Employment status at transplant influences ethnic disparities in outcomes after deceased donor kidney transplantation.

BACKGROUND: African American (AA) recipients of deceased-donor (DD) kidney transplants (KT) have shorter allograft survival than recipients of other ethnic groups. Reasons for this disparity encompass complex interactions between donors and recipients characteristics. METHODS: Outcomes from 3872 AA and 19,719 European American (EA) DDs who had one kidney transplanted in an AA recipient and one in an EA recipient were analyzed. Four donor/recipient pair groups (DRP) were studied, AA/AA, AA/EA, EA/AA, and EA/EA. Survival random forests and Cox proportional hazard models were fitted to rank and evaluate modifying effects of DRP on variables associated with allograft survival. These analyses sought to identify factors contributing to the observed disparities in transplant outcomes among AA and EA DDKT recipients. RESULTS: Transplant era, discharge serum creatinine, delayed graft function, and DRP were among the top predictors of allograft survival and mortality among DDKT recipients. Interaction effects between DRP with the kidney donor risk index and transplant era showed significant improvement in allograft survival over time in EA recipients. However, AA recipients appeared to have similar or poorer outcomes for DDKT performed after 2010 versus before 2001; allograft survival hazard ratios (95% CI) were 1.15 (0.74, 1.76) and 1.07 (0.8, 1.45) for AA/AA and EA/AA, compared to 0.62 (0.54, 0.71) and 0.5 (0.41, 0.62) for EA/EA and AA/EA DRP, respectively. Recipient mortality improved over time among all DRP, except unemployed AA/AAs. Relative to DDKT performed pre-2001, employed AA/AAs had HR = 0.37 (0.2, 0.69) versus 0.59 (0.31, 1.11) for unemployed AA/AA after 2010. CONCLUSION: Relative to DDKT performed before 2001, similar or worse overall DCAS was observed among AA/AAs, while EA/EAs experienced considerable improvement regardless of employment status, KDRI, and EPTS. AA recipients of an AA DDKT, especially if unemployed, had worse allograft survival and mortality and did not appear to benefit from advances in care over the past 20 years.

Dialysis Facility Profit Status and Early Steps in Kidney Transplantation in the Southeastern United States.

BACKGROUND AND OBJECTIVES: Dialysis facilities in the United States play a key role in access to kidney transplantation. Previous studies reported that patients treated at for-profit facilities are less likely to be waitlisted and receive a transplant, but their effect on early steps in the transplant process is unknown. The study's objective was to determine the association between dialysis facility profit status and critical steps in the transplantation process in Georgia, North Carolina, and South Carolina. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this retrospective cohort study, we linked referral and evaluation data from all nine transplant centers in the Southeast with United States Renal Data System surveillance data. The cohort study included 33,651 patients with kidney failure initiating dialysis from January 1, 2012 to August 31, 2016. Patients were censored for event (date of referral, evaluation, or waitlisting), death, or end of study (August 31, 2017 for referral and March 1, 2018 for evaluation and waitlisting). The primary exposure was dialysis facility profit status: for profit versus nonprofit. The primary outcome was referral for evaluation at a transplant center after dialysis initiation. Secondary outcomes were start of evaluation at a transplant center after referral and waitlisting. RESULTS: Of the 33,651 patients with incident kidney failure, most received dialysis treatment at a for-profit facility (85%). For-profit (versus nonprofit) facilities had a lower cumulative incidence difference for referral within 1 year of dialysis (-4.5%; 95% confidence interval, -6.0% to -3.2%). In adjusted analyses, for-profit versus nonprofit facilities had lower referral (hazard ratio, 0.84; 95% confidence interval, 0.80 to 0.88). Start of evaluation within 6 months of referral (-1.0%; 95% confidence interval, -3.1% to 1.3%) and waitlisting within 6 months of evaluation (1.0%; 95% confidence interval, -1.2 to 3.3) did not meaningfully differ between groups. CONCLUSIONS: Findings suggest lower access to referral among patients dialyzing in for-profit facilities in the Southeast United States, but no difference in starting the evaluation and waitlisting by facility profit status.

APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO): Design and Rationale.

INTRODUCTION: Much of the higher risk for end-stage kidney disease (ESKD) in African American individuals relates to ancestry-specific variation in the apolipoprotein L1 gene (APOL1). Relative to kidneys from European American deceased-donors, kidneys from African American deceased-donors have shorter allograft survival and African American living-kidney donors more often develop ESKD. The National Institutes of Health (NIH)-sponsored APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) is prospectively assessing kidney allograft survival from donors with recent African ancestry based on donor and recipient APOL1 genotypes. METHODS: APOLLO will evaluate outcomes from 2614 deceased kidney donor-recipient pairs, as well as additional living-kidney donor-recipient pairs and unpaired deceased-donor kidneys. RESULTS: The United Network for Organ Sharing (UNOS), Association of Organ Procurement Organizations, American Society of Transplantation, American Society for Histocompatibility and Immunogenetics, and nearly all U.S. kidney transplant programs, organ procurement organizations (OPOs), and histocompatibility laboratories are participating in this observational study. APOLLO employs a central institutional review board (cIRB) and maintains voluntary partnerships with OPOs and histocompatibility laboratories. A Community Advisory Council composed of African American individuals with a personal or family history of kidney disease has advised the NIH Project Office and Steering Committee since inception. UNOS is providing data for outcome analyses. CONCLUSION: This article describes unique aspects of the protocol, design, and performance of APOLLO. Results will guide use of APOL1 genotypic data to improve the assessment of quality in deceased-donor kidneys and could increase numbers of transplanted kidneys, reduce rates of discard, and improve the safety of living-kidney donation.

Genome-wide association study for time to failure of kidney transplants from African American deceased donors.

Two renal-risk variants in the apolipoprotein L1 gene (APOL1) in African American (AA) deceased donors (DD) are associated with shorter renal allograft survival after transplantation. To identify additional genes contributing to allograft survival, a genome-wide association study was performed in 532 AA DDs. Phenotypic data were obtained from the Scientific Registry of Transplant Recipients. Association and single-nucleotide polymorphism (SNP)-by-APOL1 interaction tests were conducted using death-censored renal allograft survival accounting for relevant covariates. Replication and inverse-variance-weighted meta-analysis were performed using data from 250 AA DD in the Genomics of Transplantation study. Accounting for APOL1, multiple SNPs near the Nudix Hydrolase 7 gene (NUDT7) showed strong independent effects (P = 1.6 × 10-8 -2.2 × 10-8 ). Several SNPs in the Translocation protein SEC63 homolog (SEC63; P = 2 × 10-9 -3.7 × 10-8 ) and plasmacytoma variant translocation 1 (PVT1) genes (P = 4.0 × 10-8 -7 × 10-8 ) modified the effect of APOL1 on allograft survival. SEC63 is expressed in human renal tubule cells and glomeruli, and PVT1 is associated with diabetic kidney disease. Overall, associations were detected for 41 SNPs (P = 2 × 10-9 -5 × 10-8 ) contributing independently or interacting with APOL1 to impact renal allograft survival after transplantation from AA DD. Given the small sample size of the discovery and replication sets, independent validations and functional genomic efforts are needed to validate these results.

Practical Considerations for APOL1 Genotyping in the Living Kidney Donor Evaluation.

BACKGROUND: Association between the apolipoprotein L1 gene (APOL1) and nephropathy has altered the epidemiology of chronic kidney disease. In addition, donor APOL1 genotypes play important roles in the time to allograft failure in kidneys transplanted from deceased donors and the safety of living kidney donation. METHODS: This article reviews genetic testing for inherited kidney disease in living kidney donors to improve donor safety. APOL1 genotyping in donors with recent African ancestry is considered. RESULTS: Based on current data, transplant physicians should discuss APOL1 genotyping with potential living kidney donors self-reporting recent African ancestry. Until results from APOL1 Long-term Kidney Transplant Outcomes Network ancillary studies are available, we present practical approaches from our experience for considering APOL1 genotyping in the living donor evaluation. CONCLUSIONS: Transplant physicians should inform potential living kidney donors at risk for APOL1-associated nephropathy about the gene and possibility of genetic testing early in the donor evaluation, well before scheduling the donor nephrectomy. Transplant programs must weigh risks of performing a donor nephrectomy in those with 2 APOL1 renal risk variants (high-risk genotypes), particularly younger individuals. Our program counsels kidney donors with APOL1 high-risk genotypes in the same fashion as with risk genotypes in other nephropathy genes. Because most African American kidney donor candidates lacking hypertension, proteinuria and reduced kidney function after workup will not possess APOL1 high-risk genotypes, genetic testing is unlikely to markedly increase donor declines and may reassure donors with regard to their long-term kidney outcomes, potentially increasing the number of African American donors.

Apolipoprotein L1 Gene Effects on Kidney Transplantation.

The pathogenesis of many common etiologies of nephropathy has been informed by recent molecular genetic breakthroughs. It now is apparent that the ethnic disparity in the risk for nondiabetic chronic kidney disease between African Americans and European Americans is explained largely by variation in the apolipoprotein L1 gene (APOL1). The presence of two APOL1 renal risk variants markedly increases an individual's risk for kidney disease. In transplantation, kidneys from deceased African Americans with two APOL1 renal risk variants have shorter survival intervals after engraftment, regardless of the ethnicity of the recipient. Precision medicine will transform the clinical practice of nephrology and kidney transplantation, and play an important role in the allocation of kidneys from deceased and living kidney donors with recent African ancestry. This article reviews existing data on APOL1 in deceased-donor and living-donor kidney transplantation. It considers the impact of including APOL1 genotyping in decisions on the allocation and discard of deceased-donor kidneys, as well as the selection of living donors.

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), 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.

Donor-derived myeloid sarcoma in two kidney transplant recipients from a single donor.

We report the rare occurrence of donor-derived myeloid sarcoma in two kidney transplant patients who received organs from a single deceased donor. There was no evidence of preexisting hematologic malignancy in the donor at the time of organ recovery. Both recipients developed leukemic involvement that appeared to be limited to the transplanted organ. Fluorescence in situ hybridization (FISH) and molecular genotyping analyses confirmed that the malignant cells were of donor origin in each patient. Allograft nephrectomy and immediate withdrawal of immunosuppression were performed in both cases; systemic chemotherapy was subsequently administered to one patient. Both recipients were in remission at least one year following the diagnosis of donor-derived myeloid sarcoma. These cases suggest that restoration of the immune system after withdrawal of immunosuppressive therapy and allograft nephrectomy may be sufficient to control HLA-mismatched donor-derived myeloid sarcoma without systemic involvement.

Deceased donor multidrug resistance protein 1 and caveolin 1 gene variants may influence allograft survival in kidney transplantation.

Variants in donor multidrug resistance protein 1 (ABCB1) and caveolin 1 (CAV1) genes are associated with renal allograft failure after transplantation in Europeans. Here we assessed transplantation outcomes of kidneys from 368 African American (AA) and 314 European American (EA) deceased donors based on 38 single-nucleotide polymorphisms (SNPs) spanning ABCB1 and 16 SNPs spanning CAV1, including previously associated index and haplotype-tagging SNPs. Tests for association with time to allograft failure were performed for the 1233 resultant kidney transplantations, adjusting for recipient age, sex, ethnicity, cold ischemia time, panel reactive antibody, human leukocyte antigen match, expanded-criteria donation, and APOL1-nephropathy variants in AA donors. Interaction analyses between APOL1 with ABCB1 and CAV1 were performed. In a meta-analysis of all transplantations, ABCB1 index SNP rs1045642 was associated with time to allograft failure and other ABCB1 SNPs were nominally associated, but not CAV1 SNPs. ABCB1 SNP rs1045642 showed consistent effects with the 558 transplantations from EA donors, but not with the 675 transplantations from AA donors. ABCB1 SNP rs956825 and CAV1 SNP rs6466583 interacted with APOL1 in transplants from AA donors. Thus, the T allele at ABCB1 rs1045642 is associated with shorter renal allograft survival for kidneys from American donors. Interactions between ABCB1 and CAV1 with APOL1 may influence allograft failure for transplanted kidneys from AA donors.

The impact of APOL1, CAV1, and ABCB1 gene variants on outcomes in kidney transplantation: donor and recipient effects.

Dramatic improvements have been seen in short-term kidney allograft survival over recent decades with introduction of more potent immunosuppressant medications and regimens. Unfortunately, improvements in long-term graft survival have lagged behind. The genomics revolution is providing new insights regarding the potential impact of kidney donor genotypes on long-term graft survival. Variation in the donor apolipoprotein L1 (APOL1), caveolin 1 (CAV1), and multi-drug resistance 1 encoding P-glycoprotein genes (ABCB1) are all associated with graft survival after kidney transplantation. Although the precise mechanisms whereby these donor gene variants confer risk for graft loss have yet to be determined, these findings provide novel opportunities for modifying interactive environmental factors and optimizing kidney allocation with the ultimate goal of improving long-term graft survival rates.

Association of APOL1 variants with mild kidney disease in the first-degree relatives of African American patients with non-diabetic end-stage renal disease.

Familial aggregation of non-diabetic end-stage renal disease (ESRD) is found in African Americans and variants in the apolipoprotein L1 gene (APOL1) contribute to this risk. To detect genetic associations with milder forms of nephropathy in the high-risk families, analyses were performed using generalized estimating equations to assess relationships between kidney disease phenotypes and APOL1 variants in 786 relatives of 470 families. Adjusting for familial correlations, 23.1, 46.7, and 30.2% of genotyped relatives possessed two, one, or no APOL1 risk variants, respectively. Relatives with two compared with one or no risk variants had statistically indistinguishable median systolic blood pressure, urine albumin to creatinine ratio, estimated glomerular filtration rate (GFR; MDRD equation), and serum cystatin C levels. After adjusting for age, gender, age at ESRD in families, and African ancestry, significant associations were detected between APOL1 with overt proteinuria and estimated GFR (CKD-EPI equation), with a trend toward significance for quantitative albuminuria. Thus, relatives of African Americans with non-diabetic ESRD are enriched for APOL1 risk variants. After adjustment, two APOL1 risk variants weakly predict mild forms of kidney disease. Second hits appear necessary for the initiation of APOL1-associated nephropathy.

Ranolazine-tacrolimus interaction.

OBJECTIVE: To report the case of a kidney allograft recipient on a stable regimen of tacrolimus who exhibited increased tacrolimus concentrations within 24 hours of initiating ranolazine. CASE SUMMARY: A 64-year-old kidney allograft recipient on a stable dose of tacrolimus (10 mg twice daily) was admitted for recent worsening of her chronic anginal pain. The patient was initiated on ranolazine 500 mg twice daily on hospital day 2. Tacrolimus concentrations rose from 7.0-10.1 ng/mL preadmission to 17.8 ng/mL within 24 hours of ranolazine initiation. Ranolazine therapy was continued due to the patient's beneficial response; therefore, the tacrolimus dose was eventually decreased by 70% to 3 mg twice daily to maintain steady-state trough concentrations between 6.6 and 7.9 ng/mL with ranolazine therapy. Ranolazine dechallenge on a subsequent admission produced subtherapeutic tacrolimus concentrations requiring dosage increases. DISCUSSION: Ranolazine, an antianginal agent, is both a substrate and a weak inhibitor of CYP3A as well as a substrate and moderate inhibitor of the P-glycoprotein (P-GP) efflux transport system. Tacrolimus, an immunosuppressant, is also a substrate of CYP3A and P-GP. Through possible inhibition of both P-GP- and CYP3A-mediated first-pass metabolism and CYP3A systemic metabolism, ranolazine may have significantly increased serum concentrations of tacrolimus necessitating an eventual 70% decrease in the tacrolimus dose. Based on the Horn Drug Interaction Probability Scale, this interaction is possible. CONCLUSIONS: We suggest that the eventual 70% decrease in tacrolimus dose after ranolazine initiation may indicate that ranolazine decreases the metabolism and clearance of tacrolimus, causing an elevation in tacrolimus concentrations and the potential for tacrolimus toxicity. Clinicians should be aware of this possible interaction when initiating ranolazine in patients on tacrolimus.

Is collapsing C1q nephropathy another MYH9-associated kidney disease? A case report.

C1q nephropathy is a rare kidney disease that can present with nephrotic syndrome and typically has the histologic phenotype of either minimal change disease or focal segmental glomerulosclerosis (FSGS). Disagreement exists about whether it is a distinct immune complex-mediated glomerulopathy or it resides in the spectrum of FSGS-minimal change disease. Two African American patients with C1q nephropathy histologically presenting as the collapsing variant of FSGS (collapsing C1q nephropathy) and rapid loss of kidney function were genotyped for polymorphisms in the non-muscle myosin heavy chain 9 gene (MYH9). Both cases were homozygous for the MYH9 E1 risk haplotype, the variant strongly associated with idiopathic FSGS, collapsing FSGS in human immunodeficiency virus-associated nephropathy, and focal global glomerulosclerosis (historically attributed to hypertensive nephrosclerosis). Collapsing C1q nephropathy with rapid progression to end-stage renal disease appears to reside in the MYH9-associated disease spectrum.