DelCFHR3-1 influences graft survival in transplant patients with IgA nephropathy via Complement-mediated cellular senescence

IgA nephropathy (IgAN) is a frequent cause of chronic kidney disease (CKD) and progressive renal impairment. A native renal biopsy diagnosis of IgAN is a predictor of graft loss, with a relative risk of 47% but it is difficult to predict graft survival and progressive allograft dysfunction in these patients. Deletion of Complement factor H-related genes 1 and 3 (delCFHR3-1) has been associated with a decreased risk of developing IgAN on native kidneys, but the impact on the graft in IgAN-transplanted patients is unknown. We hypothesized that delCFHR3-1 is also associated with the processes that influence graft survival in transplant recipients with IgAN and tested whether cellular senescence is involved in mediating graft damage. We found that patients carrying two copies of CFHR1-3 had a worse outcome (P =.000321) and presented increased FHR1 deposits at glomerular and tubulointerstitial level associated with higher expression of the senescence marker p16INK4a (P =.001) and tubulointerstitial fibrosis (P =.005). Interestingly, FHR1 deposits were associated with increased Complement activation as demonstrated by C5b-9 deposits. These data support both the role of FHR1 in mediating Complement activation and tubular senescence, and suggest the possibility of genotyping delCFHR3-1 to predict graft survival in IgAN-transplanted patients.