Circulating cell-free nucleosomes as biomarker for kidney transplant rejection: a pilot study.

BACKGROUND: There is an unmet need for noninvasive markers specific for kidney transplant rejection. Such a marker may eventually overcome the need for a transplant biopsy. In this pilot study, the potential of circulating cell-free nucleosomes (CCFN) to serve as a biomarker for kidney transplant rejection was evaluated. METHODS: Forty de novo kidney transplant recipients were prospectively followed as part of a randomized, controlled clinical trial. Total CCFN (H3) and CCFN with the histone modifications H3K36me3 and H3 citrulline were measured in patients at four fixed time points: before transplantation and on days 3-6, 30 and 180 after kidney transplantation. In addition, serum collected at times of transplant rejection (n = 14) was analyzed. CCFN were measured with a Nu.Q™ Assay kit (VolitionRx), an ELISA-based assay using antibodies directed against nucleosomes. RESULTS: For total CCFN (H3), H3K36me3, and H3 citrulline, the same pattern was seen over time: Concentrations were elevated shortly after transplantation (day 3-6) followed by a decline reaching baseline (pre-transplantation) values at days 30 and 180. At times of acute rejection, the median concentration of total CCFN (H3) was significantly higher compared to the stable situation (day 30): 4309 (3435-5285) versus 2885 (1668-3923) ng/mL, p < 0.05, respectively. Total CCFN (H3) had an acceptable ability to discriminate rejection from no rejection (AUC-ROC = 0.73) with a negative predictive value of 92.9%. For both histone modifications (H3K36me3 and H3 citrulline), there was no significant difference between episodes of acute rejection and the stable situation (day 30). CONCLUSION: In this pilot study, total CCFN (H3) concentrations are increased at times of acute kidney transplant rejection. The high negative predictive value implies that whenever a patient experiences loss of renal transplant function and the total CCFN (H3) is not increased, causes other than acute rejection should be considered. Clinical implementation of total CCFN (H3) measurement may avoid unnecessary and potentially harmful kidney transplant biopsies.

African American polycystic kidney patients receive higher risk kidneys, but do not face increased risk for graft failure or post-transplant mortality.

African Americans (AA) are disproportionately affected by end-stage renal disease (ESRD) and have worse outcomes following renal transplantation. Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic condition leading to ESRD necessitating transplant. We explored this population with respect to race by conducting a retrospective analysis of the UNOS database between 2005 and 2019. Our study included 10,842 (AA n = 1661; non-AA n = 9181) transplant recipients whose primary diagnosis was ADPKD. We further stratified the AA ADPKD population with respect to blood groups (AA blood type B n = 295 vs AA non-B blood type n = 1366), and also compared this cohort to AAs with a diagnosis of DM (n = 16,706) to identify unique trends in the ADPKD population. We analyzed recipient and donor characteristics, generated survival curves, and conducted multivariate analyses. African American ADPKD patients waited longer for transplants (924 days vs 747 days P < .001), and were more likely to be on dialysis (76% vs 62%; p < .001). This same group was also more likely to have AA donors (21% vs 9%; p < .001) and marginally higher KDPI kidneys (0.48 vs 0.45; p < .001). AA race was a risk factor for delayed graft function (DGF), increasing the chance of DGF by 45% (OR 1.45 95% CI 1.26-1.67; p < .001). AA race was not associated with graft failure (HR 1.10 95% CI 0.95-1.28; p = .21) or patient mortality (HR 0.84 95% CI 0.69-1.03; p = .09). Racial disparities exist in the ADPKD population. They should be continually studied and addressed to improve transplant equity.

Allograft and Patient Outcomes Between Indigenous and Nonindigenous Kidney Transplant Recipients.

BACKGROUND: Kidney transplant outcomes of indigenous Australians are poorer compared with nonindigenous Australians, but it is unknown whether the type of acute rejection differs between these patient groups or whether rejection mediates the effect between ethnicity, death-censored graft failure (DCGF), and death with a functioning graft (DWFG). METHODS: Biopsy-proven acute rejection (BPAR) rates and types were compared between indigenous and nonindigenous recipients. The associations between ethnicity, BPAR, DCGF, and DWFG were examined using adjusted competing risk analyses, and mediation analysis was conducted to determine whether BPAR mediated the adverse effects between ethnicity and outcomes. RESULTS: Fifty-seven (9.3%) of 616 patients who have received kidney-only transplants between 2000 and 2010 in Western Australia were indigenous. Compared with nonindigenous recipients, BPAR rates were higher in indigenous recipients (42 versus 74 episodes/100 recipients, P < 0.01), with an excess of antibody-mediated rejections. During a median follow-up of 8 years, indigenous recipients were more likely to experience BPAR, DCGF, and DWFG compared with nonindigenous recipients, with adjusted subdistribution hazard ratio of 1.94 (1.39-2.70), 1.53 (0.85-2.76; P = 0.159), and 2.14 (1.13-4.06; P = 0.020), respectively. Although 70% of the effect between ethnicity and DCGF was mediated by BPAR, no similar association was found for DWFG. CONCLUSIONS: Indigenous recipients experienced poorer allograft and patient outcomes compared with nonindigenous recipients, with BPAR an important determinant for DCGF. Future research identifying other risk factors and mediators associated with patient survival in indigenous recipients should be considered a priority.

Association Between Neighborhood-level Socioeconomic Deprivation and the Medication Level Variability Index for Children Following Liver Transplantation.

BACKGROUND: Neighborhood socioeconomic deprivation is associated with adverse health outcomes. We sought to determine if neighborhood socioeconomic deprivation was associated with adherence to immunosuppressive medications after liver transplantation. METHODS: We conducted a secondary analysis of a multicenter, prospective cohort of children enrolled in the medication adherence in children who had a liver transplant study (enrollment 2010-2013). Participants (N = 271) received a liver transplant ≥1 year before enrollment and were subsequently treated with tacrolimus. The primary exposure, connected to geocoded participant home addresses, was a neighborhood socioeconomic deprivation index (range 0-1, higher indicates more deprivation). The primary outcome was the medication level variability index (MLVI), a surrogate measure of adherence to immunosuppression in pediatric liver transplant recipients. Higher MLVI indicates worse adherence behavior; values ≥2.5 are predictive of late allograft rejection. RESULTS: There was a 5% increase in MLVI for each 0.1 increase in deprivation index (95% confidence interval, -1% to 11%; P = 0.08). Roughly 24% of participants from the most deprived quartile had an MLVI ≥2.5 compared with 12% in the remaining 3 quartiles (P = 0.018). Black children were more likely to have high MLVI even after adjusting for deprivation (adjusted odds ratio 4.0 95% confidence interval, 1.7-10.6). CONCLUSIONS: This is the first study to evaluate associations between neighborhood socioeconomic deprivation and an objective surrogate measure of medication adherence in children posttransplant. These findings suggest that neighborhood context may be an important consideration when assessing adherence. Differential rates of medication adherence may partly explain links between neighborhood factors and adverse health outcomes following pediatric liver transplantation.

Impact of Donor Ethnicity on Long-Term Kidney Transplant Outcomes: Analysis by Kidney Donor Profile Index Categories.

OBJECTIVES: Risk of kidney disease is heightened in African American individuals. African American donor ethnicity is one of 10 risk factors in calculating the kidney donor profile index used in assessing organ quality. We aimed to evaluate outcomes of deceased-donor kidney transplants from African American donors stratified by kidney donor profile index. MATERIALS AND METHODS: Using the Organ Procurement and Transplant Network/United Network for Organ Sharing database, we identified deceased-donor kidney transplant recipients from 2000 to 2015 who received induction and calcineurin inhibitor/mycophenolic acid maintenance. Patients were divided into 4 kidney donor profile index groups (0%-20%, 21%-50%, 51%-85%, and > 85%). Long-term outcomes of each group were compared between African American and non-African American kidney donations using Cox model. RESULTS: Among 59 648 patients, 15 250 were in the 0% to 20% group (560 African American donors, 14 690 non-African American donors), 19 355 were in the 21% to 50% group (2807 African American donors, 16 548 non-African American donors), 19 412 were in the 51% to 85% group (2774 African American donors, 16 638 non-African American donors), and 5631 were in the > 85% group (1670 African American donors, 3961 non-African American donors). Adjusted overall and death-censored graft failure risks were higher for recipients of African American donor kidneys in the 51% to 85% (hazard ratio 1.12; 95% confidence interval, 1.01-1.25; P = .009 and hazard ratio 1.12; 95% confidence interval, 1.01-1.25; P = .03) and the > 85% kidney donor profile index (hazard ratio 1.12; 95% confidence interval, 1.04-1.24; P = .025 and hazard ratio 1.33; 95% confidence interval, 1.16-1.51; P < .001) groups. CONCLUSIONS: Inferior graft outcomes in recipients of African American kidneys in our study were limited to those with > 50% kidney donor profile index. Effects of risk factors such as APOL1 risk alleles and sickle cell trait on these observations need further study.

Redefining the Influence of Ethnicity on Simultaneous Kidney and Pancreas Transplantation Outcomes: A 15-year Single-center Experience.

OBJECTIVE: To examine the largest single-center experience of simultaneous kidney/pancreas transplantation (SPK) transplantation among African-Americans (AAs). BACKGROUND: Current dogma suggests that AAs have worse survival following SPK than white recipients. We hypothesize that this national trend may not be ubiquitous. METHODS: From August 30, 1999, through October 1, 2014, 188 SPK transplants were performed at the University of Alabama at Birmingham (UAB) and 5523 were performed at other US centers. Using Kaplan-Meier survival estimates and Cox proportional hazards regression, we examined the influence of recipient ethnicity on survival. RESULTS: AAs comprised 36.2% of the UAB cohort compared with only 19.1% nationally (P < 0.01); yet, overall, 3-year graft survival was statistically higher among UAB than US cohort (kidney: 91.5% vs 87.9%, P = 0.11; pancreas: 87.4% vs 81.3%; P = 0.04, respectively) and persisted on adjusted analyses [kidney adjusted hazard ratio (aHR): 0.58, 95% confidence interval (95% CI) 0.35-0.97, P = 0.04; pancreas aHR: 0.54, 95% CI 0.34-0.85, P = 0.01]. Among the UAB cohort, graft survival did not differ between AA and white recipients; in contrast, the US cohort experienced significantly lower graft survival rates among AA than white recipients (kidney 5 years: 76.5% vs 82.3%, P < 0.01; pancreas 5 years: 72.2% vs 76.3%, P = 0.01; respectively). CONCLUSION: Among a single-center cohort of SPK transplants overrepresented by AAs, we demonstrated similar outcomes among AA and white recipients and better outcomes than the US experience. These data suggest that current dogma may be incorrect. Identifying best practices for SPK transplantation is imperative to mitigate racial disparities in outcomes observed at the national level.

Alemtuzumab Induction Is Associated With an Equalization of Outcomes Between White and African American Kidney Transplant Recipients.

OBJECTIVES: Our aim was to assess outcomes in White and African American kidney transplant recipients after induction with alemtuzumab. MATERIALS AND METHODS: We performed a retrospective study of 464 patients who received deceased-donor kidney transplants and were induced with alem-tuzumab between March 2006 and May 2015. We evaluated ethnic influences on patient and graft survival, delayed graft function, allograft failure, and rejection. RESULTS: There were 337 White (67.3%) and 127 African American (25.3%) patients. We observed no significant differences in 1-, 3-, 5-, and 7- year death-censored graft survival. We also observed no significant differences in 1-, 3-, and 5-year patient survival rates. Having African American ethnicity was not a significant predictor of rejection, graft survival, or patient survival. CONCLUSIONS: Our results indicate that recipient ethnicity is not a predictor of rejection, graft survival, or patient survival. White and African American kidney transplant recipients induced with alemtuzumab experienced an equalization of outcomes.

A Contemporary Analysis of Outcomes and Modifiable Risk Factors of Ethnic Disparities in Kidney Transplantation.

OBJECTIVE: The aim of this study was to provide a contemporary analysis of longitudinal kidney transplant outcomes and to evaluate potential causes of ethnic disparities among African American (AA) and Caucasian American (CA) patients undergoing kidney transplantation at our institution. PATIENTS AND METHODS: 1400 patients were identified who underwent kidney transplantation from 2003 to 2013 from a large, academic institution in Cleveland, OH. Relevant recipient and donor demographic and clinical covariates were obtained from an institutional transplant database. Simple descriptive statistics and comparative survival analyses were performed to assess overall survival and graft survival. RESULTS: The final cohort was comprised of 341 AA and 1059 CA patients. AAs were less likely to receive a living donor transplant (27.6% vs. 57.2%, p < 0.001) compared to CAs. Overall patient survival did not significantly differ between the two groups even when stratified by ethnicity. However, AAs had a significantly lower rate of graft survival (p < 0.001). On stratified analysis, there was no difference in the rate of graft survival among AAs and CAs who received living donor grafts. On univariate analysis, AAs demonstrated higher rates of immunosuppression non-compliance and chronic rejection (both p < 0.05). On multivariate analysis, AA recipient ethnicity (HR 1.56, p = 0.047), recipient history of diabetes (HR 1.67, p < 0.001), and AA donor ethnicity (HR 1.56, p = 0.047) were significantly associated with graft failure. CONCLUSION: AAs undergoing deceased donor renal transplantation demonstrated lower graft survival compared to CAs. Conversely, this disparity did not exist among AAs undergoing living donor transplantation. AAs had higher rates of deceased donor transplantation, immunosuppression non-compliance, chronic rejection, and diabetes. Opportunities exist to use patient education, alternative immunosuppression regimens, and living transplantation to close the ethnic disparity in renal allograft survival.

Change in Mycophenolate and Tacrolimus Exposure by Transplant Vintage and Race.

OBJECTIVES: Although both tacrolimus and mycophenolate have improved outcomes after kidney transplant, studies regarding effects of exposure on outcomes, specifically related to racial disparities, are sparse. MATERIALS AND METHODS: In this 8-year longitudinal cohort study of adult kidney transplant recipients, mycophenolate and tacrolimus levels were compared across transplant vintage stratified by non-African Americans versus African Americans. Data were analyzed with standard univariate tests and multivariable regression models. RESULTS: Our study included 1217 patients (transplanted from 2005-2013) who had tacrolimus and myco-phenolate exposure data, with follow-up through 2015 (53.7% were African Americans). Mean mycophenolate dose was 1672 ± 463 mg/day during the first 3 years posttransplant. Although transplant vintage did not appreciably impact mycophenolate dosing in non-African Americans (0.7 mg/day/y; P = .903), doses significantly decreased in African Americans across transplant vintage (-20.5 mg/day/y; P < .001). Rate of mycophenolate being held or discontinued based on transplant vintage significantly increased in African Americans but did not change in non-African Americans. At the beginning of the study, mean tacrolimus levels were lower in African Americans; however, levels then slightly decreased in non-African Americans (-0.03 ng/mL/y; P = .279) and slightly increased in African Americans (+0.03 ng/mL/y; P = .247), with similar levels by 2013. Higher tacrolimus levels were protective against rejection in African Americans only but were protective against death-censored graft loss in both race/ethnicity groups. Mycophenolate dosing had no appreciable impact on outcomes in African Americans, but higher mycophenolate dosing was a significant risk factor for death-censored graft loss in non-African Americans. CONCLUSIONS: Tacrolimus and mycophenolate exposure levels have significantly changed over time and differed by race/ethnicity. In non-African Americans, those transplanted more recently tended to have lower tacrolimus but similar mycophenolate exposure. Although mycophenolate exposure in African Americans has recently decreased, tacrolimus has increased. Differences in outcomes likely reflect improved understanding of immunosuppressant tolerability by recipient race/ethnicity.

Prolonged-Release vs Immediate-Release Tacrolimus Capsules in Black vs White Kidney Transplant Patients: A Post Hoc Analysis of Phase III Data.

BACKGROUND: Black kidney transplant patients experience inferior outcomes compared with other ethnicities. Because scrutiny is required when immunosuppressant drugs are used in such at-risk populations, we report the first large-scale clinical efficacy data assessing prolonged-release tacrolimus (PR-T) in black de novo kidney transplant patients. METHODS AND MATERIALS: We used logistic regression and proportionate hazards to compare a composite outcome measure (biopsy-proven acute rejection, graft loss, mortality, and loss to follow-up) in black and white patients in treatment groups longer than 24 weeks, from 3 large Phase III randomized controlled trials. Secondary endpoints included tacrolimus trough concentration, dose, and estimated glomerular filtration rate. RESULTS: The study included 2162 patients whose treatments belonged to two categories (immediate-release tacrolimus: 77 black patients, 721 white patients; and PR-T: 87 black patients, 1277 white patients). Despite demographic factors generally predictive of worse outcomes, efficacy failure among black patients who received PR-T was non-inferior to that among white patients who received either therapy. Compared with immediate-release tacrolimus, black patients who received PR-T achieved stable tacrolimus concentrations 2.5 times faster (21 vs 56 days, P = .04), and more achieved stable target concentrations (76.7% vs 69.3%). Treatment-emergent adverse events were consistent with those reported separately in pivotal trials. CONCLUSIONS: Overall, black patients who received PR-T achieved non-inferior outcomes compared to white patients, despite higher pretransplant risk among black patients. Moreover, PR-T improved the time to achieve, and the likelihood of reaching, stable therapeutic concentrations among black patients, suggesting that PR-T could improve the consistency of tacrolimus exposure in this patient population.

Black Ethnicity is Not a Risk Factor for Mortality or Graft Loss After Kidney Transplant in the United Kingdom.

OBJECTIVES: There are conflicting reports in the literature regarding outcomes after kidney transplant for patients of black ethnicity. To investigate further, we compared outcomes for black versus white kidney transplant recipients in a single UK transplant center. MATERIALS AND METHODS: We analyzed 1066 kidney transplant recipients (80 black patients, 986 white patients) within a single-center cohort (2007-2017) in the United Kingdom, with cumulative 4446 patient-year follow-up. Data were electronically extracted from the Department of Health Informatics database for every study recruit, with manual data linkage to the UK Transplant Registry (for graft survival, delayed graft function, and rejection data) and Office for National Statistics (for mortality data). Primary outcomes of interest were graft/patient survival. RESULTS: Black recipients have increased baseline risk profiles with longer wait times, difficulty in matching, worse HLA matching, more socioeconomic deprivation, and lower rates of living kidney donors. Postoperatively, black versus white recipients had increased risk for delayed graft function (34.3% vs 10.2%; P < .001), increased 1-year rejection (16.7% vs 7.3%; P = .012), higher 1-year creatinine levels (166 vs 138 mmol/L; P = .003), and longer posttransplant length of stay (14.5 vs 9.5 days; P = .020). Although black recipients did not have increased risk of death versus white recipients (10.0% vs 11.0%, respectively; P = .486), they did have increased risk for death-censored graft loss (23.8% vs 11.1%; P = .002). However, in an adjusted Cox regression model, black ethnicity was not associated with increased risk for death-censored graft loss (hazard ratio of 1.209, 95% confidence interval, 0.660-2.216; P = .539). CONCLUSIONS: Black kidney transplant recipients in the United Kingdom have increased risk of adverse graft-related outcomes due to high-risk baseline variables rather than their black ethnicity per se.

Donor and Recipient Ethnicity Impacts Renal Graft Adverse Outcomes.

Renal transplant outcomes have been shown to be impacted by ethnicity. Prior studies have evaluated the disparate transplant outcomes of Black recipients and recipients of Black donors. However, it has remained unclear whether other donor ethnicities independent of medical comorbidities can influence transplant outcomes. Utilizing the Scientific Registry of Transplant Recipients (SRTR) (with greater than 100,000 patients), we evaluated the effect of each ethnicity, Black, American Indian, Hispanic, Native Hawaiian or other Pacific Islander, and Asian as compared to White recipients on adverse kidney transplant outcomes, assessing for delayed graft function, positive urine protein, acute rejection, and graft failure. Additionally, we assessed the interplay of donor ethnicity on recipient transplant outcomes, which has not previously been comprehensively examined. Logistic regression analysis that took into consideration gender, age, comorbidities, graft type, donor ethnicity, body mass index (BMI), HLA mismatch, ever been on hemodialysis, and time on dialysis indicates that Black recipients have worse outcomes compared to Whites in all outcomes assessed. A logistic regression analysis showed that recipient ethnicity was an independent risk factor for adverse outcomes. Notably, we found that donor ethnicity also independently affects graft outcomes. Hispanic donors lead to better outcomes in Whites and Blacks, while Asian donors have the best outcomes amongst Asian recipients. Recipients of Black donors fared the worst of all ethnicity donors. These data suggest the potential importance of risk stratification for the donor allograft and developing risk calculators that include both donor and recipient ethnicity may be useful, which the current Kidney Donor Profile Index (KDPI) does not currently take into account as they give black donors a different weight, but the same score is assigned to Whites, Asians, and Hispanics.

Racial differences in the development of de-novo donor-specific antibodies and treated antibody-mediated rejection after heart transplantation.

BACKGROUND: Despite improvements in outcomes after heart transplantation, black recipients have worse survival compared with non-black recipients. The source of such disparate outcomes remains largely unknown. We hypothesize that a propensity to generate de-novo donor-specific antibodies (dnDSA) and subsequent antibody-mediated rejection (AMR) may account for racial differences in sub-optimal outcomes after heart transplant. In this study we aimed to determine the role of dnDSA and AMR in racial disparities in post-transplant outcomes. METHODS: This study was a single-center, retrospective analysis of 137 heart transplant recipients (81% male, 48% black) discharged from Emory University Hospital. Patients were classified as black vs non-black for the purpose of our analysis. Kaplan-Meier and Cox regression analyses were used to evaluate the association between race and selected outcomes. The primary outcome was the development of dnDSA. Secondary outcomes included treated AMR and a composite of all-cause graft dysfunction or death. RESULTS: After 3.7 years of follow-up, 39 (28.5%) patients developed dnDSA and 19 (13.8%) were treated for AMR. In multivariable models, black race was associated with a higher risk of developing dnDSA (hazard ratio [HR] 3.65, 95% confidence interval [CI] 1.54 to 8.65, p = 0.003) and a higher risk of treated AMR (HR 4.86, 95% CI 1.26 to 18.72, p = 0.021) compared with non-black race. Black race was also associated with a higher risk of all-cause graft dysfunction or death in univariate analyses (HR 2.10, 95% CI 1.02 to 4.30, p = 0.044). However, in a multivariable model incorporating dnDSA, black race was no longer a significant risk factor. Only dnDSA development was significantly associated with all-cause graft dysfunction or death (HR 4.85, 95% CI 1.89 to 12.44, p = 0.001). CONCLUSION: Black transplant recipients are at higher risk for the development of dnDSA and treated AMR, which may account for racial disparities in outcomes after heart transplantation.

Health Disparities in Kidney Transplantation for African Americans.

BACKGROUND: The persistent challenges of bridging healthcare disparities for African Americans (AAs) in need of kidney transplantation continue to be unresolved at the national level. This healthcare disparity is multifactorial: stemming from limited kidney donors suitable for AAs; inconsistent care coordination and suboptimal risk factor control; social determinants, low socioeconomic status, reduced access to care; and mistrust of clinicians and the healthcare system. SUMMARY: There are numerous opportunities to significantly lessen the disparities in kidney transplantation for AAs through the following measures: the adoption of new care and patient engagement models that include education, enhanced practice-level cultural sensitivity, and timely referral as well as increased research on the impact of the environment on genetic risk, and implementation of new transplantation-related policies. Key Messages: This systematic review describes pretransplant concerns related to access to kidney transplantation, posttransplant complications, and policy interventions to address the challenging issues associated with kidney transplantation in AAs.

Cytolytic Induction Therapy Improves Clinical Outcomes in African-American Kidney Transplant Recipients.

OBJECTIVE: Determine the impact of cytolytic versus IL-2 receptor antibody (IL-2RA) induction on acute rejection, graft loss and death in African-American (AA) kidney transplant (KTX) recipients. BACKGROUND: AAs are underrepresented in clinical trials in transplantation; thus, there is controversy regarding the optimal choice of perioperative antibody induction in KTX to improve outcomes. METHODS: National cohort study using US transplant registry data from January 1, 2000 to December 31, 2009 in adult solitary AA KTX recipients, with at least 5 years of follow-up. Multivariable logistic and Cox regression were utilized to assess the outcomes of acute rejection, graft loss, and mortality, with interaction terms to assess effect modification. RESULTS: Twenty-five thousand eighty-four adult AAs receiving solitary KTX were included, 16,927 (67.5%) received cytolytic induction and 8157 (32.5%) received IL-2RA induction. After adjustment for recipient sociodemographics, donor, and transplant characteristics, the use of cytolytic induction therapy reduced the risk of acute rejection by 32% (OR 0.68, 0.62-0.75), graft loss by 9% (HR 0.91, 0.86-0.97), and death by 12% (HR 0.88, 0.83-0.94). There were a number of significant effect modifiers, including public insurance, panel reactive antibody, delayed graft function, and steroid withdrawal; in these groups, cytolytic induction substantially improved clinical outcomes. CONCLUSIONS: These data demonstrate that cytolytic induction therapy, as compared with IL-2RA, reduces the risk of rejection, graft loss, and death in adult AA KTX recipients, particularly in those who are sensitized, receive public insurance, develop delayed graft function, or undergo steroid withdrawal.

Differences in Phenotypes and Liver Transplantation Outcomes by Age Group in Patients with Primary Sclerosing Cholangitis.

BACKGROUND: There is increasing evidence for a heterogeneity of phenotypes in primary sclerosing cholangitis (PSC), but differences across the age spectrum in adults with PSC have not been well characterized. AIMS: To characterize phenotypic variations and liver transplantation outcomes by age group in adults with PSC. METHODS: The United Network for Organ Sharing database was used to identify waitlist registrations for primary liver transplantation in adults with PSC. Patients were split into three age groups: 18-39 (young), 40-59 (middle-aged), and ≥60 (older). Their clinical characteristics and outcomes on the waitlist and post-transplant were compared. RESULTS: Overall, 8272 adults with PSC were listed for liver transplantation during the study period, of which 28.9% were young, 52.0% were middle-aged, and 19.1% were older. The young age group had the greatest male predominance (70.0 vs. 66.2 vs. 65.1%, p = 0.001), the highest proportion of black individuals (20.0 vs. 11.0 vs. 5.5%, p < 0.001), and the most patients listed with concomitant autoimmune hepatitis (2.2 vs. 1.0 vs. 0.8%, p < 0.001). Older patients experienced the greatest waitlist and post-transplant mortality. Graft survival was greatest in the middle-aged group. Young patients were most likely to experience acute rejection (31 vs. 22.8 vs. 18.0%, p < 0.001) and have graft failure due to chronic rejection or PSC recurrence (47.8 vs. 42.3 vs. 17.9%, p < 0.001). CONCLUSIONS: Age-related differences exist among adults with PSC and are associated with outcomes pre- and post-transplant. Young patients may have a more robust immune-related phenotype that is associated with poorer graft survival. Future studies are needed to further investigate these findings.

Lower kidney allograft survival in African-Americans compared to Hispanic-Americans with lupus.

Background and objective African-Americans and Hispanic-Americans with lupus are the two most common minority groups who receive kidney transplants in the USA. It is unknown if African-Americans and Hispanic-Americans with lupus have similar outcomes after kidney transplantation. In this study, we assessed whether African-Americans compared to Hispanic-Americans have worse kidney allograft survival after risk factors of rejection and other prognostic factors were matched between both groups. Methods Out of 1816 African-Americans and 901 Hispanic-Americans with lupus, who received kidney transplants between 1987 and 2006 and had complete records in the UNOS program, 478 pairs were matched in 16 baseline predictors and follow-up time employing a predicted probability of group membership. The primary outcome was kidney allograft survival. Main secondary outcomes were rejection, allograft failure attributed to rejection, and mortality. Results Matched pairs were predominantly women (81%) with the mean age of 36 years. 96% were on dialysis before transplantation. 89% of recipients received kidneys from deceased donors and 15.5% from expanded criteria donors. 12% of recipients had zero HLA mismatch. African-Americans compared to Hispanic-Americans had lower cumulative allograft survival during 12-year follow-up ( p < 0.001). African-Americans compared to Hispanic-Americans had higher rates of rejection (10.4 vs 6.73 events/100 patients-years; p = 0.0002) and allograft failure attributed to rejection (6.31 vs 3.99; p = 0.0023). However, African-Americans and Hispanic-Americans had similar mortality rates (2.71 vs 2.31; p = 0.4269). Conclusions African-Americans compared to Hispanic-Americans with lupus had lower kidney allograft survival when recognized risk factors of rejection were matched between groups.

Impact of the CYP3A5 genotype on the distributions of dose-adjusted trough concentrations and incidence of rejection in Japanese renal transplant recipients receiving different tacrolimus formulations.

BACKGROUND: We investigated the impact of the CYP3A5 genotype on the distributions of dose-adjusted trough concentrations (C 0h/D) and the incidence of rejection in Japanese recipients taking twice-daily (Tac-BID, n = 140) or modified-release once-daily (Tac-QD, n = 80) tacrolimus formulations for 1 year after renal transplantation. METHODS: Logistic regression analysis was carried out to estimate the distinction rate of CYP3A5 genotypes based on the C 0h/D of Tac-BID or Tac-QD. The coefficients of variation (%CVs) were compared in each recipient to estimate the stability of tacrolimus C 0h/D between formulations or CYP3A5 genotypes. RESULTS: Recipients with at least one CYP3A5*1 wild-type allele (EMs) and recipients with homozygous expression of the variant allele CYP3A5*3 (PMs) were significantly identified using the tacrolimus C 0h/D cut-off values of 2.77 and 0.85 ng/mL/mg, respectively, and discrimination rates of 75.3 and 85.4%, respectively, for Tac-BID and Tac-QD groups. The %CV of the tacrolimus C 0h/D in CYP3A5 EMs taking Tac-QD was significantly lower than that in those taking Tac-BID (20.4 versus 23.3%, P = 0.003). The %CV of the tacrolimus C 0h/D was an independent risk factor for rejection (odds ratio = 1.028, P = 0.033). CONCLUSIONS: The tacrolimus C 0h/D values with definite cut-offs for CYP3A5 genotypes were specifically identified in Japanese renal transplant recipients taking Tac-QD. In addition, a larger %CV for the tacrolimus C 0h/D correlated with the incidence of rejection. Consequently, the stability of the C 0h/D achieved using Tac-QD, which was clearly influenced by the CYP3A5 polymorphism, may prevent the development of rejection.

Genotype-guided tacrolimus dosing in African-American kidney transplant recipients.

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.

Outcome disparities between African Americans and Caucasians in contemporary kidney transplant recipients.

BACKGROUND: Racial disparities in African-American (AA) kidney transplant have persisted for nearly 40 years, with limited data available on the scope of this issue in the contemporary era of transplantation. METHODS: Descriptive retrospective cohort study of US registry data including adult solitary kidney transplants between Jan 1, 2005 to Dec 31, 2009. RESULTS: 60,695 recipients were included; 41,426 Caucasians (68%) and 19,269 AAs (32%). At baseline, AAs were younger, had lower college graduation rates, were more likely to be receiving public health insurance and have diabetes. At one-year post-transplant, AAs had 62% higher risk of graft loss (RR 1.62, 95% CI 1.50-1.75) which increased to 93% at five years (RR 1.93, 95% CI 1.85-2.01). Adjusted risk of graft loss, accounting for baseline characteristics, was 60% higher in AAs (HR 1.61 [1.52-1.69]). AAs had significantly higher risk of acute rejection and delayed graft function. CONCLUSION: AAs continue to experience disproportionately high rates of graft loss within the contemporary era of transplant, which are related to a convergence of an array of socioeconomic and biologic risk factors.