Do calcineurin inhibitors influence the serum concentrations of mizoribine?

Background: Mizoribine (MZR) is an antimetabolite that inhibits inosine-monophosphate dehydrogenase and has been used for preventing rejection in renal transplantation. However, the effect of calcineurin inhibitors (CNIs) on the pharmacokinetics of MZR has not been shown. This study was performed to show the influence of CNIs (tacrolimus [Tac] or cyclosporine [CyA]) on the serum concentration of MZR.Methods: Thirty-four living-donor renal transplant recipients administered a four-drug immunosuppressive therapy regimen (steroid, CNIs, basiliximab and MZR 6 mg/kg/day) were investigated. 20 recipients were treated with Tac and 14 were with CyA. Serum concentrations of MZR were obtained retrospectively at 464 points and at 243 points for each. Population pharmacokinetic (PPK) analysis was used to make pharmacokinetic models of serum MZR. After statistically evaluating the correlation of the pharmacokinetic models with the actual data, areas under the curves (AUCs) of each CNI were also estimated in these models and statistically evaluated.Results: The mean values of the PPK parameters (absorption lag time, absorption rate constant [Ka], apparent volume of distribution [V/F] and oral clearance of MZR [CLMZR/F]) were 0.600 hr and 0.643 hr, 1.14/hr and 0.911/hr, 0.732×body weight (WT) (L) and 0.784×WT (L), and 1.64×creatinine clearance (CLcr) (L/hr) and 1.81×CLcr (L/hr), respectively. Moreover, the serum concentrations of MZR at all-time points were estimated with these parameters. The correlation coefficients between the individual actual and estimated serum concentrations of MZR in the Tac group and the CyA group were 0.988 and 0.992, respectively. The average value of the AUCs of MZR corrected by the CLcr in the Tac group, and the CyA group were 0.61±0.21 and 0.55±0.19 (average value±standard deviation) for each (p=0.19).Conclusion: These findings suggest the pharmacokinetics of MZR were well-described by 1-compartment model with first-order absorption. Moreover, concomitant use of CNIs, e.g., Tac and CyA, may have no significant influence on the pharmacokinetics of MZR

Cholecalciferol Supplementation Attenuates Bone Loss in Incident Kidney Transplant Recipients: A Prespecified Secondary Endpoint Analysis of a Randomized Controlled Trial

Vitamin D deficiency, persistent hyperparathyroidism, and bone loss are common after kidney transplantation (KTx). However, limited evidence exists regarding the effects of cholecalciferol supplementation on parathyroid hormone (PTH) and bone loss after KTx. In this prespecified secondary endpoint analysis of a randomized controlled trial, we evaluated changes in PTH, bone metabolic markers, and bone mineral density (BMD). At 1 month post-transplant, we randomized 193 patients to an 11-month intervention with cholecalciferol (4000 IU/d) or placebo. The median baseline 25-hydroxyvitamin D (25[OH]D) level was 10 ng/mL and 44% of participants had osteopenia or osteoporosis. At the end of the study, the median 25(OH)D level was increased to 40 ng/mL in the cholecalciferol group and substantially unchanged in the placebo group. Compared with placebo, cholecalciferol significantly reduced whole PTH concentrations (between-group difference of −15%; 95% confidence interval [CI] −25 to −3), with greater treatment effects in subgroups with lower 25(OH)D, lower serum calcium, or higher estimated glomerular filtration rate (pint < 0.05). The percent change in lumbar spine (LS) BMD from before KTx to 12 months post-transplant was −0.2% (95% CI −1.4 to 0.9) in the cholecalciferol group and −1.9% (95% CI −3.0 to −0.8) in the placebo group, with a significant between-group difference (1.7%; 95% CI 0.1 to 3.3). The beneficial effect of cholecalciferol on LS BMD was prominent in patients with low bone mass pint < 0.05). Changes in serum calcium, phosphate, bone metabolic markers, and BMD at the distal radius were not different between groups. In mediation analyses, change in whole PTH levels explained 39% of treatment effects on BMD change. In conclusion, 4000 IU/d cholecalciferol significantly reduced PTH levels and attenuated LS BMD loss after KTx. This regimen has the potential to eliminate vitamin D deficiency and provides beneficial effects on bone health even under glucocorticoid treatment. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).Tsujita M., Doi Y., Obi Y., et al. Cholecalciferol Supplementation Attenuates Bone Loss in Incident Kidney Transplant Recipients: A Prespecified Secondary Endpoint Analysis of a Randomized Controlled Trial. Journal of Bone and Mineral Research 37, 303 (2022); https://doi.org/10.1002/jbmr.4469

14-3-3 proteins stabilize LGI1-ADAM22 levels to regulate seizure thresholds in mice

新たなてんかん治療戦略を提案 --脳の過剰興奮を阻止するタンパク質ADAM22の量が鍵--. 京都大学プレスリリース. 2021-12-15.What percentage of the protein function is required to prevent disease symptoms is a fundamental question in genetic disorders. Decreased transsynaptic LGI1-ADAM22 protein complexes, because of their mutations or autoantibodies, cause epilepsy and amnesia. However, it remains unclear how LGI1-ADAM22 levels are regulated and how much LGI1-ADAM22 function is required. Here, by genetic and structural analysis, we demonstrate that quantitative dual phosphorylation of ADAM22 by protein kinase A (PKA) mediates high-affinity binding of ADAM22 to dimerized 14-3-3. This interaction protects LGI1-ADAM22 from endocytosis-dependent degradation. Accordingly, forskolin-induced PKA activation increases ADAM22 levels. Leveraging a series of ADAM22 and LGI1 hypomorphic mice, we find that ∼50% of LGI1 and ∼10% of ADAM22 levels are sufficient to prevent lethal epilepsy. Furthermore, ADAM22 function is required in excitatory and inhibitory neurons. These results suggest strategies to increase LGI1-ADAM22 complexes over the required levels by targeting PKA or 14-3-3 for epilepsy treatment

Treatment for secondary hyperparathyroidism focusing on parathyroidectomy

Secondary hyperparathyroidism (SHPT) is a major problem for patients with chronic kidney disease and can cause many complications, including osteodystrophy, fractures, and cardiovascular diseases. Treatment for SHPT has changed radically with the advent of calcimimetics; however, parathyroidectomy (PTx) remains one of the most important treatments. For successful PTx, removing all parathyroid glands (PTGs) without complications is essential to prevent persistent or recurrent SHPT. Preoperative imaging studies for the localization of PTGs, such as ultrasonography, computed tomography, and 99mTc-Sestamibi scintigraphy, and intraoperative evaluation methods to confirm the removal of all PTGs, including, intraoperative intact parathyroid hormone monitoring and frozen section diagnosis, are useful. Functional and anatomical preservation of the recurrent laryngeal nerves can be confirmed via intraoperative nerve monitoring. Total or subtotal PTx with or without transcervical thymectomy and autotransplantation can also be performed. Appropriate operative methods for PTx should be selected according to the patients’ need for kidney transplantation. In the case of persistent or recurrent SHPT after the initial PTx, localization of the causative PTGs with autotransplantation is challenging as causative PTGs can exist in the neck, mediastinum, or autotransplanted areas. Additionally, the efficacy and cost-effectiveness of calcimimetics and PTx are increasingly being discussed. In this review, medical and surgical treatments for SHPT are described

Outbreaks of Pneumocystis Pneumonia in 2 Renal Transplant Centers Linked to a Single Strain of Pneumocystis: Implications for Transmission and Virulence

By restriction fragment length polymorphism analysis, 2 outbreaks of Pneumocystis pneumonia in renal transplant patients in Europe were shown to be caused by the same strain of Pneumocystis; another outbreak in Japan was caused by a different strai

The effect of cholecalciferol supplementation on allograft function in incident kidney transplant recipients: A randomized controlled study

It is unknown whether cholecalciferol supplementation improves allograft outcomes in kidney transplant recipients (KTRs). We conducted a single-center randomized, double-blind, placebo-controlled trial of daily 4000 IU cholecalciferol supplementation in KTRs at 1-month posttransplant. The primary endpoint was the change in eGFR from baseline to 12-month posttransplant. Secondary endpoints included severity of interstitial fibrosis and tubular atrophy (IFTA) at 12-month posttransplant and changes in urinary biomarkers. Of 193 randomized patients, 180 participants completed the study. Changes in eGFR were 1.2 mL/min/1.73 m2 (95% CI; −0.7 to 3.1) in the cholecalciferol group and 1.8 mL/min/1.73 m2 (95% CI, −0.02 to 3.7) in the placebo group, with no significant between-group difference (−0.7 mL/min/1.73 m2 [95% CI; −3.3 to 2.0], p = 0.63). Subgroup analyses showed detrimental effects of cholecalciferol in patients with eGFR <45 mL/min/1.73 m2 (Pinteraction <0.05, between-group difference; −4.3 mL/min/1.73 m2 [95% CI; −7.3 to −1.3]). The degree of IFTA, changes in urine albumin-to-creatinine ratio, or adverse events including hypercalcemia and infections requiring hospitalization did not differ between groups. In conclusion, cholecalciferol supplementation did not affect eGFR change compared to placebo among incident KTRs. These findings do not support cholecalciferol supplementation for improving allograft function in incident KTRs. Clinical trial registry: This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) as UMIN000020597 (please refer to the links below). UMIN-CTR: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000023776.Doi Y., Tsujita M., Hamano T., et al. The effect of cholecalciferol supplementation on allograft function in incident kidney transplant recipients: A randomized controlled study. American Journal of Transplantation 21, 3043 (2021); https://doi.org/10.1111/ajt.16530

Cancer Cells Expressing Toll-like Receptors and the Tumor Microenvironment

Toll-like receptors (TLRs) play a crucial role in the innate immune response and the subsequent induction of adaptive immune responses against microbial infection or tissue injury. Recent findings show that functional TLRs are expressed not only on immune cells but also on cancer cells. TLRs play an active role in carcinogenesis and tumor progression during chronic inflammation that involves the tumor microenvironment. Damage-associated molecular patterns (DAMPs) derived from injured normal epithelial cells and necrotic cancer cells appear to be present at significant levels in the tumor microenvironment, and their stimulation of specific TLRs can foster chronic inflammation. This review discusses how carcinogenesis, cancer progression, and site-specific metastasis are related to interactions between cancer cells, immune cells, and DAMPs through TLR activation in the tumor microenvironment