Human C3b

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 p16(INK4a) (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.

Background Acquired complement deficiency can occur in the setting of autoimmune syndromes, such as systemic lupus erythematosus (SLE), with very low or, occasionally, undetectable C3 levels. Based on inherited complement defects, patients with transiently low complement may be at similar risk for serious bacterial infection, but the degree of risk related to C3 level and temporal association is unknown. Methods We performed a retrospective study including pediatric patients with undetectable total complement activity or absent individual complement components measured at our institution from 2002 to 2018. We assessed annual rate of serious bacterial infection (SBI) defined as requiring hospitalization and/or parenteral antibiotics by manual chart review. Among included SLE patients, we assessed the 30-day probability of SBI for given C3 measurements using a logistic regression model to determine risk. Primary complement deficiency was analyzed for SBI rate as comparison. Covariates included age, level of immune suppression and history of lupus nephritis. Results Acquired complement deficiency secondary to SLE-related disease [n = 44] was the most common underlying diagnosis associated with depressed complement levels and were compared to a cohort of primary complement deficient patients [n = 18]. SBI per 100 person-years and cohort demographics were described in parallel. Our logistic regression analysis of pediatric patients with SLE showed low C3 level was temporally associated with having an SBI event. Given equivalent immunosuppression, patients with an SBI had lower C3 levels at the beginning of the observation period relative to patients without SBI. Conclusion Pediatric patients with the diagnosis of SLE can develop very low C3 levels that associate with risk of serious bacterial infection comparable to that of patients with primary complement deficiency. Patients prone to severe complement consumption may particularly be at risk.