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      Revisiting post-infectious glomerulonephritis in the emerging era of C3 glomerulopathy

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          Abstract

          Background

          Post-infectious glomerulonephritis (PIGN) is an immune complex-mediated glomerular injury that typically resolves. Dominant C3 deposition is characteristic of PIGN, but with the emergence of C3 glomerulonephritis (C3GN) as a distinct entity, it is unclear how the pathologic similarities between PIGN and C3GN should be reconciled. Therefore, nephrologists and nephropathologists need additional guidance at the time of biopsy.

          Methods

          We studied 23 pediatric and young adult patients diagnosed with PIGN. Patients were divided into two groups, one with co-dominance between C3 and immunoglobulins and the other meeting proposed diagnostic criteria for C3GN. Clinical and pathological features were compared.

          Results

          No clinical and/or pathological features could distinguish between those with C3-co-dominant deposits and those with C3 dominance. Nearly all patients in both groups regained their baseline renal function without clinical intervention.

          Conclusions

          Although the identification of abnormalities of the alternative pathway of complement is characteristic of C3GN, testing is not widely available and the turnaround time often exceeds 1 month. Our study found that PIGN with either co-dominant or dominant C3 deposition in a cohort of young patients has excellent short-term outcomes. Close clinical observation for persistent abnormalities, such as hypocomplementemia, prolonged hematuria or proteinuria, is recommended to single out patients that may harbor intrinsic complement abnormalities.

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          Most cited references16

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          C3 glomerulopathy: consensus report

          C3 glomerulopathy is a recently introduced pathological entity whose original definition was glomerular pathology characterized by C3 accumulation with absent or scanty immunoglobulin deposition. In August 2012, an invited group of experts (comprising the authors of this document) in renal pathology, nephrology, complement biology, and complement therapeutics met to discuss C3 glomerulopathy in the first C3 Glomerulopathy Meeting. The objectives were to reach a consensus on: the definition of C3 glomerulopathy, appropriate complement investigations that should be performed in these patients, and how complement therapeutics should be explored in the condition. This meeting report represents the current consensus view of the group.
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            C3 Glomerulonephritis: Clinicopathologic findings, complement abnormalities, glomerular proteomic profile, treatment and follow-up

            C3 Glomerulonephritis (C3GN) is a recently described disorder that typically results from abnormalities in the alternative pathway of complement. Here, we describe the clinical features, kidney biopsy findings, alternative pathway abnormalities, glomerular proteomic profile, and follow-up in 12 cases of C3GN. This disorder equally affected all ages, both genders, and typically presented with hematuria and proteinuria. In both the short and long term, renal function remained stable in the majority of patients with native kidney disease. In two patients, C3GN recurred within one year of transplantation and resulted in a decline in allograft function. Kidney biopsy mainly showed a membranoproliferative pattern; although both mesangial proliferative and diffuse endocapillary proliferative glomerulonephritis were noted. Alternative pathway abnormalities were heterogeneous; both acquired and genetic. The most common acquired abnormality was the presence of C3 nephritic factors, while the most common genetic finding was the presence of H402 and V62 alleles of Factor H. In addition to these risk factors, other abnormalities included Factor H auto-antibodies and mutations in CFH, CFI and CFHR genes. Laser dissection and mass spectrometry of glomeruli from patients with C3GN showed accumulation of alternative pathway and terminal complement complex proteins. Thus, C3GN results from diverse abnormalities of the alternative complement pathway leading to subsequent glomerular injury.
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              C3 glomerulopathy: clinicopathologic features and predictors of outcome.

              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. 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. 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. 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.
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                Author and article information

                Journal
                Clin Kidney J
                Clin Kidney J
                ckj
                ndtplus
                Clinical Kidney Journal
                Oxford University Press
                2048-8505
                2048-8513
                June 2016
                17 May 2016
                17 May 2016
                : 9
                : 3
                : 397-402
                Affiliations
                [1 ]Department of Pathology, University of Chicago , Chicago, IL, USA
                [2 ]Department of Pathology, University of Utah , Salt Lake City, UT, USA
                [3 ]Division of Kidney Diseases, Lurie Children's Hospital , Chicago, IL, USA
                Author notes
                Correspondence and offprint requests to: Mazdak A. Khalighi; E-mail: mazdak.khalighi@ 123456hsc.utah.edu
                Article
                sfw032
                10.1093/ckj/sfw032
                4886922
                27274823
                9edb934c-dff0-4d84-aebe-a244ba34a605
                © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 17 February 2016
                : 25 March 2016
                Categories
                Glomerulonephritis

                Nephrology
                alternative pathway,complement
                Nephrology
                alternative pathway, complement

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