Population pharmacokinetics of everolimus in renal transplant recipients receiving long-term multiple immunosuppressive therapy.

Everolimus is used for immunosuppression after renal transplantation. This study aimed to develop a population pharmacokinetic (PopPK) model of everolimus using therapeutic drug monitoring (TDM) data of patients under long-term multiple immunosuppressive therapy, including tacrolimus. To develop the model, 185 renal transplant recipients with 3358 everolimus blood concentrations during a median postoperative period of 35.3 months were included. The PopPK model is described as a one-compartment model with first-order absorption. The population mean of apparent clearance is 8.92 L/h (relative standard error = 3.6%), and this negatively correlated with the dose-normalized concentration (C/D) of tacrolimus and hematocrit value, and positively correlated with a daily dose of everolimus (i.e. TDM effect). The usefulness of dose adjustment using the final popPK model was assessed by a simulation study. The ratio of the first trough measurement within the therapeutic range of 3-8 ng/mL increased from 69.8% in the original dose to 87.9% in the individual dose calculated by the final PopPK model. The tacrolimus C/D ratio before initiating everolimus therapy and the hematocrit value were useful to estimate the initial dose of everolimus and can improve the safety and effectiveness of immunosuppressive therapy involving everolimus.

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.

Association of Alpha-Actinin-3 Polymorphism With Sarcopenia in Kidney Transplant Recipients.

BACKGROUND: Sarcopenia is defined as the loss of skeletal muscle mass and function and is associated with increased mortality. Certain genetic polymorphisms represent risk factors used to assess the incidence of sarcopenia; however, few studies have evaluated the association between genetic polymorphisms and sarcopenia after kidney transplantation (KTx). We examined single-nucleotide polymorphisms (SNPs) in the genes involved in sarcopenia after KTx. METHODS: Sixty-five patients who underwent KTx were enrolled in this study. We used the psoas mass index (PMI; the cross-sectional area of the bilateral psoas muscle/height) as a surrogate marker for assessing the extent of sarcopenia. We determined the PMI before KTx and 1 year after KTx, and we identified 5 SNPs in 5 genes associated with sarcopenia in the general population. Finally, the link between the changes in PMI 1 year after KTx and each SNP was examined. RESULTS: The median PMI before KTx and 1 year after KTx was 7.4 (4.6-13.2) and 7.0 (3.6-13.6), respectively. The PMI decreased in 43 patients (66.2%). The alpha-actinin-3 rs1815739 genotype was associated with changes in PMI; the distribution of CT+TT genotypes in the PMI decrease group was significantly higher than that of the CC genotype (odds ratio, 4.23; 95% CI 0.05-0.97; P = 0.025). Moreover, the T allele frequency was significantly higher in the PMI decrease group than in the PMI increase group (odds ratio, 2.34; 95% CI 0.18-0.950; P = 0.025). CONCLUSION: The alpha-actinin-3 rs1815739 genotype may represent a genetic risk factor for sarcopenia after KTx.

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.

Successful percutaneous flexible ureteroscopy for treatment of distal ureteral stones under modified Valdivia position after Cohen reimplantation.

INTRODUCTION: Endoscopic retrograde access to the upper urinary tract after Cohen reimplantation for the treatment of vesicoureteral reflux in children is usually difficult. CASE PRESENTATION: We experienced a case involving a few large ureteral stones in the right distal ureter after Cohen reimplantation. We initially failed retrograde access using flexible cystoscope. Therefore, we performed antegrade flexible ureteroscopy through the 10- to 12-Fr access sheath from the middle calyx to treat the few ureteral stones (>1.5 cm) in the right ureter with the patient in the modified Valdivia position. This one-stage procedure was successful. The patient achieved a stone-free status without major complications. CONCLUSION: The herein-described approach that was implemented after Cohen reimplantation was successful. We believe that recent endourologic developments contributed to the good outcome in this case.

Pictorial review of orthotopic neobladder reconstruction: indication, normal postsurgical anatomy, and complications.

Radical cystectomy with urinary diversion is a common urological procedure performed for the treatment of bladder cancer. Numerous surgical procedures have been developed for urinary diversion. Over the past decade, orthotopic neobladder reconstruction has been used frequently for urinary diversion because of its advantageousness in providing patients with a good quality of life compared with other urinary diversion technique. Knowledge of the indication, surgical procedure, and postsurgical anatomy of orthotopic neobladder reconstruction is essential. While the technique has many advantages, multiple postsurgical complications may occur after reconstruction, including urine leakage, bowel obstruction and fluid collection (lymphocele, urinoma, hematoma, and abscess), neobladder rupture, vesicoureteral reflux, hydronephrosis, urinary tract infection, urinary calculi, abdominal incisional hernia, bowel obstruction, intraneobladder tumor, and tumor recurrence. Radiological imaging including multiple modalities such as intravenous urography, cystography, CT, and MRI plays an important role in the postoperative evaluation of patients with orthotopic neobladder reconstruction and is an accurate method for evaluating complications. In addition, knowledge of appearances on multimodal imaging helps clinicians to select the modality required to achieve an accurate diagnosis of each complication and avoid misdiagnosis.