David Schladt

OPTN/SRTR 2015 Annual Data Report: Liver.

ABSTRACT  The current liver allocation system, introduced in 2002, decreased the importance of waiting time for allocation priorities; the number of active wait‐listed candidates and median waiting times were immediately reduced. However, the total number of adult wait‐listed candidates has increased since 2002, and median waiting time has increased since 2006. Pretransplant mortality rates have been stable, but the number of candidates withdrawn from the list as being too sick to undergo transplant nearly doubled between 2009 and 2011. Deceased donation rates have remained stable, with an increasing proportion of expanded criteria donors. Living donation has decreased over the past 10 years. Transplant outcomes remain robust, with continuously improving graft survival rates for deceased donor, living donor, and donation after circulatory death livers. Numbers of new and prevalent pediatric candidates on the waiting list have decreased. Pediatric pretransplant mortality has decreased, most dramatically for candidates aged less than 1 year. The transplant rate has increased since 2002, and is highest in candidates aged less than 1 year. Graft survival continues to improve for pediatric recipients of deceased donor and living donor livers. Incidence of acute rejections increases with time after transplant. Posttransplant lymphoproliferative disorder remains an important concern in pediatric recipients.

OPTN/SRTR 2013 Annual Data Report: Liver: OPTN/SRTR 2013 Annual Data Report: Liver

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.

Novel Polymorphisms Associated with Tacrolimus Trough Concentrations: Results from a Multicenter Kidney Transplant Consortium

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 whites 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 2722 variants in a large, ethnically diverse (144 AA and 551 non-AA) adult kidney transplant population through a seven-center consortium. Results. During the 6-month study, AAs had consistently lower median (interquartile range) troughs than non-AAs, 6.2 (4.4–8.4) ng/mL vs. 8.3 (6.4–10.4) ng/mL (P<0.0001), despite 60% higher daily doses, 8 (5–10) mg vs. 5 (4–7) mg (P<0.0001). The median tacrolimus trough concentration in week 1 posttransplant was particularly low in AAs (2.1 [1.2–3.5] ng/mL) compared with 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=2.4×10−33) associated with troughs. After adjustment for CYP3A5*3, clinical factors and race, 35 additional variants were identified (P<0.01, not significant at false discovery rate 20%). In the final multivariant, regression models beginning with these variants and clinical factors, seven variants were identified in the non-AA and seven 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.

Apolipoprotein L1 gene variants in deceased organ donors are associated with renal allograft failure

Apolipoprotein L1 gene (APOL1) nephropathy variants in African American deceased kidney donors were associated with shorter renal allograft survival in a prior single‐center report. APOL1 G1 and G2 variants were genotyped in newly accrued DNA samples from African American deceased donors of kidneys recovered and/or transplanted in Alabama and North Carolina. APOL1 genotypes and allograft outcomes in subsequent transplants from 55 U.S. centers were linked, adjusting for age, sex and race/ethnicity of recipients, HLA match, cold ischemia time, panel reactive antibody levels, and donor type. For 221 transplantations from kidneys recovered in Alabama, there was a statistical trend toward shorter allograft survival in recipients of two‐APOL1‐nephropathy‐variant kidneys (hazard ratio [HR] 2.71; p = 0.06). For all 675 kidneys transplanted from donors at both centers, APOL1 genotype (HR 2.26; p = 0.001) and African American recipient race/ethnicity (HR 1.60; p = 0.03) were associated with allograft failure. Kidneys from African American deceased donors with two APOL1 nephropathy variants reproducibly associate with higher risk for allograft failure after transplantation. These findings warrant consideration of rapidly genotyping deceased African American kidney donors for APOL1 risk variants at organ recovery and incorporation of results into allocation and informed‐consent processes.

Delayed hepatocellular carcinoma model for end-stage liver disease exception score improves disparity in access to liver transplant in the United States.

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. (Hepatology 2015;61:1643–1650)

APOL1 Genotype and Kidney Transplantation Outcomes From Deceased African American Donors.

Background Two apolipoprotein L1 gene (APOL1) renal-risk variants in donors and African American (AA) recipient race are associated with worse allograft survival in deceased-donor kidney transplantation (DDKT) from AA donors. To detect other factors impacting allograft survival from deceased AA kidney donors, APOL1 renal-risk variants were genotyped in additional AA kidney donors. Methods The APOL1 genotypes were linked to outcomes in 478 newly analyzed DDKTs in the Scientific Registry of Transplant Recipients. Multivariate analyses accounting for recipient age, sex, race, panel-reactive antibody level, HLA match, cold ischemia time, donor age, and expanded criteria donation were performed. These 478 transplantations and 675 DDKTs from a prior report were jointly analyzed. Results Fully adjusted analyses limited to the new 478 DDKTs replicated shorter renal allograft survival in recipients of APOL1 2-renal-risk-variant kidneys (hazard ratio [HR], 2.00; P = 0.03). Combined analysis of 1153 DDKTs from AA donors revealed donor APOL1 high-risk genotype (HR, 2.05; P = 3 × 10−4), older donor age (HR, 1.18; P = 0.05), and younger recipient age (HR, 0.70; P = 0.001) adversely impacted allograft survival. Although prolonged allograft survival was seen in many recipients of APOL1 2-renal-risk-variant kidneys, follow-up serum creatinine concentrations were higher than that in recipients of 0/1 APOL1 renal-risk-variant kidneys. A competing risk analysis revealed that APOL1 impacted renal allograft survival, but not recipient survival. Interactions between donor age and APOL1 genotype on renal allograft survival were nonsignificant. Conclusions Shorter renal allograft survival is reproducibly observed after DDKT from APOL1 2-renal-risk-variant donors. Younger recipient age and older donor age have independent adverse effects on renal allograft survival.

Genetic and Clinical Determinants of Early, Acute Calcineurin Inhibitor-Related Nephrotoxicity: Results from a Kidney Transplant Consortium

Background. Calcineurin inhibitor (CNI)-related acute nephrotoxicity is a common complication of transplantation. Clinical factors and elevated CNI levels are associated with nephrotoxicity; however, they do not fully explain the risk. Genetic factors may also predispose individuals to nephrotoxicity. Methods. We enrolled 945 kidney recipients into a multicenter, prospective study. DNA was genotyped for 2724 single-nucleotide polymorphisms (SNPs) using a customized chip. Cox models, unadjusted and adjusted for clinical factors, examined the association between SNPs and time to early CNI-related acute nephrotoxicity in the first 6 months posttransplant. Results. Cyclosporine was associated with a 1.49 hazard (95% confidence interval, 1.04–2.14) of acute nephrotoxicity relative to tacrolimus. Acute nephrotoxicity occurred in 22.6% of cyclosporine and 19.8% of tacrolimus recipients. The median (interquartile range) daily dose and trough concentration at time of nephrotoxicity were 400 mg (400–500 mg) and 228 ng/mL (190–272 ng/mL) in the cyclosporine group, and 6 mg (4–8 mg) and 12.6 ng/mL (10.2–15.9 ng/mL) in the tacrolimus group, respectively. In single-SNP adjusted analysis, nine SNPs in the XPC, CYP2C9, PAX4, MTRR, and GAN genes were associated with cyclosporine nephrotoxicity. In a multi-SNP analysis, SNPs from the same genes remained significant after adjusting for the clinical factors, showing that the SNPs are jointly and independently predictive of cyclosporine nephrotoxicity. No SNPs were associated with tacrolimus nephrotoxicity. Conclusion. We identified SNPs that were potentially associated with early, acute cyclosporine-related nephrotoxicity. Identifying risk SNPs before transplantation provides an opportunity for personalization of immunosuppression by identifying those who may benefit from CNI-avoidance or minimization, or assist in selecting CNI type. These SNPs require independent validation.

Lower Calcineurin Inhibitor Doses in Older Compared to Younger Kidney Transplant Recipients Yield Similar Troughs

The number of older adults undergoing kidney transplantation has increased, yet little is known about calcineurin inhibitor (CNI) metabolism in this group. We studied CNI troughs and doses to determine if there were age‐related differences in metabolism and dose requirements. We studied 348 young (18–34 years), 1831 middle (35–64 years) and 374 older (65–84 years) adult kidney transplant recipients enrolled in a seven‐center prospective study. Troughs were obtained from each patient 2×/week in weeks 1–8 and 2×/month in months 3–6. A multivariable linear‐mixed model examined the effect of age on log dose and weight normalized troughs. Older recipients had higher normalized tacrolimus troughs than middle or young age adults despite receiving doses a median of 1–2 mg/day lower. Age and CYP3A5*1 genotype had the largest effect on tacrolimus troughs. Older recipients also had higher normalized cyclosporine troughs than middle or young adults despite receiving median doses 100 mg/day lower. After normalization for dose and weight, CNI troughs were more than 50% higher in older adults than young adults. These data support age‐related changes in CNI metabolism. Further studies are needed to determine optimal dosing of CNIs in the elderly.

Genetic determinants of mycophenolate-related anemia and leukopenia after transplantation

Background. Mycophenolate-related anemia and leukopenia are well-known toxicities after transplantation. Toxicity leads to dose reduction, addition of colony-stimulating factors or erythropoietin, or discontinuation of immunosuppressive therapy. The causes of and risk factors associated with toxicity are unclear. Methods. We studied the association between mycophenolate-related anemia and leukopenia and 2724 single nucleotide polymorphisms (SNP) in 978 patients undergoing living or deceased donor kidney transplant. Patients were followed up to time of first anemia (hemoglobin<10 gm/dL or hematocrit<30%) or first leukopenia (white blood cell [WBC] count <3000 cells/mm3), which required clinical intervention in the first 6 months after transplant. Results. Anemia occurred in 87 (9.5%) subjects and leukopenia in 224 (22.9%). In single SNP analyses, none of the SNPs were associated with time to leukopenia at a false discovery rate (FDR) of 20%. However, SNPs from the IL12A, HUS, CYP2C8 genes were associated with time to anemia, allowing for an FDR of 20%. To assess the independence of these SNPs as predictors of anemia, we conducted a multi-SNP analysis including one SNP from each of the three genes. All three SNPs were associated with time to anemia, after adjusting for recipient age, weight, posttransplant dialysis and antiviral drug use, and stratifying by clinical center. Conclusion. Although these SNPs require validation in an independent population, our results suggest that genetics may play a role in risk of mycophenolate-related hematologic toxicity. This may ultimately provide for better management of maintenance immunosuppression and gives insights into potential mechanism(s) by which toxicity occurs.

Single-Nucleotide Polymorphisms, Acute Rejection, and Severity of Tubulitis in Kidney Transplantation, Accounting for Center-to-Center Variation

Background. Acute rejection (AR) is associated with worse renal allograft outcomes. Therefore, this study investigated single-nucleotide polymorphisms (SNPs) to identify genetic variants associated with AR, accounting for center variation, in a multicenter, prospective, observation study. Methods. We enrolled patients from six transplant centers, five in the United States and one in Canada. A total of 2724 SNPs were genotyped. We accounted for center variation in AR rates by stratifying by transplant center and using novel knowledge discovery methods. Results. There was significant center variation in AR rates across the six transplant sites (P<0.0001). Accounting for this difference and clinical factors independently associated with AR, we identified 15 novel SNPs associated with AR with stratification by transplant center (P<0.05). We also identified 15 novel SNPs associated with severity of tubulitis scores, after adjusting for transplant center and other clinical factors independently associated with severity of tubulitis (P<0.05). There was some overlap with one SNP associated with AR and also associated with severity of tubulitis, among the top 15 SNPs. Conclusion. Center-to-center variation is a major challenge to genomic studies focused on AR. The SNPs associated with AR and severity of tubulitis in this study will need to be validated in independent cohort of kidney transplant recipients.