C3 Glomerulopathy

Nicholas R. Medjeral-Thomas1,2, Michelle M. O’Shaughnessy3, John O’Regan3, Carol Traynor3, Michael Flanagan3, Limy Wong3, Chia Wei Teoh4, Atif Awan4, Mary Waldron5, Tom Cairns2, Patrick O’Kelly3, Anthony Dorman6, Matthew C. Pickering1, Peter J. Conlon3, H. Terence Cook1,2
1Centre for Complement and Inflammation Research, Imperial College, London, United Kingdom
2West London Renal and Transplant Centre, Imperial College Healthcare National Health Service Trust, London, United Kingdom
3Department of Transplant, Urology and Nephrology, Beaumont Hospital, Dublin, Ireland
4Children's University Hospital, Temple Street, Dublin, Ireland
5Our Lady's Children's Hospital, Crumlin, Dublin, Ireland
6Department of Renal Pathology, Beaumont Hospital, Royal College of Surgeons in Ireland, Dublin, Ireland

Tóm tắt

Summary Background 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.

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Tài liệu tham khảo

Walport, 2001, Complement. First of two parts., N Engl J Med, 344, 1058, 10.1056/NEJM200104053441406

Rodríguez de Córdoba, 2004, The human complement factor H: Functional roles, genetic variations and disease associations., Mol Immunol, 41, 355, 10.1016/j.molimm.2004.02.005

Appel, 2005, Membranoproliferative glomerulonephritis type II (dense deposit disease): An update., J Am Soc Nephrol, 16, 1392, 10.1681/ASN.2005010078

Fakhouri, 2010, C3 glomerulopathy: A new classification., Nat Rev Nephrol, 6, 494, 10.1038/nrneph.2010.85

Barbour, 2013, Recent insights into C3 glomerulopathy., Nephrol Dial Transplant, 28, 1685, 10.1093/ndt/gfs430

Gale, 2010, Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis., Lancet, 376, 794, 10.1016/S0140-6736(10)60670-8

Servais, 2012, Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies., Kidney Int, 82, 454, 10.1038/ki.2012.63

Sethi, 2012, C3 glomerulonephritis: Clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up., Kidney Int, 82, 465, 10.1038/ki.2012.212

Nasr, 2009, Dense deposit disease: Clinicopathologic study of 32 pediatric and adult patients., Clin J Am Soc Nephrol, 4, 22, 10.2215/CJN.03480708

Vernon, 2012, Acute presentation and persistent glomerulonephritis following streptococcal infection in a patient with heterozygous complement factor H-related protein 5 deficiency., Am J Kidney Dis, 60, 121, 10.1053/j.ajkd.2012.02.329

Sethi, 2013, Atypical postinfectious glomerulonephritis is associated with abnormalities in the alternative pathway of complement., Kidney Int, 83, 293, 10.1038/ki.2012.384

Little, 2006, Severity of primary MPGN, rather than MPGN type, determines renal survival and post-transplantation recurrence risk., Kidney Int, 69, 504, 10.1038/sj.ki.5000084

Licht, 2005, Successful plasma therapy for atypical hemolytic uremic syndrome caused by factor H deficiency owing to a novel mutation in the complement cofactor protein domain 15., Am J Kidney Dis, 45, 415, 10.1053/j.ajkd.2004.10.018

Bomback, 2012, Eculizumab for dense deposit disease and C3 glomerulonephritis., Clin J Am Soc Nephrol, 7, 748, 10.2215/CJN.12901211

Daina, 2012, Eculizumab in a patient with dense-deposit disease., N Engl J Med, 366, 1161, 10.1056/NEJMc1112273

McCaughan, 2012, Recurrent dense deposit disease after renal transplantation: An emerging role for complementary therapies., Am J Transplant, 12, 1046, 10.1111/j.1600-6143.2011.03923.x

Vivarelli, 2012, Eculizumab for the treatment of dense-deposit disease., N Engl J Med, 366, 1163, 10.1056/NEJMc1111953