Influence Of Donor Selection On Tacrolimus Metabolism And Clinical Outcomes After Pediatric Living Donor Liver Transplantation

Aims:To evaluate the influence of donor CYP3A5 genotype and graft-to-recipient body weight ratio(GRWR)on tacrolimus' pharmacological effects and clinical outcomes after pediatric living donor liver transplantation(LDLT).Methods: The clinical database for pediatric liver transplantation(LT)in our center was retrospectively reviewed,and this study included two parts.In the first part,we investigated 174 LDLT recipients under the age of 6 and grouped them according to donor CYP3A5 genotypes [non-expressor(NEX)or expressor(EX)] and GRWR [<3.0%(SFS,small-for-size)or ?3.0%(LFS,large-for-size)]: SFS/NEX group(n = 40),SFS/EX group(n = 38),LFS/NEX group(n = 48)and LFS/EX group(n = 48).This part comprehensively analyzed characteristics and differences of tacrolimus' pharmacokinetics and pharmacodynamics among these groups.In the second part,129 infantile patients weighing no more than 8kg at LDLT were included and were categorized into 3 groups by GRWR: GRWR<3.0%(group A,n = 38),3.0%?GRWR<4.0%(group B,n = 61),and GRWR?4.0%(group C,n = 30).Different groups' clinical characteristics,liver funtions,postoperative complications and survival outcomes were compared.Results: In the first part,compared with the SFS/NEX group,tacrolimus' trough levels and concentration/dose(C/D)ratios within 12 months after transplantation were significantly lower but dose requirements were significantly higher in SFS/EX and LFS/EX groups,while C/D ratios within 3 months were significantly lower and dose requirements were significantly higher in the LFS/NEX group.The multifactor regression analysis results showed that donor CYP3A5 genotypes and GRWR were both independent predicors for tacrolimus C/D ratios within 1 month posttransplantation.Additionally,incidences of sepsis in the SFS/EX group and LFS/EX group were both significantly higher than that in the SFS/NEX group,whereas the 4 groups had similar incidences of acute rejections.In the sencond part,posttransplant alanine aminotransferase and aspartate aminotransferase within 7 days were significantly higher in the group C than in groups A and B;however,differences of total bilirubin and albumin after transplantation were not prominent.Moreover,incidences of surgical complications,perioperative deaths,infections and acute rejections were all comparable among the 3 groups.Five-year patient survival rates for groups A,B and C were 89.5%,88.9%,and 81.6%,respectively(P=0.872),and the graft survival rates were 89.5%,86.6% and 81.6%,respectively(P=0.846).Conclusion: In contrast to patients receiving a NEX-type graft,the tacrolimus' metabolic rate after pediatric LDLT was significantly faster and dose requirement was significantly greater in patients with an EX-type graft,which induced an increased risk of posttransplant sepsis.The increase of GRWR facilitated the metabolism of tacrolimus and thus caused an added dose requirement,but it did not have a significant impact on posttransplant infections.Moreover,as for infantile LDLT recipients weighing no more than 8 kg,GRWR between 1.9% and 5.8% would not cause noticeable adverse events.However,there is still a role for considering graft reduction in left lateral segment grafts as an applicable strategy in selected cases to reduce collateral risks of oversizing.