calcitriol and Renal-Insufficiency

Elevated serum levels of parathyroid hormone (PTH) contribute to the increased morbidity and mortality in renal failure patients. Parathyroid gland hyperplasia is a major cause of high serum PTH. The present studies used the rat model of renal failure to address the mechanisms underlying uremia-induced parathyroid hyperplasia and the antiproliferative properties of vitamin D therapy (1,25-dihydroxyvitamin D (1,25(OH)(2)D(3)) or its less calcemic analogs). Enhanced TGFalpha/EGFR co-expression is the major mitogenic signal in uremic parathyroid glands. At early stages of renal failure, vitamin D therapy efficiently counteracts uremia- and high phosphorus-induced hyperplasia by inhibiting the increases in parathyroid-TGFalpha/EGFR co-expression. In established hyperparathyroidism, characterized by highly enhanced-TGFalpha/EGFR co-expression, vitamin D therapy arrests growth by suppressing EGFR-growth signals from the plasma membrane and nuclear EGFR actions as a transactivator of the cyclin D1 gene, an important contributor to parathyroid hyperplasia in humans. In advanced renal failure, reduced-parathyroid vitamin D receptor levels limits the antiproliferative efficacy of vitamin D therapy. However, non-antiproliferative doses of 1,25-dihydroxyvitamin D enhance the anti-EGFR actions of EGFR-tyrosine kinase inhibitors (TKI). In fact, combined 1,25-dihydroxyvitamin D/TKI therapy inhibits parathyroid hyperplasia more efficiently than phosphorus restriction, the most powerful promoter of parathyroid growth arrest available at present.

Topics: Cell Division; ErbB Receptors; Humans; Hyperplasia; Parathyroid Glands; Renal Insufficiency; Signal Transduction; Transforming Growth Factor alpha; Vitamin D

Primary hyperparathyroidism manifests biochemically as a disturbance in serum calcium homeostasis. The central organ setting serum calcium level is the kidney. It not only has the highest rate of active calcium transport, but the kidney also modulates serum calcium homeostasis by virtue of its endocrine role in 1,25-hydroxyvitamin D secretion. Receptors for PTH are widely expressed throughout the renal tubule and are involved in both calcium transport and endocrine function. Biochemical manifestations of primary hyperparathyroidism by the kidney include increased tubular reabsorption of calcium, decreased reabsorption of phosphate and bicarbonate, and hypercalciuria. A reduction in glomerular filtration may occur in some patients with primary hyperparathyroidism, which perturbs the diagnostic relationships among biochemical variables and induces further increases in PTH secretion. Parathyroidectomy rapidly restores the biochemical abnormalities to normal apart from chronic reduced glomerular filtration. Clinical manifestations are nephrolithiasis, which is common, and nephrocalcinosis, which is uncommon. Nephrocalcinosis may occur with or without nephrolithiasis. Risk factors for nephrolithiasis are oversaturation of urine with calcium phosphate and with calcium oxalate. Risk factors for nephrocalcinosis are not clearly defined. Parathyroidectomy greatly reduces the incidence of nephrolithiasis but has little effect on nephrocalcinosis.

Topics: Bicarbonates; Calcium; Glomerular Filtration Rate; Humans; Hypercalcemia; Hyperparathyroidism; Kidney; Kidney Diseases; Phosphates; Renal Insufficiency; Vitamin D

This study aims to evaluate BMD and bone biomarkers and to investigate the effects of immunosuppressives on bone disease after RTx. Thirty-three RTR aged 16.7 ± 3.7 yr and healthy controls (n = 32) were enrolled. There was no difference between pre-RTx BMD and BMD at the time of study (45.9 ± 30.9 months after RTx), while both values were lower than controls (p < 0.01 and p < 0.05, respectively). Worst BMD scores were obtained at sixth month after RTx (-0.2 ± 0.9) and best at fourth year (1.4 ± 1.3). 25-hydroxy-(OH) vitamin D and OPG were higher in RTR (p < 0.001). BMD z scores negatively correlated with OPG and cumulative CS doses at the time of study (r = -0.344, p < 0.05 and r = -0.371, p < 0.05, respectively). Regression analysis revealed OPG as the only predictor of BMD (β -0.78, 95% CI -0.004 to -0.013, p < 0.001). The increase in OPG, a significant predictor of BMD, could either be secondary to graft dysfunction or for protection against bone loss. CS doses should be minimized to avoid their untoward effects on bone metabolism.

Topics: Adolescent; Anthropometry; Biomarkers; Bone and Bones; Bone Density; Case-Control Studies; Child; Child, Preschool; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Osteoprotegerin; Parathyroid Hormone; RANK Ligand; Renal Insufficiency; Vitamin D; Young Adult

Impaired mineral homeostasis and inflammation are hallmarks of chronic kidney disease (CKD), yet the underlying mechanisms of electrolyte regulation during CKD are still unclear. Here, we applied two different murine models, partial nephrectomy and adenine-enriched dietary intervention, to induce kidney failure and to investigate the subsequent impact on systemic and local renal factors involved in Ca(2+) and Pi regulation. Our results demonstrated that both experimental models induce features of CKD, as reflected by uremia, and elevated renal neutrophil gelatinase-associated lipocalin (NGAL) expression. In our model kidney failure was associated with polyuria, hypercalcemia and elevated urinary Ca(2+) excretion. In accordance, CKD augmented systemic PTH and affected the FGF23-αklotho-vitamin-D axis by elevating circulatory FGF23 levels and reducing renal αklotho expression. Interestingly, renal FGF23 expression was also induced by inflammatory stimuli directly. Renal expression of Cyp27b1, but not Cyp24a1, and blood levels of 1,25-dihydroxy vitamin D3 were significantly elevated in both models. Furthermore, kidney failure was characterized by enhanced renal expression of the transient receptor potential cation channel subfamily V member 5 (TRPV5), calbindin-D28k, and sodium-dependent Pi transporter type 2b (NaPi2b), whereas the renal expression of sodium-dependent Pi transporter type 2a (NaPi2a) and type 3 (PIT2) were reduced. Together, our data indicates two different models of experimental kidney failure comparably associate with disturbed FGF23-αklotho-vitamin-D signalling and a deregulated electrolyte homeostasis. Moreover, this study identifies local tubular, possibly inflammation- or PTH- and/or FGF23-associated, adaptive mechanisms, impacting on Ca(2+)/Pi homeostasis, hence enabling new opportunities to target electrolyte disturbances that emerge as a consequence of CKD development.

Topics: Animals; Biological Transport; Calcium; Electrolytes; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glucuronidase; Homeostasis; Kidney; Klotho Proteins; Male; Mice, Inbred C57BL; Phosphates; Renal Insufficiency; Signal Transduction; Vitamin D

Topics: Calcifediol; Clinical Laboratory Techniques; Diagnosis, Differential; Dietary Supplements; Ergocalciferols; Humans; Malabsorption Syndromes; Osteoporosis; Polymorphism, Genetic; Receptors, Calcitriol; Reference Values; Renal Insufficiency; Sarcoidosis; Sunscreening Agents; Vitamin D; Vitamin D Deficiency

We aimed to determine the serum level of fibroblast growth factor-23 (FGF-23) in patients with primary hyperparathyroidism (pHPT) to understand its physiological role in the disorder.. Ninety-eight patients with pHPT who underwent parathyroidectomy formed the study group. We also measured serum FGF-23 in 11 of these patients on postoperative day 6.. Serum FGF-23 levels was significantly higher in pHPT patients than in healthy controls (35.6+/-17.8 ng/l vs 28.9+/-11.2 ng/l (mean+/-s.d.); P<0.001 (Pearson's correlation coefficient)), but there was no significant difference in the serum FGF-23 level between pHPT patients with normal renal function (creatinine clearance (Ccr) of >or=70 ml/min) and healthy controls. Serum FGF-23 correlated positively with serum calcium (P<0.0001) and intact parathyroid hormone (PTH) (P<0.01), and negatively with Ccr (P<0.001), serum phosphate (P<0.05), and serum 1,25-dihydroxyvitamin D (1,25(OH)(2)D) (P<0.05). Multiple linear regression analysis of factors potentially determining serum FGF-23 levels in pHPT patients showed serum calcium (P<0.01) and Ccr (P<0.001) to be significant predictors. The serum levels of FGF-23 did not change after parathyroidectomy despite the normalization of serum calcium values. Multiple linear regression analysis revealed that serum FGF-23 was not a significant predictor of serum phosphate or 1,25(OH)(2)D in pHPT patients.. FGF-23 may not play a significant role in regulating phosphate or 1,25(OH)(2)D in pHPT patients, especially in those with normal renal function. Further studies are warranted to determine the role of FGF-23 in renal insufficiency or failure.

Topics: Adult; Aged; Calcium; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hyperparathyroidism; Linear Models; Male; Middle Aged; Phosphates; Renal Insufficiency; Vitamin D

Topics: Adult; Alkaline Phosphatase; Anticonvulsants; Female; Humans; Hyperparathyroidism, Secondary; Intellectual Disability; Osteomalacia; Renal Insufficiency; Vitamin D