C3 glomerulonephritis secondary to mutations in factors H and I: rapid recurrence in deceased donor kidney transplant effectively treated with eculizumab

Neetika Garg; Yuzhou Zhang; Anne Nicholson-Weller; Eliyahu V Khankin; Nicolò Ghiringhelli Borsa; Nicole C Meyer; Susan McDermott; Isaac E Stillman; Helmut G Rennke; Richard J Smith; Martha Pavlakis

doi:10.1093/ndt/gfx369

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C3 glomerulonephritis secondary to mutations in factors H and I: rapid recurrence in deceased donor kidney transplant effectively treated with eculizumab

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C3 glomerulonephritis secondary to mutations in factors H and I: rapid recurrence in deceased donor kidney transplant effectively treated with eculizumab

Neetika Garg, Yuzhou Zhang, Anne Nicholson-Weller, Eliyahu V Khankin, Nicolò Ghiringhelli Borsa, Nicole C Meyer, Susan McDermott, Isaac E Stillman, Helmut G Rennke, Richard J Smith, …

Nephrology, dialysis, transplantation, Vol.33(12), pp.2260-2265

12/01/2018

DOI: 10.1093/ndt/gfx369

PMCID: PMC6275145

PMID: 29370420

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Abstract

C3 glomerulonephritis (C3GN) is caused by alternate complement pathway over-activation. It frequently progresses to end-stage renal disease, recurs in two-thirds of transplants and in half of these cases progresses to allograft loss. There is currently no proven treatment for C3GN. We describe a family segregating pathogenic alleles of complement factor H and I (CFH and CFI). The only member carrying both mutations developed C3GN. Prolonged delayed graft function after deceased donor transplantation, heavy proteinuria and isolated C3 hypocomplementemia prompted an allograft biopsy confirming diagnosis of recurrent C3GN. This is the first report of early recurrence of C3GN in an allograft in a patient with known mutations in complement regulatory genes and no preexisting para-proteinemia. Complement activation resulting from ischemia-reperfusion injury from prolonged cold ischemia time unabated in the setting of deficiency of two major complement regulators likely led to the early and severe recurrence. In atypical hemolytic uremic syndrome, the terminal complement cascade activation in the sentinel event initiating endothelial injury; blockade at the level of C5 convertase with eculizumab is uniformly highly effective in management. C3 glomerulopathies (C3GN and dense deposit disease) are a more complex and heterogeneous group. The relative degree of dysregulation at the levels of C3 and C5 convertases and therefore response to eculizumab varies among patients. In our patient, the clinical response to eculizumab was dramatic with recovery of allograft function and complete resolution of proteinuria. We review all cases of recurrent C3 glomerulopathy treated with eculizumab and discuss how complement biomarkers may aid in predicting response to therapy.

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Title: Subtitle: C3 glomerulonephritis secondary to mutations in factors H and I: rapid recurrence in deceased donor kidney transplant effectively treated with eculizumab
Creators: Neetika Garg - Department of Medicine, Nephrology Division, Beth Israel Deaconess Medical Center, Boston, MA, USA
Yuzhou Zhang - Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Anne Nicholson-Weller - Department of Medicine, Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, MA, USA
Eliyahu V Khankin - Department of Medicine, Nephrology Division, Beth Israel Deaconess Medical Center, Boston, MA, USA
Nicolò Ghiringhelli Borsa - Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Nicole C Meyer - Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Susan McDermott - Department of Medicine, Nephrology Division, Beth Israel Deaconess Medical Center, Boston, MA, USA
Isaac E Stillman - Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
Helmut G Rennke - Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
Richard J Smith - Iowa Institute of Human Genetics, University of Iowa, Iowa City, IA, USA
Martha Pavlakis - Department of Medicine, Nephrology Division, Beth Israel Deaconess Medical Center, Boston, MA, USA
Resource Type: Journal article
Publication Details: Nephrology, dialysis, transplantation, Vol.33(12), pp.2260-2265
DOI: 10.1093/ndt/gfx369
PMID: 29370420
PMCID: PMC6275145
NLM abbreviation: Nephrol Dial Transplant
ISSN: 0931-0509
eISSN: 1460-2385
Publisher: England
Grant note: K08 DK101560 / NIDDK NIH HHS R01 DK110023 / NIDDK NIH HHS
Language: English
Date published: 12/01/2018
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
Record Identifier: 9984006493502771

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