Efficacy and Safety of Mycophenolate Mofetil in Refractory IgA Nephropathy

Overview

This study is testing whether a medicine called mycophenolate mofetil (MMF) works better than the usual treatment for people whose kidney disease, called IgA nephropathy, has not improved with standard care. IgA nephropathy is a kidney disease that can cause protein to leak into the urine and, over time, can damage the kidneys. Some people with this disease do not get better even after standard treatment. Doctors call this "refractory" disease. Right now, there is no proven best treatment for these patients in Bangladesh. This study will include 116 adults with kidney disease that has been confirmed by a kidney tissue sample and has not improved with standard treatment. Participants will be split into two equal groups by chance, like a coin flip. One group will take MMF by mouth for 6 months, along with the usual supportive care. The other group will take a steroid medicine called prednisolone, along with the usual supportive care. Both groups will also continue treatments like blood pressure medicines that are already part of standard care for this condition. Researchers want to find out how many people in each group get better, meaning their urine protein drops to a low level and their kidney function stays stable. They will also look at changes in kidney function and any side effects from the medicines. The study will take place at the National Institute of Kidney Diseases and Urology Hospital in Dhaka, Bangladesh, over about one year. Each participant will be followed for 6 months, with check-up visits and blood and urine tests at the start, at 3 months, and at 6 months.

IgA nephropathy is one of the most common forms of primary glomerulonephritis worldwide, with disease burden concentrated in Asia. In Bangladesh, epidemiological data remain limited, though hospital-based biopsy series suggest it accounts for roughly 5-10% of biopsy-proven primary glomerular disease. A subset of patients fail to achieve adequate reduction in proteinuria despite optimized renin-angiotensin-system blockade and a course of corticosteroid therapy; this refractory phenotype carries an elevated long-term risk of progression to end-stage kidney disease and currently lacks a clearly defined, evidence-based treatment pathway. Mycophenolate mofetil (MMF), a selective and reversible inhibitor of inosine monophosphate dehydrogenase, suppresses T- and B-lymphocyte proliferation and has shown biological plausibility for reducing pathogenic galactose-deficient IgA1 immune complex formation in IgA nephropathy. However, clinical trial results to date have been markedly heterogeneous by population: several Chinese cohort studies report meaningful reductions in proteinuria and renal protection, while Western multicentre randomized trials have largely shown neutral or inconclusive results. This geographic divergence has shaped conditional, population-specific guidance in current KDIGO recommendations. No randomized trial has yet evaluated MMF in a South Asian population, where genetic background, immune response profiles, and healthcare delivery context differ from both previously studied East Asian and Western cohorts. This trial is designed to generate the first prospective, randomized evidence on MMF for refractory IgA nephropathy in a Bangladeshi population, using an active comparator (prednisolone) rather than placebo, reflecting that corticosteroid-based therapy remains the existing standard of care in this setting. MMF was selected as the intervention of interest because it is already available, relatively affordable, and familiar to local nephrologists through established use in transplant medicine, making it a pragmatic candidate for repurposing should efficacy be demonstrated locally - in contrast to newer agents (e.g., targeted-release budesonide, complement inhibitors) that remain largely inaccessible in this setting due to cost and regulatory constraints. Randomization will use a block design (block size of 6) generated by a computer-based program to maintain balanced allocation across the two arms throughout the enrollment period. As this is an open-label trial with no blinding, outcome assessments rely on objective laboratory measures (24-hour urinary protein, serum creatinine, eGFR by the CKD-EPI equation) rather than subjective clinician-rated endpoints, to limit the impact of unblinding on result interpretation. Statistical analyses will be performed on an intention-to-treat basis, with a per-protocol analysis conducted as a supplementary sensitivity analysis. Binary outcomes will be modeled using generalized linear mixed-effects models with a logit link, adjusting for baseline proteinuria, baseline eGFR, age, and sex, with treatment effects expressed as adjusted odds ratios and model-based marginal risk differences. Continuous outcomes will be analyzed using linear mixed-effects models with random intercepts for participants to account for within-subject correlation across repeated measures. The composite renal outcome will be analyzed using Kaplan-Meier estimation with Cox proportional hazards regression. Missing data will be handled under a missing-at-random assumption using maximum likelihood estimation within the mixed models, supplemented by multiple imputation and complete-case sensitivity analyses. Independent oversight will be provided by a Data and Safety Monitoring Board comprising a nephrologist, medicine specialist, epidemiologist, and statistician not otherwise involved in the trial, reviewing interim safety and efficacy data at three-monthly intervals.