Donor-Specific Antibodies, Glomerulitis, and Human Leukocyte Antigen B Eplet Mismatch Are Risk Factors for Peritubular Capillary C4d Deposition in Renal Allografts
The complement system plays a critical role in the immune response to transplantation, and the diagnostic significance of peritubular capillary (PTC) C4d deposition (C4d+) in renal allografts remains a topic of debate. This study aimed to comprehensively investigate the risk factors for PTC C4d+ and analyze its significance in the biopsy pathology of kidney transplantation. The findings highlight that donor-specific antibodies (DSAs), glomerulitis, and human leukocyte antigen (HLA) B eplet mismatch (MM) are independent risk factors for PTC C4d+ in renal allografts.
Introduction
The complement system is intricately involved in the immune response to transplantation, with C4d serving as a common marker of both the classical antibody-mediated pathway and the non-antibody-mediated lectin pathway. PTC C4d+ is widely recognized as a specific marker of alloantibody-dependent graft injury in kidney allografts and is included in the Banff 2003 diagnostic criteria for antibody-mediated rejection (AMR). However, C4d deposition is not exclusive to AMR; it is also observed in cases of delayed graft function (DGF), T cell-mediated rejection (TCMR), and ischemia-reperfusion injury. This complexity underscores the need for a deeper understanding of the factors contributing to PTC C4d+.
HLA eplet mismatch has emerged as a refined method for determining HLA antigen mismatch, with recent studies suggesting that eplet matching can improve organ selection and reduce the risk of de novo donor-specific antibody (dnDSA) development and graft rejection. Despite these advancements, the relationship between HLA eplet mismatch and PTC C4d+ remains unclear. This study sought to address this gap by analyzing the impact of DSAs, glomerulitis, and HLA eplet mismatch on PTC C4d+ in renal allografts.
Methods
This retrospective study included 124 kidney transplant recipients who underwent graft biopsy and DSA testing between January 2017 and December 2019 at a single center. High-resolution HLA typing was performed using sequence-specific primer technology, and HLA eplet mismatch was assessed using HLAMatchmaker software. Post-transplant monitoring of DSAs was conducted at regular intervals, and serum samples were analyzed using flow cytometry panel reactive antibody (PRA) beads.
Immunosuppression protocols included induction therapy with rabbit anti-human thymocyte globulin (rATG) and maintenance therapy with tacrolimus (TAC) or cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone. Clinically indicated allograft biopsies were performed for patients with proteinuria exceeding 0.5 g/day or a serum creatinine (sCr) increase of more than 25% from baseline. Biopsy samples were evaluated based on Banff 2017 criteria, and C4d deposition was assessed using immunohistochemistry.
Results
Of the 124 cases included in the study, 35 (28%) exhibited PTC C4d+. Among these, 21 cases were diagnosed with AMR, eight with renal tubular injury, three with TCMR, one with glomerular disease, and two with other conditions. Univariate analysis revealed that DSAs, glomerulitis, peritubular capillaritis, and HLA B eplet mismatch were significant influencing factors for PTC C4d+. Multivariate analysis further identified DSAs, glomerulitis, and HLA B eplet mismatch as independent risk factors for PTC C4d+.
The area under the curve (AUC) for predicting PTC C4d+ increased to 0.831 when considering glomerulitis, DSAs, and HLA B eplet mismatch together. The study also found that HLA class I DSAs were predominantly associated with active AMR (aAMR), while HLA class II DSAs were more common in chronic active AMR (caAMR). Additionally, higher PTC C4d+ scores were associated with more severe urinary occult blood and proteinuria at the time of biopsy.
Discussion
The findings of this study underscore the critical role of DSAs, glomerulitis, and HLA B eplet mismatch in the development of PTC C4d+ in renal allografts. DSAs were identified as the primary risk factor, consistent with their role in activating the classical complement pathway and inducing AMR. Glomerulitis, a hallmark of AMR, was also a significant predictor of PTC C4d+, reflecting the immune-mediated damage to the glomerular endothelium.
HLA B eplet mismatch emerged as an independent risk factor, highlighting the importance of HLA matching in reducing the risk of PTC C4d+. While the sample size and follow-up duration of this study were limited, the results suggest that HLA B eplet mismatch contributes to PTC C4d+ by increasing the likelihood of DSAs and AMR. This finding aligns with previous studies demonstrating that HLA eplet mismatch is associated with dnDSA development and graft rejection.
The study also revealed differences in the patterns of PTC C4d+ between aAMR and caAMR. PTC C4d+ was more prevalent in aAMR, with HLA class I DSAs being the predominant antibody type. In contrast, HLA class II DSAs were more common in caAMR, and PTC C4d+ scores were lower in these cases. This observation may reflect differences in the complement activation pathways involved in aAMR and caAMR, with the classical pathway being more prominent in aAMR and the alternative pathway playing a role in caAMR.
The impact of PTC C4d+ on graft function was also explored, with the study finding that PTC C4d+ was associated with more severe urinary occult blood and proteinuria. However, no significant differences were observed in serum creatinine or estimated glomerular filtration rate (eGFR) between PTC C4d+ and PTC C4d0 cases. This discrepancy may be due to the timing of the biopsies, as PTC C4d+ may reflect early immune-mediated damage that has not yet significantly impacted overall graft function.
Limitations and Future Directions
While this study provides valuable insights into the risk factors for PTC C4d+, it has several limitations. The single-center design and relatively small sample size may limit the generalizability of the findings. Additionally, the study did not explore the role of other complement pathways, such as the alternative pathway, which may also contribute to PTC C4d+ in certain cases.
Future research should aim to address these limitations by conducting multicenter studies with larger sample sizes and longer follow-up periods. Additionally, further investigation into the role of different IgG subclasses and complement pathways in PTC C4d+ could provide a more comprehensive understanding of the mechanisms underlying this phenomenon.
Conclusion
In summary, this study identifies DSAs, glomerulitis, and HLA B eplet mismatch as independent risk factors for PTC C4d+ in renal allografts. DSAs were the primary risk factor, reflecting their role in activating the classical complement pathway and inducing AMR. Glomerulitis and HLA B eplet mismatch also contributed to PTC C4d+, highlighting the importance of immune-mediated damage and HLA matching in renal transplantation. The findings underscore the need for comprehensive monitoring of DSAs and HLA eplet mismatch in kidney transplant recipients to reduce the risk of PTC C4d+ and improve graft outcomes.
doi.org/10.1097/CM9.0000000000001685
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