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We previously reported that tacrolimus (TAC) trough blood concentrations for African American (AA) kidney allograft recipients were lower than those observed in white patients. Subtherapeutic TAC troughs may be associated with acute rejection (AR) and AR-associated allograft failure. This variation in TAC troughs is due, in part, to differences in the frequency of the cytochrome P450 CYP3A5*3 allele (rs776746, expresses nonfunctional enzyme) between white and AA recipients; however, even after accounting for this variant, variability in AA-associated troughs is significant. We conducted a genomewide association study of TAC troughs in AA kidney allograft recipients to search for additional genetic variation. We identified two additional CYP3A5 variants in AA recipients independently associated with TAC troughs: CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343). All three variants and clinical factors account for 53.9% of the observed variance in troughs, with 19.8% of the variance coming from demographic and clinical factors including recipient age, glomerular filtration rate, anticytomegalovirus drug use, simultaneous pancreas-kidney transplant and antibody induction. There was no evidence of common genetic variants in AA recipients significantly influencing TAC troughs aside from the CYP3A gene. These results reveal that additional and possibly rare functional variants exist that account for the additional variation.

African American (AA) kidney transplant recipients (KTRs) have poor outcomes, which may in-part be due to tacrolimus (TAC) sub-optimal immunosuppression. We previously determined the common genetic regulators of TAC pharmacokinetics in AAs which were CYP3A5 *3, *6, and *7. To identify low-frequency variants that impact TAC pharmacokinetics, we used extreme phenotype sampling and compared individuals with extreme high (n = 58) and low (n = 60) TAC troughs (N = 515 AA KTRs). Targeted next generation sequencing was conducted in these two groups. Median TAC troughs in the high group were 7.7 ng/ml compared with 6.3 ng/ml in the low group, despite lower daily doses of 5 versus 12 mg, respectively. Of 34,542 identified variants across 99 genes, 1406 variants were suggestively associated with TAC troughs in univariate models (p-value < 0.05), however none were significant after multiple testing correction. We suggest future studies investigate additional sources of TAC pharmacokinetic variability such as drug-drug-gene interactions and pharmacomicrobiome., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Acute rejection (AR) after kidney transplantation is an important allograft complication. To reduce the risk of post-transplant AR, determination of kidney transplant donor-recipient mismatching focuses on blood type and human leukocyte antigens (HLA), while it remains unclear whether non-HLA genetic mismatching is related to post-transplant complications., Methods: We carried out a genome-wide scan (HLA and non-HLA regions) on AR with a large kidney transplant cohort of 784 living donor-recipient pairs of European ancestry. An AR polygenic risk score (PRS) was constructed with the non-HLA single nucleotide polymorphisms (SNPs) filtered by independence (r2 < 0.2) and P-value (< 1×10-3) criteria. The PRS was validated in an independent cohort of 352 living donor-recipient pairs., Results: By the genome-wide scan, we identified one significant SNP rs6749137 with HR = 2.49 and P-value = 2.15×10-8. 1,307 non-HLA PRS SNPs passed the clumping plus thresholding and the PRS exhibited significant association with the AR in the validation cohort (HR = 1.54, 95% CI = (1.07, 2.22), p = 0.019). Further pathway analysis attributed the PRS genes into 13 categories, and the over-representation test identified 42 significant biological processes, the most significant of which is the cell morphogenesis (GO:0000902), with 4.08 fold of the percentage from homo species reference and FDR-adjusted P-value = 8.6×10-4., Conclusions: Our results show the importance of donor-recipient mismatching in non-HLA regions. Additional work will be needed to understand the role of SNPs included in the PRS and to further improve donor-recipient genetic matching algorithms. Trial registry: Deterioration of Kidney Allograft Function Genomics (NCT00270712) and Genomics of Kidney Transplantation (NCT01714440) are registered on ClinicalTrials.gov., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Cao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The OPTN/SRTR 2022 Annual Data Report presents the status of the solid organ transplant system in the United States from 2011 through 2022. Organ-specific chapters are presented for kidney, pancreas, liver, intestine, heart, and lung transplant. Each organ-specific chapter is organized to present waitlist information, donor information (both deceased and living, as appropriate), transplant information, and patient outcomes. Data pertaining to pediatric patients are generally presented separately from the adult data. In addition to the organ-specific chapters, the reader will find chapters dedicated to deceased organ donation, vascularized composite allografts, and the COVID-19 pandemic. The data presented in the Annual Data Report are descriptive in nature. In other words, most tables and figures present raw data without statistical adjustment for possible confounding or changes over time. Therefore, the reader should keep in mind the observational nature of the data when attempting to draw inferences before trying to ascribe a cause to any observed patterns or trends. This introduction provides a brief overview of trends in waitlist and transplant activity from 2012 through 2022. More detailed descriptions can be found in the respective organ-specific chapters., (Copyright © 2024. Published by Elsevier Inc.)

This chapter updates the COVID-19 chapter from the 2021 Annual Data Report with trends through November 12, 2022, and introduces trends in recovery and use of organs from donors with a positive COVID-19 test. Posttransplant mortality and graft failure, which remained a concern in all organs at the last report due to the Omicron variant wave, have returned to lower levels in the most recent available data through November 2022. Use of organs from donors with a positive COVID-19 test has grown, particularly after the first year of the pandemic. Mortality due to COVID-19 should continue to be monitored, but most other measures have sustained their recovery and may now be responding more to changes in policy than to ongoing concerns with COVID-19., (Copyright © 2024. Published by Elsevier Inc.)

In 2022, liver transplant activity continued to increase in the United States, with an all-time high of 9,527 transplants performed, representing a 52% increase over the past decade (2012-2022). Of these transplants, 8,924 (93.7%) were from deceased donors and 603 (6.3%) were from living donors. Liver transplant recipients were 94.5% adult and 5.5% pediatric. The overall size of the liver transplant waiting list contracted, with more patients being removed than added, although 10,548 adult patients still remained on the waiting list at the end of 2022. Alcohol-associated liver disease continued to be the leading diagnosis among both candidates and recipients, followed by metabolic dysfunction-associated steatohepatitis. Simultaneous liver-kidney transplant was the most common multiorgan combination, with 800 liver-kidney transplants performed in 2022; in addition, there were 303 new listings for kidney transplant via the safety net mechanism. Among adults added to the liver waiting list in 2021, 39.9% received a deceased donor liver transplant within 3 months; 45.7%, within 6 months; and 54.5%, within 1 year. Pretransplant mortality decreased to 12.3 deaths per 100 patient-years in 2022, although still 15.6% of removals from the waiting list were for death or being too sick for transplant. Graft and patient survival outcomes after deceased donor liver transplant improved, approximating pre-COVID-19 pandemic levels, with 5.1% mortality observed at 6 months; 6.8%, at 1 year; 12.7%, at 3 years; 19.8%, at 5 years; and 35.7%, at 10 years. Five-year graft and patient survival rates after living donor liver transplant exceeded those of deceased donor liver transplant. Candidates receiving model for end-stage liver disease exception points for hepatocellular carcinoma constituted 15.5% of transplants performed in 2022, with similar transplant rates and posttransplant outcomes compared to cases without hepatocellular carcinoma exception. In 2022, more pediatric liver transplant candidates were added to the waiting list and underwent transplant compared with either of the preceding 2 years, with an uptick in living donor liver transplant volume. Although pretransplant mortality has improved after the recent policy change prioritizing pediatric donors for pediatric recipients, still, in 2022, 50 children died or were removed from the waiting list for being too sick to undergo transplant. Posttransplant mortality among pediatric liver transplant recipients remained notable, with death occurring in 4.0% at 6 months, 6.0% at 1 year, 8.2% at 3 years, 9.8% at 5 years, and 13.9% at 10 years. Similar to adult living donor recipients, pediatric living donor recipients had better 5-year patient survival compared with deceased donor recipients., (Copyright © 2024. Published by Elsevier Inc.)

For the first time since the COVID-19 pandemic, the annual number of lung transplants performed in the United States increased. The year 2022, encompassed in this report, marks the last full calendar year where the Lung Allocation Score was used for ranking transplant candidates based on their estimated transplant benefit and donor lung allocation in the United States. In March 2023, a major change in transplant allocation policy occurred with the implementation of the Composite Allocation Score. Transplant rates have increased over the past decade, although there is variability among age, diagnosis, racial and ethnic, and blood groups. Over half of candidates received a lung transplant within 3 months of placement on the waiting list, with nearly 75% of candidates accessing transplant by 1 year. Pretransplant mortality rates remained stable, with approximately 13% of lung transplant candidates dying or being removed from the waiting list within a year of listing. Posttransplant survival remained stable; however, variability exists by age, diagnosis, and racial and ethnic groups., (Copyright © 2024. Published by Elsevier Inc.)

In 2021, liver transplant volume continued to grow, with a record 9,234 transplants performed in the United States, 8,665 (93.8%) from deceased donors and 569 (6.2%) from living donors. There were 8,733 (94.6%) adult and 501 (5.4%) pediatric liver transplant recipients. An increase in the number of deceased donor livers corresponded to an increase in the overall transplant rate and shorter waiting times, although still 10.0% of livers that were recovered were not transplanted. Alcohol-associated liver disease was the leading indication for both waitlist registration and liver transplant in adults, outpacing nonalcoholic steatohepatitis, while biliary atresia remained the leading indication for children. Related to allocation policy changes implemented in 2019, the proportion of liver transplants performed for hepatocellular carcinoma has decreased. Among adult candidates listed for liver transplant in 2020, 37.7% received a deceased donor liver transplant within 3 months, 43.8% within 6 months, and 53.3% within 1 year. Pretransplant mortality improved for children following implementation of acuity circle-based distribution. Short-term graft and patient survival outcomes up to 1 year worsened for adult deceased and living donor liver transplant recipients, which is a reversal of previous trends and coincided with the onset of the COVID-19 pandemic in early 2020. Longer-term outcomes among adult deceased donor liver transplant recipients were unaffected, with overall posttransplant mortality rates of 13.3% at 3 years, 18.6% at 5 years, and 35.9% at 10 years. Pretransplant mortality improved for children following implementation of acuity circle-based distribution and prioritization of pediatric donors to pediatric recipients in 2020. Pediatric living donor recipients had superior graft and patient survival outcomes compared with deceased donor recipients at all time points., (Copyright © 2023. Published by Elsevier Inc.)

The number of lung transplants has continued to decline since 2020, a period that coincides with the onset of the COVID-19 pandemic. Lung allocation policy continues to undergo considerable change in preparation for adoption of the Composite Allocation Score system in 2023, beginning with multiple adaptations to the calculation of the Lung Allocation Score that occurred in 2021. The number of candidates added to the waiting list increased after a decline in 2020, while waitlist mortality has increased slightly with a decreased number of transplants. Time to transplant continues to improve, with 38.0% of candidates waiting fewer than 90 days for a transplant. Posttransplant survival remains stable, with 85.3% of transplant recipients surviving to 1 year; 67%, to 3 years; and 54.3%, to 5 years., (Copyright © 2023. Published by Elsevier Inc.)

The OPTN/SRTR 2021 Annual Data Report presents the status of the solid organ transplantation system in the United States from 2010 through 2021. Organ-specific chapters are presented for kidney, pancreas, liver, intestine, heart, and lung transplant. Each organ-specific chapter is organized to present waitlist information, donor information (both deceased and living, as appropriate), transplant information, and patient outcomes. Data pertaining to pediatric patients are generally presented separately from the adult data. In addition to the organ-specific chapters, you will find chapters dedicated to deceased organ donation, vascularized composite allograft, and the COVID-19 pandemic. The data presented in the Annual Data Report are descriptive in nature. In other words, most tables and figures present raw data without statistical adjustment for possible confounding or changes over time. Therefore, the reader should keep in mind the observational nature of the data when attempting to draw inferences before trying to ascribe a cause to any observed patterns or trends. This introduction provides a brief overview of trends in waitlist and transplant activity. More detailed descriptions can be found in the respective organ-specific chapters., (Copyright © 2023. Published by Elsevier Inc.)

This year was marked by the COVID-19 pandemic, which altered transplant program activity and affected waitlist and transplant outcomes. Still, 8906 liver transplants were performed, an all-time high, across 142 centers in the United States, and pretransplant as well as graft and patient survival metrics, continued to improve. Living donation activity decreased after several years of growth. As of June 30, 2020, 98989 liver transplant recipients were alive with a functioning graft, and in the context of increasing liver transplant volume, the size of both the adult and pediatric liver transplant waitlists have decreased. On February 4, 2020, shortly before the pandemic began, a new liver distribution policy based on acuity circles was implemented, replacing donor service area- and region-based boundaries. A policy change to direct pediatric livers to pediatric recipients led to an increase in deceased donor transplant rates and a decrease in pretransplant mortality rate among children, although the absolute number of pediatric transplants did not increase in 2020. Among adults, alcohol-associated liver disease became the predominant indication for liver transplant in 2020. After implementation of the National Liver Review Board and lower waitlist priority for most exception cases in 2019, fewer liver transplants were being performed via exception points, and the transplant rate between those with and without hepatocellular carcinoma has equalized. Women continue to experience higher pretransplant mortality and lower rates of liver transplant than men., (.)

Genetic variation in the CYP3A4 and CYP3A5 (CYP3A4/5) genes, which encode the key enzymes in tacrolimus metabolism, is associated with tacrolimus clearance and dose requirements. Tacrolimus has a narrow therapeutic index with high intra- and intersubject variability, in part because of genetic variation. High tacrolimus clearance and low trough concentration are associated with a greater risk for rejection, whereas high troughs are associated with calcineurin-induced toxicity. The objective of this study was to develop a model of tacrolimus clearance with a dosing equation accounting for genotypes and clinical factors in adult kidney transplant recipients of European ancestry that could preemptively guide dosing. Recipients receiving immediate-release tacrolimus for maintenance immunosuppression from 2 multicenter studies were included. Participants in the GEN03 study were used for tacrolimus model development (n = 608 recipients) and was validated by prediction performance in the DeKAF Genomics study (n = 1361 recipients). Nonlinear mixed-effects modeling was used to develop the apparent oral tacrolimus clearance (CL/F) model. CYP3A4/5 genotypes and clinical covariates were tested for their influence on CL/F. The predictive performance of the model was determined by assessing the bias (median prediction error [ME] and median percentage error [MPE]) and the precision (root median squared error [RMSE]) of the model. CYP3A5*3, CYP3A4*22, corticosteroids, calcium channel blocker and antiviral drug use, age, and diabetes significantly contributed to the interindividual variability of oral tacrolimus apparent clearance. The bias (ME, MPE) and precision (RMSE) of the final model was good, 0.49 ng/mL, 6.5%, and 3.09 ng/mL, respectively. Prospective testing of this equation is warranted., (© 2021, The American College of Clinical Pharmacology.)

Major gaps remain in our understanding of antibody-mediated rejection (AMR) after kidney transplant. We examined the incidence, risk factors, response to treatment, and effects on outcomes of AMR at seven transplant programs in the long-term Deterioration of Kidney Allograft Function prospective study cohort. Among 3131 kidney recipients, there were 194 observed AMR cases (6.2%) during (mean ± SD) 4.85 ± 1.86 years of follow-up. Time to AMR was 0.97 ± 1.17 (median, 0.48) years. Risk factors for AMR included younger recipient age, human leukocyte antigen DR mismatches, panel-reactive antibody >0%, positive T- or B-cell cross-match, and delayed graft function. Compared with no AMR, the adjusted time-dependent hazard ratio for death-censored graft failure is 10.1 (95% confidence interval, 6.5-15.7) for all AMR patients, 4.0 (2.5, 9.1) for early AMR (<90 days after transplant), and 24.0 (14.0-41.1) for late AMR (≥90 days after transplant). Patients were treated with different therapeutic combinations. Of 194 kidney transplant recipients with AMR, 50 (25.8%) did not respond to treatment, defined as second AMR within 100 days or no improvement in estimated glomerular filtration rate by 42 days. Long-term outcomes after AMR are poor, regardless of the initial response to treatment. Better prevention and new therapeutic strategies are needed to improve long-term allograft survival., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This year was notable for changes to exception points determined by the geographic median allocation Model for End-Stage Liver Disease (MELD) and implementation of the National Liver Review Board, which took place on May 14, 2019. The national acuity circle liver distribution policy was also implemented but reverted to donor service area- and region-based boundaries after 1 week. In 2019, growth continued in the number of new waiting list registrations (12,767) and transplants performed (8,896), including living-donor transplants (524). Compared with 2018, living-donor liver transplants increased 31%. Women continued to have a lower deceased-donor transplant rate and a higher pretransplant mortality rate than men. The median waiting time for candidates with a MELD of 15-34 decreased, while the number of transplants performed for patients with exception points decreased. These changes may have been related to the policy changes that took effect in May 2019, which increased waiting list priority for candidates without exception status. Hepatitis C continued to decline as an indication for liver transplant, as the proportion of liver transplant recipients with alcohol-related liver disease and clinical profiles consistent with non-alcoholic steatohepatitis increased. Graft and patient survival have improved despite changing recipient demographics including older age, higher MELD, and higher prevalence of obesity and diabetes., (.)

The current pediatric end-stage liver disease (PELD) score underestimates pediatric waitlist mortality. Children frequently require PELD exception points to achieve appropriate priority ranking. We developed a new PELD score using serum sodium, creatinine, and updated original PELD components to more accurately rank children and equalize children's mortality risk with the age-standardized mortality rate of adults. We included children aged younger than 12 years with chronic liver disease, listed for deceased donor livers January 1, 2005-December 31, 2017. Pediatric candidates (n = 5111) were followed from listing to the earliest of waitlist mortality (death or removal from the list due to being too sick to undergo transplant, n = 339) or 180 days. We incorporated linear splines for the current components of PELD and added sodium and creatinine to the equation. The updated PELD-Na-Cr had a cross-validated AUC ROC of 0.854, vs 0.799 for the original PELD. PELD-Na-Cr required 9.44 additional points to equalize children's mortality risk with the age-standardized mortality rate of adults. PELD-Na-Cr better ordered the sickest children and should better prioritize children relative to adults. As a result, PELD-Na-Cr could increase pediatric transplant rates and reduce pediatric liver transplant waitlist mortality., (© 2020 Published 2020. This article is a U.S. Government work and is in the public domain in the USA.)

What Is Known and Objective: Pharmacogenomic biomarkers are now used in many clinical care settings and represent one of the successes of precision medicine. Genetic variants are associated with pharmacokinetic and pharmacodynamic changes leading to medication adverse effects and changes in clinical response. Actionable pharmacogenomic variants are common in transplant recipients and have implications for medications used in transplant, but yet are not broadly incorporated into practice., Methods: From the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group guidelines, and PharmGKB databases, 12 pharmacogenomic genes with 30 variants were selected and used to create diplotypes and actionable pharmacogenomic phenotypes. A total of 853 kidney allograft recipients who had genomic information available from a genome-wide association study were included., Results: Each recipient had at least one actionable pharmacogenomic diplotype/phenotype, whereas the majority (58%) had three or four actionable diplotypes/phenotypes and 17.4% had five or more among the 12 genes. The participants carried actionable diplotypes/phenotypes for multiple medications, including tacrolimus, azathioprine, clopidogrel, warfarin, simvastatin, voriconazole, antidepressants and proton-pump inhibitors., What Is New and Conclusion: Pharmacogenomic variants are common in transplant recipients, and transplant recipients receive medications that have actionable variants., Clinical Trial: Genomics of Transplantation, clinicaltrials.gov (NCT01714440)., (© 2020 John Wiley & Sons Ltd.)

Data on adult liver transplants performed in the US in 2018 are notable for (1) continued growth in numbers of new waitlist registrants (11,844) and transplants performed (8250); (2) continued increase in the transplant rate (54.5 per 100 waitlist-years); (3) a precipitous decline in waitlist registrations and transplants for hepatitis-C-related indications; (4) increases in waitlist registrants and recipients with alcoholic liver disease and with clinical profiles consistent with non-alcoholic fatty liver disease; (5) increased use of hepatitis C virus antibody-positive donor livers; and (6) continued improvement in graft survival despite changing recipient characteristics such as older age and higher rates of obesity and diabetes. Variability in transplant rates remained by candidate race, hepatocellular carcinoma status, urgency status, and geography. The volume of pediatric liver transplants was relatively unchanged. The highest rate of pre-transplant mortality persisted for children aged younger than 1 year. Children underwent transplant at higher acuity than in the past, as evidenced by higher model for end-stage liver disease/pediatric end-stage liver disease scores and listings at status 1A and 1B at transplant. Despite higher illness severity scores at transplant, pediatric graft and patient survival posttransplant have improved over time., (.)

Tacrolimus trough and dose requirements vary dramatically between individuals of European and African American ancestry. These differences are less well described in other populations. We conducted an observational, prospective, multicenter study from which 2595 kidney transplant recipients of European, African, Native American, and Asian ancestry were studied for tacrolimus trough, doses, and genetic determinants of metabolism. We studied the well-known variants and conducted a CYP3A4/5 gene-wide analysis to identify new variants. Daily doses, and dose-normalized troughs were significantly different between the four groups (P < .001). CYP3A5*3 (rs776746) was associated with higher dose-normalized tacrolimus troughs in all groups but occurred at different allele frequencies and had differing effect sizes. The CYP3A5*6 (rs10264272) and *7 (rs413003343) variants were only present in African Americans. CYP3A4*22 (rs35599367) was not found in any of the Asian ancestry samples. We identified seven suggestive variants in the CYP3A4/5 genes associated with dose-normalized troughs in Native Americans (P = 1.1 × 10 -5 -8.8 × 10 -6 ) and one suggestive variant in Asian Americans (P = 5.6 × 10 -6 ). Tacrolimus daily doses and dose-normalized troughs vary significantly among different ancestry groups. We identified potential new variants important in Asians and Native Americans. Studies with larger populations should be conducted to assess the importance of the identified suggestive variants., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

An extreme phenotype sampling (EPS) model with targeted next-generation sequencing (NGS) identified genetic variants associated with tacrolimus (Tac) metabolism in subjects from the Deterioration of Kidney Allograft Function (DeKAF) Genomics cohort which included 1,442 European Americans (EA) and 345 African Americans (AA). This study included 48 subjects separated into 4 groups of 12 (AA high, AA low, EA high, EA low). Groups were selected by the extreme phenotype of dose-normalized Tac trough concentrations after adjusting for common genetic variants and clinical factors. NGS spanned > 3 Mb of 28 genes and identified 18,661 genetic variants (3961 previously unknown). A group of 125 deleterious variants, by SIFT analysis, were associated with Tac troughs in EAs (burden test, p = 0.008), CYB5R2 was associated with Tac troughs in AAs (SKAT, p = 0.00079). In CYB5R2, rs61733057 (increased allele frequency in AAs) was predicted to disrupt protein function by SIFT and PolyPhen2 analysis. The variants merit further validation.

Genetic variation across the human leukocyte antigen loci is known to influence renal-transplant outcome. However, the impact of genetic variation beyond the human leukocyte antigen loci is less clear. We tested the association of common genetic variation and clinical characteristics, from both the donor and recipient, with posttransplant eGFR at different time-points, out to 5 years posttransplantation. We conducted GWAS meta-analyses across 10 844 donors and recipients from five European ancestry cohorts. We also analyzed the impact of polygenic risk scores (PRS), calculated using genetic variants associated with nontransplant eGFR, on posttransplant eGFR. PRS calculated using the recipient genotype alone, as well as combined donor and recipient genotypes were significantly associated with eGFR at 1-year posttransplant. Thirty-two percent of the variability in eGFR at 1-year posttransplant was explained by our model containing clinical covariates (including weights for death/graft-failure), principal components and combined donor-recipient PRS, with 0.3% contributed by the PRS. No individual genetic variant was significantly associated with eGFR posttransplant in the GWAS. This is the first study to examine PRS, composed of variants that impact kidney function in the general population, in a posttransplant context. Despite PRS being a significant predictor of eGFR posttransplant, the effect size of common genetic factors is limited compared to clinical variables., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Identifying kidney allograft recipients who are predisposed to acute rejection (AR) could allow for optimization of clinical treatment to avoid rejection and prolong graft survival. It has been hypothesized that a part of this predisposition is caused by the inheritance of specific genetic variants. There are many publications reporting a statistically significant association between a genetic variant, usually in the form of a single-nucleotide polymorphism (SNP), and AR. However, there are additional publications reporting a lack of this association when a different cohort of recipients is analyzed for the same single-nucleotide polymorphism., Methods: In this report, we attempted to validate 75 common genetic variants, which have been previously reported to be associated with AR, using a large kidney allograft recipient cohort of 2390 European Americans and 482 African Americans., Results: Of those variants tested, only 1 variant, rs2910164, which alters the expression of the microRNA MIR146A, was found to exhibit a significant association within the African American cohort. Suggestive variants were found in the genes CTLA and TLR4., Conclusions: Our results show that most variants previously reported to be associated with AR were not validated in our cohort. This shows the importance of validation when reporting the associations with complex clinical outcomes such as AR. Additional work will need to be done to understand the role of MIR146A in the risk of AR in kidney allograft recipients.

Background: The immunosuppressants tacrolimus and mycophenolate are important components to the success of organ transplantation, but are also associated with adverse effects, such as nephrotoxicity, anemia, leukopenia, and new-onset diabetes after transplantation. In this report, we attempted to identify genetic variants which are associated with these adverse outcomes., Methods: We performed a genome-wide association study, using a genotyping array tailored specifically for transplantation outcomes containing 722 147 single nucleotide polymorphisms, and 2 cohorts of kidney allograft recipients-a discovery cohort and a confirmation cohort-to identify and then confirm genetic variants associated with immunosuppressant pharmacokinetics and adverse outcomes., Results: Several genetic variants were found to be associated with tacrolimus trough concentrations. We did not confirm variants associated with the other phenotypes tested although several suggestive variants were identified., Conclusions: These results show that adverse effects associated with tacrolimus and mycophenolate are complex, and recipient risk is not determined by a few genetic variants with large effects with but most likely are due to many variants, each with small effect sizes, and clinical factors.

Data on adult liver transplants performed in the US in 2017 are notable for (1) continued growth in numbers of new waitlist registrants (11,514) and of transplants performed (8,082); (2) continued increase in the transplant rate (51.5 per 100 waitlist-years); (3) a precipitous decrease in waitlist registrations and transplants for hepatitis C-related indications; (4) reciprocal increases in waitlist registrants and recipients with alcoholic liver disease and with clinical profiles consistent with non-alcoholic fatty liver disease; and (5) continued improvement in graft survival despite changing recipient characteristics such as older age and higher rates of obesity. Variability in transplant rates remained by candidate race, presence of hepatocellular carcinoma, urgency status (status 1A versus model for end-stage liver disease (MELD) score >35), and geography. More than half of all children listed for liver transplant in 2017 were aged younger than 5 years in 2017, and the highest rate of pretransplant mortality persisted for children aged younger than 1 year. Children underwent transplant at higher acuity than the past, as evidenced by higher MELD/pediatric end-stage liver disease scores and listings at status 1A and 1B. Higher acuity at transplant is likely due to lack of access to suitable donor organs, which has been compensated for by persistent trends toward use of partial or split liver grafts and ABO-incompatible grafts. Despite higher illness severity scores at transplant, pediatric graft and patient survival posttransplant have improved over time., (.)

Background: Suboptimal immunosuppression after kidney transplantation contributes to toxicity and loss of efficacy. Little is known regarding the impact of intra-patient variability of tacrolimus (TAC) doses and troughs in the early post-transplant period or the influence of genetic variants on variability., Methods: Coefficients of variation (CV) of TAC troughs and doses of 1226 European American (EA) and 246 African American (AA) adult recipients enrolled in DeKAF Genomics were compared for association with acute rejection and graft failure. Additionally, the influence of recipients' number of CYP3A5 loss-of-function alleles was assessed., Results: Acute rejection was associated with greater CV of dose in AA (P < 0.001) and EA recipients (P = 0.012). Graft failure was associated with a greater CV of dose (P = 0.022) and trough (P < 0.001) in AA, and higher CV of trough (P = 0.024) in EA recipients. In EA, CYP3A5 loss-of-function alleles were associated with decreased CV of trough (P = 0.0042) and increased CV of dose (P < 0.0001)., Conclusion: CYP3A5 loss-of-function alleles influence intra-patient TAC trough and dose variability. High variability of TAC dose increases risk of acute rejection. High variability of TAC trough increases risk of graft failure. Early clinical recognition of TAC dose and trough variability may improve patient management and outcomes., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: We performed a study to identify differences in the urinary microbiome associated with chronic allograft dysfunction (CAD) and compared the urinary microbiome of male and female transplant recipients with CAD., Methods: This case-control study enrolled 67 patients within the Deterioration of Kidney Allograft Function (DeKAF) Genomics cohort at two transplant centers. CAD was defined as a greater than 25% rise in serum creatinine relative to a 3 month post-transplant baseline. Urine samples from patients with and without CAD were analyzed using 16S V4 bacterial ribosomal DNA sequences., Results: Corynebacterium was more prevalent in female and male patients with CAD compared to non-CAD female patients (P = 0.0005). A total 21 distinct Operational Taxonomic Unit (OTUs) were identified as significantly different when comparing CAD and non-CAD patients using Kruskal-Wallis (P < 0.01). A subset analysis of female patients with CAD compared to non-CAD females identified similar differentially abundant OTUs, including the genera Corynebacterium and Staphylococcus (Kruskal-Wallis; P = 0.01; P = 0.004, respectively). Male CAD vs female CAD analysis showed greater abundance of phylum Proteobacteria in males., Conclusion: There were differences in the urinary microbiome when comparing female and male CAD patients with their female non-CAD counterparts and these differences persisted in the subset analysis limited to female patients only., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The immunosuppressant tacrolimus (TAC) is metabolized by both cytochrome P450 3A4 (CYP3A4) and CYP3A5 enzymes. It is common for European Americans (EA) to carry two CYP3A5 loss-of-function (LoF) variants that profoundly reduces TAC metabolism. Despite having two LoF alleles, there is still considerable variability in TAC troughs and identifying additional variants in genes outside of the CYP3A5 gene could provide insight into this variability. We analyzed TAC trough concentrations in 1345 adult EA recipients with two CYP3A5 LoF alleles in a genome-wide association study. Only CYP3A4*22 was identified and no additional variants were genome-wide significant. Additional high allele frequency genetic variants with strong genetic effects associated with TAC trough variability are unlikely to be associated with TAC variation in the EA population. These data suggest that low allele frequency variants, identified by DNA sequencing, should be evaluated and may identify additional variants that contribute to TAC pharmacokinetic variability.

Background: The liver simulated allocation model (LSAM) can be used to study likely effects of liver transplant allocation policy changes on organ offers, acceptance, waitlist survival, and posttransplant survival. Implementation of Share 35 in June 2013 allowed for testing how well LSAM predicted actual changes., Methods: LSAM projections for 1 year of liver transplants before and after the Share 35 policy change were compared with observed data during the same period. Numbers of organs recovered, organ sharing, transplant rates, and waitlist mortality rates (per 100 waitlist years) were evaluated by LSAM and compared with observed data., Results: Candidate, recipient, and donor characteristics in the LSAM cohorts were similar to those in the observed population before and after Share 35. LSAM correctly predicted more accepted organs and fewer discarded organs with Share 35. LSAM also predicted increased regional and national sharing, consistent with observed data, although the magnitude was overestimated. Transplant rates were correctly projected to increase and waitlist death rates to decrease., Conclusions: Although the absolute number of transplants was underestimated and waitlist deaths overestimated, the direction of change was consistent with observed data. LSAM correctly predicted change in discarded organs, regional and national sharing, waitlist mortality, and transplants after Share 35 implementation.

Offer acceptance practices may cause geographic variability in allocation Model for End-Stage Liver Disease (aMELD) score at transplant and could magnify the effect of donor supply and demand on aMELD variability. To evaluate these issues, offer acceptance practices of liver transplant programs and donation service areas (DSAs) were estimated using offers of livers from donors recovered between January 1, 2016, and December 31, 2016. Offer acceptance practices were compared with liver yield, local placement of transplanted livers, donor supply and demand, and aMELD at transplant. Offer acceptance was associated with liver yield (odds ratio, 1.32; P < 0.001), local placement of transplanted livers (odds ratio, 1.34; P < 0.001), and aMELD at transplant (average aMELD difference, -1.62; P < 0.001). However, the ratio of donated livers to listed candidates in a DSA (ie, donor-to-candidate ratio) was associated with median aMELD at transplant (r = -0.45; P < 0.001), but not with offer acceptance (r = 0.09; P = 0.50). Additionally, the association between DSA-level donor-to-candidate ratios and aMELD at transplant did not change after adjustment for offer acceptance. The average squared difference in median aMELD at transplant across DSAs was 24.6; removing the effect of donor-to-candidate ratios reduced the average squared differences more than removing the effect of program-level offer acceptance (33% and 15% reduction, respectively). Offer acceptance practices and donor-to-candidate ratios independently contributed to geographic variability in aMELD at transplant. Thus, neither offer acceptance nor donor-to-candidate ratios can explain all of the geographic variability in aMELD at transplant. Liver Transplantation 24 478-487 2018 AASLD., (© 2018 by the American Association for the Study of Liver Diseases.)

Aim: Multiple genetic variants have been associated with variation in tacrolimus (TAC) trough concentrations. Unfortunately, additional studies do not confirm these associations, leading one to question if a reported association is accurate and reliable. We attempted to validate 44 published variants associated with TAC trough concentrations., Materials & Methods: Genotypes of the variants in our cohort of 1923 kidney allograft recipients were associated with TAC trough concentrations., Results: Only variants in CYP3A4 and CYP3A5 were significantly associated with variation in TAC trough concentrations in our validation., Conclusion: There is no evidence that common variants outside the CYP3A4 and CYP3A5 loci are associated with variation in TAC trough concentrations. In the future rare variants may be important and identified using DNA sequencing.

Data on adult liver transplants performed in the US in 2016 are no-table for (1) the largest total number of transplants performed (7841); (2) the shortest median waiting time in recent history (11.3 months); (3) continued reduction in waitlist registrations and transplants for hepatitis C-related indications; (4) increasing numbers of patients whose clinical profiles are consistent with non-alcoholic fatty liver disease; and (5) equilibration of transplant rates in patients with and without hepatocellular carcinoma. Despite the increase in the number of available organs, waitlist mortality remained an important concern. Graft survival rates continued to improve. In 2016, 723 new active candidates were added to the pediatric liver transplant waiting list, down from a peak of 826 in 2005. The number of prevalent candidates (on the list on December 31 of the given year) was stable, 408 active and 169 inactive. The number of pediatric living donor liver transplants decreased from a peak of 79 in 2015 to 62 in 2016, with most from donors closely related to the recipients. Graft survival continued to improve over the past decade among recipients of deceased donor and living donor livers., (.)

Renal allografts from deceased African American donors with two apolipoprotein L1 gene (APOL1) renal-risk variants fail sooner than kidneys from donors with fewer variants. The Kidney Donor Risk Index (KDRI) was developed to evaluate organ offers by predicting allograft longevity and includes African American race as a risk factor. Substituting APOL1 genotype for race may refine the KDRI. For 622 deceased African American kidney donors, we applied a 10-fold cross-validation approach to estimate contribution of APOL1 variants to a revised KDRI. Cross-validation was repeated 10 000 times to generate distribution of effect size associated with APOL1 genotype. Average effect size was used to derive the revised KDRI weighting. Mean current-KDRI score for all donors was 1.4930 versus mean revised-KDRI score 1.2518 for 529 donors with no or one variant and 1.8527 for 93 donors with two variants. Original and revised KDRIs had comparable survival prediction errors after transplantation, but the spread in Kidney Donor Profile Index based on presence or absence of two APOL1 variants was 37 percentage points. Replacing donor race with APOL1 genotype in KDRI better defines risk associated with kidneys transplanted from deceased African American donors, substantially improves KDRI score for 85-90% of kidneys offered, and enhances the link between donor quality and recipient need., (© 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Tacrolimus is dependent on CYP3A5 enzyme for metabolism. Expression of the CYP3A5 enzyme is controlled by several alleles including CYP3A5*1, CYP3A5*3, CYP3A5*6 and CYP3A5*7. African Americans (AAs) have on average higher tacrolimus dose requirements than Caucasians; however, some have requirements similar to Caucasians. Studies in AAs have primarily evaluated the CYP3A5*3 variant; however, there are other common nonfunctional variants in AAs (CYP3A5*6 and CYP3A5*7) that do not occur in Caucasians. These variants are associated with lower dose requirements and may explain why some AAs are metabolically similar to Caucasians. We created a tacrolimus clearance model in 354 AAs using a development and validation cohort. Time after transplant, steroid and antiviral use, age and CYP3A5*1, *3, *6 and *7 alleles were significant toward clearance. This study is the first to develop an AA-specific genotype-guided tacrolimus dosing model to personalize therapy.

Several notable developments in adult liver transplantation in the US occurred in 2015. The year saw the largest number of liver transplants to date, leading to reductions in median waiting time, in waitlist mortality for all model for end-stage liver disease categories, and in the number of candidates on the waiting list at the end of the year. Numbers of additions to the waiting list and of liver transplants performed in patients with hepatitis C virus infection decreased for the first time in recent years. However, other diagnoses, such as non-alcoholic fatty liver disease and alcoholic cirrhosis, became more prevalent. Despite large numbers of severely ill patients undergoing liver transplant, graft survival rates continued to improve. The number of new active candidates added to the pediatric liver transplant waiting list in 2015 was 689, down from a peak of 826 in 2005. The number of prevalent pediatric candidates (on the list on December 31 of the given year) continued to decline, to 373 active and 195 inactive candidates. The number of pediatric liver transplants peaked at 613 in 2008 and was 580 in 2015. The number of living donor pediatric liver transplants increased to its highest level, 79, in 2015; most were from donors closely related to the recipients. Pediatric graft survival rates continued to improve., (.)

Background: The probability of liver transplant and death on the waiting list in the United States varies greatly by donation service area (DSA) due to geographic differences in availability of organs and allocation of priority points, making it difficult for providers to predict likely outcomes after listing. We aimed to develop an online calculator to report outcomes by region and patient characteristics., Methods: Using the Scientific Registry of Transplant Recipients database, we included all prevalent US adults aged 18 years or older waitlisted for liver transplant, examined on 24 days at least 30 days apart over a 2-year period. Outcomes were determined at intervals of 30 to 365 days. Outcomes are reported by transplant program, DSA, region, and the nation for comparison, and can be shown by allocation or by laboratory model for end-stage liver disease (MELD) score (6-14, 15-24, 25-29, 30-34, 35-40), age, and blood type., Results: Outcomes varied greatly by DSA; for candidates with allocation MELD 25-29, the 25th and 75th percentiles of liver transplant probability were 30% and 67%, respectively, at 90 days. Corresponding percentiles for death or becoming too sick to undergo transplant were 5% and 9%. Outcomes also varied greatly for candidates with and without MELD exception points., Conclusions: The waitlist outcome calculator highlights ongoing disparities in access to liver transplant and may assist providers in understanding and counseling their patients about likely outcomes on the waiting list.

The median waiting time for patients with MELD ≥ 35 decreased from 18 days in 2012 to 9 days in 2014, after implementation of the Share 35 policy in June 2013. Similarly, mortality among candidates listed with MELD ≥ 35 decreased from 366 per 100 waitlist years in 2012 to 315 in 2014. The number of new active candidates added to the pediatric liver transplant waiting list in 2014 was 655, down from a peak of 826 in 2005. The number of prevalent candidates (on the list on December 31 of the given year) continued to decline, 401 active and 173 inactive. The number of deceased donor pediatric liver transplants peaked at 542 in 2008 and was 478 in 2014. The number of living donor liver pediatric transplants was 52 in 2014; most were from donors closely related to the recipients. Graft survival continued to improve among pediatric recipients of deceased donor and living donor livers., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

We performed RNA sequencing (RNAseq) on peripheral blood mononuclear cells (PBMCs) to identify differentially expressed gene transcripts (DEGs) after kidney transplantation and after the start of immunosuppressive drugs. RNAseq is superior to microarray to determine DEGs because it's not limited to available probes, has increased sensitivity, and detects alternative and previously unknown transcripts. DEGs were determined in 32 adult kidney recipients, without clinical acute rejection (AR), treated with antibody induction, calcineurin inhibitor, mycophenolate, with and without steroids. Blood was obtained pre-transplant (baseline), week 1, months 3 and 6 post-transplant. PBMCs were isolated, RNA extracted and gene expression measured using RNAseq. Principal components (PCs) were computed using a surrogate variable approach. DEGs post-transplant were identified by controlling false discovery rate (FDR) at < 0.01 with at least a 2 fold change in expression from pre-transplant. The top 5 DEGs with higher levels of transcripts in blood at week 1 were TOMM40L, TMEM205, OLFM4, MMP8, and OSBPL9 compared to baseline. The top 5 DEGs with lower levels at week 1 post-transplant were IL7R, KLRC3, CD3E, CD3D, and KLRC2 (Striking Image) compared to baseline. The top pathways from genes with lower levels at 1 week post-transplant compared to baseline, were T cell receptor signaling and iCOS-iCOSL signaling while the top pathways from genes with higher levels than baseline were axonal guidance signaling and LXR/RXR activation. Gene expression signatures at month 3 were similar to week 1. DEGs at 6 months post-transplant create a different gene signature than week 1 or month 3 post-transplant. RNAseq analysis identified more DEGs with lower than higher levels in blood compared to baseline at week 1 and month 3. The number of DEGs decreased with time post-transplant. Further investigations to determine the specific lymphocyte(s) responsible for differential gene expression may be important in selecting and personalizing immune suppressant drugs and may lead to targeted therapies.

Unlabelled: The current system granting liver transplant candidates with hepatocellular carcinoma (HCC) additional Model for End-Stage Liver Disease (MELD) points is controversial due to geographic disparity and uncertainty regarding optimal prioritization of candidates. The current national policy assigns a MELD exception score of 22 immediately upon listing of eligible patients with HCC. The aim of this study was to evaluate the potential effects of delays in granting these exception points on transplant rates for HCC and non-HCC patients. We used Scientific Registry of Transplant Recipients data and liver simulated allocation modeling software and modeled (1) a 3-month delay before granting a MELD exception score of 25, (2) a 6-month delay before granting a score of 28, and (3) a 9-month delay before granting a score of 29. Of all candidates waitlisted between January 1 and December 31, 2010 (n = 28,053), 2773 (9.9%) had an HCC MELD exception. For HCC candidates, transplant rates would be 108.7, 65.0, 44.2, and 33.6 per 100 person-years for the current policy and for 3-, 6-, and 9-month delays, respectively. Corresponding rates would be 30.1, 32.5, 33.9, and 34.8 for non-HCC candidates., Conclusion: A delay of 6-9 months would eliminate the geographic variability in the discrepancy between HCC and non-HCC transplant rates under current policy and may allow for more equal access to transplant for all candidates., (© 2015 by the American Association for the Study of Liver Diseases.)

During 2013, 10,479 adult candidates were added to the liver transplant waiting list, compared with 10,185 in 2012; 5921 liver transplants were performed, and 211 of the transplanted organs were from living donors. As of December 31, 2013, 15,027 candidates were registered on the waiting list, including 12,407 in active status. The most significant change in allocation policy affecting liver waitlist trends in 2013 was the Share 35 policy, whereby organs from an entire region are available to candidates with model for end-stage liver disease scores of 35 or higher. Median waiting time for such candidates decreased dramatically, from 14.0 months in 2012 to 1.4 months in 2013, but the effect on waitlist mortality is unknown. The number of new active pediatric candidates added to the liver transplant waiting list increased to 693 in 2013. Transplant rates were highest for candidates aged younger than 1 year (275.6 per 100 waitlist years) and lowest for candidates aged 11 to 17 years (97.0 per 100 waitlist years). Five-year graft survival was 71.7% for recipients aged younger than 1 year, 74.9% for ages 1 to 5 years, 78.9% ages 6 to 10 years, and 77.4% for ages 11 to 17 years., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: A biological marker that would allow clinicians to determine the length of time an allograft will remain functional after transplantation would greatly aid the ability to stratify donors by risk and to use biologically "young" allografts in young recipients, maximizing the use of this rare resource. Telomere length (TL) has been proposed to be such a marker to determine the biological age of a tissue., Methods: We genotyped DNA from 1805 recipients and 1038 living kidney donors for TL to determine the association of TL with acute rejection (AR), chronic graft dysfunction (CGD), and graft failure of kidney allografts. DNA was isolated from peripheral blood white blood cells and TL was measured in DNA using the multiplexed monochrome quantitative polymerase chain reaction assay., Results: As has been previously shown, we found a significant association between log-transformed TL and donor age (P=3.8×10) and recipient age (P=5.6×10). Univariate and multivariate analysis did not show any significant associations between log-transformed TL in donor or recipient DNA with AR, CGD, or graft failure, although we did observe an association between donor chronological age and CGD (P=0.018)., Conclusion: Although older allografts have been shown to be at greater risk for AR and CGD, this does not appear to be associated with shorter TL. Different markers will need to be identified to determine how biological age impacts transplant outcome, such as age-related fibrosis or tubular atrophy and tubular loss.

Liver transplant in the us remains a successful life-saving procedure for patients with irreversible liver disease. In 2012, 6256 adult liver transplants were performed, and more than 65,000 people were living with a transplanted liver. The number of adults who registered on the liver transplant waiting list decreased for the first time since 2002; 10,143 candidates were added, compared with 10,359 in 2011. However, the median waiting time for active wait-listed adult candidates increased, as did the number of candidates removed from the list because they were too sick to undergo transplant. The overall deceased donor transplant rate decreased to 42.3 per 100 patient-years, and varied geographically from 18.9 to 228.0 per 100 patient-years. Graft survival continues to improve, especially for donation after circulatory death livers. The number of new active pediatric candidates added to the waiting list also decreased. Almost 75% of pediatric candidates listed in 2009 underwent transplant within 3 years; the 2012 rate of deceased donor transplants among active pediatric wait-listed candidates was 136 per 100 patient-years. Graft survival for deceased donor pediatric transplants was 92.8% at 30 days. Medicare paid for some or all of the care for more than 30% of liver transplants in 2010., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)

There have been many reports showing significant associations between recipient genetic variants and allograft outcomes, including acute rejection and graft failure, but less is known about the contribution of the donor genotype. We analyzed 37 single-nucleotide polymorphisms (SNPs) within the toll-like receptor 4 (TLR4) gene from deceased donor liver allografts transplanted into 738 recipients to determine their effects on liver graft failure (LGF). Two SNPs exhibited a significant association with LGF after adjustments for donor race and recipient race and corrections for multiple test comparisons: rs11536865 [hazard ratio (HR) = 2.5, P = 0.0003] and rs5030717 (HR = 1.67, P = 0.0008). An additional SNP, rs913930, exhibited a significant association in Caucasian donors (HR = 1.62, P = 0.0006), and 2 SNPs exhibited a suggestive association in African American donors: rs11536865 (HR = 2.45, P = 0.002) and rs5030717 (HR = 2.32, P = 0.002). Additionally, the liver donor risk index (HR = 2.56, 95% confidence interval = 1.54-4.26, P = 0.0003) and the recipient hepatitis C virus (HCV) status (HR = 1.53, 95% confidence interval = 1.04-2.24, P = 0.032) increased the risk of all-cause LGF in a Cox proportional hazards model adjusted for recipient race. Donor polymorphisms in TLR4 could be important factors in modulating TLR4 activity and, therefore, affect the risk of graft loss. Additionally, there is a suggestion of an interaction between polymorphisms within TLR4 and the HCV status., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Aim: Tacrolimus is an immunosuppressant used in transplantation. This article reports the validation of the authors' recently developed genetics-based tacrolimus equation that predicts troughs., Methods: Validation was performed in an independent cohort of 795 kidney transplant recipients receiving tacrolimus. The performance of the equation to predict initial troughs was assessed by calculating the bias and precision of the equation. For all troughs in the first 6 months post-transplant, a comparison was made between the troughs predicted using the equation versus those predicted using a basic apparent clearance model with no covariates., Results: For initial troughs, the equation had a low bias (0.2 ng/ml) and high precision (1.8 ng/ml). For all troughs, the equation predicted troughs significantly better than the basic apparent clearance model., Conclusion: The tacrolimus equation had good bias and precision in predicting initial troughs and performed better than a basic apparent clearance model for all the troughs.

There have been numerous reports proposing a statistically significant association between a genetic variant, usually in the form of a single nucleotide polymorphism (SNP), and acute rejection (AR). Unfortunately, there are additional publications reporting a lack of association with AR when a different cohort of recipients was analyzed for the same SNP. The objective of this report was to attempt replication of these published finding in our own kidney allograft recipient cohort. We analyzed 23 genetic variants, previously reported to have a significant association with AR, using a cohort of 969 clinically well-defined kidney transplant recipients. Only one SNP, rs6025 (Leiden mutation), within the coagulation factor V gene, showed a significant association with a P-value of 0.011 in a race-adjusted analysis and a P-value of 0.0003 in multiple variable analysis. An additional SNP, rs11706052 in IMPDH2, gave a modest P-value of 0.044 using multiple variable analysis, which is not significant when multiple testing is taken into consideration. Our results suggest that careful validation of previously reported associations with AR is necessary, and different strategies other than candidate gene studies can help to identify causative genetic variants associated with AR., (© 2011 The Authors. Transplant International © 2011 European Society for Organ Transplantation.)