Deceased donor kidney allocation was reorganized in the United States to address several problems, including the highly sensitized patients disadvantaged with large, diverse repertoires of antibodies. Here, five transplant surgeons review their center's experience with the new allocation changes: highlighting areas of accomplishment, opportunities for improvement and, in some cases, stark differences in practice. Across these five centers the highly sensitized patients (CPRA ⩾98%) range from 5.5 to 9.2% of the 12,364 candidates on their collective waitlist. All centers reported greater rates of kidney transplantations in highly sensitized patients (12.4-27%). Three of the programs (Emory, UCSF, UW) relied upon the virtual crossmatch prior to organ acceptance in a majority of cases (70-86%)-the mere presence of antibody on HLA antibody screen was sufficient to exclude the donor in most cases at Emory and UCSF. Penn and UAB relied upon the physical flow crossmatch in almost all cases prior to proceeding with transplantation. Current or historical donor-specific antibody was occasionally crossed in certain cases at UW and UAB necessitating IVIG/plasmapheresis and/or B cell depletion perioperatively. Some authors raised concerns for cost efficiency given the increased need for organ/specimen transportation, and extensive use of hospital resources and ancillary services. In general, we found that the new allocation system has successfully achieved one of its primary goals-increased kidney transplantation in the disadvantaged, highly sensitized patients; the long-term outcomes in all patients and the cost ramifications of these changes will require continued reassessment and clarification.

Rationale

Biologic pathways with significant genetic conservation across human populations have been implicated in the pathogenesis of primary graft dysfunction (PGD). The evaluation of the role of recipient genetic variation in PGD has thus far been limited to single, candidate gene analyses.

Objectives

We sought to identify genetic variants in lung transplant recipients that are responsible for increased risk of PGD using a two-phase large-scale genotyping approach.

Methods

Phase 1 was a large-scale candidate gene association study of the multicenter, prospective Lung Transplant Outcomes Group cohort. Phase 2 included functional evaluation of selected variants and a bioinformatics screening of variants identified in phase 1.

Measurements and main results

After genetic data quality control, 680 lung transplant recipients were included in the analysis. In phase 1, a total of 17 variants were significantly associated with PGD, four of which were in the prostaglandin E2 family of genes. Among these were a coding variant in the gene encoding prostaglandin E2 synthase (PTGES2; P = 9.3 × 10(-5)) resulting in an arginine to histidine substitution at amino acid position 298, and three variants in a block containing the 5' promoter and first intron of the PTGER4 gene (encoding prostaglandin E2 receptor subtype 4; all P < 5 × 10(-5)). Functional evaluation in regulatory T cells identified that rs4434423A in the PTGER4 gene was associated with differential suppressive function of regulatory T cells.

Conclusions

Further research aimed at replication and additional functional insight into the role played by genetic variation in prostaglandin E2 synthetic and signaling pathways in PGD is warranted.