GENETIC DETERMINANTS AND PROGNOSTIC PREDICTORS OF C3 GLOMERULOPATHY AND COMPLEMENT-MEDIATED TMA:  PROSPECTIVE OBSERVATIONAL INDIAN STUDY

Complement-mediated kidney diseases, including C3 glomerulopathy (C3G) and complement-mediated thrombotic microangiopathy (c-TMA), result from dysregulation of the alternative complement pathway. Genetic variants in complement genes contribute substantially to disease pathogenesis, prognosis, and risk of recurrence, but data on Indian populations remain limited. This study aimed to comprehensively analyze genetic mutations, clinical features, and prognostic predictors in biopsy-proven C3G and c-TMA.

A single-centre, prospective observational study was conducted at the Institute of Nephro-Urology, Bengaluru, India, from January 2022 to April 2025. Inclusion criteria: patients with biopsy-proven C3G (C3>2 orders than any Ig) and complement-mediated TMA (hematologic, renal, or biopsy findings). Exclusions: autoimmune conditions, infections, paraproteinemia, monoclonal gammopathy, malignancy, dual diagnoses, lost follow-up, or lack of consent. Genomic evaluation used whole-exome sequencing and multiplex ligation-dependent probe analysis, with reporting per ACMG guidelines. Clinical, biochemical, and treatment data were systematically recorded and patients were followed up for a minimum period of 12 months. Outcomes: complete remission (functional and biochemical recovery), partial remission, end-stage kidney disease (ESKD), and mortality.

73 patients (C3G n=25, c-TMA n=48) were enrolled. c-TMA cases were younger (mean age 29 vs. 38), with more AKI and systemic TMA (68% vs. 4%). Frothy urine and nephrotic syndrome were exclusive to C3G. Laboratory analysis revealed significantly higher serum creatinine and urea, lower hemoglobin and platelet counts in c-TMA, while C3G had higher proteinuria. No significant difference in serum C3/C4 levels. Need for hemodialysis and plasmapheresis was markedly elevated in c-TMA (75% and 62.5% vs. 16% each for C3G). Complete remission rate was better in c-TMA (52% vs. 28%, p=0.03), while ESKD rates were similar. Mortality occurred exclusively in c-TMA (12.5%). Genetic analysis detected higher prevalence of pathogenic mutations in c-TMA (83%) than C3G (56%). Monogenic mutations predominated, with CFHR1-CFHR3 deletions most common, potentially associated with better prognosis. Rare mutations associated with C3G - ANLN, NPHP1, CD46, THBD, were identified. Digenic mutations were also seen.Limitations - single centre study and electron microscopy was not done due to financial constraints.

c-TMA in Indian patients has a younger demographic, more severe clinical presentation, and higher prevalence of genetic mutations, particularly CFHR1-CFHR3 deletions, than C3G. Exclusive mortality in c-TMA underscores its aggressive nature, demanding early genetic testing and personalized therapy. Novel mutations were identified. Proteinuria above 1g/day was a poor prognostic marker in c-TMA. Findings affirm urgent need for improved diagnostic and management strategies for complement-mediated renal diseases in resource-limited settings.