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

Antony Brayan Campos-Salazar,José Medina-Pestana,Alvaro Cerda,Fabiana Dalla Vecchia Genvigir,Helio Tedesco-Silva,Gabriela Vieira Monteiro,Rodrigo De Gouveia Basso,Claudia Rosso Felipe,Rosario Dominguez Crespo Hirata,Mario Hiroyuki Hirata

doi:10.3389/fphar.2018.01296

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.

Highlights

The calcineurin inhibitor (CNI), such as tacrolimus (TAC) and mechanistic target of rapamycin (mTOR) inhibitor, such as everolimus (EVR) are immunosuppressive drugs helpful to prevent allograft rejection and simultaneously improve graft and patient survival in kidney transplantation (Lim et al, 2017).TAC and EVR binding to their cytoplasmic protein receptor, the FK506-binding protein 12 (FKBP12)
This study investigated the influence of polymorphisms in MTOR, PPP3CA, FKBP1A (FKBP12), FKBP2, and FOXP3 on long-term clinical outcomes of kidney recipients treated with TAC and EVRbased immunosuppressive therapy
Kidney grafts were mainly obtained from deceased donors (69.1%). The proportion of these variables did not differ among the therapy groups, except for graft loss which was higher in the TAC10/mycophenolate sodium (MPS) group (7.5%) compared to TAC5/EVR (1.3%) and TAC10/EVR (1.0%) (p = 0.026)

Summary

Introduction

The calcineurin inhibitor (CNI), such as tacrolimus (TAC) and mTOR inhibitor (mTORi), such as everolimus (EVR) are immunosuppressive drugs helpful to prevent allograft rejection and simultaneously improve graft and patient survival in kidney transplantation (Lim et al, 2017).TAC and EVR binding to their cytoplasmic protein receptor, the FK506-binding protein 12 (FKBP12). The therapeutic monitoring of these immunosuppressants is widely accepted because there is high between-patient variability in their pharmacokinetics and concentration–effect relationship (van Gelder, 2014). In this way, in addition to biodemographic and clinical factors, genetics play an important role. The key genetic variants involved in the metabolism and distribution of the immunosuppressive drugs have been largely investigated (Picard et al, 2016; Zhang et al, 2018) On the contrary, those involved with drug targets and molecular signaling pathway remain poorly known in solid organ transplantation

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Conclusion