Evidence of antibody-mediated injury (DSA or C4d) is common (57%) in patients with new onset late kidney allograft dysfunction. The risk of subsequent graft failure is significantly worse in the presence of C4d+ staining.

Further, these results did not qualitatively change after additional adjustments for C4d staining or donor specific antibody. Stepwise regression identified the most significant markers of graft failure which include iatr score. We propose that a more global assessment of inflammation in kidney allograft biopsies to include inflammation in atrophic areas may provide better prognostic information. Phenotypic characterization of these inflammatory cells and appropriate treatment may ameliorate late allograft failure.

Background The CYP4503A5*1 genotype is associated with lower tacrolimus concentrations. Although its effect is important, it incompletely explains the variability in tacrolimus concentrations and has a relatively low minor allele frequency in Caucasians relative to African Americans (AA). Methods We studied clinical and recipient genetic correlates of dose-normalized tacrolimus troughs (n=12,277) in the first 6 months posttransplant using a customized single nucleotide polymorphism chip with 2,722 variants in a large, ethnically diverse (144 AA and 551 non-AA) adult kidney transplant population through a 7-center consortium. Results Over the 6 month study, AAs had consistently lower median (interquartile range) troughs than non-AAs, 6.2 (4.4–8.4) vs 8.3 (6.4–10.4) ng/mL (p<0.0001), in spite of 60% higher daily doses, 8 (5–10) vs 5 (4–7) mg (p<0.0001). The median tacrolimus trough concentration in week one posttransplant was particularly low in AAs [2.1 (1.2–3.5)] compared to non-AAs [5.0 (3.1–8.2) ng/mL](p<0.0001) despite similar initial doses. In single variant analysis, CYP3A5*3 (rs776746) was the top variant (p=2.4x10−33) associated with troughs. After adjustment for CYP3A5*3, clinical factors and race, thirty-nine additional variants were identified (p<0.01, not significant at FDR 20%). In the final multivariant, regression models beginning with these variants and clinical factors, 7 variants were identified in the non-AA and 7 variants in the AA group towards the first trough concentrations. Rs776746 (CYP3A5), rs2239393 (COMT) and diabetes were the only factors common in both populations. Conclusion We identified variants beyond CYP3A5*3 which may further explain pharmacokinetic variability of tacrolimus and demonstrated that important variants differ by race.

We are studying two cohorts of kidney transplant recipients, with the goal of defining specific clinicopathologic entities that cause late graft dysfunction: (1) prevalent patients with new onset late graft dysfunction (Cross-Sectional Cohort); and (2) newly transplanted patients (Prospective Cohort). For the cross-sectional cohort (n=440), mean time from transplant to biopsy was 7.5±6.1 years. Local pathology diagnoses included CAN (48%), CNI toxicity (30%), and, perhaps surprisingly, acute rejection (cellular- or Ab-mediated) (23%). Actuarial rate of death-censored graft loss at 1 year post-biopsy was 17.7%; at 2 years, 29.8%. There was no difference in post-biopsy graft survival for recipients with vs. without CAN (p=0.9). Prospective cohort patients (n=2427) developing graft dysfunction >3 months posttransplant undergo “index” biopsy. The rate of index biopsy was 8.8% between months 3 and 12, and 18.2% by 2 years. Mean time from transplant to index biopsy was 1.0 ± 0.6 years. Local pathology diagnoses included CAN (27%), and acute rejection (39%). Intervention to halt late graft deterioration cannot be developed in the absence of meaningful diagnostic entities. We found CAN in late posttransplant biopsies to be of no prognostic value. The DeKAF study will provide broadly applicable diagnostic information to serve as the basis for future trials.