Exploring genetic and non‐genetic risk factors for delayed graft function, acute and subclinical rejection in renal transplant recipients

Abstract

AIMSThis study aimed at identifying pharmacological factors such as pharmacogenetics and drug exposure as new predictive biomarkers for delayed graft function (DGF), acute rejection (AR) and/or subclinical rejection (SCR). METHODSAdult renal transplant recipients (n = 361) on cyclosporine-based immunosuppression were followed for the first 6 months after transplantation. The incidence of DGF and AR were documented as well as the prevalence of SCR at 6 months in surveillance biopsies. Demographic, transplant-related factors, pharmacological and pharmacogenetic factors (ABCB1, CYP3A5, CYP3A4, CYP2C8, NR1I2, PPP3CA and PPP3CB) were analysed in a combined approach in relation to the occurrence of DGF, AR and prevalence of SCR at month 6 using a proportional odds model and time to event model. RESULTSFourteen per cent of the patients experienced at least one clinical rejection episode and only DGF showed a significant effect on the time to AR. The incidence of DGF correlated with a deceased donor kidney transplant (27% vs. 0.6% of living donors). Pharmacogenetic factors were not associated with risk for DGF, AR or SCR. A deceased donor kidney and acute rejection history were the most important determinants for SCR, resulting in a 52% risk of SCR at 6 months (vs. 11% average). In a sub-analysis of the patients with AR, those treated with rejection treatment including ATG, significantly less frequent SCR was found in the 6-month biopsy (13% vs. 50%). CONCLUSIONSTransplant-related factors remain the most important determinants of DGF, AR and SCR. Furthermore, rejection treatment with depleting antibodies effectively prevented SCR in 6-month surveillance biopsies. British Journal of Clinical Pharmacology WHAT IS ALREADY KNOW ABOUT THIS SUBJECT• Acute rejection rates have decreased dramatically in the past decades. However, long-term outcome has not improved accordingly.• Transplant-related factors are important determinants of delayed graft function, acute rejection and subclinical rejection, which in its turn leads to progressive fibrosis and loss of graft function.• Pharmacogenetics can have an influence on cyclosporine A pharmacokinetics, but whether this also influences delayed graft function, acute rejection and subclinical rejection is subject to debate. WHAT THIS STUDY ADDS• The combined approach of analysing a wide range of time-varying and time-constant pharmacological factors in addition to known transplant-related factors did not identify new factors suitable for prediction of delayed graft function, acute rejection and subclinical rejection.• Transplant-related factors currently remain the most important determinants of delayed graft function, acute rejection and subclinical rejection in this therapeutic drug monitoring (TDM)-guided setting. Furthermore, rejection treatment with ATG prevented SCR.• Pharmacogenetic factors, although theoretically plausible, are not suitable as predictive factors for delayed graft function, acute rejection and subclinical rejection and subsequently long-term graft survival.

Association of the <em>PPP3CA</em> c.249G&gt;A variant with clinical outcomes of tacrolimus-based therapy in kidney transplant recipients

“…In accord with these findings, five other SNPs (rs13146281, rs7665292, rs2201677, rs10031159, and rs13117493) and one short tandem repetition (rs45441997) in PPP3CA were also not associated with risk of acute or subclinical rejection, or with serious infections in renal transplant recipients treated with calcineurin inhibitors. 11 , 12 Similarly, variants in other genes that encode components of the calcineurin pathway, such as FKBP1A (FKBP12), PPP3CB and PPP3R1 (calcineurin B, α subunit), CALM1 , 2 , and 3 (calmodulin 1–3 isoforms), showed no association with the outcomes of treatment in renal patients. 11 , 12 …”

“… 11 , 12 Similarly, variants in other genes that encode components of the calcineurin pathway, such as FKBP1A (FKBP12), PPP3CB and PPP3R1 (calcineurin B, α subunit), CALM1 , 2 , and 3 (calmodulin 1–3 isoforms), showed no association with the outcomes of treatment in renal patients. 11 , 12 …”

“…Several studies have explored the association of genetic variants at the PPP3CA locus with physiological and pathological conditions, such as athletic status, susceptibility to addiction, and cardiac hypertrophy 5,9,10. However, to the best of our knowledge, only two studies have evaluated the association of the PPP3CA SNPs with the efficacy and toxicity of calcineurin inhibitors in renal transplantation 11,12…”

“… 5 , 9 , 10 However, to the best of our knowledge, only two studies have evaluated the association of the PPP3CA SNPs with the efficacy and toxicity of calcineurin inhibitors in renal transplantation. 11 , 12 …”

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

“…In kidney transplant recipients on CNI-based immunosuppression, some polymorphisms in three calcineurin subunit genes ( PPP3CA , PPP3CB , and PPP3R1 ) were not associated with renal function and incidence of rejection or adverse events ( Moes et al, 2016 ; Pouché et al, 2016a ; Salgado et al, 2017 ).…”