Alternative Living Kidney Donation Programs Boost Genetically Unrelated Donation

Donor-recipient ABO and/or HLA incompatibility used to lead to donor decline. Development of alternative transplantation programs enabled transplantation of incompatible couples. How did that influence couple characteristics? Between 2000 and 2014, 1232 living donor transplantations have been performed. In conventional and ABO-incompatible transplantation the willing donor becomes an actual donor for the intended recipient. In kidney-exchange and domino-donation the donor donates indirectly to the intended recipient. The relationship between the donor and intended recipient was studied. There were 935 conventional and 297 alternative program transplantations. There were 66 ABO-incompatible, 68 domino-paired, 62 kidney-exchange, and 104 altruistic donor transplantations. Waiting list recipients (n=101) were excluded as they did not bring a living donor. 1131 couples remained of whom 196 participated in alternative programs. Genetically unrelated donors (486) were primarily partners. Genetically related donors (645) were siblings, parents, children, and others. Compared to genetically related couples, almost three times as many genetically unrelated couples were incompatible and participated in alternative programs (P<0.001). 62% of couples were genetically related in the conventional donation program versus 32% in alternative programs (P<0.001). Patient and graft survival were not significantly different between recipient programs. Alternative donation programs increase the number of transplantations by enabling genetically unrelated donors to donate

Tacrolimus Monotherapy is Safe in Immunologically Low-Risk Kidney Transplant Recipients: A Randomized-Controlled Pilot Study

In this randomized-controlled pilot study, the feasibility and safety of tacrolimus monotherapy in immunologically low-risk kidney transplant recipients was evaluated [NTR4824, www.trialregister.nl]. Low immunological risk was defined as maximal 3 HLA mismatches and the absence of panel reactive antibodies. Six months after transplantation, recipients were randomized if eGFR >30 ml/min, proteinuria <50 mg protein/mmol creatinine, no biopsy-proven rejection after 3 months, and no lymphocyte depleting therapy given. Recipients were randomized to tacrolimus/mycophenolate mofetil (TAC/MMF) or to taper and discontinue MMF at month 9 (TACmono). 79 of the 121 recipients were randomized to either TACmono (n = 38) or TAC/MMF (n = 41). Mean recipient age was 59 years and 59% received a living donor transplant. The median follow-up was 62 months. After randomization, 3 TACmono and 4 TAC/MMF recipients experienced a biopsy-proven rejection. At 5 years follow-up, patient survival was 84% in TACmono versus 76% in TAC/MMF with death-censored graft survival of 97% for both groups and no differences in eGFR and proteinuria. Eleven TACmono recipients had an infectious episode versus 22 TAC/MMF recipients (p < 0.03). Donor-specific anti-HLA antibodies were not detected during follow-up in both groups. Tacrolimus monotherapy in selected immunologically low-risk kidney transplant recipients appears safe and reduces the number of infections

Alternative Living Kidney Donation Programs Boost Genetically Unrelated Donation

Donor-recipient ABO and/or HLA incompatibility used to lead to donor decline. Development of alternative transplantation programs enabled transplantation of incompatible couples. How did that influence couple characteristics? Between 2000 and 2014, 1232 living donor transplantations have been performed. In conventional and ABO-incompatible transplantation the willing donor becomes an actual donor for the intended recipient. In kidney-exchange and domino-donation the donor donates indirectly to the intended recipient. The relationship between the donor and intended recipient was studied. There were 935 conventional and 297 alternative program transplantations. There were 66 ABO-incompatible, 68 domino-paired, 62 kidney-exchange, and 104 altruistic donor transplantations. Waiting list recipients (n = 101) were excluded as they did not bring a living donor. 1131 couples remained of whom 196 participated in alternative programs. Genetically unrelated donors (486) were primarily partners. Genetically related donors (645) were siblings, parents, children, and others. Compared to genetically related couples, almost three times as many genetically unrelated couples were incompatible and participated in alternative programs (P < 0.001). 62% of couples were genetically related in the conventional donation program versus 32% in alternative programs (P < 0.001). Patient and graft survival were not significantly different between recipient programs. Alternative donation programs increase the number of transplantations by enabling genetically unrelated donors to donate

Genetic variants of FOXP3 influence graft survival in kidney transplant patients

FOXP3+ regulatory T cells (Treg) play a role in controlling alloreactivity. It has been shown that short (GT)n dinucleotide repeats ((GT)15; S) in the promoter region of the FOXP3 gene enhance the promoter activity when compared to long (GT)n repeats ((GT)16; L). The present study retrospectively investigated the influence of this (GT)n FOXP3 gene polymorphism on renal allograft survival. A total of 599 consecutive first-time kidney transplant patients (median follow-up time 7.7years) were subdivided according to their FOXP3 genotype into the S-genotype group (SG) and the L-genotype group (LG). The SG was superior to the LG in both general graft survival censored for death (logrank test, p=0.013) and graft survival following acute rejection (p=0.021). Multivariate analysis defined the (GT)n FOXP3 dinucleotide repeat polymorphism as an independent factor and confirmed an advantage for the SG in renal allograft survival (HR=0.67, 95% CI 0.48-0.94, p=0.02). This gene association study identified a beneficial effect of FOXP3 genetic variants on graft survival in kidney transplant patients

Increasing Kidney-Exchange Options Within the Existing Living Donor Pool With CIAT: A Pilot Implementation Study

Computerized integration of alternative transplantation programs (CIAT) is a kidney-exchange program that allows AB0- and/or HLA-incompatible allocation to difficult-to-match patients, thereby increasing their chances. Altruistic donors make this available for waiting list patients as well. Strict criteria were defined for selected highly-immunized (sHI) and long waiting (LW) candidates. For LW patients AB0i allocation was allowed. sHI patients were given priority and AB0i and/or CDC cross-match negative HLAi allocations were allowed. A local pilot was established between 2017 and 2022. CIAT results were assessed against all other transplant programs available. In the period studied there were 131 incompatible couples; CIAT transplanted the highest number of couples (35%), compared to the other programs. There were 55 sHI patients; CIAT transplanted as many sHI patients as the Acceptable Mismatch program (18%); Other programs contributed less. There were 69 LW patients; 53% received deceased donor transplantations, 20% were transplanted via CIAT. In total, 72 CIAT transplants were performed: 66 compatible, 5 AB0i and 1 both AB0i and HLAi. CIAT increased opportunities for difficult-to-match patients, not by increasing pool size, but through prioritization and allowing AB0i and “low risk” HLAi allocation. CIAT is a powerful addition to the limited number of programs available for difficult-to-match patients

The functional polymorphism Ala258Ser in the innate receptor gene ficolin-2 in the donor predicts improved renal transplant outcome

BACKGROUND: Innate immunity plays a role in controlling adaptive immune responses.METHODS: We investigated the clinical relevance of single nucleotide polymorphisms in 22 genes encoding innate, secreted, and signaling pattern recognition receptors in a total of 520 donor-recipient pairs of postmortem, human leukocyte antigen-DR-compatible kidney transplantations. Associations with rejection incidence were tested in an a priori randomized training set and validation set. RESULTS: Polymorphisms in TLR-3 (rs3775296) in the recipients and in Ficolin-2 (rs7851696; Ala258Ser) and C1qR1 (rs7492) in the donors showed the strongest association with severe rejection. In multivariate analysis, presence of the Ficolin-2 Ala258Ser variant in the donor predicted lower incidence of severe rejection (odds ratio=0.3; 95% confidence interval, 0.1-0.9; P=0.024) and of graft loss (hazard ratio=0.5; 95% confidence interval, 0.2-1.0; P=0.046) independently of clinical risk factors. Ficolin-2 messenger RNA expression was detected in pretransplantation biopsies from 69 donor grafts. Serum and tissue Ficolin-2 levels were unaffected by genotype. Ficolin-2 protein, which bound to dying cells, was detected in donor kidneys in a passenger leukocyte-like pattern. Indeed, monocytes, monocyte-derived macrophages, and peripheral blood mononuclear cells expressed Ficolin-2. Donor grafts with the Ficolin-2 Ala258Ser variant contained significantly elevated expression of interleukin 6, having ascribed cytoprotective effects. It has been described that Ala258Ser leads to increased binding capacity of Ficolin-2 to N-acetylglucosamine. CONCLUSIONS:Presence of the Ficolin-2 Ala258Ser polymorphism in the donor independently predicts improved graft outcome. Based on mechanistic data, we propose that this functional polymorphism leads to more efficient handling of injured cells by phagocytozing cells, resulting in decreased intragraft exposure to danger signals and dampened alloimmune responses.</p