C3 Glomerulopathy Recurs Early after Kidney Transplantation in Serial Biopsies Performed within the First 2 Years after Transplantation

Abstract

Background: C3 glomerulopathy (C3G), which encompasses C3GN and dense deposit disease (DDD), results from dysregulation of the alternative complement pathway. Data on disease recurrence after kidney transplantation are limited, and details on histologic features of recurrent C3G are scarce. We aimed to evaluate C3G recurrence in the allograft, with a focus on histologic presentation and progression.

Methods: We retrospectively analyzed 18 patients with native kidney failure attributed to C3G (12 C3GN and six DDD), who received a kidney transplant from January 2016 to January 2023. Demographic, genetic, clinical, and histologic data were studied. The NanoString 770 genes PanCancer Immune Profiling Panel was used for transcriptomic analysis. Disease recurrence was the primary outcome.

Results: During a median (interquartile range) follow-up period of 37 (18–56) months, C3G recurrence occurred in 16 (89%) patients (11 with C3GN and five with DDD) at a median (interquartile range) of 33 (13–141) days after transplantation. Over a third (38%) of recurrent cases were detected in protocol biopsies, and only 31% of patients presented with >300 mg/g of proteinuria. Recurrence in index biopsies was mainly established through a combination of immunofluorescence and electron microscopy findings, while it showed only subtle histologic alterations and no characteristic transcriptomic signals. Over time, histologic chronicity indices increased, but all the allografts were functioning at the end of follow-up. Patients with recurrence of C3GN and DDD showed overlapping immunofluorescence and electron microscopy findings and had similar recurrence rate and time to recurrence.

Conclusions: Most of the patients with native kidney failure attributed to C3G developed disease recurrence very early after kidney transplantation, usually with minimal proteinuria, mild histologic alterations, and favorable short-term allograft survival. Immunofluorescence and electron microscopy played a crucial role in detecting early, subclinical recurrence of C3GN and DDD, which showed significant overlapping features.

Graphical abstract

Figure 1

Recurrence-free allograft survival. Kaplan–Meier plot of C3G recurrence-free survival in patients with a previous diagnosis of DDD or C3GN (P = 0.4, log-rank). C3G, C3 glomerulopathy; DDD, dense deposit disease.

Figure 2

Histologic findings of patients with post-transplant recurring C3G. (A) Index kidney transplant biopsy performed 26 days after transplantation, showing focal mesangial proliferation with some glomeruli, with no significant increase in mesangial cellularity (A, periodic acid–Schiff, original magnification ×600) and some showing mild mesangial proliferation (B, periodic acid–Schiff, original magnification –×600). (C and D) Immunofluorescence images of index biopsy of patient C3GN4, performed 3 months after transplant, showing C3 in the glomeruli (C) and along tubular basement membranes (D) (original magnification ×400). (E) Electron microscopy (original magnification ×6000) of patient DDD1's index biopsy at 3 weeks after transplant, showing ill-defined and waxy electron-dense deposits.

Figure 3

Transcriptomic analysis of biopsies with C3G. (A) Heat map hierarchical clustering of normalized gene expression in native kidney biopsies with C3G (N=18) and other glomerular diseases (glomerular disease controls, n=36). Each column represents an individual biopsy, and each row represents a single gene. Color indicates normalized counts of each gene, with orange representing higher expression and blue reflecting lower expression. While C3G tends to cluster together, there was no observed difference in clustering among biopsies with C3GN (pink) versus DDD (green). (B) Volcano plot showing differentially expressed genes in native kidney biopsies with C3G versus native glomerular disease controls. The 45 genes with significantly increased and decreased expression in C3G compared with glomerular disease controls are presented in Supplemental Table 3. (C) Total inflammatory leukocytes and (D) relative leukocyte profile score for exhausted CD8 T cells versus total infiltrating leukocytes (P = 0.0007). The latter reached statistical significance using a Bonferroni-corrected cutoff of 0.003. (E) Volcano plot showing differentially expressed genes in allograft kidney biopsies with C3G versus allograft glomerular disease controls. Note that none of the genes demonstrate significant differences in expression.

Figure 4

C3G histologic scores and C3 staining intensity at index biopsy, year 1 biopsy, and year 2 biopsy. Evolution of activity index, chronicity index, and C3 staining intensity of the six patients with biopsies at all the time points. C3 staining of 0.5 is interpreted as± or trace. For DDD2, index biopsy was the year 1 biopsy.