A. Reeves-Daniel

The APOL1 Gene and Allograft Survival after Kidney Transplantation

Coding variants in the apolipoprotein L1 gene (APOL1) are strongly associated with nephropathy in African Americans (AAs). The effect of transplanting kidneys from AA donors with two APOL1 nephropathy risk variants is unknown. APOL1 risk variants were genotyped in 106 AA deceased organ donors and graft survival assessed in 136 resultant kidney transplants. Cox‐proportional hazard models tested for association between time to graft failure and donor APOL1 genotypes. The mean follow‐up was 26.4 ± 21.8 months. Twenty‐two of 136 transplanted kidneys (16%) were from donors with two APOL1 nephropathy risk variants. Twenty‐five grafts failed; eight (32%) had two APOL1 risk variants. A multivariate model accounting for donor APOL1 genotype, overall African ancestry, expanded criteria donation, recipient age and gender, HLA mismatch, CIT and PRA revealed that graft survival was significantly shorter in donor kidneys with two APOL1 risk variants (hazard ratio [HR] 3.84; p = 0.008) and higher HLA mismatch (HR 1.52; p = 0.03), but not for overall African ancestry excluding APOL1. Kidneys from AA deceased donors harboring two APOL1 risk variants failed more rapidly after renal transplantation than those with zero or one risk variants. If replicated, APOL1 genotyping could improve the donor selection process and maximize long‐term renal allograft survival.

Kidney transplantation from donation after cardiac death donors: lack of impact of delayed graft function on post-transplant outcomes.

Singh RP, Farney AC, Rogers J, Zuckerman J, Reeves‐Daniel A, Hartmann E, Iskandar S, Adams P, Stratta RJ. Kidney transplantation from donation after cardiac death donors: lack of impact of delayed graft function on post‐transplant outcomes. 
Clin Transplant 2011: 25: 255–264.

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.

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.

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 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 percent of genotyped relatives possessed two, one, or no APOL1 risk variants, respectively. Relatives with two compared to one or no risk variants had statistically indistinguishable median systolic blood pressure, urine albumin to creatinine ratio, estimated 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.

Impact of race and gender on live kidney donation.

Abstract:  Background:  African Americans (AA) and women are less likely to receive a live kidney donor (LKD) transplant than Caucasians or men. Reasons for non‐donation are poorly understood.

Pancreas transplantation: lessons learned from a decade of experience at Wake Forest Baptist Medical Center.

This article reviews the outcome of pancreas transplantations in diabetic recipients according to risk factors, surgical techniques, and immunosuppression management that evolved over the course of a decade at Wake Forest Baptist Medical Center. A randomized trial of alemtuzumab versus rabbit anti-thymocyte globulin (rATG) induction in simultaneous kidney-pancreas transplantation (SKPT) at our institution demonstrated lower rates of acute rejection and infection in the alemtuzumab group. Consequently, alemtuzumab induction has been used exclusively in all pancreas transplantations since February 2009. Early steroid elimination has been feasible in the majority of patients. Extensive experience with surveillance pancreas biopsies in solitary pancreas transplantation (SPT) is described. Surveillance pancreas biopsy-directed immunosuppression has contributed to equivalent long-term pancreas graft survival rates in SKPT and SPT recipients at our center, in contrast to recent registry reports of persistently higher rates of immunologic pancreas graft loss in SPT. Furthermore, the impact of donor and recipient selection on outcomes is explored. Excellent results have been achieved with older (extended) donors and recipients, in recipients of organs from donation after cardiac death donors managed with extracorporeal support, and in African-American patients. Type 2 diabetics with detectable C-peptide levels have been transplanted successfully with outcomes comparable to those of insulinopenic diabetics. Our experiences are discussed in the light of findings reported in the literature.

Donor–recipient relationships in African American vs. Caucasian live kidney donors

Reeves‐Daniel A, Bailey A, Assimos D, Westcott C, Adams PL, Hartmann EL, Rogers J, Farney AC, Stratta RJ, Daniel K, Freedman BI. Donor–recipient relationships in African American vs. Caucasian live kidney donors.
Clin Transplant 2011: 25: E487–E490.

Dual kidney transplants from adult marginal donors successfully expand the limited deceased donor organ pool

The need to expand the organ donor pool remains a formidable challenge in kidney transplantation (KT). The use of expanded criteria donors (ECDs) represents one approach, but kidney discard rates are high because of concerns regarding overall quality. Dual KT (DKT) may reduce organ discard and optimize the use of kidneys from marginal donors.

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 1,233 resultant kidney transplantations, adjusting for recipient age, sex, ethnicity, cold ischemia time, PRA, HLA 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.