C3 Glomerulopathy

Abstract

SummaryBackground and objectives The term C3 glomerulopathy describes renal disorders characterized by the presence of glomerular deposits composed of C3 in the absence of significant amounts of Ig. On the basis of electron microscopy appearance, subsets of C3 glomerulopathy include dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). The full spectrum of histologic change observed in C3 glomerulopathy has yet to be defined and pathologic predictors of renal outcome within this patient population remain largely unknown. This study thus characterized a large C3 glomerulopathy cohort and identified clinicopathologic predictors of renal outcome.Design, setting, participants, & measurements All patients with kidney biopsies fulfilling criteria for C3 glomerulopathy from two quaternary renal centers within the United Kingdom and Ireland between 1992 and 2012 were retrospectively reviewed. We recorded histologic, demographic, and clinical data and determined predictors of ESRD using the Cox proportional hazards model.Results Eighty patients with C3 glomerulopathy were identified: 21 with DDD and 59 with C3GN. Patients with DDD were younger, more likely to have low serum C3 levels, and more likely to have crescentic GN than patients with C3GN. Patients with C3GN were older and had more severe arteriolar sclerosis, glomerular sclerosis, and interstitial scarring than patients with DDD. Of 70 patients with available follow-up data, 20 (29%) progressed to ESRD after a median of 28 months. Age .16 years, DDD subtype, and crescentic GN were independent predictors of ESRD within the entire cohort. Renal impairment at presentation predicted ESRD only among patients with DDD.Conclusions Although detailed serologic and genetic data are lacking, this study nevertheless identifies important clinicopathologic distinctions between patients with DDD and C3GN. These include independent predictors of renal outcome. If replicated in other cohorts, these predictors could be used to stratify patients, enabling application of emerging mechanism-based therapies to patients at high risk for poor renal outcome.

The role of the alternative pathway of complement activation in glomerular diseases

“…C3G is a sporadic disease (~ 2 per million), which is characterized by predominant glomerular deposits of C3 in the absence of a significant amount of Ig on immunofluorescence (IF) [8,10,81]. Based on electron microscopy (EM), it is further divided into DDD and C3 glomerulonephritis (C3GN).…”

“…In general, the prognosis in C3GN is very poor with 23% patients progressing to the ESRD during a median follow-up period of 28 months [82,85]. DDD is a rare entity usually diagnosed in early childhood, affecting both genders equally [62,81]. Clinically, it presents with hematuria (76-89%) and subnephrotic proteinuria, but acute nephritic or nephrotic syndrome may also occur.…”

“…Clinically, it presents with hematuria (76-89%) and subnephrotic proteinuria, but acute nephritic or nephrotic syndrome may also occur. In most affected individuals, it leads to ESRD (in approximately half of the patients within 10 years from diagnosis) [81,84]. Features of (PD), diabetes mellitus type 1, and ocular drusen can accompany DDD, but they have not been reported in C3GN [84].…”

“…PD is a condition appearing in early childhood, characterized by bilaterally symmetrical loss of subcutaneous facial and upper extremity fat. It is a result of complement activation in the adipose tissue [81]. PD usually precedes the DDD onset, and it has been estimated that approximately 22% of PD patients develop DDD during 8 years from the diagnosis [85].…”

American Society of Nephrology Clinical Pathological Conference

“…It is very likely that this patient has a C3GN. In light of the rapid increase in the serum creatinine concentration, she might well have the more unusual form of MPGN/C3GN that is associated with presence of crescents (20)(21)(22). The C3GNs are associated with disorders of the alternate complement regulatory pathway (13).…”