C3 Glomerulopathy: Clinicopathologic Features and Predictors of Outcome

Discussion

This study provides a detailed description of the histopathologic features observed in a large cohort of patients with C3 glomerulopathy. Consistent with previous reports (5,10), our analysis demonstrates that a membranoproliferative pattern of injury is not universal in C3 glomerulopathy and that both DDD and C3GN recur after renal transplantation, often resulting in allograft loss. We found low serum C3 levels with preserved serum C4 levels to be frequent but not universal among patients with C3 glomerulopathy.

We identified key clinicopathologic differences between patients with DDD and 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 on renal biopsy than patients with DDD. Older age, crescentic GN, and DDD subtype were independent predictors of ESRD. Renal impairment at the time of renal biopsy predicted a poor prognosis only in patients with DDD.

These findings have important clinical implications. Patients presenting with multiple poor prognostic markers (age ≥16 years, DDD, crescentic GN, and renal impairment) are at high risk for progression to ESRD. Such patients should be counseled appropriately and targeted for aggressive intervention. Patients with C3 glomerulopathy planning to undergo renal transplantation should be informed that their disease can recur and cause allograft failure after transplantation.

We were particularly interested in examining differences between patients with DDD and C3GN. Patients with DDD presented more acutely (with crescentic GN), at a younger age, and were more likely to progress to ESRD than patients with C3GN, demonstrating that C3 glomerulopathy is a heterogeneous disorder and suggesting that DDD is the clinically more aggressive subtype. This heterogeneity may result from a combination of genetic and environmental factors. In the case of DDD, the responsible acquired or genetic defect may cause particularly profound dysregulation of the alternative complement pathway, resulting in a rapidly progressive disease course. Conversely, as was observed in our cohort, patients with C3GN may present more indolently, allowing time for histologic markers of chronicity (interstitial fibrosis, glomerulosclerosis) to develop before renal biopsy.

We discovered some incidental EM findings of particular interest. The presence of intramembranous deposits lacking the “classic” DDD appearance in a substantial proportion of patients with C3GN may imply that deposit morphology better informs our understanding of disease pathogenesis than deposit location. The restriction of tubular basement membrane and Bowman’s capsular basement membrane deposits to the DDD subgroup may also provide a clue to differences in underlying pathogenesis.

Another interesting observation was the high frequency of elevated ASOT among patients with DDD and C3GN, suggesting that infection may trigger exacerbations of renal disease in patients with C3 glomerulopathy. We included some patients who were initially diagnosed as having postinfectious GN but with persistent renal or complement dysfunction in our analysis, because these patients are likely to represent true cases of C3 glomerulopathy (14). However, we excluded patients who achieved complete recovery of their renal function after resolution of their infection because, at this time, we feel that inclusion of such patients may compromise our study’s validity and clinical applicability. Our findings highlight the importance of considering a diagnosis of C3 glomerulopathy in patients with apparent postinfectious GN, however, particularly if the patient’s clinical history is atypical and regardless of the presence or absence of a history of preceding infective symptoms or subepithelial humps on EM. Our data also support a role for complement dysfunction in the pathogenesis of postinfectious GN and suggest that postinfectious GN could potentially be considered within the spectrum of C3 glomerulopathy (14).

The comparison of our patient cohort with previously reported cohorts of patients with C3 glomerulopathy reveals striking similarities. Our data are consistent with existing literature describing C3 glomerulopathy as a disease that presents with hematuria and proteinuria (6,13), predominantly in young adults (6,13), without a significant sex predilection (6,13), and with progression to ESRD in approximately one-third of patients (9). As was observed in our study, a previous report suggested that patients with DDD were younger, more likely to have low serum C3 levels, and more likely to progress to ESRD than patients with C3GN (13). Furthermore, age and serum creatinine at the time of biopsy were also identified as predictors of ESRD in a previously described cohort of patients with DDD (11). Finally, a study of Irish patients with membranoproliferative GN, some with C3 glomerulopathy, also identified serum creatinine at presentation and crescents on biopsy as strong predictors of ESRD (15).

Our study is novel in a number of respects. It provides a comprehensive description of the histologic features, including EM findings, observed among patients with heterogeneous forms of C3 glomerulopathy. It also provides a detailed comparison of pathologic differences between DDD and C3GN and associates histologic features with renal prognosis. Finally, it is the first report to provide an estimate of disease incidence, confirming the status of C3 glomerulopathy as a rare kidney disease.

This study is not without limitations. As a retrospective study, data may be incomplete. In particular, treatment details were inadequately documented in some cases, which may explain why, in contrast with previous reports (9,11), we did not identify an effect of treatment on renal outcome. It is also noteworthy that only three patients received plasma exchange, a therapeutic option for DDD patients with specific CFH mutations (16). Similarly, no patient received eculizumab, an anti-complement therapy recently reported to mitigate disease in selected patients with C3 glomerulopathy (17–20). Another limitation is that we were unable to collect a sufficient number of patients to allow for multiple intergroup comparisons. Consequently, important differences between subgroups or novel predictors of renal outcome may have gone undetected. Patients' height from the time of original presentation were not available, prohibiting calculation of estimated GFRs in children.

The diagnostic criteria we adopted for C3 glomerulopathy were stricter than those recently developed by a C3 glomerulopathy consensus group (Pickering et al., 2013, Unpublished data). Specifically, we excluded patients with any amount of IgG or IgA positivity on immunostaining and allowed only weak (1+) IgM staining. This contrasts with the consensus group statement that suggests that biopsies containing IgM, IgG, or IgA can still be considered to be C3 dominant glomerulonephritis if the intensity of the C3 staining is at least two orders of magnitude greater than that of any other immune reactant. Due to the inception of our study before the development of these consensus group criteria, combined with our desire to describe as well defined a cohort as possible, we accept that we may have excluded a small number of true cases of C3 glomerulopathy and consequently that our disease incidence estimate may be overly conservative. However, we feel the adoption of such strict exclusion criteria strengthens our findings because they are derived from a relatively pure population of patients who not only meet existing established criteria for a diagnosis of C3 glomerulopathy but who also now clearly meet the proposed consensus group criteria.

A major limitation of this study is the fact that few patients have undergone genetic and serologic testing for inherited and acquired abnormalities of alternative complement pathway regulation. Consequently, we cannot comment on underlying disease mechanisms or whether the presence of specific genetic or serologic markers can predict prognosis. This limitation reflects the rarity of C3 glomerulopathy and consequently our need to retrospectively collect patients from a large catchment population over 20 years, some of whom are no longer alive or contactable. We are at present inviting all surviving patients to centrally undergo serum and DNA collection and will report emerging results in due course. We at the same time recognize that such genotyping and detailed serologic analyses are not readily available at many centers, nor has the clinical utility of such testing been proven. Therefore, the absence of genetic and serologic data in this study may not necessarily detract from the clinical applicability of our findings.

In summary, we have described clinical and pathologic findings among a large cohort of patients with C3 glomerulopathy. We have observed important clinicopathologic distinctions between patients with DDD and C3GN and have identified independent predictors of renal outcome within this population. These data are particularly relevant when considering emerging complement therapeutic interventions, because understanding the natural history of this rare disease is a prerequisite for optimal trial design and patient selection.