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

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

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

Two-year outcomes in de novo renal transplant recipients receiving everolimus-facilitated calcineurin inhibitor reduction regimen from TRANSFORM study

TRANSFORM was a 24-month, prospective, open-label trial in 2037 de novo renal transplant recipients (RTxRs) randomized (1:1) within 24 hours of transplantation to receive everolimus (EVR) with reduced-exposure calcineurin inhibitor (EVR+rCNI) or mycophenolate with standard-exposure CNI (MPA+sCNI). Consistent with previously reported 12-month findings, noninferiority of the EVR+rCNI regimen for the primary endpoint of treated biopsy-proven acute rejection (tBPAR) or estimated glomerular filtration rate (eGFR) <50 mL/min/1.73 m2 was achieved at Month 24 (47.9% vs 43.7%; difference = 4.2%; 95% confidence interval [CI] = -0.3, 8.7; P = 0.006). Mean eGFR was stable up to Month 24 (52.6 vs 54.9 mL/min/1.73m2 ) in both arms. The incidence of de novo donor-specific antibodies (dnDSA) was lower in the EVR+rCNI arm (12.3% vs 17.6%) among on-treatment patients. Although discontinuation rates due to adverse events were higher with EVR+rCNI (27.2% vs 15.0%), rates of cytomegalovirus (2.8% vs 13.5%) and BK virus (5.8% vs 10.3%) infections were lower. Cytomegalovirus infection rates were significantly lower with EVR+rCNI even in the D+/R- high-risk group (P<0.0001). In conclusion, the EVR+rCNI regimen offers comparable efficacy and graft function with low tBPAR and dnDSA rates and significantly lower incidence of viral infections relative to standard-of-care up to 24 months. This article is protected by copyright. All rights reserved

Renal failure due to tubulointerstitial nephropathy in an infant with cranioectodermal dysplasia

Cranioectodermal dysplasia (CED) is a rare autosomal recessive disease with characteristic craniofacial, skeletal, and ectodermal-derived tissue abnormalities. In this disease, tubulointerstitial nephropathy (TIN) has been reported as one of the life-threatening combinations. Here we report a sporadic case of CED showing signs of renal failure during the perinatal period. Renal biopsy at the age of 6 months revealed TIN consisting of marked interstitial fibrosis with inflammatory cell infiltration accompanied by scattered tubular atrophy. Glomeruli were often sclerosed and others showed prominent immaturity; the findings are supportive of progressive deterioration of renal function in this infant. This case suggests that TIN in CED can occur during the fetal period and progress rapidly, leading to end-stage renal failure in infancy

Pediatric kidney transplantation is safe and available for patients with urological anomalies as well as those with primary renal diseases

The aim of the current study was to evaluate long-term outcomes of pediatric live kidney transplantation in patients with genitourinary anomalies relative to those with primary kidney diseases. The study included 35 pediatric patients who received a live kidney transplantation during the last 25 yr (28 males, six females). Median age at the time of transplantation was nine yr (range 1–15 yr), and the median follow-up period was 151 months (range 6–239 month). The patients were divided into two groups. The urological group (n = 14) included patients with primary obstructive/reflux nephropathy. The renal group (n = 20) included patients with primary renal disorders. Differences between groups in graft survival, clinical course, and final graft function were evaluated. Original diseases represented in the urological group included five cases with primary VUR and eight cases with secondary VUR. Diseases in the renal group included eight cases with bilateral hypo-dysplastic kidney, three cases with focal/segmental glomerular sclerosis, two cases with membranous proliferative glomerulonephritis, two cases with congenital nephrotic syndrome and five cases with other forms of chronic nephritis. Ten of 14 cases in the urological group, relative to six of 20 in the renal group, were preemptive. Median age at transplantation was 7.5 or 10 yr old, respectively, in the urological or renal group. Twelve kidney recipients in the urological group had also undergone other urinary surgeries, including upper urinary tract drainage, ureteroneocystostomy, augmentation cystoplasty, endoscopic incision of posterior-urethral valve, urethroplasty, etc. Cumulative post-operative complications occurred in nine or 16, respectively, in the urological or renal group. The acute rejection free and overall graft survival were similar in both groups. One patient in the urological group lost his graft while six patients in the renal group lost their grafts. Thus, the post-transplant clinical outcome of pediatric transplantation in patients with urological anomalies is comparable to that of recipients with primary renal disease. Appropriate urinary tract reconstruction and management is essential to reduce the risk of graft dysfunction because of urinary problems

Management of Pneumonia in Kidney Transplantation to Prevent Further Outbreak

The outbreak of Pneumocystis jirovecii pneumonia (PJP) among kidney transplant recipients is emerging worldwide. It is important to control nosocomial PJP infection. A delay in diagnosis and treatment increases the number of reservoir patients and the number of cases of respiratory failure and death. Owing to the large number of kidney transplant recipients compared to other types of organ transplantation, there are greater opportunities for them to share the same time and space. Although the use of trimethoprim-sulfamethoxazole (TMP-SMX) as first choice in PJP prophylaxis is valuable for PJP that develops from infections by trophic forms, it cannot prevent or clear colonization, in which cysts are dominant. Colonization of P. jirovecii is cleared by macrophages. While recent immunosuppressive therapies have decreased the rate of rejection, over-suppressed macrophages caused by the higher levels of immunosuppression may decrease the eradication rate of colonization. Once a PJP cluster enters these populations, which are gathered in one place and uniformly undergoing immunosuppressive therapy for kidney transplantation, an outbreak can occur easily. Quick actions for PJP patients, other recipients, and medical staff of transplant centers are required. In future, lifelong prophylaxis may be required even in kidney transplant recipients

Intact parathyroid hormone levels localize causative glands in persistent or recurrent renal hyperparathyroidism: A retrospective cohort study.

Persistent or recurrent renal hyperparathyroidism may occur after total parathyroidectomy and transcervical thymectomy with forearm autograft under continuous stimulation due to uremia. Parathyroid hormone (PTH) levels may reflect persistent or recurrent renal hyperparathyroidism because of the enlarged autografted parathyroid glands in the forearm or remnant parathyroid glands in the neck or mediastinum. Detailed imaging requires predictive localization of causative parathyroid glands. Casanova and simplified Casanova tests may be convenient. However, these methods require avascularization of the autografted forearm for >10 min with a tourniquet or Esmarch. The heavy pressure during avascularization can be incredibly painful and result in nerve damage. An easier method that minimizes the burden on patients in addition to predicting the localization of causative parathyroid glands was developed in this study. Ninety patients who underwent successful re-parathyroidectomy for persistent or recurrent renal hyperparathyroidism after parathyroidectomy between January 2000 and July 2019 were classified according to the localization of causative parathyroid glands (63 and 27 patients in the autografted forearm and the neck or mediastinum groups, respectively). Preoperatively, intact PTH levels were measured from bilateral forearm blood samples following a 5-min avascularization of the autografted forearm. Cutoff values of the intact PTH ratio (intact PTH level obtained from the non-autografted forearm before re-parathyroidectomy/intact PTH level obtained from the autografted forearm before re-parathyroidectomy) were investigated with receiver operating characteristic curves to localize the causative parathyroid glands. Intact PTH ratios of 0.859 with an AUC 0.744 (95% CI: 0.587-0.901; P = 0.013) could predict causative parathyroid glands in the autografted forearm and the neck or mediastinum with diagnostic accuracies of 81.1% and 83.3%, respectively. Therefore, we propose that the intact PTH ratio is useful for predicting the localization of causative parathyroid glands for re-parathyroidectomy