Objective Tacrolimus, an immunosuppressive drug widely prescribed in kidney transplantation, requires therapeutic drug monitoring due to its marked interindividual pharmacokinetic variability and narrow therapeutic index. Previous studies have established that CYP3A5 rs776746 is associated with tacrolimus clearance, blood concentration, and dose requirement. The importance of other drug absorption, distribution, metabolism, and elimination (ADME) gene variants has not been well characterized. Methods We used novel DNA biobank and electronic medical record resources to identify ADME variants associated with tacrolimus dose requirement. Broad ADME genotyping was performed on 446 kidney transplant recipients who had been dosed to steady state with tacrolimus. The cohort was obtained from Vanderbilt's DNA biobank, BioVU, which contains linked, de-identified electronic medical record data. Genotyping included Affymetrix DMET Plus (1936 polymorphisms), custom Sequenom MassARRAY iPLEX Gold assay (95 polymorphisms), and ancestry-informative markers. The primary outcome was tacrolimus dose requirement defined as blood concentration-to-dose ratio. Results In analyses that adjusted for race and other clinical factors, we replicated the association of tacrolimus blood concentration-to-dose ratio with CYP3A5 rs776746 (p = 7.15 × 10−29), and identified associations with nine variants in linkage disequilibrium with rs776746, including eight CYP3A4 variants. No NR1/2 variants were significantly associated. Age, weight, and hemoglobin were also significantly associated with the outcome. In final models, rs776746 explained 39% of variability in dose requirement, and 46% was explained by the model containing clinical covariates. Conclusion This study highlights the utility of DNA biobanks and electronic medical records for tacrolimus pharmacogenomic research.

For patients with ESRD, kidney transplant offers significant survival and quality-of-life advantages compared with dialysis. But for patients seeking transplant who are highly sensitized, wait times have traditionally been long and options limited. The approach to the highly sensitized candidate for kidney transplant has changed substantially over time owing to new advances in desensitization, options for paired donor exchange (PDE), and changes to the deceased-donor allocation system. Initial evaluation should focus on determining living-donor availability because a compatible living donor is always the best option. However, for most highly sensitized candidates this scenario is unlikely. For candidates with an incompatible donor, PDE can improve the prospects of finding a compatible living donor but for many highly sensitized patients the probability of finding a match in the relatively small pools of donors in PDE programs is limited. Desensitization of a living donor/recipient pair with low levels of incompatibility is another reasonable approach. But for pairs with high levels of pathologic HLA antibodies, outcomes after desensitization for the patient and allograft are less optimal. Determining the degree of sensitization by calculated panel-reactive antibody (cPRA) is critical in counseling the highly sensitized patient on expected wait times to deceased-donor transplant. For candidates with a high likelihood of finding a compatible deceased donor in a reasonable time frame, waiting for a kidney is a good strategy. For the candidate without a living donor and with a low probability of finding a deceased-donor match, desensitization on the waiting list can be considered. The approach to the highly sensitized kidney transplant candidate must be individualized and requires careful discussion among the transplant center, patient, and referring nephrologist.Clin J Am Soc Nephrol 11: 684-693, 2016. doi: 10.2215/CJN.05930615 Case PresentationA 38-year-old black man with type 2 diabetes and ESRD due to diabetic nephropathy presented for evaluation for a second kidney transplant. He was receiving hemodialysis for 1 year before undergoing his first deceased-donor kidney transplant in 1997. His immediate post-transplant course was uncomplicated, without known episodes of rejection. The graft began to fail about 4 years before his resumption of dialysis. A renal allograft biopsy at that time showed calcineurin inhibitor toxicity and chronic allograft nephropathy but no acute rejection. He resumed peritoneal dialysis in 2010, at which time his immunosuppression was weaned to low-dose prednisone, 5 mg daily. He is blood type A, which portends wait times of 3-4 years in our organ procurement organization (OPO), the geographically defined unit of organ allocation. An historical panel-reactive antibody (PRA) on full immunosuppression was 0% but repeat testing at current evaluation reveals a calculated panel-reactive antibody (cPRA) of 100% with multiple HLA antibodies against class II antigens. See candidate HLA t...

In the US, African Americans and other minority groups have longer wait times to deceased donor kidney transplantation than Caucasians. To date, the role of geographic distribution of racial and ethnic groups as a determinant of wait times has not been fully elucidated. Using the Scientific Registry of Transplant Recipients database, all registrants for kidney transplant between 2004 and 2007 (n = 126 094) were analyzed from time of waitlisting until nonzero antigen mismatched deceased donor kidney transplant. Nationally, deceased donor transplantation occurred at a lower rate for African Americans (hazard ratio [HR] 0.85, confidence interval [CI] 0.83–0.87), Hispanics (HR 0.68, CI 0.66–0.70), Asians/Pacific Islanders (HR 0.77, CI 0.73–0.80) and Other minority groups (HR 0.74, CI 0.69–0.81) compared to Caucasians. Multivariate modeling for age, gender, cause of end-stage renal disease, ABO type, panel reactive antibody, HLA-DR frequency, expanded criteria donor status and prior kidney donation only partially accounted for this difference. Adjusting for these variables and organ procurement organization of listing, African Americans (HR 1.03, CI 1.00–1.06), Hispanics (HR 1.15, CI 1.10–1.19), Asians/Pacific Islanders (HR 1.36, CI 1.30–1.43) and Other minority groups (HR 1.00, CI 0.92–1.09) were transplanted at similar or higher rates than Caucasians. Our findings show that geographic location of waitlisted candidates is the most important contributor to racial disparities in waiting times for deceased donor kidney transplantation.

Among adults, living donor kidney transplant rates began declining in the United States after 2004 but whether a similar decline is occurring in the pediatric candidates has not been well studied. Share 35, a change in allocation rules implemented in October of 2005, may also have influenced rates of living donation. We sought to determine whether a decline in rates was occurring in pediatric candidates and whether the Share 35 program was the cause of the decline. All children listed for a kidney transplant or transplanted with a living donor without listing between 1996 and 2011 were identified in the United States (N=14 911) of which 6046 had received a living donor transplant during follow-up. Kaplan-Meier analysis showed a decline in living donor rates in candidates listed after 2001. Logistic regression analysis for living donor kidney transplantation confirmed the timing of the drop but also showed that changes in candidate demographics and center listing practices were impacting rates. A large drop in parental donation was the main cause for the drop. The rate of living donor transplant among pediatric candidates declined after 2001 predating by 4 years the implementation of Share 35, suggesting that factors other than changes in allocation rules are responsible for the decline.

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Introduction: Patients undergoing solid-organ transplantation demonstrate pain arising from both the surgical intervention and pre-existing comorbidities. High levels of opioid use both pre-and post-transplant are associated with unfavorable transplant outcomes. Patient education, multimodal therapy, and discharge planning have all been demonstrated to reduce opioid use after transplant.Methods: This is a single-center, retrospective study analyzing patients before and after implementation of a multimodal, multidisciplinary pain management protocol.Morphine milligram equivalents (MMEs) use during the index transplant hospitalization and the need for opioids at discharge was compared between the pre-and post-protocol groups.Results: A total of 52 patients were included in the study, 31 in the pre and 21 in the post-protocol groups. Inpatient MME use was reduced from 135.5 to 67.5 MMEs after protocol implementation. Additionally, the number of patients discharged on opioids following transplant decreased from 90.3% to 47.6%. Pain scores, length of stay (LOS), and return of bowel function was not different between groups. Conclusion:The implementation of a multimodal, multidisciplinary pain management protocol significantly decreased opioid use during the post-surgical hospitalization and in the 6 months following transplantation. A combination of non-opioid analgesics, patient education, and discharge planning can be beneficial elements in pancreas transplant pain management.