American Kidney Transplant Recipients Research Articles

Assessing the Utility of a Genotype-Guided Tacrolimus Equation in African American Kidney Transplant Recipients: A Single Institution Retrospective Study.

Tacrolimus metabolism is heavily influenced by the CYP3A5 genotype, which varies widely among African Americans (AA). We aimed to assess the performance of a published genotype-informed tacrolimus dosing model in an independent set of adult AA kidney transplant (KTx) recipients. CYP3A5 genotypes were obtained for all AA KTx recipients (n = 232) from 2010 to 2019 who met inclusion criteria at a single transplant center in Philadelphia, Pennsylvania, USA. Medical record data were used to calculate predicted tacrolimus clearance using the published AA KTx dosing equation and two modified iterations. Observed and model-predicted trough levels were compared at 3 days, 3 months, and 6 months post-transplant. The mean prediction error at day 3 post-transplant was 3.05 ng/mL, indicating that the model tended to overpredict the tacrolimus trough. This bias improved over time to 1.36 and 0.78 ng/mL at 3 and 6 months post-transplant, respectively. Mean absolute prediction error-a marker of model precision-improved with time to 2.33 ng/mL at 6 months. Limiting genotype data in the model decreased bias and improved precision. The bias and precision of the published model improved over time and were comparable to studies in previous cohorts. The overprediction observed by the published model may represent overfitting to the initial cohort, possibly limiting generalizability.

Design, cohort profile and comparison of the KTD-Innov study: a prospective multidimensional biomarker validation study in kidney allograft rejection.

There is an unmet need for robust and clinically validated biomarkers of kidney allograft rejection. Here we present the KTD-Innov study(ClinicalTrials.gov, NCT03582436), an unselected deeplyphenotyped cohort of kidney transplant recipients with a holistic approach to validate the clinical utility of precision diagnostic biomarkers. In 2018-2019, we prospectively enrolled consecutive adult patients who received a kidney allograft at seven French centers and followed them for a year. We performed multimodal phenotyping at follow-up visits, by collecting clinical, biological, immunological, and histological parameters, and analyzing a panel of 147 blood, urinary and kidney tissue biomarkers. The primary outcome was allograft rejection, assessed at each visit according to the internationalBanff 2019 classification. We evaluated the representativeness of participants by comparing them with patients from French, European, and American transplant programs transplanted during the same period. A total of 733 kidney transplant recipients (64.1% male and 35.9% female) were included during the study. The median follow-up after transplantation was 12.3months (interquartile range, 11.9-13.1months). The cumulative incidence of rejection was 9.7% at one year post-transplant. We developed a distributed and secured data repository in compliance with the general data protection regulation. We established a multimodal biomarker biobank of 16,736 samples, including 9331 blood, 4425 urinary and 2980 kidney tissue samples, managed and secured in a collaborative network involving 7 clinical centers, 4 analytical platforms and 2 industrial partners. Patients' characteristics, immune profiles and treatments closely resembled those of 41,238 French, European and American kidney transplant recipients. The KTD-Innov study is a unique holistic and multidimensional biomarker validation cohort of kidney transplant recipients representative of the real-world transplant population. Future findings from this cohort are likely to be robust and generalizable.

466 A Single-center Experience of Hypertension in Native American Kidney Transplant Recipients

466 A Single-center Experience of Hypertension in Native American Kidney Transplant Recipients

Evaluation of the Modified Oxford Score in Recurrent IgA Nephropathy in North American Kidney Transplant Recipients: The Banff Recurrent Glomerulonephritis Working Group Report.

The modified Oxford classification mesangial and endocapillary hypercellularity, segmental sclerosis, interstitial fibrosis/tubular atrophy, and the presence of crescents (MEST-C) of immunoglobulin A nephropathy (IgAN) was recently shown to be a predictor of graft failure in Asians with recurrent IgAN. We aimed to validate these findings in a cohort from North American centers participating in the Banff Recurrent Glomerulopathies Working Group. We examined 171 transplant recipients with end-stage kidney disease because of IgAN; 100 of them with biopsy-proven recurrent IgAN (57 of them had complete MEST-C scores) and 71 with no recurrence. IgAN recurrence, which was associated with younger age at transplantation ( P = 0.012), strongly increased the risk of death-censored graft failure (adjusted hazard ratio, 5.10 [95% confidence interval (CI), 2.26-11.51]; P < 0.001). Higher MEST-C score sum was associated with death-censored graft failure (adjusted hazard ratio, 8.57 [95% CI, 1.23-59.85; P = 0.03] and 61.32 [95% CI, 4.82-779.89; P = 0.002] for score sums 2-3 and 4-5 versus 0, respectively), and so were the single components endocapillary hypercellularity, interstitial fibrosis/tubular atrophy, and crescents ( P < 0.05 each). Overall, most of the pooled adjusted hazard ratio estimates associated with each MEST-C component were consistent with those from the Asian cohort (heterogeneity I2 close to 0%, and P > 0.05). Our findings may validate the prognostic usefulness of the Oxford classification for recurrent IgAN and support the inclusion of the MEST-C score in allograft biopsies diagnostic reports.

Impact of CYP3A5 Status on the Clinical and Financial Outcomes Among African American Kidney Transplant Recipients.

Background.Pharmacogenetic profiling of transplant recipients demonstrates that the marked variation in the metabolism of immunosuppressive medications, particularly tacrolimus, is related to genetic variants. Patients of African ancestry are less likely to carry loss-of-function (LoF) variants in the CYP3A5 gene and therefore retain a rapid metabolism phenotype and higher clearance of tacrolimus. Patients with this rapid metabolism typically require higher dosing to achieve therapeutic trough concentrations. This study aims to further characterize the impact of CYP3A5 genotype on clinical outcomes and financial expenditure.Methods.The CYP3A5 phenotype status was identified in 438 adult kidney transplant (KTx) recipients (96% were African American) using 3 LoF alleles (CYP3A5*3, *6 or *7). Individuals were categorized as rapid metabolism phenotype without LoF alleles‚ intermediate phenotype for 1 LoF allele‚ and slow phenotype for 2 LoF alleles. KTx outcomes (patient/kidney survival and Medicare spending) were determined using linked transplant registry and claims data.Results.Among the cohort, 23% had a rapid, 47% intermediate, and 30% a slow metabolism phenotype based on genotype. At 3 y, the rate of death censored graft failure and all cause graft failure was highest in the rapid metabolism phenotype and lowest in the intermediate metabolism phenotype group. First-year Medicare reimbursement differed significantly by genotype (rapid: $79 535, intermediate: $72 796, slow: $79 346, P = 0.03). After adjustment for donor and recipient characteristics, care for patients with intermediate metabolism was $4790 less expensive (P = 0.003).Conclusions.Pharmacogenomic assessment of African American KTx recipients may be useful to guide therapy when as CYP3A5 functional variants appear to be associated with differential outcome and spending after transplant.

COVID-19 Among a Population of Predominantly American Indian and Hispanic American Kidney Transplant Recipients

COVID-19 Among a Population of Predominantly American Indian and Hispanic American Kidney Transplant Recipients

Acute Kidney Injury in a Predominantly African American Cohort of Kidney Transplant Recipients With COVID-19 Infection.

Renal involvement in severe or critical acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is frequent. Acute kidney injury (AKI) in African American (AA) kidney transplant recipients (KTRs) with COVID-19 is not well described. We report our experience with a predominantly AA cohort (79%) of KTRs with COVID-19 infections in the Detroit Metropolitan area. In this retrospective, single-center study, we identified 39 KTRs who tested positive for SARS-CoV-2 between March 16 and April 25, 2020. Data from electronic medical records were retrieved and compared between KTRs without AKI and KTRs with AKI. One patient was excluded due to delayed graft function. Final analysis of AKI in KTRs with proven COVID-19 was done on 38 patients of which 30 were AA (79%). AKI occurred in 71.1% of COVID-19 KTRs (n = 27), of whom 6 (22.2%) patients required HD. The incidence of AKI in our cohort was 71% (27/38). AKI rate among AA was 76.7% versus 50% in non-AA cohort (P = 0.195). In a univariate logistic regression analysis, AA race was not significantly associated with AKI odds ratio (3.4; CI, 0.68-17.4; P = 0.14). After risk adjustment by race, patients with diabetes showed a significantly higher risk of AKI (adjusted odds ratio, 19.85; CI, 1.65-58.66; P = 0.012). KTRs with AKI had more preexisting renin angiotensin aldosterone system inhibitor use than KTRs without AKI (P = 0.03). KTRs infected with SARS-CoV-2 have a high incidence of AKI, with associated increased morbidity and mortality. Although no racial differences in mortality were noted in our KTRs with AKI, we await data from registries to help elucidate this difference.

P1706THE GRAFT SURVIVAL OF KIDNEY TRANSPLANTATION ACCORDING TO ETHNICITY IN KIDNEY TRANSPLANT RECIPIENTS

Abstract Background African American kidney transplant recipients experience disproportionately high rates of graft loss. The aim of this analysis was to use a UNOS data set that contains detailed baseline and longitudinal clinical data to establish and quantify the impact of the current overall graft loss definition on suppressing the true disparity magnitude in US AA kidney transplant outcomes. Methods Longitudinal cohort study of kidney transplant recipients using a data set created by United Network for Organ Sharing (UNOS), including 266,128 (African American 70,215, Non-African American 195,913) transplant patient between 1987 and December 2016. Multivariable analysis was conducted using 2-stage joint modeling of random and fixed effects of longitudinal data (linear mixed model) with time to event outcomes (Cox regression). Results 195,913 non-African American (AA) (73.6%) were compared with 70,215 AA (26.4%) recipients. 10-year-graft survival of AA in all era is lower than that of non-AA (31% in deceased kidney transplants (DKT) AA recipient and 42% in living kidney transplantation (LKT) non-AA recipient). 10-year-patient survival of AA with functioning graft in all era is similar that of non-AA. Multivariate Cox regression of factors associated with patient survival with functioning graft are acute rejection within 6 months, DM, hypertension and etc. Pre-transplant recipient BMI in AA show the trend as a protective factor in patient survival with functioning graft although not significantly in statistics Conclusions African American kidney transplant recipients experience a substantial disparity in graft loss, but not patient death with functioning graft.

Dosing Requirements of Extended-Release Tacrolimus (Astagraf XL) in African American Kidney Transplant Recipients Converted from Immediate-Release Tacrolimus (AAAKTRS).

The formal recommendation for converting twice-daily tacrolimus immediate release (IR) to once-daily tacrolimus extended release (ER) is a 1:1 dose conversion. However, more recent clinical analysis has shown that this may not be true; some patients may require a higher dose. In addition, de novo dosing tacrolimus ER has revealed that African Americans require approximately 20%-30% higher doses than Caucasians to achieve similar levels. As a result, this study sought to identify the appropriate dose conversion in the African American kidney transplant population, a population at high risk of rejection. This was a single-center, prospective, open-label study comparing the difference in dose-normalized trough and total daily dose necessary to reach steady-state therapeutic goal, after conversion from tacrolimus IR to tacrolimus ER, in 25 African American kidney transplant recipients. After conversion to tacrolimus ER, there was a significant decrease in dose-normalized trough (C0) (0.44 versus 0.59, P = 0.03). Statistically significant differences were seen in both total daily and weight-based doses, when reported as actual values (15 versus 10 mg and 0.16 versus 0.11 mg/kg, respectively), as well as when standardized to achieve a target tacrolimus C0 of 8 ng/mL (18.1 versus 13.6 mg and 0.17 versus 0.15 mg/kg, respectively). The median standardized dose conversion required was 1.3 [1.0, 1.4], for the overall population. There were no instances of biopsy-proven acute rejection, allograft loss, or study drug discontinuation. This single-center, open-label conversion study demonstrated that there was a statistically and clinically significant decrease in dose-normalized trough after conversion from tacrolimus IR to tacrolimus ER in an African American kidney transplant population and that a 1:1 dose conversion is unlikely to meet therapeutic goals.

Impact of CYP3A5 genomic variances on clinical outcomes among African American kidney transplant recipients.

Little is known about the impact of CYP3A5 polymorphisms on transplantation outcomes among African American (AA) kidney transplant recipients (KTRs). To assess this issue, clinical outcomes were compared between AA CYP3A5*1 expressers and nonexpressers. This retrospective cohort study analyzed AA KTRs. Biopsy-proven acute rejection (BPAR), delayed graft function (DGF), glomerular filtration rate (GFR), infections, and tacrolimus dosing requirements were examined in 106 immunologically high-risk AA kidney transplant patients over a 2-year follow-up period. In CYP3A5*1 expressers compared to nonexpressers, the incidence of BPAR was significantly higher in the first 6months (13% vs 0%; P=.016) compared to 24months (13% vs 7%; P=.521). Tacrolimus total daily dose at first therapeutic level was significantly higher in CYP3A5*1 expressers (12mg/day) compared to nonexpressers (8mg/day; P<.001). Compared to CYP3A5*1 nonexpressers, DGF incidence was significantly higher among CYP3A5*1 expressers (27.6% vs 6.7%; P=.006). By contrast, median GFR was significantly higher in CYP3A5*1 expressers compared to nonexpressers (54.5mL/min vs 50.0mL/min; P=.003) at 24months. The findings from this retrospective study suggest that AAs with CYP3A5*1 expression require 50% more tacrolimus and have an increased incidence of DGF and acute rejection.

Prevalence of skin cancer in Native American kidney transplant recipients.

Skin cancer prevalence is well-characterized for white solid organ transplant recipients. Although the prevalence of skin cancer in non-white (Black, Asian, Hispanic) kidney transplant recipients (KTRs) has been assessed, no study has reported the prevalence of skin cancer in Native American (NA) KTRs. The aim of this study is to determine if the prevalence of skin cancer in NAKTRs is the same as in white KTRs. We conducted a case-controlled retrospective review from a single transplant center. One hundred thirteen NAKTRs who received a transplant between 2001 and 2011 were age- and transplant-year matched with 113 white controls. The 226 KTRs consisted of 141 (62.4%) men and 85 (37.6%) women, with a mean age of 50.2 ± 10.8 years. There was no skin cancer found in NAKTRs prior to or post transplantation, while seven (6.2%) white KTRs had eight skin cancers prior to transplantation, and 28 (24.8%) white KTRs developed 66 skin cancers post transplantation. Twenty-two (19.5%) NAKTRs did not follow-up with dermatology at this institution. The median follow-up in NAKTRs was 3.3 years compared to 3.0 years in white KTRs. NAKTRs have a decreased prevalence of skin cancer compared to their white counterparts.

Tacrolimus Trough Concentration Variability and Disparities in African American Kidney Transplantation.

Low tacrolimus concentrations have been associated with higher risk of acute rejection, particularly within African American (AA) kidney transplant recipients; little is known about intrapatient tacrolimus variabilities impact on racial disparities. Ten year, single-center, longitudinal cohort study of kidney recipients. Intrapatient tacrolimus variability was assessed using the coefficient of variation (CV) measured between 1 month posttransplant and the clinical event, with a comparable period assessed in those without events. Pediatrics, nontacrolimus/mycophenolate regimens, and nonrenal transplants were excluded. Multivariable Cox regression models were used to analyze data. One thousand four hundred eleven recipients were included (54.4% AA) with 39 521 concentrations used to assess intrapatient tacrolimus CV. Overall, intrapatient tacrolimus CV was higher in AAs versus non-AAs (39.9 ± 19.8 % vs 34.8 ± 15.8% P < 0.001). Tacrolimus variability was a significant risk factor for deleterious clinical outcomes. A 10% increase in tacrolimus CV augmented the risk of acute rejection by 20% (adjusted hazard ratio, 1.20, 1.13-1.28; P < 0.001) and the risk of graft loss by 30% (adjusted hazard ratio, 1.30, 1.23-1.37; P < 0.001), with significant effect modification by race for acute rejection, but not graft loss. High tacrolimus variability (CV >40%) was a significant explanatory variable for disparities in AAs; the crude relative risk of acute rejection in AAs was reduced by 46% when including tacrolimus variability in modeling and reduced by 40% for graft loss. These data demonstrate that intrapatient tacrolimus variability is strongly associated with acute rejection in AAs and graft loss in all patients. Tacrolimus variability is a significant explanatory variable for disparities in AA recipients.

Results of ASERTAA, a Randomized Prospective Crossover Pharmacogenetic Study of Immediate-Release Versus Extended-Release Tacrolimus in African American Kidney Transplant Recipients

Differences in tacrolimus dosing across ancestries is partly attributable to polymorphisms in CYP3A5 genes that encode tacrolimus-metabolizing cytochrome P450 3A5 enzymes. The CYP3A5*1 allele, preponderant in African Americans, is associated with rapid metabolism, subtherapeutic concentrations, and higher dose requirements for tacrolimus, all contributing to worse outcomes. Little is known about the relationship between CYP3A5 genotype and the tacrolimus pharmacokinetic area under the curve (AUC) profile in African Americans or whether pharmacogenetic differences exist between conventional twice-daily, rapidly absorbed, immediate-release tacrolimus (IR-Tac) and once-daily extended-release tacrolimus (LifeCycle Pharma Tac [LCPT]) with a delayed absorption profile. Randomized prospective crossover study. 50 African American maintenance kidney recipients on stable IR-Tac dosing. Recipients were randomly assigned to continue IR-Tac on days 1 to 7 and then switch to LCPT on day 8 or receive LCPT on days 1 to 7 and then switch to IR-Tac on day 8. The LCPT dose was 85% of the IR-Tac total daily dose. Tacrolimus 24-hour AUC (AUC0-24), peak and trough concentrations (Cmax and Cmin), time to peak concentration, and bioavailability of LCPT versus IR-Tac, according to CYP3A5 genotype. CYP3A5 genotype, 24-hour tacrolimus pharmacokinetic profiles. ∼80% of participants carried the CYP3A5*1 allele (CYP3A5 expressers). There were no significant differences in AUC0-24 or Cmin between CYP3A5 expressers and nonexpressers during administration of either IR-Tac or LCPT. With IR-Tac, tacrolimus Cmax was 33% higher in CYP3A5 expressers compared with nonexpressers (P=0.04): With LCPT, this difference was 11% (P=0.4). This was primarily a pharmacogenetic study rather than an efficacy study; the follow-up period was too short to capture clinical outcomes. Achieving therapeutic tacrolimus trough concentrations with IR-Tac in most African Americans results in significantly higher peak concentrations, potentially magnifying the risk for toxicity and adverse outcomes. This pharmacogenetic effect is attenuated by delayed tacrolimus absorption with LCPT. Registered at ClinicalTrials.gov, with study number NCT01962922.

Twenty years of evolving trends in racial disparities for adult kidney transplant recipients

Disparities in outcomes for African American (AA) kidney transplant recipients have persisted for 40 years without a comprehensive analysis of evolving trends in the risks associated with this disparity. Here we analyzed U.S. transplant registry data, which included adult Caucasian or AA solitary kidney recipients undergoing transplantation between 1990 and 2009 comprising 202,085 transplantations. During this 20-year period, the estimated rate of 5-year graft loss decreased from 27.6% to 12.8%. Notable trends in baseline characteristics that significantly differed by race over time included the following: increased prevalence of diabetes from 2001 to 2009 in AAs (5-year slope difference: 3.4%), longer time on the waiting list (76.5 more days per 5 years in AAs), fewer living donors in AAs from 2003 to 2009 (5-year slope difference: -3.36%), more circulatory death donors in AAs from 2000-09 (5-year slope difference: 1.78%), and a slower decline in delayed graft function in AAs (5-year slope difference: 0.85%). The absolute risk difference between AAs and Caucasians for 5-year graft loss significantly declined over time (-0.92% decrease per 5 years), whereas the relative risk difference actually significantly increased (3.4% increase per 5 years). These results provide a mixed picture of both promising and concerning trends in disparities for AA kidney transplant recipients. Thus, although the disparity for graft loss has significantly improved, equity is still far off, and other disparities, including living donation rates and delayed graft function rates, have widened during this time.

A randomized, prospective comparison of transition to sirolimus-based CNI-minimization or withdrawal in African American kidney transplant recipients.

There is a lack of conclusive evidence to suggest if calcineurin inhibitor (CNI) withdrawal or minimization with sirolimus is the best strategy for African Americans. This was a randomized, prospective, open-label, pilot study comparing the two mammalian target of rapamycin (mTOR) transition strategies in adult African Americans between six and 24 wk post-transplant. The primary outcome was a comparison of the eGFR at one yr after conversion. Forty patients were randomized and analyzed in an intent-to-treat fashion. Median day of transition was day 96 (withdrawal) and 68 (minimization). Patients in the CNI-withdrawal group (n = 23) had significantly higher eGFR at one yr compared to the CNI-minimization group (n = 17, 73 vs. 56 mL/min, p = 0.03), as well as a significantly larger increase in eGFR from baseline (12 vs. 5 mL/min, p = 0.03). There were no differences in infections, acute rejection, death, or graft loss. Both regimens were constrained by disproportionately high discontinuation rates despite modest toxicity profiles. In spite of considerable withdrawal rate across both study arms, African American kidney transplant recipients who underwent early transition to a sirolimus-based CNI-withdrawal regimen had significantly better graft function at one yr compared to those transitioned to a sirolimus-based CNI-minimization regimen. Clinicaltrials.gov identifier: NCT01005706.

Genomewide Association Study of Tacrolimus Concentrations in African American Kidney Transplant Recipients Identifies Multiple CYP3A5 Alleles

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.

Patient-Centered mHealth Living Donor Transplant Education Program for African Americans: Development and Analysis.

BackgroundThere is a critical need to expand the pool of available kidneys for African Americans who are on the transplant wait-list due to the disproportionally lower availability of deceased donor kidneys compared with other races/ethnic groups. Encouraging living donation is one method to fill this need. Incorporating mHealth strategies may be a way to deliver educational and supportive services to African American transplant-eligible patients and improve reach to those living in remote areas or unable to attend traditional group-session-based programs. Before program development, it is essential to perform formative research with target populations to determine acceptability and cultivate a patient-centered and culturally relevant approach to be used for program development.ObjectiveThe objectives of this study were to investigate African American kidney transplant recipients’ and kidney donors’/potential donors’ attitudes and perceptions toward mobile technology and its viability in an mHealth program aimed at educating patients about the process of living kidney donation.MethodsUsing frameworks from the technology acceptance model and self-determination theory, 9 focus groups (n=57) were administered to African Americans at a southeastern medical center, which included deceased/living donor kidney recipients and living donors/potential donors. After a demonstration of a tablet-based video education session and explanation of a group-based videoconferencing session, focus groups examined members’ perceptions about how educational messages should be presented on topics pertaining to the process of living kidney donation and the transplantation. Questionnaires were administered on technology use and perceptions of the potential program communication platform. Transcripts were coded and themes were examined using NVivo 10 software.ResultsQualitative findings found 5 major themes common among all participants. These included the following: (1) strong support for mobile technology use; (2) different media formats were preferred; (3) willingness to engage in video chats, but face-to-face interaction sometimes preferred; (4) media needs to be user friendly; (5) high prevalence of technology access. Our results show that recipients were willing to spend more time on education than the donors group, they wanted to build conversation skills to approach others, and preferred getting information from many sources, whereas the donor group wanted to hear from other living donors. The questionnaires revealed 85% or more of the sample scored 4+ on a 5-point Likert scale, which indicates high degree of interest to use the proposed program, belief that other mHealth technologies would help with adherence to medical regimens, and doctors would make regimen adjustments quicker. In addition, high utilization of mobile technology was reported; 71.9% of the participants had a mobile phone and 43.9% had a tablet.ConclusionsOur study supports the use of an mHealth education platform for African Americans to learn about living donation. However, potential recipients and potential donors have differing needs, and therefore, programs should be tailored to each target audience.

RE: Long‐term outcomes in African American kidney transplant recipients under contemporary immunosuppression: a four‐yr analysis of the Mycophenolic acid (MORE) study

RE: Long‐term outcomes in African American kidney transplant recipients under contemporary immunosuppression: a four‐yr analysis of the Mycophenolic acid (<scp>MORE</scp>) study

Long‐term outcomes in African American kidney transplant recipients under contemporary immunosuppression: a four‐yr analysis of the Mycophenolic acid Observational REnal transplant (MORE) study

Mycophenolic acid Observational REnal transplant (MORE) was a prospective, observational study of de novo kidney transplant patients receiving mycophenolic acid (MPA). Four-yr data on 904 patients receiving tacrolimus and enteric-coated mycophenolate sodium (EC-MPS) or mycophenolate mofetil (MMF) were analyzed to evaluate immunosuppression and graft outcomes in African American (AA, n = 218) vs. non-AA (n = 686) patients. Mean tacrolimus dose was higher in AA vs. non-AA patients but mean tacrolimus trough concentration was similar. Use of the recommended MPA dose in AA patients decreased from 78.9% at baseline to 33.1% at year 3. More AA patients received the recommended MPA dose with EC-MPS than MMF at month 6 (56.2% vs. 35.7%, p = 0.016) and month 36 (46.6% vs. 16.7%, p = 0.029), with no safety penalty. Significantly, more AA patients received corticosteroids than non-AA patients. Biopsy-proven acute rejection was higher in AA vs. non-AA patients (18.9% vs. 10.7%, p = 0.003), as was graft loss (10.9% vs. 4.4%, p = 0.003); differences were confirmed by Cox regression analysis. Patient survival was similar. Estimated GFR was comparable in AA vs. non-AA patients. Kidney allograft survival remains lower for AA vs. non-AA recipients even under the current standard of care.

Genetic Differences in Native Americans and Tacrolimus Dosing After Kidney Transplantation

Tacrolimus pharmacokinetics vary due to single nucleotide polymorphisms (SNPs) in metabolizing enzymes and membrane transporters that alter drug elimination. Clinically we observed that Native Americans require lower dosages of tacrolimus to attain trough levels similar to Caucasians. We previously demonstrated that Native Americans have decreased oral clearance of tacrolimus, suggesting that Native Americans may have more variant SNPs and, therefore, altered tacrolimus pharmacokinetic parameters. We conducted 12-hour pharmacokinetic studies on 24 adult Native American kidney transplant recipients on stable doses of tacrolimus for at least 1 month posttransplantation. Twenty-four Caucasian kidney transplant recipients were compared as controls. SNPs encoding the genes for the enzymes (CYP3A4, CYP3A5) and transporters (ABCB1, BCRP, and MRP1) were typed using TaqMan. The mean daily tacrolimus dose in the Native Americans was 0.03 ± 0.02 compared with the Caucasians 0.5 ± 0.3 (mg/kg/d; P = .002), with no significant differences in trough levels, (6.7 ± 3.1 vs 7.4 ± 2.1 ng/dL; P = .4). Many Native Americans, but not Caucasians, demonstrated the 3/*3 - C3435T CC and the *3/*3 -G2677T GG genotype combination previously associated with low tacrolimus dosing. Native Americans required significantly lower tacrolimus doses than Caucasians to achieve similar tacrolimus trough levels, in part due to lower tacrolimus clearance from decreased drug metabolism and excretion.