C3 glomerulopathy (C3G) is a rare, progressive disease that commonly leads to end-stage renal disease (ESRD). C3G is a form of glomerulonephritis (GN) associated with dysregulation of the alternative complement pathway. C3 dominance with minimal or absent immunoglobulin deposition on immunofluorescence staining is the defining histological finding for C3G. Findings on light microscopy include patterns of membranoproliferative GN (MPGN), mesangioproliferative GN, diffuse endocapillary proliferative GN, or crescentic GN.
The absence or presence of intramembranous highly electron-dense deposits on electron microscopy divides C3G into C3GN or dense deposit disease (DDD), respectively. More than 50% of patients with either C3GN and DDD progress to ESRD within the first two decades of diagnosis.
Due to the rarity of C3G, there are few available data on the results of kidney transplantation in patients with this disease. Renu Regunathan-Shenk, MD, and colleagues presented a case series of 19 patients with C3G (both C3GN and DDD). The series was reported in the American Journal of Kidney Diseases [2019;73(3):316-323].
The case series included 19 patients evaluated at the Columbia University Medical Center (New York, New York) who received a kidney allograft between 1999 and 2016. The outcomes of interest were (1) time to recurrence, recorded as time from transplantation to biopsy diagnosis of true or probable recurrent disease; and (2) time to graft failure, defined as estimated glomerular filtration rate <15 mL/min/1.73m2 using the Modification of Diet in Renal Disease Study equation, initiation of dialysis therapy, or repeat transplantation. Follow-up continued until the final clinical encounter or death.
The date of the initial native biopsy was considered the date of diagnosis and follow-up after transplantation continued from the date of the transplantation to the last available clinical data. Data were presented as median and range based on the sample size of the case series.
Of the 19 patients in the case series, 12 had C3GN and seven had DDD. Approximately half of the patients underwent kidney transplantation in outside institutions. Among the C3GN group, median age at native biopsy diagnosis was 22 years (range, 12-60 years); among the patients with DDD, median age at native biopsy diagnosis was 30 years (range, 7-60 years). Median time from biopsy to ESRD among the patients with C3GN was 48 months (range, 0-190 months); among the DDD group, it was 37 months (range, 3-118 months).
A total of 14 patients (8, C3GN; and 6, DDD) received some form of immunosuppression prior to reaching ESRD. Six patients in the C3GN group and five in the DDD group received dialysis prior to transplantation. Nine of the 11 patients in the C3GN group and five of the seven in the DDD group underwent living door transplants; of those, nine were living related transplants and five were living unrelated transplants.
Ten patients were screened for complement-associated mutations and antibodies. Of those, eight had an identified abnormality in the alternate complement pathway (3 in the C3GN group and 5 in the DDD group). Five tested positive for the presence of C3 nephritic factor and one for a C5 nephritic factor. Patient DDD3 had an autoantibody to factor I deficiency and DDD1 had an autoantibody to factor H. Three of the 10 screened patients had known or potential genetic risk factors.
Median follow-up was 76 months. During follow-up, 16 of the 19 patients had recurrent C3G disease (10/12 with C3GN and 6/7 with DDD). Of the 10 C3GN patients, eight had true and two had probable recurrence. Of the six DDD patients, four had true and two had probable recurrence.
During the 76 months of median follow-up, the overall percentage of graft failure was 47% (n=9/19), including three of 12 patients in the C3GN group (2/3 with true recurrence) and six of seven patients in the DDD group (4/6 with true recurrence).
Seven patients received eculizumab for recurrent disease; of those, five experienced graft failure. All of the three graft failures in the C3GN group and four of the six in the DDD group were attributed to recurrent disease.
The median time from transplantation to graft failure was 42 months (range, 0-91 months). Median time from transplantation to graft failure in the C3GN group was 59 months (range, 27-91 months); in the DDD group, median time from transplantation to graft failure was 41 months (range, 0-71 months). During the follow-up period, three patients underwent retransplantation.
The retrospective design and small sample size are the primary limitations to the study. In addition, there was no central review of biopsy material.
“Despite the limitations, this series is one of the largest posttransplantation experiences in this rare disease and is particularly reflective of current developments in complement testing and complement-directed therapies. Disease recurrence was frequent in patients with C3GN and DDD, although graft loss appeared to occur more often in DDD. The proportion of graft failure remained high despite advancements in complement-directed therapy. Overall, our data show that the current available therapies have had limited success in treating disease recurrence and that more anticomplement therapies are desperately needed,” the researchers said.
Takeaway Points
- C3 glomerulopathy (C3G) is a rare form of glomerulonephritis (GN); researchers present a case series of clinical outcomes in a cohort of 19 patients with C3G who underwent kidney transplantation from 1999 to 2016.
- Twelve of the patients had C3GN and seven had dense deposit disease (DDD). During follow-up (median, 76 months), 10 patients with C3GN and six with DDD had recurrent disease.
- Graft failure was more frequent in patients with DDD (n=6/7) than in patients with C3GN (n=3/12).
