Dataset Information

Polymorphisms in mTOR and Calcineurin Signaling Pathways Are Associated With Long-Term Clinical Outcomes in Kidney Transplant Recipients.

ABSTRACT: Monitoring of immunosuppressive drugs, such as calcineurin and mTOR inhibitors, is essential to avoid undesirable kidney transplant outcomes. Polymorphisms in pharmacokinetics-related genes have been associated with variability in blood levels of immunosuppressive drugs and adverse effects, but influence of pharmacodynamics-related genes remains to be elucidated. The influence of polymorphisms in genes of the mTOR and calcineurin signaling pathways on long-term clinical outcomes was investigated in Brazilian kidney transplant recipients within the 1-year post-transplant. Two-hundred and sixty-nine kidney transplant recipients were enrolled at a kidney transplant center in São Paulo city, Brazil, and treated with tacrolimus plus everolimus or mycophenolate sodium (clinical trial NCT01354301). Clinical and laboratory data, including renal function parameters and drug blood levels were recorded. Genomic DNA was extracted from blood samples. Polymorphisms in MTOR rs1057079 (c.4731G>A), rs1135172 (c.1437T>C), and rs1064261 (c.2997C>T); PPP3CA rs3730251 (c.249G>A); FKBP1A rs6033557 (n.259+24936T>C); FKBP2 rs2159370 (c.-2110G>T); and FOXP3 rs3761548 (c.-23+2882A>C) and rs2232365 (c.-22-902A>G) were analyzed by real-time PCR. Frequencies of gene polymorphisms did not differ among the treatment groups. Analysis of primary outcomes showed that patients carrying MTOR c.1437CC and FOXP3 c.-23+2882CC genotypes had higher serum creatinine than non-carriers (p < 0.05) at 1-year post-transplant. MTOR c.4731G allele (AG+GG genotype) was associated with increased risk for acute rejection (OR = 3.53, 95% CI = 1.09-11.48, p = 0.037). Moreover, 1-year cumulative incidence of rejection was higher in MTOR c.4731G allele carriers compared to AA genotype carriers (p = 0.027). Individually, analysis of secondary outcomes revealed that FKBP2 c.-2110GG genotype carriers had higher risk of leukopenia, FKBP1A n.259+24936C allele carriers had increased risk of constipation, and FOXP3 c.-22-902A or c.-23+2882A allele had higher risk of gastrointestinal disorders (p < 0.05). However, these results were not maintained in the multivariable analysis after p-value adjustment. In conclusion, variants in genes of mTOR and calcineurin pathways are associated with long-term impaired renal function, increased risk of acute rejection, and, individually, with adverse events in Brazilian kidney transplant recipients.

SUBMITTER: Campos-Salazar AB

PROVIDER: S-EPMC6246626 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Polymorphisms in mTOR and Calcineurin Signaling Pathways Are Associated With Long-Term Clinical Outcomes in Kidney Transplant Recipients.

Campos-Salazar Antony Brayan AB Genvigir Fabiana Dalla Vecchia FDV Felipe Claudia Rosso CR Tedesco-Silva Helio H Medina-Pestana José J Monteiro Gabriela Vieira GV Basso Rodrigo de Gouveia RG Cerda Alvaro A Hirata Mario Hiroyuki MH Hirata Rosario Dominguez Crespo RDC

Frontiers in pharmacology 20181114

Monitoring of immunosuppressive drugs, such as calcineurin and mTOR inhibitors, is essential to avoid undesirable kidney transplant outcomes. Polymorphisms in pharmacokinetics-related genes have been associated with variability in blood levels of immunosuppressive drugs and adverse effects, but influence of pharmacodynamics-related genes remains to be elucidated. The influence of polymorphisms in genes of the mTOR and calcineurin signaling pathways on long-term clinical outcomes was investigated ...[more]

PMID: 30487748

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Project description:ImportanceThe complications of corticosteroids make the inclusion of these drugs in immunosuppressive protocols for kidney transplant patients undesirable. However, cessation of corticosteroids is associated with a higher risk of short-term rejection, and the long-term outcomes of patients withdrawn from corticosteroids remain uncertain.ObjectiveTo compare long-term kidney transplant outcomes of patients randomized to continue or withdraw corticosteroids.Design, setting, and participantsThis prospective multicenter randomized double-blind placebo-controlled trial was conducted between November 1999 and December 2002 with linkage to a mandatory national registry with validated outcome ascertainment until June 8, 2018. The study included 28 kidney transplant centers in the United States, including 386 low- to moderate-immune risk adult recipients of a living or deceased donor kidney transplant without delayed graft function or short-term rejection in the first week after transplant. Analyses were intention to treat. Analysis began September 2018 and ended June 2019.InterventionsPatients were randomized to receive tacrolimus and mycophenolate mofetil with or without corticosteroids 7 days after transplant.Main outcomes and measuresKidney allograft failure from any cause including death and allograft failure censored for patient death defined by the requirement for long-term dialysis or repeat transplant.ResultsOf 385 patients, 191 were assigned to withdraw from corticosteroids (mean [SD] age, 46.5 [12.1] years), and 194 patients were assigned to continued corticosteroids (mean [SD] age, 46.3 [12.6] years). The median (interquartile range) follow-up time was 15.8 (12.0-16.3) years after transplant. The adjusted hazard ratios of allograft failure from any cause including death was 0.83 (95% CI, 0.62-1.10; P = .19) and for allograft failure censored for patient death was 0.78 (95% CI, 0.52-1.19; P = .25) and did not differ between the patients assigned to withdraw from corticosteroids vs assigned to continued corticosteroids. Results were consistent in a per-protocol analysis among 223 patients who continued the trial-assigned treatment of corticosteroid withdrawal (n = 114) or corticosteroids (n = 109) through at least 5 years after transplant. The outcomes of trial participants in either treatment group did not differ from similarly treated contemporary registry patients who met trial eligibility criteria and were treated with the same immunosuppressive drugs.Conclusions and relevanceLong-term corticosteroids may not be necessary as part of a calcineurin-based multiple drug immunosuppressive regimen in low- to moderate-immune risk kidney transplant recipients.

Project description:ObjectivesTo determine the long-term survival rates and prognostic factors in kidney transplant (KT) recipients in Jakarta, Indonesia.DesignRetrospective cohort study.SettingA KT centre in Jakarta.ParticipantsWe enrolled 754 consecutive adult recipients who underwent KT between 2010 and 2020.Main outcome measuresRates of 10-year patient, all-cause and death-censored graft survival and their prognostic factors in KT recipients.ResultsThe 10-year patient survival, all-cause survival and death-censored graft survival rates of KT recipients were 74%, 68% and 81%, respectively. The prognostic factors for poor patient survival were a pretransplant dialysis duration>24 months (HR 1.64, 95% CI, 1.08 to 2.49; p=0.02), cardiovascular disease (HR 1.59, 95% CI, 1.11 to 2.31; p=0.01), delayed graft function (DGF) (HR 4.94, 95% CI, 2.76 to 8.82; p<0.001), post-transplant infection (HR 2.63, 95% CI, 1.56 to 4.43; p<0.001) and acute rejection (HR 2.49, 95% CI, 1.20 to 5.15; p=0.01). All-cause graft survival was prognosticated by a pretransplant dialysis duration>24 months (HR 1.74, 95% CI, 1.15 to 2.47; p=0.007), cardiovascular disease (HR 1.65, 95% CI, 1.18 to 2.33; p=0.004), DGF (HR 5.39, 95% CI, 3.13 to 9.28; p<0.001), post-transplant infection (HR 2.46, 95% CI, 1.05 to 4.02; p<0.001) and acute rejection (HR 4.18, 95% CI, 2.23 to 7.84; p<0.001). Factors associated with poor death-censored graft survival were a pretransplant dialysis duration >24 months (HR 2.19, 95% CI, 1.32 to 3.63; p=0.002), cardiovascular disease (HR 1.65, 95% CI, 1.02 to 2.68; p=0.04) and acute rejection (HR 5.52, 95% CI, 2.80 to 10.83; p<0.001).ConclusionsThe survival rates of KT recipients are prognosticated by pretransplant dialysis duration, cardiovascular disease, DGF, post-transplant infection and acute rejection. Stricter eligibility criteria for recipients, more sensitive cross-match testing methods and better infection management strategies may be beneficial for improving the survival rates.

Dataset Information

Polymorphisms in mTOR and Calcineurin Signaling Pathways Are Associated With Long-Term Clinical Outcomes in Kidney Transplant Recipients.

Publications

Polymorphisms in mTOR and Calcineurin Signaling Pathways Are Associated With Long-Term Clinical Outcomes in Kidney Transplant Recipients.

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