C3 glomerulopathy post kidney transplantation: A single center experience

Abstract

Background: C3 glomerulopathies (C3G) are a rare cause of kidney failure resulting from complement dysregulation. Small studies demonstrate a high rate of recurrence and poor outcomes in kidney transplantation. Treatment efficacy in this setting with eculizumab, a terminal complement inhibitor, is largely unknown.

Aim: To determine the outcomes of kidney transplantation in patients with C3G and the potential impact of eculizumab.

Methods: We retrospectively studied kidney transplant recipients who underwent a post-transplant biopsy confirming C3G between January 1, 1993 and December 31, 2023 at a single center. Only the first episode of kidney transplant was reviewed. The electronic medical records were reviewed for post-transplant allograft function, indication for biopsy, time to biopsy from transplant, time to allograft failure from transplantation, post-C3G treatment, complement laboratory testing, and concurrent malignancy/infection. Reports, and when available slides and immunofluorescence/electron microscopic images, were re-reviewed by a renal pathologist.

Results: A total of fifteen patients were included in this study. Fourteen patients had suspected recurrent disease, with a pre-transplant native kidney report of C3G. One patient developed de novo C3G. Median post kidney transplant clinical follow up time was 91 months. Median time to recurrence was 7 months with median graft survival of 48 months post kidney transplantation. The most common index biopsy pattern of injury was endocapillary proliferative glomerulonephritis (often with exudative features) with or without mesangial hypercellularity (56%) followed by membranoproliferative glomerulonephritis (25%). Most patients developed membranoproliferative glomerulonephritis pattern of injury on follow up biopsies (63%). Seven patients with recurrent disease received treatment with eculizumab with a median graft survival of 73 months, with five functioning grafts by the end of the study period. Seven patients with recurrent disease did not receive therapy, and all lost their graft with a median graft survival of 22 months (P = 0.003).

Conclusion: C3G following kidney transplantation is mostly a recurrent disorder with a poor prognosis in untreated patients. Untreated recurrence has a poor prognosis with median allograft survival < 2 years. Early treatment with eculizumab may improve transplant outcomes in patients with recurrent C3G.

Keywords: C3 glomerulonephritis; C3 glomerulopathy; Complement disorder; Dense deposit disease; Kidney transplant; Recurrent disease; Renal pathology, Kidney biopsy.

Figure 1

Recurrence-free survival in C3 glomerulonephritis and dense deposit disease recurrence cases. P = 0.424, log-rank test. C3GN: C3 glomerulonephritis; DDD: Dense deposit disease.

Figure 2

Representative histologic findings of patients with post-transplant recurring C3 glomerulopathies. A: Glomerulus from patient C3 glomerulonephritis-3 (C3GN-3). 4 months post-transplant demonstrating global endocapillary hypercellularity with neutrophil margination (exudative pattern) (Hematoxylin and eosin stain, original magnification 400 ×); B: Glomerulus from patient dense deposit disease-8. 2 months post-transplant demonstrating mild neutrophilic endocapillary hypercellularity and a segmental cellular crescent (arrow) (Periodic acid-Schiff stain, original magnification 400 ×); C: Glomeruli from patient C3GN-1. 38 months post-transplant demonstrating well developed membranoproliferative glomerulonephritis pattern of injury (Jones silver stain, original magnification 400×); D: 4+ global granular to smudgy mesangial and capillary wall immunofluorescence staining with C3 (400 ×); E: Electron micrograph from patient C3GN-1. 12 months post-transplant demonstrating large subepithelial “hump-like” granular deposits (arrows) (original magnification 4000 ×); F: Electron micrograph from patient dense deposit disease-8. 2 months post-transplant demonstrating extensive highly osmiophilic intramembranous fusiform deposits (arrow) (original magnification 2500 ×).

Figure 3

Death censored allograft survival from index biopsy in C3 glomerulopathies recurrence untreated and treated cohorts. The patients in the treatment cohort received steroids (n = 1), eculizumab (n = 4), or eculizumab and plasmapheresis (n = 2). P = 0.003, log-rank test.