The purpose of this study was to evaluate the effects of NR1I2 (7635G>A and 8055C>T) and ABCB1 (1236C>T, 2677G>T/A, and 3435C>T) genetic polymorphisms on everolimus pharmacokinetics in 98 Japanese renal transplant patients. On day 15 after everolimus administration, blood samples were collected just prior to and 1, 2, 3, 4, 6, 9, and 12 h after administration. The dose-adjusted area under the blood concentration–time curve (AUC_0-12) of everolimus was significantly lower in patients with the NR1I2 8055C/C genotype than in those with other genotypes (p = 0.022) and was significantly higher in male patients than female patients (p = 0.045). Significant correlations between the dose-adjusted AUC_0-12 of everolimus and age (p = 0.001), aspartate transaminase (p = 0.001), and alanine transaminase (p = 0.005) were found. In multivariate analysis, aging (p = 0.008) and higher alanine transaminase levels (p = 0.032) were independently predictive of a higher dose-adjusted everolimus AUC_0-12. Aging and hepatic dysfunction in patients may need to be considered when evaluating dose reductions in everolimus. In renal transplant patients, management using everolimus blood concentrations after administration may be more important than analysis of NR1I2 8055C>T polymorphism before administration.

Background: Obesity is increasingly prevalent among kidney transplant candidates; however, its impact on graft outcomes in Asian populations is not well characterized. We evaluated the association between preoperative obesity and living-donor kidney transplantation outcomes in Japan. Methods: We analyzed 623 living-donor kidney transplants performed from 1998 to 2021 at six centers in northern Japan. Recipients were categorized by body mass index (BMI) at transplant, and multivariable Cox regression was employed for assessing graft outcomes. Results: Obesity (BMI, ≥30 kg/m²; n = 27 [4.3%]) was the strongest graft failure predictor (hazard ratio, 4.62) compared with normal-weight recipients. Moreover, overweight status (BMI, 25–29.9 kg/m²), acute rejection, and older donor age were independent risk factors. Despite similar rejection rates across the BMI groups, recipients with obesity exhibited persistently impaired kidney function from 1-week posttransplant to the 5-year follow-up. Patient survival was comparable across BMI groups; however, underweight status (BMI < 18.5 kg/m²) was associated with higher mortality. Conclusions: Preoperative obesity and overweight status were significant risk factors for graft failure in Japanese living-donor kidney transplant recipients. Meanwhile, the mortality rate was significantly higher in the patients with underweight status at transplant. Pre-transplant weight optimization and shared decision-making with candidates warrant consideration.

Chronic allograft dysfunction, driven by interstitial fibrosis and tubular atrophy, remains a major cause of long-term renal allograft loss. Everolimus (EVR), a mammalian target of rapamycin (mTOR) inhibitor, may reduce fibrosis through antifibrotic effects and calcineurin inhibitor minimization. This study aimed to evaluate the impact of EVR-involving immunosuppression on renal allograft fibrosis and to identify predictors of fibrotic progression. A total of 104 living-donor kidney transplant recipients transplanted between 2011 and 2017 were retrospectively analyzed (EVR, n = 61; non-EVR, n = 43). Interstitial fibrosis was quantified in protocol biopsies using digital image analysis. Phosphorylation of the mTOR-signaling proteins p70 ribosomal S6 kinase and eukaryotic translation initiation factor 4E-binding protein 1 was assessed using a semiquantitative immunoreactive score. Multivariable regression analyses identified independent predictors of fibrotic progression. Cytomegalovirus infection was less frequent in the EVR group, whereas acute rejection, graft function, and graft survival were comparable between groups. At 1-year posttransplantation, interstitial fibrosis was significantly lower in the EVR group. EVR significantly suppressed p-4EBP1 phosphorylation and effectively modulated the mTOR-signaling pathway. Multivariable analysis identified the absence of EVR therapy as an independent predictor of accelerated fibrosis. EVR-involving immunosuppression attenuated renal interstitial fibrosis, likely through suppression of mTOR-signaling.