#NephJC Chat
Tuesday March 28th, 2023 at 9 pm Eastern
Wednesday March 29th, 2023, at 9 pm Indian Standard Time and 3:30 pm GMT
JAMA Netw Open. 2023;6(2):e2254054. doi:10.1001/jamanetworkopen.2022.54054
Effectiveness of Mycophenolate Mofetil Among Patients With Progressive IgA Nephropathy
Fan Fan Hou, Di Xie, Jun Wang, Xin Xu, Xiaobing Yang, Jun Ai, Sheng Nie, Min Liang, Guobao Wang, Nan Jia; MAIN Trial Investigators
PMID: 36745456
Introduction
It’s a cliche to say that IgA nephropathy (IgAN) is the most common glomerular disease, and a common cause of kidney failure. But why does the most common glomerular disease have so few large, randomized controlled trials? Until now. Over the last few years we have seen STOP-IGAN, TESTING, TESTING-2 and NEFIGARD in quick succession, which have made the excellent 2021 KDIGO guidelines in need of a fresh update.
Conservative care remains the backbone with BP control, RAS inhibition, cardiovascular risk management, and now also including the addition of flozins (based on DAPA-CKD and EMPA-KIDNEY, but also missing from the KDIGO guidelines). The use of immunosuppression in IgAN has been a topic of perpetual debate (see NephMadness 2023 scouting report for more), which the recent trials are helping to settle.
Summary of immunosuppression evidence in IgAN, from the NephMadness scouting report
The figure below from Landmark Nephrology summarizes the important studies until 2017, many of which included steroids as part of the treatment. Since then, we have had TESTING 2.0 which helped establish the role of steroids, followed by NEFIGARD with its claim of a ‘safer’ alternative walking away with an FDA approval. However, alternate immunosuppression options which might be safer do exist - such as mycophenolate mofetil (MMF). But the 2021 KDIGO guidelines say ‘Beyond glucocorticoids, other immunosuppressive therapies are not recommended in IgAN …..The use of mycophenolate mofetil (MMF) in IgAN is not recommended in non-Chinese patients, whereas it may be used as a glucocorticoid-sparing agent in Chinese patients.’ Why is that so?
Let’s take a bit more of an in depth look at our IgAN trials looking at MMF. First up, one study examined a group of patients with IgAN, all of whom were on salt restriction and an ACEi, and randomized them to MMF or placebo, finding no difference in 3 years follow up of renal function or proteinuria (Maes et al, Kidney Int 2004). Next, a study which looked at a small group of patients with IgAN both, with significant clinical risk factors and with glomerulosclerosis or tubulointerstitial atrophy and fibrosis on biopsy, and randomized them to MMF or placebo, and ultimately did not see a benefit in the MMF group (Frisch et al, Nephrol Dial Transplant 2005). In 2015, a small trial of children and adults with biopsy-proven IgAN on lisinopril who were randomly assigned to MMF or placebo failed to demonstrate a reduction in proteinuria in the MMF group compared to placebo group, though all patients had an eGFR > 50 ml/min/1.73m2 (Hogg et al, Am J Kidney Dis 2015). In 2017, a study comparing MMF plus prednisone versus full-dose prednisone in patients with IgAN and active proliferative lesions concluded they did not differ in reducing proteinuria, but there were fewer adverse events in the MMF group (Hou et al, Am J Kidney Dis 2017) . All of these are negative - the only one with any promising results was from Hong Kong (Tang et al, Kidney Int 2005) of 40 patients with IgAN and persistent proteinuria (> 1 g/day) in whom more patients (16 vs 6) achieved the outcome of proteinuria reduction by 50%, accompanied by normalization of polymeric IgA binding to mesangial cells in vitro.
Hence, we were faced with a conundrum of whether this potentially steroid sparing strategy using MMF is even effective at all - enter the MAIN trial.
The Study
This is a single center, randomized, open-label, blinded end-point, trial of adults with persistent proteinuria after optimized supportive care, in the Nanfang hospital in China.
Methods
Study participants
Adults with biopsy-proven IgAN
proteinuria of greater than 1.0 g/day
eGFR of 30-60 ml/min/1.73m2 or persistent hypertension (greater than 140/90 in 2 visits or 1 day apart [or] on an antihypertensive)
proteinuria remained greater than 0.75 g/day or greater after 3 months of optimal supportive care.
Exclusion
Secondary, familial, or crescentic IgAN
presence of another cause for CKD
prior immunosuppression
eGFR less than 30 ml/min/1.73m2.
Interventions
In the run-in phase, patients received losartan to maintain their blood pressure at 130/80 mmHg and were advised lifestyle modifications which included quitting smoking, low salt diet, and avoiding nephrotoxic medications. In patients whose proteinuria remained at 0.75 g/d or greater despite BP control, the dose of losartan was increased to the tolerable maximum daily dose. Patients who continued to show inadequate BP control were given an additional antihypertensive agent, excluding a RASi. All patients with anemia and a hemoglobin level less than 11 g/dL were treated with erythropoietin. A statin was used ‘when necessary’.
Patients who had persistent proteinuria and tolerated RAS blockade after the run-in phase were randomized into two groups, one group to receive MMF at a dose of 1.5 g/day for 12 months then maintenance dose of 0.75-1 g/day for 6 months with supportive care, and the second group received supportive care alone. The patients who could not tolerate RAS blockade due to persistent hyperkalemia or worsening eGFR, or who had proteinuria <0.75 g/day, were excluded from randomization. The patients were followed regularly after the trial period, and they continued the treatment of supportive care with or without MMF as per their physician recommendations.
Outcome
Primary Outcomes
Composite outcome of doubling of serum creatinine over baseline, onset of ESKD (need for dialysis, kidney transplant, or eGFR < 15 ml/min/1.73m2 and clinical indication for KRT), or death due to kidney or cardiovascular cause.
Progression of CKD, which was defined by an eGFR decline of 30% or more of the baseline, and to a level of less than 60 ml/min/1.73m2 if starting eGFR was greater than 60 ml/min/1.73m2, or decrease of 50% or more of the baseline if baseline eGFR was less than 60 ml/min/1.73m2.
Secondary Outcomes
Time to a 30% reduction in eGFR
Annual rate of eGFR loss
Proportion of patients with rapid eGFR decline
Percentage change in urinary protein
Sample Size and Analysis
This was an intention-to-treat analysis. Survival rates were estimated using a Kaplain-Meier method with differences tested with a log-rank test. Treatment effects for primary outcomes were analyzed using a Cox proportional hazards model. This model was done with and without adjustment for age, sex, BMI, systolic blood pressure, eGFR, UPER, and baseline MEST-C scores. Modification of treatment effect by these factors was tested using an analysis of variance test. None of the analyses were adjusted for multiple testing. Based on their preliminary study of IgAN the 3 year rate of the outcome in the control group was assumed to be 36%. The authors planned for a 20% absolute risk reduction of this with MMF (from 36% to 16%). Enrollment of 76 per group gave them a statistical power of 80% at a two-sided significance level of 0.05. Considering 10% of participants lost to follow-up over 3 years, the final sample size was 84 per group.
Funding
Funding for this study was obtained from grants from the National Natural Science Foundation of China, the Program of Introducing Talents of Discipline to Universities, from Guangdong Provincial Clinical Research for Kidney Disease, and from Guangdong Key Program of Precision Medicine. The study drug was in part provided by Hangzhou Zhongmei Huadong Pharamceutical Co, Ltd. The authors note that: “The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.”
Results
The authors enrolled 238 patients who met the above criteria and after the run-in phase, 170 ultimately underwent randomization.
Figure 1 from the MAIN trial, Hou et al, JNO 2023
Both groups received optimal supportive care for 3 years, and the MMF group also received MMF at a daily dose of 1.5g for one year, then 0.75-1g/day for at least 6 months after that. The mean dose of MMF was 1g/day and the mean treatment period was 30 months.
Below we can see the characteristics of the trial participants at randomization. Overall, just over half were men, with a well preserved mean GFR ~ 50, and a baseline proteinuria ~ 2 g/day. The mean dose of losartan in the run-in period was ~ 120 mg/day.
Table 1 from the MAIN trial, Hou et al, JNO 2023
Outcomes
They reported a significant reduction in the primary composite outcomes in the MMF group (7.1% vs 21.2%, p = 0.008), as well as a reduction in CKD progression by 30% (8.2% vs 27.1% p=0.001). Overall they reported a whopping 77% reduction in the primary outcomes in the MMF group.
Figure 2 from the MAIN trial, Hou et al, JNO 2023
The composite primary outcome was mostly driven by the doubling of creatinine (see below, table 2).
Table 2 from the MAIN trial, Hou et al, JNO 2023
With respect to their secondary outcomes, they reported that MMF reduced the annual rate of eGFR decline from an average of 3.8 ml/min/1.73m2 per year in the optimal care group to 1.2 ml/min/1.73m2/year in the MMF group.
Post trial phase
They also followed a cohort of 157 patients in a post trial phase for roughly 60 months, and reported a sustained reduction in eGFR decline and urinary protein excretion rate only in those who continued MMF throughout the post trial phase. This is not a randomised, but observational phase (e.g. responders may have chosen to continue MMF) so caveat emptor.
eFigure from the MAIN trial, Hou et al, JNO 2023
Subgroup analysis
The subgroup analysis as shown below. The results are mostly consistent across all subgroups, except for a hint of an interaction by sex - but this p value was not adjusted for multiple comparisons.
Figure 3 from the MAIN trial, Hou et al, JNO 2023
Safety
The overall number of patients with adverse events were higher in the MMF group, though this was not statistically significant. Interestingly, MMF was withheld due to adverse effects only in 3 patients (despite many more having AEs compared to the control group - 6 with pneumonia, 10 with GI side effects from table below). Notably, the only death in this trial (despite the 3 years of RCT and ~ 60 months of post trial follow up) was in the supportive care group, and this death was due to an MI.
eTable from the MAIN trial, Hou et al, JNO 2023
Discussion
We all know IgA is the most common primary glomerular disease in the world, and hopefully one day that will mean that we will all know how to treat it. Until that time, however, this study attempts to fill that knowledge gap and give MMF another shot. Just when the KDIGO guidelines tell us there is not enough evidence, this trial comes in and all of a sudden you’re thinking of giving MMF another chance.
Have we been asking the wrong question?
Perhaps the question isn’t IF we should use MMF, or any immunosuppression for that matter. Maybe the real question is when and in whom. In context of the recent research on importance of complement pathways, B-cell modulation, Gut-Associated Lymphoid Tissue and gut microbiota in the pathogenesis of IgAN, targeted and timely immunosuppression vis-a-vis the current approach of broad spectrum immunosuppressive agents started at varying timepoints in disease course, may hold the answers for future. Why this trial showed benefit where so many before it failed is still unknown, but one potential hypothesis is that this trial fills a gap looking at people who are at a higher risk of progression based on a lower eGFR. However, more trials are needed to definitively demonstrate this. Of course IgAN is a heterogeneous entity, which is why risk scores have been developed to predict progression (see NephJC discussion) which was not used in this trial, but hopefully will guide future trial design and prognostication.
Strengths
The strengths of this trial include the long follow up period of three years as well as an additional 60 month post trial phase tracking eGFR decline and degree of proteinuria in patients who did or did not continue MMF. Additionally, for a single center IgAN trial this had a relatively large sample size, minimal loss to follow up, as well as excellent overall adherence to the trial protocol.
Limitations
Of course, any trial that is open-label and single center needs a healthy dose of skepticism. Although funding and logistics may present barriers to placebo controlled trials, an open-label trial certainly isn’t necessary when it comes to this study and we always need to consider how this affects other co-interventions physicians may prescribe, the counseling being provided, adoption of and adherence to lifestyle modifications by those who know they are or are not receiving the drug, etc, even with outcomes adjudicators being blinded to group. This trial was also conducted in China, which, if you remember from our introduction, appears to be the only population where KDIGO hints at considering MMF. Results from this Asian cohort where IgAN is known to have a ‘malignant’ behavior may not be generalizable worldwide, especially given the negative trials we discussed in the introduction. They also excluded patients with proteinuria > 3.5g/day and patients with crescentic IgAN, so we need to keep in mind these results don’t apply to patients who come in with a bad flare or very advanced disease.
Conclusion
So far, other studies have not shown significant benefit of MMF in patients with IgAN. Here, the MAIN trial does show a benefit in patients with persistent proteinuria despite optimal conservative therapy. However, this was in a cohort of patients in China and generalizability is still unknown. Since this trial was designed, we now have data supporting flozins (DAPA-CKD and EMPA-KIDNEY), steroids (TESTING) and targeted release budesonide (NEFIGARD). How does MMF fit in this treatment strategy jigsaw? Just when we thought MMF was down and out, this study is here to emphasize that we still need more data, and perhaps the right question to ask is not if there is benefit, but when and in whom. As the NephMadness summary goes- “Put me in, coach!” - the evidence for using immunosuppression of some sort in IgAN is becoming quite robust. Specifically for MMF however, we are not sure this makes the cut given the limitations and questions of generalizability. At least the KDIGO guideline for MMF in IgAN remains fairly accurate!
Summary prepared by
AC Gomez, MD
Division of Nephrology,
Mass General Brigham, Boston Children’s Hospitals
And
Nihal Bashir,
Nephrology Specialist
MD Seha Kidney Care - Alain, UAE
NSMC Interns, Class of 2023
Reviewed by Anand Chellappan, Sayali Thakare,
Tiffany Caza, Swapnil Hiremath, and Jamie Willows
Header image created by AI with prompts from Evan Zeitler