| Abstract|| |
Few controlled trials have studied the treatment of relapse in adults with minimal change disease. Repeated courses of steroids, cyclophosphamide, cyclosporine and even mycophenolate mofetil (MMF), all seem to play a role. The aim of this study was to review and critically analyze the literature regarding the use of immunosuppressive therapy for the treatment of relapse in adults with minimal change nephrotic syndrome (MCNS). An intensive search was done for published trials in the general medical database. Retrieved studies were further sorted according to specific inclusion and exclusion criteria. Selected trials were critically analyzed and evaluated using the Oxford Centre for Evidence-based Medicine Levels of Evidence, 2009 rating. Six studies were selected and systematically reviewed. One randomized controlled trial compared the use of cyclophosphamide versus cyclosporine (11 adults) and showed that both drugs are effective in the treatment of frequent relapses [level 1b evidence (grade B)]. Three trials (total of 20 patients) tested the use of cyclosporine therapy and showed that cyclosporine, though effective in the treatment of relapse, is associated with an extremely high incidence of subsequent relapses following drug withdrawal. A long-term follow-up cross-sectional study of 95 patients, with 69 relapsers, supported the use of steroids in the treatment of occasional relapses [level 2c evidence (grade C)]. One case series described the benefits of MMF [level 4 evidence (grade C)]. Most of the the clinical trials studied were heterogeneous, underpowered by small adult populations, open-labelled, non-randomized, with poor statistical analysis, validity and utility. We conclude that there is poor evidence that successful treatment of the first relapse of adult MCNS can be achieved with a second course of steroids or cyclosporine. Also, there is weak evidence that frequent relapses can be treated using cyclophosphamide, cyclosporine or MMF. Powered, multi-centered, randomized, blinded, controlled trials, with long-term follow-up are required to know the optimal treatment for relapsing adult MCNS.
|How to cite this article:|
Shigidi MM. The treatment of relapse in adults with minimal change nephrotic syndrome: Myths and facts. Saudi J Kidney Dis Transpl 2011;22:10-7
|How to cite this URL:|
Shigidi MM. The treatment of relapse in adults with minimal change nephrotic syndrome: Myths and facts. Saudi J Kidney Dis Transpl [serial online] 2011 [cited 2020 Jun 5];22:10-7. Available from: http://www.sjkdt.org/text.asp?2011/22/1/10/74335
| Introduction|| |
Minimal Change Disease (MCD) accounts for 10-15% of all cases of primary adult nephritic syndrome (NS). , Most cases of MCD are idiopathic and not directly associated with an underlying disease or event. Adult patients with minimal change nephrotic syndrome (MCNS) are usually treated with a trial of steroid therapy as the disease is highly sensitive to steroid therapy and the serious complications associated with untreated NS can be life threatening.  While MCNS is known to be highly steroid-responsive, relapses are frequent in adults, with reported rates of 31-76%. ,,,,,, Only few trials have examined the use of immunosuppressive therapy in the treatment of relapse. The aim of this study was to review the medical literature and evaluate the strength of evidence regarding the use of immunosuppressive therapeutic agents for the treatment of relapse in adults with MCNS.
| Methods|| |
Literature was located by searching the general medical databases, including Google Scholar, PubMed, EMBASE and the Cochrane Central Register of Controlled Trials. The search was also extended to include the reference lists of articles obtained. All randomized controlled trials (RCTs), cohort studies, cross-sectional studies and case reports focusing on immunosuppressive agents as interventions for the treatment of adult relapsing MCNS were targeted. The search terms used were mostly based on various combinations of the terms "adult, relapse, minimal change, nephrotic syndrome, nephrosis", together with individual drug therapies "prednisolone, cyclosporine, tacrolimus, cyclophosphamide, chlorambucil, mycophenolate mofetil, azathioprine, rituximab".
Data search was done between the 15 June 2009 and 31 July 2009; it covered the years from 1950 to July 2009. It was restricted to English language publications and by the availability of data in the stated search sites.
All titles and abstracts identified as being potentially relevant were provisionally included. Full texts were retrieved and papers were selected for critical appraisal if they included adults with biopsy proven MCD, clinical presentation with relapsing NS, clearly stated immunosuppressive therapeutic intervention for the treatment of relapses and detailed outcomes of treated relapses. On the other hand, studies were excluded if they were heterogeneous and failed to differentiate between adults and children and their outcomes; failed to differentiate between MCD and other glomerulopathies; and inclusion of relapsing, steroid dependent and steroid resistant NS. Additionally, trials were also excluded if they included patients with secondary MCD or those with MCD not presenting with the NS.
Retrieved evidence was assessed for quality, bias, validity and utility. Assessment for quality was done using a critical appraisal checklist based on existing models of appraising qualitative or quantitative research.  Information about the characteristics and results of each study was summarized. Strengths and weaknesses of studies were recorded. Using the most updated rating for levels of evidence, recommendations were graded from A to D based on the level of evidence of the supporting studies [Table 1]. 
|Table 1: Level of evidence for rating studies and grading recommendations, as per the Oxford Centre for Evidence-based Medicine (OCEBM), March 2009.|
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| Results|| |
Out of 621 titles and abstracts, 29 studies were retrieved, their full text was reviewed and accordingly, only six studies were selected as per the inclusion/exclusion criteria. These include two controlled trials, two cohorts, one retrospective long-term follow-up cross-sectional study and one case report series. The characteristics of these trials are shown in [Table 2].
|Table 2: Characteristics of the studies involved in the treatment of adult relapsing minimal change nephrotic syndrome.|
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Ponticelli et al,  in an RCT (level 1b evidence), compared the use of cyclosporine and cyclophosphamide in the treatment of frequently relapsing MCNS. The use of either cyclosporine or cyclophosphamide was a valid therapeutic option as subsequent courses of steroids failed to achieve complete remission. Randomization was tested, the study followed an intention to treat analysis, and optimal statistical packages were used. The studied population was heterogeneous including both children and adults. The interventions used, follow-up, follow-up parameters, cross-over and primary end-point were all demonstrated.
Both cyclosporine and cyclophosphamide were effective and well tolerated; their use in adults follows a grade B recommendation. The drug side effects seen in the study were minimal, thus making both the agents of high utility. The prior use of steroids to induce remission of proteinuria is of grade D recommendation. There were no statistically significant differences between adults and children in the results obtained. On the other hand, the adult population tested was small in size (11 patients) and thus, the conclusions for adults were extrapolated, interventions were open, and subsequent relapses of MCNS might still be seen with longer follow-up periods.
In an open-labelled, non-randomized, controlled trial (level 2b evidence), Matsumoto et al  studied three different therapeutic protocols to determine the long-term efficacy of cyclosporine with or without steroids in the treatment of initial presentations or occasional relapses of MCNS. The study was well designed, started with clear definitions of the study population and its inclusion criteria, interventions, primary end-points, follow-up parameters and drug side effects. Interventions were applied following a wash-out period; adherence to therapy and crossovers were not stated. Again, the study was heterogeneous and included a small-sized adult population with relapsing MCNS (10 patients). Throughout the study, all patients could be traced. Cyclosporine therapy, with or without methylprednisolone, was successful in inducing remission in all adults with relapsing MCNS, and thus, using the drug to attain a remission in adults with occasional relapses was graded as level C recommendation. The benefits of adding pulse methylprednisolone prior to cyclosporine could not be validated in the treatment of relapse, and its use carries grade C recommendation.
Clasen et al,  in an open-labelled, non-randomized cohort study (level 4 evidence), prospectively studied the use of cyclosporine in seven adults with initial presentation of MCNS as well as relapsing or frequently relapsing MCNS. No other immunosuppressive medications were given at the time of interventions. All patients could be traced throughout the study, their outcomes and drug side effects were all monitored. Cyclosporine was found to be safe and effective, induced remission in all relapsers, although responders tended to become cyclosporine-dependent and required long-term cyclosporine therapy. The results obtained were not statistically tested. The use of cyclosporine in the treatment of frequent relapses follows grade C recommendation. The exact dose, drug levels and duration of cyclosporine therapy could not be validated. The small-sized heterogeneous population studied together with the absence of blinding, randomization, controls and statistical re-enforcement greatly reduces the validity and utility of the results obtained. The strength of evidence acquired in this study was mostly due to the gross initial response attained with the use of cyclosporine in all participants, although that might have been due to selection, intervention and attrition bias, as well as possible confounders.
In an open-labelled, prospective cohort study (level 4 evidence), Chan et al,  studied eight adults with severe relapsing NS; of these, only six had biopsy proven MCD. Almost all participants were frequent or multiple adult relapsers of NS who had even failed cyclophosphamide therapy; these factors validated the use of cyclosporine for treatment. The cyclosporine dosage was derived from that used in transplant patients. Cyclosporine level was monitored, though not on regular basis. All patients could be monitored throughout the study and reported to show good adherence to therapy. The study was heterogeneous and included patients with MCD as well as FSGS. It did not show clearly the criteria used for the diagnosis of NS, MCD, relapses and remissions of NS. No wash-out period was stated. The results obtained were not statistically analyzed. Overall, cyclosporine failed to achieve complete re-mission in seven patients after eight weeks of therapy. The treatment effect was negative in almost all patients, and showed no benefit of cyclosporine in adults with multiple or frequent relapses who had even failed cyclophosphamide therapy (grade C recommendation). This result cannot be generalized as the studied population was small in size, with a high probability of selection, observer and attrition bias. The use of appropriate statistical methods could have ruled out the possibility that the results were obtained by chance. The results obtained are thus of low validity and utility.
Waldman et al  in a cross-sectional study, retrospectively reviewed the clinical records of 95 adult patients with MCD, studying their demography, initial clinical presentation, response to steroids, frequency and timing of relapses, response of the initial relapsing episodes to steroids, outcome of frequently relapsing episodes after the use of cyclosporine, cyclophosphamide, mycophenolate mofetil (MMF) and tacrolimus (level 2 C evidence). It relied on retrospective data from the medical records in a single center and during a fixed period of time, with clearly stated inclusion and exclusion criteria. Like most similar studies, collection of data was open, depended on the medical recording system, might not have described the sequence of events appropriately, thus allowing for a high incidence of observer bias and does not eliminate confounders. Details of follow-up parameters for relapses were not clearly demonstrated in the study. Patients' adherence to therapy, drop outs and cross-over were not specified.
This is considered as one of the few studies with MCNS, which excludes children and patients with FSGS, has a long-term follow-up and a relatively large studied adult population. The study demonstrated the benefit of subsequent courses of steroids in treating occasional relapses of adult MCNS (grade C), but failed to determine the role and response rate of secondline immunosuppressive therapy in the treatment of frequent relapses.
Pesavento et al  reported a series of four adults with MCNS, who continued to show multiple relapses despite repeated courses of steroids and cyclophosphamide therapy; accordingly, MMF was used as a valid therapeutic option (level 4 evidence). The population studied was small in size, no wash-out period was available and the doses of MMF were not uniform for all patients. MMF and steroids were combined together, with or without cyclosporine. All cases reported were followed up and all outcomes were included in the conclusion. No statistical analysis was done for the results obtained. The treatment effect using MMF was enormous as all patients have had severe multiple or frequently relapsing NS and all were able to attain remissions for 19-42 months, only after using a less toxic therapeutic agent, MMF. On the other hand, the study was descriptive in nature depending on recorded data and MMF was not used as sole therapy; these facts allow for selection, intervention and observer bias, as well as the presence of confounders. The lack of descriptive and regression analysis further weakens the recommendations concluded (grade C) and does not rule-out the possibility of chance.
Overall, the studies assessed were poor in quality. No eligible trials were found testing the use of chlorambucil, tacrolimus, azathioprine, levamisole or rituximab for the treatment of relapse in adults with MCNS as per the inclusion and exclusion criteria set.
| Discussion|| |
The optimal therapy for the treatment of relapse in adults with MCNS remains unclear due to the lack of large trials comparing the use of the various therapeutic modalities available. A number of immunosuppressant medications have been tried extensively in children; these include alkylating agents, cyclosporine, MMF, azathioprine and levamisole. Our search revealed a total of six relevant studies testing the use of immunosuppressive therapy for the treatment of relapse in adults with MCNS. Among these trials, the use of cyclophosphamide and cyclosporine was compared in one randomized, controlled trial;  three trials, one non-randomized, controlled and two cohort studies, studied the use of cyclosporine in adults with relapsing MCNS. ,,
So far, there is weak evidence that frequent relapses can be treated using cyclophosphamide or cyclosporine.  Cyclophosphamide is relatively cheap and seems to be associated with much more stable long-term sustained remissions, which puts this drug as a first therapeutic option in the treatment of frequently relapsing MCNS. , On the other hand, cyclosporine seems to be safer than cyclophosphamide and repeated exposure to cyclophosphamide for the treatment of subsequent relapses should be avoided. It is known that the side effects of cyclophosphamide are due to cumulative dosage.  Ponticelli et al, compared the use of cyclophosphamide versus cyclosporine in their study. The small number of adults tested in the study was justified by the authors by the good statistical methods applied;  but good statistical methods will not improve the power of the study and will regrettably give misleading results. The use of steroids to induce the remission of proteinuria before the introduction of cyclophosphamide is entirely based on the author's personal experience and is not supported by good evidence.
There is poor evidence that cyclosporine is effective in the treatment of adult relapsing  and frequently relapsing MCNS. , Cyclosporine therapy is known to be associated with an extremely high incidence of relapse with drug withdrawal, and accordingly causing cyclosporine dependence in most cases. ,, The risk of cyclosporine nephrotoxicity was not significant in all reviewed studies. ,,, Again, cyclosporine might be disappointing in patients with protracted relapsing disease, as one study showed no benefit of using cyclosporine, with or without steroids, in patients who had multiple relapses and had failed cyclophosphamide therapy. 
All these prospective studies ,,, were hetero geneous, open-labelled and included small numbers of adult participants, thus markedly reducing the validity and utility of the results obtained and strength of recommendations concluded.
There are no RCTs or cohorts demonstrating the use of steroids for the treatment of relapses in adults with MCNS. There is poor evidence that subsequent courses of steroids might be effective in the treatment of occasional relapses, which was demonstrated and recommended in a retrospective long-term follow-up cross-sectional study.  The role of subsequent use of steroids has thus not been validated by controlled steroids against placebo or second-line immunosuppressive agents. Also, the dose and duration of steroids sufficient to prevent further relapses is unknown, keeping in mind that repeated courses of steroids will increase the risk of potential drug toxicity.
A case series report described the use of MMF in four patients who continued to develop relapsing MCNS despite repeated courses of steroids and cyclophosphamide therapy.  MMF seems to be much well tolerated when compared to cyclosporine and cyclophosphamide.  The drug is not commonly used in the treatment of MCD, although it was successful and thus might have a role in the treatment of relapse.  So far, there is poor evidence that MMF is effective and RCTs are essential.
In conclusion, the studies analyzed showed a response of relapsing adult MCNS to some immunosuppressive therapeutic agents although they failed to prove that. Also, they could not provide clear guidance to the optimal doses or duration of therapy. The lack of available wellpowered, randomized, controlled studies with long-term follow-up leaves important questions unanswered regarding the treatment of relapse; these include the appropriate agent to be used, the dose, duration of therapy and frequency at which agents can be repeated for subsequent relapses. , Being a rare condition, most of the studies which had monitored or discussed the treatment of relapse in adults with MCNS are heterogeneous, including children as well as adults or considering other pathological variants such as FSGS, mixing steroid dependent and relapsers and single as well as frequently relapsing episodes. Even after successful, well-defined therapeutic interventions and attaining remission, the final outcome of relapsing MCNS will remain obscure; it is often difficult to make firm therapeutic conclusions in such a condition which always tends to relapse if followed long enough.
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Mazin M.T. Shigidi
Nephrology Division, Department of Medicine, Ribat University Hospital, Khartoum
[Table 1], [Table 2]