Kumar, Rajiv

Abstract The sections in this article are: Physiological Effects of Vitamin D and its Active Metabolites on Calcium and Phosphorus Homeostasis Sources of Vitamin D Transport of Vitamin D and its Metabolites in Plasma Metabolism of Vitamin D 3 to 25‐Hydroxyvitamin D 3 Metabolism of 25‐Hydroxyvitamin D 3 Regulation of the 25‐Hydroxyvitamin D 3 –1α‐Hydroxylase Enzyme Parathyroid Hormone Phosphorus Concentrations Calcium: Direct Effects 1,25‐Dihydroxyvitamin D 3 Calcitonin Hydrogen Ion Sex Steroids Glucocorticoids Pituitary Hormones Thyroid Hormone Pregnancy Catabolism of 1,25‐Dihydroxyvitamin D 3 Physiological Adaptations that Occur in Response to Changes in Serum Calcium and Phosphate Concentrations Hypocalcemia and Hypercalcemia Hypophosphatemia and Hyperphosphatemia Pathophysiology and Physiology of the 1,25‐Dihydroxyvitamin D 3 System Mechanisms of Action of 1,25‐Dihydroxyvitamin D 3 1,25‐Dihydroxyvitamin D 3 in the Intestine Processes in the Cell That Are Mediated by 1,25‐Dihydroxyvitamin D 3 Intestinal Brush Border Events Induced by 1,25‐Dihydroxyvitamin D 3 Events at the Contraluminal Border Effects of 1,25‐Dihydroxyvitamin D 3 on the Intestinal Cell 1,25‐Dihydroxyvitamin D 3 in the Kidney

Abstract Calcitriol-induced hypercalcemia is most frequently caused by granulomatous and inflammatory conditions such as sarcoidosis as well as lymphoma. Recently, pathogenic CYP24A1 variants resulting in inability of the 24-hydroxylase enzyme to deactivate 1,25(OH)2D has been found to be a cause of calcitriol-induced hypercalciuria and hypercalcemia in children and adults. Patients may present with hypercalcemia, suppressed PTH, hypercalciuria, and renal stones. We describe 4 young women and 1 man with calcitriol-associated hypercalcemia in whom pathogenic CYP24A1 variants were found to be the cause. In 2 of the 3 women who became pregnant, hypercalcemia worsened (the calcium was not checked during pregnancy in the third). Lactation was associated with worsened hypercalcemia in the 2 women who breast-fed. In the other woman who did not become pregnant, serum calcium levels varied from high normal to markedly elevated often without an explanation. The male patient was a middle-aged man with a long history of kidney stones and hypercalcemia as well as a family history of kidney stones. Gene sequencing confirmed that each patient had 2 variants in CYP24A1. We share 5 cases of a rare condition and further broaden the presentation of CYP24A1 variants to not only include worsening hypercalcemia in pregnancy, but also during lactation. Further calcium levels may vary markedly in patients with this condition. Physicians should consider pathogenic CYP24A1 variants in patients with unexplained calcitriol-associated hypercalcemia/hypercalciuria.

Abstract In a previous study, we observed decreased 1,25-dihydroxyvitamin D levels, secondary hyperparathyroidism, and increased bone turnover markers in living kidney donors (LKDs) at 3 months and 36 months after kidney donation. In our recent survey-based study, we found no increased risk of fractures of all types but observed significantly more vertebral fractures in LKDs compared with matched controls. To elucidate the long-term effects of kidney donation on bone health, we recruited 139 LKDs and 139 age and sex matched controls from the survey-based participants for further mechanistic analyses. Specifically, we assessed whether LKDs had persistent abnormalities in calcium- and phosphorus-regulating hormones and related factors, in bone formation and resorption markers, and in density and microstructure of bone compared with controls. We measured serum markers, bone mineral density (BMD), bone microstructure and strength (via high-resolution peripheral quantitative computed tomography and micro-finite element analysis [HRpQCT]), and advanced glycation end-products in donors and controls. LKDs had decreased 1,25-dihydroxyvitamin D concentrations (donors mean 33.89 pg/mL vs. controls 38.79 pg/mL, percent difference = -12.6%; P < .001), increases in both parathyroid hormone (when corrected for ionized calcium; donors mean 52.98 pg/mL vs. controls 46.89 pg/mL,% difference 13%; P = .03) and ionized calcium levels (donors mean 5.13 mg/dL vs. controls 5.04 mg/dL; P < .001), and increases in several bone resorption and formation markers versus controls. LKDs and controls had similar measures of BMD; however, HRpQCT suggested that LKDs have a statistically insignificant tendency toward thinner cortical bone and lower failure loads as measured by micro-finite element analysis. Our findings suggest that changes in the hormonal mileu after kidney donation and the long-term cumulative effects of these changes on bone health persist for decades after kidney donation and may explain later-life increased rates of vertebral fractures.

Importance Living kidney donors may have an increased risk of fractures due to reductions in kidney mass, lower concentrations of serum 1,25-dihydroxyvitamin D, and secondary increases in serum parathyroid hormone. Objective To compare the overall and site-specific risk of fractures among living kidney donors with strictly matched controls from the general population who would have been eligible to donate a kidney but did not do so. Design, Setting, and Participants This survey study was conducted between December 1, 2021, and July 31, 2023. A total of 5065 living kidney donors from 3 large transplant centers in Minnesota were invited to complete a survey about their bone health and history of fractures, and 16 156 population-based nondonor controls without a history of comorbidities that would have precluded kidney donation were identified from the Rochester Epidemiology Project and completed the same survey. A total of 2132 living kidney donors and 2014 nondonor controls responded to the survey. Statistical analyses were performed from May to August 2023. Exposure Living kidney donation. Main Outcomes and Measures The rates of overall and site-specific fractures were compared between living kidney donors and controls using standardized incidence ratios (SIRs). Results At the time of survey, the 2132 living kidney donors had a mean (SD) age of 67.1 (8.9) years and included 1245 women (58.4%), and the 2014 controls had a mean (SD) age of 68.6 (7.9) years and included 1140 women (56.6%). The mean (SD) time between donation or index date and survey date was 24.2 (10.4) years for donors and 27.6 (10.7) years for controls. The overall rate of fractures among living kidney donors was significantly lower than among controls (SIR, 0.89; 95% CI, 0.81-0.97). However, there were significantly more vertebral fractures among living kidney donors than among controls (SIR, 1.42; 95% CI, 1.05-1.83). Conclusions and Relevance This survey study found a reduced rate of overall fractures but an excess of vertebral fractures among living kidney donors compared with controls after a mean follow-up of 25 years. Treatment of excess vertebral fractures with dietary supplements such as vitamin D 3 may reduce the numbers of vertebral fractures and patient morbidity.

Skeletal muscle insulin resistance contributes to the pathogenesis of type 2 diabetes mellitus. Epidemiological studies have demonstrated that vitamin D deficiency is associated with the presence of type 2 diabetes in humans. To probe the role of the vitamin D receptor (VDR), an intracellular and nuclear protein that mediates the bioactivity of the active vitamin D ligand, 1,25‐dihydroxyvitamin D, in skeletal muscle mediated glucose disposal, we deleted the skeletal muscle VDR in adult mice. We assessed glucose disposal, insulin concentrations and sensitivity, and skeletal muscle gene expression in Vdr knockout and wild‐type Vdr mice. Following the induction of a skeletal muscle‐specific Cre recombinase with tamoxifen in adult male Vdr fl/fl mice, efficient deletion of the Vdr was demonstrated. In skeletal muscle‐specific Vdr knockout mice, basal glucose concentrations were similar to those in wild‐type Vdr mice. In Vdr knockout mice, blood glucose concentrations decreased more rapidly following the administration of intraperitoneal glucose than in control mice expressing wild‐type Vdr (Figure 1A and Figure 1B). The AUC for glucose concentrations in Vdr fl/fl .actin iCre mice treated with tamoxifen was reduced by 20% (p=0.015) compared to the AUC of blood glucose concentrations prior to tamoxifen treatment. Pre‐and post‐treatment AUC’s for blood glucose in Vdr fl/fl .actin iCre mice treated with vehicle and in Vdr fl/fl mice treated with tamoxifen were unchanged (p=0.97,0.23). Plasma insulin concentrations were identical in knockout and wild‐type Vdr mice following a bolus of glucose, demonstrating that deletion of the Vdr in skeletal muscle did not influence the release of insulin in response to glucose (one‐way ANOVA, p=0.45). Insulin sensitivity was similar in Vdr knockout and wild‐type Vdr mice. Gene expression analysis of skeletal muscle mRNA derived from Vdr knockout mice and wild‐type mice demonstrated an increase in the expression of genes associated with oxidative phosphorylation, fatty acid oxidation and adipogenesis pathways that could potentially alter glucose utilization. We conclude that selective deletion of the Vdr in the skeletal muscle of adult mice results in more efficient glucose disposal than in wild‐type Vdr mice; basal and glucose‐stimulated insulin serum concentrations are identical in knock‐out and wild type VDR mice with no changes in insulin sensitivity. The data suggest that modulation of the vitamin‐D endocrine system is unlikely to improve glucose utilization.

Full-length parathyroid hormone (PTH 1–84) is crucial for the regulation of calcium and phosphate homeostasis and bone remodeling. PTH 1–84 is metabolized into various PTH fragments, which are measured with varying levels of efficiency by PTH immunoassays. These PTH fragments, which increase in serum as CKD progresses, could potentially modulate the effects of PTH 1–84 and contribute to CKD-associated bone disorders. To obtain a true biologic representation of total PTH bioactivity, it is necessary to measure not only PTH 1–84 but also PTH fragments that are present in circulation. Traditional second-generation PTH immunoassays collectively measure PTH 1–84, PTH fragments, and post-translationally modified PTH 1–84, making it difficult to accurately predict the character of underlying renal osteodystrophy. This review highlights current advances in methods available for PTH measurement and the clinical relevance of PTH fragments in CKD. We emphasize the usefulness of mass spectrometry as a potential reference method for PTH measurement.