Preformed Donor-Specific Antibodies and Risk of Antibody-Mediated Rejection in Repeat Renal Transplantation

BACKGROUND: Allograft outcomes in patients undergoing repeat renal transplantation are inferior compared to first-time transplant recipient outcomes. Donor-specific antibodies detected by solid-phase assays (DSA-SPA) may contribute to the worse prognosis. The influence of DSA-SPA on repeat renal transplantation outcomes has not been previously studied in detail.
DESIGN: This study reports the findings in 174 patients who underwent repeat renal transplantation between years 2007 and 2012. These included 62 patients with preformed DSA-SPA detected by Luminex at the time of transplantation. Patients received standard and consistent immunosuppression and were monitored closely for evidence of rejection. Recipients who underwent desensitization were excluded from this analysis. Endpoints included development of biopsy-proven acute rejection and analysis of graft survival and function.
RESULTS: Patients in the DSA-SPA-positive and DSA-SPA-negative groups received similar immunosuppression, and a similar proportion of recipients had a peak panel reactive antibody greater than 20%; the two groups differed with respect to human leukocyte antigen mismatches (4.7±1.1 vs. 4.1±1.7, P=0.024). Recipients with preformed DSA-SPA had higher rejection rates (54.8% vs. 34.8%, P=0.01), including higher rates of antibody-mediated rejection (AMR) (32.3% vs. 7.1%, P<0.001). Recipients who were DSA-SPA-positive and flow cytometry crossmatch (FCXM)-positive had a higher incidence of both AMR (OR 4.6, P=0.009) and of acute rejection (OR 3.57, P=0.02) as compared to those who were DSA-SPA-positive and FCXM-negative. Overall allograft survival was similar in the DSA-SPA-positive and DSA-SPA-negative groups (log-rank test=0.63, P=0.428). Differences in allograft function were detectable after 2 years (32.8±13.1 vs. 47±20.2 mL/min/1.73 m, P=0.023) and may be reflective of more AMR among DSA-SPA-positive patients.
CONCLUSIONS: This analysis suggests that DSA-SPA increases the overall risk of acute rejection but does not appear to adversely impact allograft survival during the early follow-up period. Close monitoring of renal function and early biopsy for AMR detection appear to allow for satisfactory short-term allograft outcomes in repeat transplant recipients (read more)

HLA-DQ Barrier: Effects on cPRA Calculations

Background: Panel-reactive antibody (PRA) testing provides assessment of the breadth of sensitization a patient might have against human leukocyte antigen (HLA) antigens. The evolution of calculated PRA (cPRA) reflects the commitment of the transplant community to increase accessibility and promote equity to all patients awaiting kidney transplantation. Recent data from our center and others, however, suggested that a significant diversity of HLA-DQ antigens is not captured, which may lead to inequity in allocating cPRA points. Methods: HLA-DRB1-DQA1-DQB1 typing of 2182 individuals was evaluated for this study using Luminex-based sequence-specific oligonucleotide typing. A total of 3182 haplotypes were confirmed to have the level of resolution required for this study. Results: The diversity of HLA-DQαβ alleles is greater than what is apparent using the serologic equivalents. The distribution of these alleles within a serologic group varies, with some alleles being more frequent than others; therefore, their representation within the current cPRA system is inaccurate. Three informative examples are given. Haplotypes of DR antigens with DQαβ alleles did not always follow the common published linkage disequilibrium, especially in populations where there is greater genetic diversity. Conclusions: The current cPRA system does not take into account the distribution of molecular equivalents within DQ serologic specificities. This can result is inequitable allocation of sensitization points and disadvantaging the more sensitized patients. To ameliorate this situation, the United Network for Organ Sharing system should allow inputting HLA-DQαβ alleles both for donor typing and as antibody specificities, which will lead to better representation of unacceptable DQ alleles and improve organ allocation equity (read more)

Latent IgA deposition from donor kidneys does not affect transplant prognosis, irrespective of mesangial expansion

Introduction : Latent mesangial immunoglobulin A (IgA) deposition in the donated kidney has been investigated in the context of kidney transplantation. However, few studies have examined the impact of mesangial expansion accompanied with IgA deposition. Therefore, we investigated the effects of latent IgA deposition and mesangial expansion on transplant prognosis following living-donor kidney transplantation.

Methods : We retrospectively analyzed 68 consecutive adult living-donor kidney transplantations performed at Kagawa University Hospital. Biopsies were performed at pre-implantation and at one yr after transplantation.
Results : Twenty kidneys exhibited latent IgA deposition in pre-implantation biopsies, including 14 with mesangial expansion. Latent IgA deposition was not associated with renal function or donor urinalysis after donation, irrespective of mesangial expansion. Latent IgA deposition was not significantly associated with graft survival rate, allograft function, abnormal urinalysis, or the recurrence of IgA nephropathy, irrespective of mesangial expansion. At one yr after transplantation, IgA deposition had disappeared in 14/20 allografts. Estimated glomerular function rate >40 mL/min/1.73 m2 was significantly associated with the disappearance of IgA deposition.
Conclusions : The present study showed that latent IgA deposition from the donor kidney, irrespective of mesangial expansion, does not affect transplant prognosis following living-donor kidney transplantation (read more)

Clinicopathological relevance of granular C4d deposition in peritubular capillaries of kidney allografts

While linear C4d staining in peritubular capillaries (PTC) is established as a marker of antibody-mediated rejection, the significance of a distinct granular C4d deposition pattern has not yet been clarified. In this study, 329 renal allograft recipients who underwent indication biopsies were analysed for immunohistochemical C4d staining characteristics. Fifty-six (17%) recipients showed granular C4d in PTC, without any relationship to conventional risk factors and morphological features of rejection. We found a strong association with long-term overall graft survival (7-year survival: 41% versus 66% in granular C4d-negative subjects, P=0.001), which was mainly driven by a greater risk of mortality [hazard ratio: 3.12 (95% confidence interval: 1.23-7.94); P=0.02]. Granular C4d was associated with delayed graft function [39% versus 22% (C4d-negative subjects), P=0.007], higher 1-year serum creatinine [median 2.1 (interquartile range: 1.7-2.6) mg/dL versus 1.6 (1.3-2.0) mg/dL, P=0.001], and a trend towards worse death-censored graft survival (P=0.07). In support of a role of capillary immune complex formation, granular C4d was associated with electron-dense deposits in PTC basement membranes, which were occasionally accompanied by focally distributed capillary IgG deposits. In conclusion, our study suggests clinical relevance of detecting capillary granular C4d deposition. Our results point to a pathogenetic role of alloimmune-independent immune complex deposition (read more)