Genetic Study of a Cohort Presenting with Proliferative Glomerulonephritis

Background: Nephritic syndrome is characterized by the acute onset of hematuria, RBC casts, varying degrees of proteinuria, azotemia, hypertension, and oliguria, reflecting glomerular inflammation and injury [1]. Complement level assessment serves as a valuable tool in differentiating etiologies of nephritic syndrome, mainly Thrombotic Microangiopathy (TMA). Genetic mutations are implicated in C3 glomerulopathy. Methods: A prospective, descriptive study evaluated for phenotypical, histopathological & genotypical spectrum of nephritic syndrome and diagnostic role genetic analysis. Kidney biopsy was processed for LM, IF. Genetic analysis by MLPA method was carried out. Results: Ten patients presented with nephritic syndrome, out of which two were post-transplant. Seven (70%) males, six (60%) had pedal oedema, five (50%) had dyspnea, one each with gross hematuria (10%), fever (10%) and rash (10%). Four (40%) had oliguria, three (30%) had anuria and rest three had urine output >800ml/day. eGFR by CKD- EPI was less than 15ml/min/1.73m2 in eight (80%) patients, one had eGFR of 21ml/min/1.73m2 and one presented with 120ml/min/1.73m2. C3 levels were low in four (40%) (Ref. range 80-120 mg/dL), but C4 levels were normal in all patients (Ref. range 10-40 mg/dL). Out of 10 kidney biopsies, seven (70%) had mesangial proliferation, three (30%) revealed changes of TMA. Immunofluorescence revealed ‘3+’ C3 staining in three (30%), ‘2+’ C3 staining in one (10%), ‘1+’ C3 staining in two (20%) and ‘3+’ IgG in one patient. In two graft biopsy, LM exhibited no active glomerular lesions & IF was negative, but showed ct1, ci1 as per Banff classification. Genetic abnormalities were evident in seven (70%). Four (40%) patients had heterozygous deletions, out of which three patients with CFHR1&3 heterozygous deletions, one with CFHR1,3&5 heterozygous deletions. Homozygous CFHR 1&3 deletions were observed in three (30%) patients, rest three had no mutations. Conclusion: Genetic analysis (70%) was more sensitive in diagnosing disease spectrum of proliferative GN, compared to serological complement levels (40%) and histopathological finding (30%) TMA & (40%) C3 deposit. Post transplant patients required renal replacement therapy and had heterozygous deletion. Hence, genetic analysis may help in predicting graft survival, also prognosticating risk for renal transplant recepient and donor selection.