Retrospective Analysis of the Outcomes of Mycophenolate Therapy in Retarding the Progression of Immunoglobulin A Nephropathy (REMISSION IgA)

Introduction

IgA nephropathy (IgAN) is the most prevalent form of glomerulonephritis and a leading cause of end-stage kidney disease (ESKD) globally. In India, IgAN accounts for 10% to 15% of all kidney biopsies, often presenting with a high incidence of nephrotic syndrome and renal impairment.^1–6 The Glomerular Research and Clinical Experiments–IgA Nephropathy in Indians (GRACE-IgANI) study, conducted at our center, established the first prospective South Asian cohort on IgAN. This study reported the initial clinical, biochemical, and histopathological characteristics of GRACE-IgANI, along with the baseline risk assessment for disease progression.⁷ The present investigation aims to evaluate the efficacy of mycophenolate mofetil therapy in mitigating the progression of IgA nephropathy.

Materials and Methods

This retrospective, single-center study was conducted at Christian Medical College, Vellore, Tamil Nadu, India after approval from the Institutional Review Board. Since it is a retrospective study, patient consent was not required. The study included adult patients (18 years and older) with biopsy-confirmed IgA nephropathy who were observed between January 1, 2010, and December 31, 2017, and had an estimated glomerular filtration rate (eGFR) greater than 15 mL/min/1.73m². Data were retrieved from the electronic medical records within the Departments of Nephrology and Nephropathology. Figure 1 illustrates the study’s flowchart. Treatment protocols included angiotensin receptor blockers (ARBs)/angiotensin-converting enzyme inhibitors (ACEi), oral steroids, and mycophenolic acid (MPA), tailored according to the treating physician’s decision based on the patient’s eGFR and biopsy findings. Patients were categorized into three groups based on the treatment received: ARB group, ARB & steroid group, and ARB, steroid & MPA group. Maximum tolerated doses of ARB/ACEi were administered in all groups before initiating immunosuppression treatment. Steroid therapy was initiated at 1 mg/kg body weight for two months, followed by gradual tapering over four months in the steroid group. Two treatment protocols were followed for the initiation of mycophenolate therapy. In the first protocol, patients received both steroid and MPA together (prednisolone at 0.5 mg/kg and mycophenolate at a dosage of 500 mg to 1 gram twice daily [equivalent dose of sodium preparation]), with steroids tapered over three months and MPA continued for 3–5 years. In the second protocol, patients received mycophenolate at the end of two months during the tapering. The dose of mycophenolate was adjusted according to the MPA area under the curve (AUC) level, with a target of 30–60 mg·h/L, as adopted from kidney transplant protocols. MPA levels were checked using high-performance liquid chromatography (HPLC). Sodium-glucose cotransporter inhibitors (SGLT2i) were not administered to any patients, as they were not part of the standard of care during the study period. Data on eGFR and urine protein-creatinine ratio (Up/Uc) were collected at diagnosis, 12, 36, and 60 months across the three treatment groups. The data were collected using EpiData version 4.6, and statistical analysis was performed using STATA version 16. Categorical variables were presented as frequencies and proportions, and continuous variables were expressed as means with standard deviations or medians with interquartile ranges. Comparative analyses were performed for the steroid and MPA groups, as the ARB group had higher baseline eGFR with minimal interstitial fibrosis and tubular atrophy (IFTA) on the biopsy. The comparative analysis for the steroid and MPA groups was conducted using the Mann-Whitney U test for continuous variables and the Chi-squared test for categorical variables. Kaplan-Meier survival analysis was performed for patients who had at least 12 months of follow-up.

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Figure 1:

Study flow chart. ACEi: Angiotensin converting enzyme inhibitors, ARB: Angiotension receptor blockers, eGFR: Estimated glomerular filtration rate, ESKD: End stage kidney disease, HD: Hemodilaysis, IgAN: Immunoglobulin A neprhopathy, MMF: Mycophenolic acid, RPGN: Rapidly progressive glomerulonephriti.

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Results

During the study period, 9,243 patients underwent native kidney biopsies, of whom 1,543 (16.7%) were diagnosed with IgA nephropathy. A total of 992 (64%) patients were excluded from the study, with 623 patients (62.8%) exhibiting an eGFR < 15 mL/min/1.73m² and 339 patients (34.1%) having ESKD requiring dialysis at presentation. Patients <18 years of age accounted for 17 (1.7%), while 13 (1.31%) presented with rapidly progressive glomerulonephritis (RPGN). The remaining 543 patients included in the study were categorized based on treatment into three groups: ARB group (100 patients), ARB and steroid (A+S) group (130 patients), and ARB, steroid and mycophenolate mofetil (MMF) group (285 patients). Hypertension was present at presentation in 88.9% (458/515) of patients across all three groups. Other clinical features included non-visible hematuria in 41% (212/515), hematuria with proteinuria and a rise in serum creatinine in 39% (201/515), and nephrotic-range proteinuria in 20% (102/515).

Comparison of ESKD Progression

At the end of the follow-up period, 18.4% of patients in the A+S group progressed to ESKD, compared to 16.4% in the A+S+M group. However, this difference was not statistically significant (P = 0.65). The estimated median time to progression to ESKD was 132.3 months (95% CI = 122–142.5) in the A+S group and 126.9 months (95% CI = 119.4–134.4) in the A+S+M group as depicted in Figure 2. The comparison of eGFR and proteinuria was between steroid and MPA groups was detailed in Table 2.

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Figure 2:

Survival analysis comparing Steroid and MPA groups. MPA: Mycophenolate.

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Table 2: Comparison of ARB+Steroid and ARB+Sterois+MPA groups

Variable	ARB + Steroid group	ARB + Steroid + MPA	p value
Age	37.04±10.43	37.41±9.94	0.73
eGFR (ml/min/1.73m2) at
Baseline	48.73 (35.77, 75.84)	45.60 (32.00, 62.85)	0.01
12 months	57.74 (40.05, 86.58)	48.71 (37.07, 70.30)	0.02
36 months	50.00 (35.40, 83.84)	48.90 (33.95, 68)	0.13
60 months	49.21 (23.10, 82.10)	43.60 (26.05, 68.73)	0.42
Up/Uc (g/g) at
Baseline	1.59 (0.79, 2.54)	1.88 (0.97, 3.29)	0.14
12 months	0.38 (0.15, 0.94)	0.56 (0.23, 1.10)	0.02
36 months	0.48 (0.15, 1.10)	0.55 (0.23, 1.00)	0.38
60 months	0.67 (0.21,1.17)	0.62 (0.26, 1.28)	0.56
No. of patients progressed to ESKD at 60 months	24	47	RR-0.96

Mann-Whitney test, Age expressed in mean + standard deviation, eGFR and Up/Uc– expressed in Median & Inter Quartile ranges (0.25, 0.75), Relative risk 0.96 and the chi-square statistic is 0.24, the p-value is 0.62. ARB: Angiotensin receptor blocker, MPA: mycopheolate acid, RR: Relative risk, Up/Uc: Urine protein creatinine ratio, eGFR: estimated glomerular filtration rate, ESKD: End stage kidney disease.

Discussion

In this study, IgAN accounted for 16.7% of native kidney biopsies, a figure consistent with findings from the GRACE-IgANI⁷ study and an international survey on IgAN in Europe and North America.⁸ The mean age of patients was 36.6 ± 10.1 years, with a male-to-female ratio of 2:1, aligning with findings from European studies and the GRACE-IgANI study.^9-13 Patients were treated with either non-immunosuppressive therapy (ACEi/ARB) or immunosuppressive treatment (steroids and MPA), depending on baseline eGFR and histological parameters. Steroid therapy, primarily recommended based on the TESTING and STOP IgAN studies,^14,15 was supplemented by MPA, which was particularly suggested as a steroid-sparing agent for Chinese patients, according to the KDIGO 2022 guidelines.¹⁶ Although the target MPA level has not been defined for glomerular diseases, we adopted the MPA AUC range of 30-60 mg.h/L from kidney transplant protocols.^17,18

Our results are consistent with prior studies investigating the role of MPA in IgAN. Chen et al.¹⁹ However, the difference in progression to ESKD between the steroid and MPA groups in our study did not reach statistical significance, echoing findings from other trials that reported mixed results regarding the benefits of steroid-sparing therapies.^20,21 Notably, Frisch et al. found no benefit of MMF over renin-angiotensin system inhibitors in preventing ESKD,²⁰ while Hou et al. reported similar remission rates with MMF and prednisone.²² The recent MAIN trial,²³ compared mycophenolate with standard of care and concluded that 8.2% of patients in the Mycophenolate group progressed to ESKD, compared to 27.1% in the standard of care group. In the MAIN trial, the Mycophenolate group had a mean eGFR of 50.9 ± 18.2 ml/min/1.73m² and Up/Uc of 2.1 ± 1.9, whereas the standard of care group had a mean eGFR of 49.3 ± 17.7 ml/min/1.73m² and Up/Uc of 1.7 ± 1.3. A comparison of the present study with previous studies on Mycophenolate therapy in IgA nephropathy is detailed in Table 3.

The findings from this study highlight the potential role of MPA therapy as a disease-modifying treatment in IgAN. The addition of MPA to steroid therapy may offer a protective effect against progression to ESKD, as evidenced by a lower proportion of patients progressing to ESKD in the MPA group compared to the steroid-alone group, over a 60-month follow-up. This difference, was not statistically significant, but suggests a trend toward a more favorable long-term kidney outcome in the MPA group. Mesangial C3 deposition and the potential role of the complement system in disease progression is an area of interest, as it has been associated with adverse long-term outcomes in IgAN.^24-26

Though it is one of the largest studies from India to assess the outcomes of MPA therapy in IgAN and compare them with steroid treatment, is has several limitations. First, its retrospective nature may introduce selection bias, as patients were treated according to clinical decision-making rather than randomized assignment. The sample sizes across the three groups were unequal, which may affect the generalizability of the findings. The incomplete documentation of side effects, particularly those related to drug use, limits the ability to fully assess the safety profile of the treatments. Moreover, the unavailability of MEST-C scoring for all patients reduces the precision of histological risk assessment. Despite these limitations, this study is the first large retrospective analysis from India to assess the outcomes of MPA therapy in IgAN and compare them to steroid treatment.

Future studies, particularly randomized controlled trials, are needed to validate the findings of this study. The development of a clear target MPA AUC for glomerular diseases would also help guide therapy in clinical practice. Investigating the role of the complement system in IgAN pathogenesis, particularly through the use of complement inhibitors like Iptacopan, could provide valuable insights into novel therapeutic strategies for IgAN. Prospective studies with larger sample sizes and long-term follow-ups are warranted to better evaluate the impact of MPA therapy on disease progression and long-term kidney outcomes in IgAN patients.

In conclusion, the lower percentage of patients undergoing CKD due to MPA therapy with steroids and ARBs, warrants an exploration through appropriately powered randomized controlled trials.