Introduction:
Membranous nephropathy (MN) is a common cause of nephrotic syndrome. Although approximately 30% undergo spontaneous remission, an equal number of patients experience renal failure at 15 years follow up who do not respond to immunotherapy. According to the KDIGO guidelines, patients with MN and proteinuria should receive conservative treatment such as diuretics, ACE/ARBs, sodium restriction. Cyclic use of cyclophosphamide and corticosteroids have proven to be a highly effective therapy for MN. The GEMRITUX and MENTOR trials were the initial controlled trials that solidified rituximab’s role in MN. As it stands, Calcineurin Inhibitors, Rituximab, or cyclophosphamide and corticosteroids are acceptable treatments for moderate to high-risk MN per KDIGO The study aimed to compare the outcomes of the various of treatment modalities in patients with Primary Membranous Nephropathy.
Methods:
This retrospective, single-centre study, conducted in tertiary care centre in south India, and received approval from the Institutional Review Board (IRB) vide minute number 2407167 dated 24.07.2024. The study encompassed all patients with biopsy-confirmed primary membranous nephropathy, observed between January 1, 2015 and December 31, 2018. Data retrieval was done from electronic medical records within the departments of Nephrology and Nephropathology. The data was collected in Epidata version 4.6 and the results were analysed in SPSS ver.16. The data included clinical features, serological profile, induction protocols and maintenance immunosuppression regimens used in the treatment of primary membranous nephropathy. The outcomes of the patients with various treatment protocols (as per KDIGO guidelines), in terms of clinical remission were studied at 6 months, 12 months, 36 months and 60 months. The clinical remission was defined as 24 hours proteinuria <500 mg/dl, and serum creatinine less than 1.2 mg/dl. Relapse was defined re appearance of proteinuria (24-hour urine protein more than 500miligram/day). The categorical variables were presented as frequencies and proportions, and continuous variables were expressed as mean with standard deviation or median with interquartile range. The Comparative analyses was done by the Chi-squared test for categorical variables.
Results:
During the study period, 4262 patients underwent native kidney biopsies at this centre, among whom 432 patients (10.1%) were diagnosed to have membranous nephropathy, after excluding secondary causes, 193 patients (4.52%) were diagnosed to have primary membranous. The male to female ratio was 2.2:1. The mean age of the patients was 44+14.8 years. Median creatinine at diagnosis was 0.9mg/dl (IQR 0.7 – 1.4mg/dl). Mean eGFR at diagnosis was 86.1+39.1 ml/min/1.73m2. Mean Up/Uc at diagnosis was 7.2+ 3.2 g/g. Immunohistochemistry phospholipase A2 receptor was positive in 47(24.3%) of the patients.
The maximum tolerated dose of Angiotensin Converting Enzyme inhibitors (ACEi) or Angiotensin Receptor Blocker (ARB) were given to all the patients. The concurrent steroid (0.5mg/kg body weight/day) and oral cyclophosphamide (1.5 – 2mg/kg body weight/day) regimen was used at this centre. Calcineurin Inhibitors (CNI), with target Tacrolimus CO of 4-6 ng/ml and Cyclosporine C0 of 150-200ng/ml, and Rituximab were used as per KDIGO guidelines.
36(18.6%) patients responded to the maximum tolerated antiproteinuric measures. 138(71.5%) patients received concurrent steroid and cyclophosphamide regimen. 16(8.3%) received CNI and 3(1.55%) patients received Rituximab.
At 6 months, 46(23.8%) patients had achieved remission – 6(16.6%) patients on antiproteinuric measures achieved remission, 42(30.4%) patients on steroid and cyclophosphamide achieved remission and 3(5%) patients on CNI achieved remission.
At 12 months, 100 patients had follow up, out of which 61(61%) patients had maintained remission – 8(8%) patients on antiproteinuric measures maintained remission, 47(47%) patients on steroid and cyclophosphamide maintained remission and 6(6%) patients on CNI maintained remission.
At 36 months, 67 patients had follow up, out of which 47(70.1%) patients were in remission – 6(8.9%) patients on antiproteinuric measures were in remission, 36(53.7%) patients on steroid and cyclophosphamide were in remission and 5(7.46%) patients on CNI were in remission.
At 60 months, 60 patients had follow up, out of which 43(71.6%) patients were in remission – 8(13.3%) patients on antiproteinuric measures were in remission, 31(51.6%) patients on steroid and cyclophosphamide were in remission and 4(6.6%) patients on CNI were in remission. At the end of 60 months, there was no statistically significant difference between the three treatment regimens, however infections (15.2%) and leucopenia (28.3%) were more common amongst the patients receiving steroid and cyclophosphamide. Steroid induced complications – steroid induced diabetes was seen in 12.8% patients, Avascular Necrosis of hip joint was seen in 1.52% patients. The mean tacrolimus trough concentation was 3.8 + 0.2 ng/ml.
Conclusions:
This is one of the largest retrospective studies from India on Membranous Nephropathy which compared various treatment regiments over 60 months follow up period.
Our study showed that there was no statistically significant difference between the different treatment regimens in terms of clinical remission, however complications in form of infections and leukopenia were more common in patients receiving cyclophosphamide. A striking difference from the previous studies was use of concurrent steroid and cyclophosphamide in place of modified Ponticelli regimen (cyclical steroid and cyclophosphamide regimen). The patients receiving CNI had a much lower cumulative steroid exposure when compared to cyclophosphamide group.
I have no potential conflict of interest to disclose.
I did not use generative AI and AI-assisted technologies in the writing process.