remission on two or more immuno貞uppressant agents. Therefore, if patients in the lupus group relapsed after completing prednisone and cyclophosphamide therapy, they were considered candidates for MMF therapy.


   Results Top


The average age of patients was 33 years and average final serum creatinine was 127 pmol/L. Five out of 17 (5/17) patients had a complete remission (CR) on MMF therapy. This group consisted of one membranous GN, two lupus (stage IV and V) patients and one with idiopathic focal and segmental sclerosis (FSGS) and one with membrano proliferative GN (MPGN). Seven out of 17 patients had a partial remission (PR) to MMF therapy. This group consisted of two idiopathic membranous

The average dose in all patients who tole訃ated MMF was 1.8 g/d and average duration of therapy was 15 months. In Complete Res計onders (CR), average dose of MMF was 1.5 gm/d, and average duration of treatment was 17 months. In Partial Responders (PR), the average dose was 2 gm/d and average duration of therapy was 12 months. MMF was tolerated in the majority of patients without significant hematological or gastrointestinal toxicity.

Four out of 17 patients were non-responders whose renal biopsy showed FSGS in three and IgA nephropathy in one. One of the patients did not tolerate MMF due to the side effects of therapy, namely gastrointestinal. The average BP achieved in all patients was 140/80.

[Table - 1] shows the characteristics of the twelve patients who responded to MMF therapy. Serum creatinine remained stable in all twelve patients except one. The diagnosis of all patients is also listed along with the degree of success of therapy.

The use of ACE inhibitor and the dose of prednisone employed (at the end of review) are represented in [Table - 2].

The characteristics of non-responders and one patient who did not tolerate MMF are provided in [Table - 3].

The benefit noted with MMF therapy was apparent even though the ACE inhibitors were used in some patients [Table - 4]. Similary, prednisone therapy was tapered in all 12 patients except one (patient #10, [Table - 5]).


   Discussion Top


Our study is part of an emerging group of studies which demonstrate efficacy of MMF in GN. Briggs, et al has demonstrated a similar benefit of MMF in a cohort of nine GN patients. [6] We have demonstrated a definite benefit in a subset of resistant GN patients. MMF was generally well tolerated.

This study also consolidates the theory whereby MMF is seemingly more effective in immune mediated diseases. Lupus is one such disease entity in which it has already shown great potential.

Data from Hauser, et al, demonstrated that cultured mesangial cells are very sensitive to the antiproliferative effects of MMF and this might explain the excellent results seen in our two patients with MPGN. [7]

Our limited understanding of the etiology behind the majority of GN limits our ability to accurately define the patients in whom MMF therapy would be most beneficial. This sub茆roup of patients needs to be more accurately defined in large, multi-center, placebo controlled, double blinded study.


   Conclusion Top


We conclude from our preliminary data that the use of MMF in resistant GN appears to be effective in type IV lupus, as previously shown. [1] In addition, our results demonstrate its efficacy in membranous GN as well.

An exciting finding was the benefit seen within MPGN, a disease hitherto with limited treatment options. MMF therapy also allowed the use of minimum amounts of prednisone, or none at all. This steroid-sparing effect is a major advantage to patients already on long term steroid therapy. MMF appeared to be predominantly ineffective in FSGS.

We have identified three categories of GN namely lupus nephritis, membranous nephro計athy and perhaps MPGN, in which MMF is probably beneficial.

 
   References Top

1.Chan TM, Li FK, Tang CS, et al. Efficacy of mycophenolate mofetil in patients with diffuse proliterative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. N Eng J Med 2000;19:343(16):1156-62.  Back to cited text no. 1    
2.Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology 2000;47(2-3):85-118.  Back to cited text no. 2    
3.Ziswiler R, Steinmann-Niggli K, Kappeler A, Daniel C, Marti HP. Mycophenolic acid: a new approach to the therapy of experi衫ental mesangial proliferative glomerulo要ephritis. J Am Soc Nephrol 1998;9(11): 2055-66.  Back to cited text no. 3    
4.Jayne DG. Non-transplant uses of myco計henolate mofetil. Curr Opin Nephrol Hypertens 1999;8(5):563-7.  Back to cited text no. 4    
5.Eugui EM, Mirkovich A, Allison AC. Lymphocyte-selective antiproliferative and immunosuppressive effects of mycophenolic acid in mice. Scand J Immunol 1991;33: 175-83.  Back to cited text no. 5  [PUBMED]  
6.Briggs WA, Choi MJ, Scheel PJ Jr. Successful mycophenolate mofetil treat衫ent of glomerular disease. Am J Kidney Dis 1998;31(2):213-7.  Back to cited text no. 6    
7.Hauser IA, Renders L, Radeke HH, Sterzel RB, Goppelt-Struebe M. Mycophenolate mofetil inhibits rat and human mesangial cell proflieration by guanosine depletion. Nephrol Dial Transplant 1999;14:58-63.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]

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Correspondence Address:
Junaid I Qureshi
Nephrology, Hypertension & Renal Transplant Division 1531, King Fahad National Guard Hospital, P.O. Box 22490, Riyadh 11426
Saudi Arabia
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PMID: 18209455

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    Tables

  [Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5]



 

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    Abstract
    Introduction
    Mode of Action
    Hypothesis
    Methods
    Definitions
    Results
    Discussion
    Conclusion
    References
    Article Tables
 

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