Myosteatosis as a novel predictor of new-onset diabetes mellitus after kidney transplantation.

OBJECTIVES: We evaluate the effect of myosteatosis on new-onset diabetes mellitus after kidney transplantation. METHODS: Consecutive patients who had renal transplant between 2006 and 2021 were reviewed, and 219 patients were finally included. Psoas muscle index was used to evaluate sarcopenia and average total psoas density (calculated by computed tomography before surgery) for myosteatosis. We used Cox proportional regression analyses in investigation of whether skeletal muscle depletion before surgery inclusive of sarcopenia and myosteatosis is a new additional predictor of new-onset diabetes mellitus. RESULTS: Median recipient age and body mass index were 45 years and 21.1 kg/m2 , respectively, and 123 patients (56%) were male. Preoperative impaired glucose tolerance was present in 58 patients (27%) and new-onset diabetes mellitus in 30 patients (14%), with median psoas muscle index of 6 cm2 /m2 and average total psoas density of 41 Hounsfield Unit. In multivariate analysis, significant risk factors were body mass index ≥25 kg/m2 (p < 0.01), impaired glucose tolerance (p < 0.01), and average total psoas density < 41.9 Hounsfield Unit (p = 0.03). New-onset diabetes mellitus had incidence rates of 3.7% without risk factors, 10% with a single risk factor, 33% with two, and 60% with three. Patients with new-onset diabetes mellitus were effectively stratified by the number of risk factors (p < 0.01). CONCLUSIONS: Myosteatosis could be a new risk factor used to predict new-onset diabetes mellitus.

No Influence of Everolimus on Mycophenolic Acid Area Under the Concentration-Time Curve: Limited Sampling Strategy for Mycophenolic Acid in Japanese Kidney Transplant Recipients Treated With Tacrolimus, Mycophenolate Mofetil, Steroid, and Everolimus.

BACKGROUND: Despite a growing need for everolimus (EVR) to reduce calcineurin inhibitor toxicity in kidney transplantation (KTx), the influence of EVR on the pharmacokinetics of mycophenolic acid (MPA), a mycophenolate mofetil (MMF) active metabolite, is obscure, and no suitable limited sampling strategy (LSS) for MPA when EVR is concomitantly present exists. We aimed to investigate the influence of EVR on MPA pharmacokinetics in KTx. MATERIALS AND METHODS: This study complied with all principles of the Declaration of Helsinki. Twenty patients were initially administered tacrolimus, MMF, and methylprednisolone and then received EVR 4 months after KTx. Approximately 4 weeks before and after EVR administration, the estimated value of the area under the concentration-time curve for MPA from 0 to 12 hours (MPA-AUC0-12) was calculated using MPA blood concentration just before and 1, 2, 4, and 6 hours after MMF administration. We compared several MPA pharmacokinetics parameters before and after EVR addition and determined the best estimation equation for LSS of MPA-AUC0-12. RESULTS: Although MPA-C6 per dose (MPA-C6/D) significantly decreased after EVR addition (from 3.4 [±2.2] ng/mL/g to 2.5 [±0.9] ng/mL/g), MPA-C0/D, -C1/D, -C2/D, -C4/D, and MPA-AUC0-12/D showed no significant change. MPA-AUC0-12/D did not correlate with EVR-AUC0-12/D. The best estimation equation for LSS of MPA-AUC0-12 by 2 time points was [(2.94 × C2) + (5.09 × C4) + 5.32] (R2 = 0.73) and [(5.70 × C0) + (1.39 × C1) + 22.45] (R2 = 0.72) before and after EVR addition, respectively. CONCLUSIONS: EVR can be safely combined with MMF after KTx once our results have been reevaluated.

Suppression of Allograft Fibrosis by Regulation of Mammalian Target of Rapamycin-Related Protein Expression in Kidney-Transplanted Recipients Treated with Everolimus and Reduced Tacrolimus.

BACKGROUND Although renoprotective effects of everolimus (EVR) in kidney transplantation (KTx) have been widely reported, its pathophysiological mechanism remains unclear. MATERIAL AND METHODS We compared changes in eGFR (ΔGFR, ml/min/1.73 m²) and the ratio of the fibrotic area in biopsy specimens (ΔFI,%) from 3 months to 3 years after KTx between the EVR+ group (EVR addition and Tac reduction early after KTx, n=32), and the EVR- group (normal Tac without EVR, n=28). We also immunohistochemically evaluated mTOR-related protein expression. RESULTS ΔGFR and ΔFI in the EVR+ vs. EVR- groups were -0.27±6.8 vs. -9.8±12.8 (p<0.001) and 2.4±4.9 vs. 9.5±10.5 (p<0.001), respectively. Phosphorylated mTOR and phosphorylated 4EBP1 expression at 3 years in the EVR+ group was significantly lower than that in the EVR- group. Moreover, in the subgroup analysis comparing ΔGFR and ΔFI among groups stratified by immunosuppressive regimen and mTOR signal enhancement, the ΔFI in patients with EVR+ with decreased mTOR signal enhancement was significantly milder than that in other patients. In addition, in the multivariate analysis, EVR addition was the only independent predictor for allograft fibrosis, whereas the Tac C0 concentration at neither 1 nor 3 years proved to be a risk factor. CONCLUSIONS These results suggested that EVR addition and Tac reduction may attenuate kidney allograft fibrosis, and that the suppression of mTOR signaling process may be involved in the anti-fibrotic effect of this immunosuppressive regimen. These results provide suggestions of how to utilize EVR for patients with KTx and improve graft function.