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.

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 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-two-renal-risk-variant kidneys (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-two-renal-risk-variant kidneys, follow-up serum creatinine concentrations were higher than in recipients of zero/one 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 non-significant. Conclusions Shorter renal allograft survival is reproducibly observed after DDKT from APOL1-two-renal-risk-variant donors. Younger recipient age and older donor age have independent adverse effects on renal allograft survival.

Previously

Islets of Langerhans treated with donor-specific anti-Ia serum and complement were transplanted across a major histocompatibility barrier into nonimmunosuppressed diabetic mice. The allografts survived in all recipients for at least 200 days after transplantation. Rejection of an established allograft could be induced by intravenous injection of donor splenocytes. This demonstrates that allografts can serve as targets for immune rejection and supports the possible role ofIa-positive passenger lymphoid cells in initiation ofimmune rejection. The results show that immunosuppression of the recipient is not a prerequisite for successful transplantation.The survival of islet of Langerhans allografts and xenografts can be prolonged by in vitro culture prior to transplantation (1-4). It has been suggested that organ culture removes passenger lymphoid cells and that these cells are required for immune rejection. Support for this idea comes from the observation that islets successfully transplanted into allogeneic recipients after culture are promptly rejected following injection of donor lymphoid cells (5). Similar prolongation of allografts by culture has been described for ovary and thyroid.It has been demonstrated in vitro that stimulation of cellmediated immunity depends on Ia-bearing macrophages or dendritic cells (6, 7). Furthermore, Ia antisera have been shown to enhance skin and probably kidney grafts (8-10). In view of our previous demonstration that beta cells lack Ia determinants (11), we have investigated the influence of Ia antisera on islet transplantation. Here we show that brief treatment ofislets with donor-specific Ia antisera and complement in vitro permits transplantation across major histocompatibility barriers without immunosuppression ofthe recipient. This suggests that the passenger cell that is removed by culture bears Ia determinants. MATERIALS AND METHODSMice. Recipients were C57BL/6J (H-2b; B6) male mice made diabetic by the intravenous injection of streptozotocin (160 m kg). Islets for allografts came from male B10. BR/SgSnJ (H-2; B10. BR) mice; islets for isografts were from B6 male mice. All mice were from The Jackson Laboratory, Bar Harbor, ME.Islet Isolation. Islets were isolated by the collagenase technique (12). The method was modified for mouse islets by directly injecting the pancreas at numerous sites with Hanks' balanced salt solution. Twenty mice were used for each isolation, with a yield of -50 islets per mouse. Isolated islets were separated on a Ficoll (Pharmacia) gradient (13). To distinguish islets from lymph nodes and other contaminating structures, the reflected green light technique (14) was used and the islets were hand picked with a dissecting microscope. Islets were transplanted either immediately or after exposure to antiserum and complement.Islet Culture and Transplantation. The hand-picked clean islets that were to be incubated with antiserum and complement were placed in 6 X 50 mm glass tubes. These islets were cultured for 90 min at room temperature with a...

Reciprocal immunization of congenic lines differing in the middle portion of the H-2 complex leads to the production of antibodies which react with an antigen or antigens controlled by the Ir region. The antigen designated Ir-1.1 seems to be present only on a subpopulation of lymphocytes from lymph nodes and spleen. It is absent on bone marrow cells.