C4d deposition in acute rejection: an independent long-term prognostic factor
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Published on: March 20, 2026
Andrew M Herzenberg1, John S Gill1, Ognjenka Djurdjev1
1Departments of *Pathology and Laboratory Medicine and Medicine and Centre for Health Evaluation and Outcome Sciences, St. Paul's Hospital, and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Insights
Peritubular C4d deposition in kidney transplants predicts lower graft survival. This finding is independent of rejection type and other clinical factors, highlighting its importance in predicting long-term outcomes.
Area of Science:
- Nephrology
- Transplantation Immunology
- Pathology
Background:
- Peritubular capillary C4d deposition is linked to acute rejection and graft loss.
- Its independent role in long-term graft survival remains unclear.
Purpose of the Study:
- To determine if peritubular C4d deposition independently predicts long-term graft survival rates.
- To assess the association of C4d deposition with different types of acute rejection.
Main Methods:
- Retrospective analysis of 126 biopsies from 93 kidney transplant patients diagnosed with acute rejection.
- Immunostaining for C4d on fresh frozen tissue.
- Classification of rejection using Cooperative Clinical Trials in Transplantation (CCTT) criteria.
- Multivariate analyses to identify independent predictors of graft survival.
Main Results:
- 34 patients (C4d+ group) showed peritubular C4d deposition.
- The C4d+ group had higher rates of graft loss (38% vs. 7%) and associated with female patients, high panel-reactive antibody levels, and resistance to therapy.
- Peritubular C4d deposition was associated with significantly lower graft survival in both CCTT type I (interstitial) and type II (vascular) rejection.
- Multivariate analysis identified C4d deposition, donor age, cold ischemic time, and HLA matches as independent determinants of graft survival.
Conclusions:
- Peritubular C4d deposition is a significant independent predictor of kidney graft survival.
- This association holds true regardless of the histologic rejection type or other clinical prognostic factors.
Abstract:
Peritubular capillary deposition of C4d has been demonstrated to be associated with both acute humoral and vascular rejection and increased graft loss. Whether it is an independent predictor of long-term graft survival rates is uncertain. The biopsies (n = 126) from all patients (n = 93) with a tissue diagnosis of acute rejection that were performed between July 1, 1995, and December 31, 1997, were classified according to Cooperative Clinical Trials in Transplantation (CCTT) criteria. Fresh frozen tissue was immunostained for C4d. There were 58 patients with CCTT type I (interstitial) rejection and 35 with CCTT type II (vascular) rejection. For 34 patients, at least one biopsy exhibited peritubular C4d deposition (C4d+ group). The C4d+ group had proportionately more female patients (P = 0.003), more patients with high (>30%) panel-reactive antibody levels (P = 0.024), more patients with resistance to conventional antirejection therapy (P = 0.010), and fewer patients with postrejection hypertension (P = 0.021) and exhibited a greater rate of graft loss (38 versus 7%, P = 0.001). Peritubular C4d deposition was associated with significantly lower graft survival rates in the CCTT type I rejection group (P = 0.003) and the CCTT type II rejection group (P = 0.003). Multivariate analyses demonstrated that peritubular C4d deposition (P = 0.0002), donor age (P = 0.0002), cold ischemic time (P = 0.0211), and HLA matches (P = 0.0460) were significant independent determinants of graft survival rates. Peritubular C4d deposition is a significant predictor of graft survival rates and is independent of histologic rejection type and a variety of clinical prognostic factors.