calcitriol and Kidney-Diseases

Despite adherence to evidence-based guidelines, heart failure [HF] still results in 5-year mortality rates of 50%, indicating a need to implement additional preventive/intervention strategies. This review summarizes data on alterations in the calciotropic and phosphaturic hormones 1,25-dihydroxyvitamin D [1,25(OH)

Topics: Age Factors; Animals; Biomarkers; Calcium, Dietary; Dietary Supplements; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Heart Failure; Humans; Kidney Diseases; Male; Phosphorus, Dietary; Risk Factors; Sedentary Behavior; Treatment Outcome; Vitamin D; Vitamin D Deficiency

Reduction in serum 1,25 (OH) (2)D level plays an important role in the pathophysiology of altered bone and mineral metabolism among patients with advanced stages of CKD. The use of vitamin D receptor activators (VDRA) has brought great progress in medical management of CKD-MBD. A number of observational studies have shown that the nonuse of VDRA, and low serum concentrations of 1,25 (OH) (2)D or 25 (OH) D are the predictors of poor clinical outcomes in CKD patients including dialysis patients, raising a possibility that the pleiotropic actions of vitamin D may be systemically involved in the poor survival of patients with CKD-MBD. Randomized controlled trials are needed to clarify whether or not VDRA could be beneficial in the protection of the cardiovascular system and good longevity.

Topics: Bone Diseases, Metabolic; Cardiovascular Diseases; Cholecalciferol; Chronic Disease; Ergocalciferols; Humans; Kidney Diseases; Minerals; Randomized Controlled Trials as Topic; Receptors, Calcitriol; Risk; Vitamin D

Phosphate retention and, later, hyperphosphatemia are key contributors to chronic kidney disease (CKD)-mineral and bone disorder (MBD). Phosphate homeostatic mechanisms maintain normal phosphorus levels until late-stage CKD, because of early increases in parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23). Increased serum phosphorus, and these other mineral abnormalities, individually and collectively contribute to bone disease, vascular calcification, and cardiovascular disease. Earlier phosphate control may, therefore, help reduce the early clinical consequences of CKD-MBD, and help control hyperphosphatemia and secondary hyperparathyroidism in late-stage CKD. Indeed, it is now widely accepted that achieving normal phosphorus levels is associated with distinct clinical benefits. This therapeutic goal is achievable in CKD stages 3 to 5 but more difficult in dialysis patients. Currently, phosphate control is only initiated when hyperphosphatemia occurs, but a potentially beneficial and simple approach may be to intervene earlier, for example, when tubular phosphate reabsorption is substantially diminished. Early CKD-MBD management includes dietary phosphate restriction, phosphate binder therapy, and vitamin D supplementation. Directly treating phosphorus may be the most beneficial approach because this can reduce serum phosphorus, PTH, and FGF-23. This involves dietary measures, but these are not always sufficient, and it can be more effective to also consider phosphate binder use. Vitamin D sterols can improve vitamin D deficiency and PTH levels but may worsen phosphate retention and increase FGF-23 levels, and thus, may also require concomitant phosphate binder therapy. This article discusses when and how to optimize phosphate control to provide the best clinical outcomes in CKD-MBD patients.

Topics: Chelating Agents; Chronic Disease; Dietary Supplements; Fibroblast Growth Factor-23; Homeostasis; Humans; Hyperphosphatemia; Kidney Diseases; Metabolic Diseases; Phosphorus, Dietary; Practice Guidelines as Topic; Time Factors; Treatment Outcome; Vitamin D

Fibroblast growth factor 23 (FGF23) is a circulating hormone that is synthesized by osteocytes and osteoblasts. This glycosylated peptide controls phosphate balance by modulating urinary phosphate excretion and indirectly intestinal phosphate absorption by reducing expression of the renal and intestinal sodium phosphate transporters. In a feedback loop, 1,25-dihydroxyvitamin D and phosphate intake control FGF23 production. FGF23 is inactivated by cleavage by a still unidentified enzyme. FGF23 cleavage occurs within cells and probably in the circulation. Klotho, a protein expressed at the cell surface of few organs, forms complexes with FGF receptors, which increases their affinity for FGF23. Klotho is also released into the plasma and urine by an enzymatic cleavage. FGF23 plays a central role in vitamin D metabolism: It inhibits calcitriol synthesis in the kidney and stimulates the catabolism of active vitamin D sterols. In turn, calcitriol stimulates FGF23 and Klotho expression. In chronic kidney diseases, FGF23 concentration increases as GFR declines, whereas Klotho tissue expression decreases. The modifications of FGF23 and Klotho expression are probably involved in the genesis of hyperparathyroidism and the resistance to vitamin D receptor (VDR) activation in chronic kidney disease. Low vitamin D, high FGF23 concentrations, and defects in VDR activation are associated with similar risks, which evoke the possibility that potential FGF23 toxicity might be partly mediated by FGF23-induced decrease in calcitriol or 25-hydroxyvitamin D. Conversely, VDR activators could be used to modulate Klotho or FGF23 expression.

Topics: Animals; Chronic Disease; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glomerular Filtration Rate; Glucuronidase; Homeostasis; Humans; Kidney; Kidney Diseases; Klotho Proteins; Phosphorus, Dietary; Receptors, Calcitriol; Vitamin D; Vitamin D Deficiency

Fibroblast growth factor 23 (FGF23) is a hormone which is produced by osteocytes and lowers serum phosphate and 1,25-dihydroxyvitamin D levels by binding to Klotho-FGF receptor complex in kidney. It has been shown that excess actions of FGF23 cause hypophosphatemic diseases white deficient actions of FGF23 result in hyperphosphatemic disorders. It should be tested in the future whether development of methods to modify FGF23 actions leads to novel therapeutic approaches for bone and mineral disorders.

Topics: Animals; Bone Diseases, Metabolic; Calcium; Chronic Disease; Drug Design; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glucuronidase; Humans; Kidney Diseases; Klotho Proteins; Phosphates; Receptors, Fibroblast Growth Factor; Vitamin D

The serum 25-hydroxyvitamin D [25(OH)D] concentration that is the threshold for vitamin D toxicity has not been established. Hypercalcemia is the hazard criterion for vitamin D. Past policy of the Institute of Medicine has set the tolerable upper intake level (UL) for vitamin D at 50 mug (2000 IU)/d, defining this as "the highest level of daily nutrient intake that is likely to pose no risks of adverse health effects to almost all individuals in the general population." However, because sunshine can provide an adult with vitamin D in an amount equivalent to daily oral consumption of 250 mug (10,000 IU)/d, this is intuitively a safe dose. The incremental consumption of 1 mug (40 IU)/day of vitamin D(3) raises serum 25(OH)D by approximately 1 nM (0.4 ng/ml). Therefore, if sun-deprived adults are to maintain serum 25(OH)D concentrations >75 nM (30 ng/ml), they will require an intake of more than the UL for vitamin D. The mechanisms that limit vitamin D safety are the capacity of circulating vitamin D-binding protein and the ability to suppress 25(OH)D-1-alpha-hydroxylase. Vitamin D causes hypercalcemia when the "free" concentration of 1,25-dihydroxyvitamin D is inappropriately high. This displacement of 1,25(OH)(2)D becomes excessive as plasma 25(OH)D concentrations become higher than at least 600 nM (240 ng/ml). Plasma concentrations of unmetabolized vitamin D during the first days after an acute, large dose of vitamin D can reach the micromolar range and cause acute symptoms. The clinical trial evidence shows that a prolonged intake of 250 mug (10,000 IU)/d of vitamin D(3) is likely to pose no risk of adverse effects in almost all individuals in the general population; this meets the criteria for a tolerable upper intake level.

Topics: Humans; Kidney Diseases; Nutrition Policy; Vitamin D

Vitamin D plays an important role in regulation of calcium homeostasis and bone metabolism. Among vitamin D metabolites, 25-hydroxyvitamin D (25-OH-D) can be used for the evaluation of vitamin D nutritional status. In contrast, 1,25-dihydroxyvitamin D (1,25 [OH] 2D) can be used for the diagnosis of hyperparathyroidism, renal malfunctions, and other calcium metabolism-related diseases. Serum 25-OH-D concentration can be measured with radioimmunoassay (RIA), enzyme immunoassay (EIA), enzyme-linked immunosorbent assay (ELISA), chemiluminescence protein-binding assay (CLPBA), high performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry/mass spectrometry (LC-MS) methods. Likewise, serum 1,25 (OH) 2D can be measured with RIA, EIA, radioreceptorassay (RRA) and ELISA methods. Clinicians are required to recognize the characteristics of each method and use serum concentrations of 25-OH-D and 1,25 (OH) 2D as biochemical markers for the diagnosis of bone diseases.

Topics: Bone Diseases; Humans; Hyperparathyroidism; Kidney Diseases; 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

Calcium balance in chronic kidney disease is poorly understood as calcium deficiency is a stimulus for secondary hyperparathyroidism and consequent bone loss while calcium excess promotes extraosseous calcifications. To help resolve this, we evaluated calcium balance in normal individuals and in patients with chronic kidney disease (CKD) on daily diets containing 800 and 2000 mg elemental calcium. Both normal individuals and patients with late stage 3 and stage 4 CKD were in slightly negative to neutral calcium balance on the 800-mg calcium diet. Normal individuals were in modest positive calcium balance on the 2000-mg diet, while patients with CKD on the same diet were in marked positive calcium balance at least over the 9 days of study; and significantly greater than the normal individuals. Increased calcium intake significantly decreased 1,25-dihydroxy-vitamin D and intact parathyroid hormone levels but did not alter the serum calcium concentration. Thus, our findings have important implications for both preventing calcium deficiency and loading in individuals with late stage 3 and stage 4 CKD.

Topics: Adult; Aged; Biomarkers; Calcium; Calcium, Dietary; Chronic Disease; Colorado; Creatinine; Cross-Over Studies; Female; Glomerular Filtration Rate; Homeostasis; Humans; Kidney; Kidney Diseases; Male; Middle Aged; Nutrition Policy; Parathyroid Hormone; Severity of Illness Index; Time Factors; Vitamin D

This study examined differences in the concentration of markers of mineral metabolism across race in patients with advanced CKD not requiring dialysis and ESRD.. Concentrations of 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)(2)D), intact parathyroid hormone (iPTH), and fibroblast growth factor 23 (FGF-23) were measured in stored plasma samples of 1497 patients with advanced CKD not yet on dialysis and ESRD who participated in the Homocysteine in Kidney and End Stage Renal Disease study. Linear regression models were used to examine the relationship between race and 25(OH)D, 1,25(OH)(2)D, iPTH, and FGF-23 concentrations.. Non-Hispanic white patients comprised 58% of the cohort, whereas non-Hispanic blacks comprised 42%. Median (interquartile range) FGF-23 concentrations were lower in blacks compared with whites with CKD (323 [181-655] versus 431 [232-1026] RU/ml; P<0.001) but not in ESRD. In adjusted linear regression models, blacks with CKD not requiring dialysis had significantly lower plasma FGF-23 concentrations (difference, -159; 95% confidence interval, -205 to -106; P<0.001) compared with whites, independent of plasma 25(OH)D, 1,25(OH)(2)D, and iPTH concentrations. This difference was not observed in the ESRD group. The magnitude of correlation for the relationships between 1,25(OH)(2)D with iPTH, FGF-23 with 1,25(OH)(2)D, and FGF-23 with iPTH were stronger among blacks than whites with CKD not requiring dialysis.. In advanced CKD not requiring dialysis, blacks have lower FGF-23 concentrations than whites. Blacks with CKD and ESRD have lower 25(OH)D and higher iPTH compared with whites, independent of FGF-23 concentrations.

Topics: Aged; Biomarkers; Black or African American; Bone and Bones; Chi-Square Distribution; Chronic Disease; Cross-Sectional Studies; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Kidney Diseases; Kidney Failure, Chronic; Linear Models; Male; Metabolic Diseases; Middle Aged; Multivariate Analysis; Parathyroid Hormone; Prospective Studies; United States; Vitamin D; White People

Renal fibrosis, the characteristic feature of progressive chronic kidney disease, is associated with unremitting renal inflammation. Although it is reported that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the active form of vitamin D, elicits an anti-renal fibrotic effect, its molecular mechanism is still unknown. In this study, renal fibrosis and inflammation observed in the kidney of unilateral ureteral obstruction (UUO) mice were reduced by the treatment of 1,25(OH)2D3. The plasma protein level of alpha-1-acid glycoprotein (AGP), a downstream molecule of 1,25(OH)2D3, was increased following administration of 1,25(OH)2D3. Additionally, increased mRNA expression of ORM1, an AGP gene, was observed in HepG2 cells and THP-1-derived macrophages that treated with 1,25(OH)2D3. To investigate the involvement of AGP, exogenous AGP was administered to UUO mice, resulting in attenuated renal fibrosis and inflammation. We also found the mRNA expression of CD163, a monocyte/macrophage marker with anti-inflammatory potential, was increased in THP-1-derived macrophages under stimulus from 1,25(OH)2D3 or AGP. Moreover, AGP prevented lipopolysaccharide-induced macrophage activation. Thus, AGP could be a key molecule in the protective effect of 1,25(OH)2D3 against renal fibrosis. Taken together, AGP may replace vitamin D to function as an important immune regulator, offering a novel therapeutic strategy for renal inflammation and fibrosis.

Topics: Animals; Disease Models, Animal; Fibrosis; Hep G2 Cells; Humans; Kidney Diseases; Lipopolysaccharides; Macrophages; Male; Mice, Inbred ICR; Orosomucoid; Ureteral Obstruction; Vitamin D

Circulating levels of fibroblast growth factor 23 (FGF23) increase during the early stages of kidney disease, but the underlying mechanism remains incompletely characterized. We investigated the role of vitamin D metabolites in regulating intact FGF23 production in genetically modified mice without and with adenine-induced uremia. Exogenous calcitriol (1,25-dihydroxyvitamin D) and high circulating levels of calcidiol (25-hydroxyvitamin D) each increased serum FGF23 levels in wild-type mice and in mice with global deficiency of the Cyp27b1 gene encoding 25-hydroxyvitamin D 1-α-hydroxylase, which produces 1,25-hydroxyvitamin D. Compared with wild-type mice, normal, or uremic mice lacking Cyp27b1 had lower levels of serum FGF23, despite having high concentrations of parathyroid hormone, but administration of exogenous 1,25-dihydroxyvitamin D increased FGF23 levels. Furthermore, raising serum calcium levels in Cyp27b1-depleted mice directly increased FGF23 levels and indirectly enhanced the action of ambient vitamin D metabolites via the vitamin D receptor. In chromatin immunoprecipitation assays, 25-hydroxyvitamin D promoted binding of the vitamin D receptor and retinoid X receptor to the promoters of osteoblastic target genes. Conditional osteoblastic deletion of Cyp27b1 caused lower serum FGF23 levels, despite normal circulating levels of vitamin D metabolites. In adenine-induced uremia, only a modest increase in serum FGF23 levels occurred in mice with osteoblastic deletion of Cyp27b1 (12-fold) compared with a large increase (58-fold) in wild-type mice. Therefore, in addition to the direct effect of high circulating concentrations of 25-hydroxyvitamin D, local osteoblastic conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D appears to be an important positive regulator of FGF23 production, particularly in uremia.

Topics: Animals; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Osteoblasts; Vitamin D

Topics: Bone and Bones; Calcium; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hypophosphatemia; Kidney Diseases; Parathyroid Hormone; Phosphates; Vitamin D

Sarcoidosis is a multi-system disorder characterized by non-caseating epithelioid granulomas in multiple organs. Renal involvement may usually occur as granulomatous interstitial nephritis, but renal failure is uncommon. We report a case of renal-limited sarcoidosis diagnosed by renal biopsy, associated with abnormal calcium metabolism.. A 30-year-old Caucasian male presented with unexplained renal function impairment and hypercalcemia. The patient did not have any history of kidney disease, cough, skin rash, dysuria, hematuria or any other symptoms. Physical examination was unremarkable. Serum creatinine was 2.2 mg/dl and serum calcium was 11.5 mg/dl. Serum intact parathyroid hormone level (12 pg/mL) was decreased. Serum angiotensin-converting enzyme (ACE), 1,25-dihydroxyvitamin D (1,alpha-25 vit D) and pre-proparathyroid hormone (PTHrP) levels and urinary calcium excretion were all in normal range. The renal biopsy showed severe interstitial nephritis with non-caseating granuloma. The patient was treated with prednisone with starting dose of 1 mg/kg. After 2 months of prednisone therapy, serum creatinine decreased. However, because of continued of hypercalcemia unresponsive to low calcium diet and prednisone, chloroquine was prescribed. Six months after the onset, the patient's serum creatinine is stable at 1.30 mg/dl, serum calcium is 10.8 mg/dl, and serum ACE and 1,alpha-25 vit D levels are in normal range. He does not have any signs of extra-renal relapse.. The mechanisms of abnormal calcium metabolism in this patient with renal-limited sarcoidosis are unclear.

Topics: Adult; Biopsy; Humans; Hypercalcemia; Kidney; Kidney Diseases; Male; Sarcoidosis; Vitamin D

The transient receptor potential cation channel C6 (TRPC6) is a slit diaphragm protein expressed by podocytes. TRPC6 gain-of-function mutations cause autosomal dominant focal segmental glomerulosclerosis. In acquired proteinuric renal disease, glomerular TRPC6 expression is increased. We previously demonstrated that acquired increased TRPC6 expression is ameliorated by antiproteinuric angiotensin receptor blockers and angiotensin-converting enzyme inhibitors. Vitamin D also has an antiproteinuric effect. We hypothesized that vitamin D reduces proteinuria by affecting TRPC6 expression in podocytes. Adriamycin-induced nephropathy increased TRPC6 mRNA and protein expression and induced proteinuria in rats. Treatment with 1,25-dihydroxyvitamin D3 (1,25-D3) normalized TRPC6 expression and reduced proteinuria. In vitro, podocyte injury induced by adriamycin exposure in cultured podocytes increased TRPC6 expression. Treatment of injured podocytes with 1,25-D3 dose dependently reduced adriamycin-induced TRPC6 expression. Chromatin immunoprecipitation analysis demonstrated that the vitamin D receptor directly binds to the TRPC6 promoter. Moreover, 1,25-D3 reduced TRPC6 promoter activity in a luciferase reporter assay. In 1,25-D3-deficient 25-hydroxy-1α-hydroxylase knockout mice, TRPC6 expression was increased, accompanied by podocyte foot process effacement and proteinuria. 1,25-D3 supplementation normalized TRPC6 expression, podocyte morphology, and proteinuria in these mice. These results demonstrate that vitamin D down-regulates the enhanced TRPC6 expression in in vivo and in vitro podocyte injury, possibly through a direct effect on TRPC6 promoter activity. This TRPC6 down-regulation could contribute to the antiproteinuric effect of vitamin D.

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Animals; Chromatin Immunoprecipitation; Down-Regulation; Glomerulosclerosis, Focal Segmental; Humans; Kidney Diseases; Kidney Glomerulus; Mice; Podocytes; Promoter Regions, Genetic; Protein Binding; Proteinuria; Rats; Rats, Wistar; Receptors, Calcitriol; TRPC Cation Channels; TRPC6 Cation Channel; Vitamin D

Renal impairment is a risk factor for poor clinical outcome in cardiac surgical patients and low circulating levels of the vitamin D hormone 1,25-dihydroxyvitamin D (1,25[OH](2)D) may contribute to this risk.. We investigated the association between glomerular filtration rate (GFR) and 1,25(OH)(2)D in 151 heart transplant recipients and 59 other cardiac surgical patients in postoperative week 1 and at postoperative month 1. GFR estimates (eGFR) were calculated from cystatin C (CysC) and serum creatinine (SCr)-based formulas.. With both formulas, linear models provided a better fit between eGFR and circulating 1,25(OH)(2)D than nonlinear models. Nonetheless, the association between 1,25(OH)(2)D and eGFR in the early postoperative period was stronger with the CysC-based formula (r = 0.560; P <0.001) than with the SCr-based equation (r = 0.386; P <0.001). CysC-eGFR and SCr-eGFR displayed considerably lack of agreement in the early postoperative period, especially in heart transplant recipients.. There is a relatively close association between CysC-eGFR and circulating 1,25(OH)(2)D in cardiac surgical patients. Data underline the importance of preserved kidney function in cardiac surgery for adequate circulating 1,25(OH)(2)D levels. The SCr-based formula is probably too imprecise for estimating GFR in the early postoperative period correctly.

Topics: Adult; Aged; Biomarkers; Cardiac Surgical Procedures; Creatinine; Cystatin C; Female; Glomerular Filtration Rate; Heart Transplantation; Humans; Kidney; Kidney Diseases; Linear Models; Male; Middle Aged; Models, Biological; Nonlinear Dynamics; Risk Factors; Time Factors; Treatment Outcome; Vitamin D; Vitamin D Deficiency

Circulating levels of fibroblast growth factor 23 (FGF23) are elevated in patients with early chronic kidney disease (CKD) and are postulated to cause low blood levels of 1,25-dihydroxyvitamin D, as well as normal phosphate levels. In order to provide more direct evidence for the pathophysiological role of FGF23 in the settings of mineral ion homeostasis typically seen in early CKD, we studied rats with progressive CKD treated with anti-FGF23 neutralizing antibody. Without antibody treatment, rats with CKD exhibited high circulating levels of FGF23 and parathyroid hormone, low 1,25-dihydroxyvitamin D, and normal serum phosphate levels, accompanied by increased fractional excretion of phosphate. Antibody treatment, however, lessened fractional excretion of phosphate, thus increasing serum phosphate levels, and normalized serum 1,25-dihydroxyvitamin D by increased 1α-OHase and decreased 24-OHase expressions in the kidney. These antibody-induced changes were followed by increased serum calcium levels, leading to decreased serum parathyroid hormone. Hence, our study shows that FGF23 normalizes serum phosphate and decreases 1,25-dihydroxyvitamin D levels in early-stage CKD, and suggests a pathological sequence of events for the development of secondary hyperparathyroidism triggered by increased FGF23, followed by a reduction of 1,25-dihydroxyvitamin D and calcium levels, thereby increasing parathyroid hormone secretion.

Topics: Animals; Antibodies, Monoclonal; Autoantibodies; Calcium; Chronic Disease; Disease Models, Animal; Fibroblast Growth Factors; Homeostasis; Kidney; Kidney Diseases; Male; Minerals; Parathyroid Hormone; Phosphates; Rats; Rats, Inbred WKY; Vitamin D

Cadmium is a widespread environmental pollutant, which is associated with increased risk of osteoporosis. It has been proposed that cadmium's toxic effect on bone is exerted via impaired activation of vitamin D, secondary to the kidney effects. To test this, we assessed the association of cadmium-induced bone and kidney effects with serum 1,25-dihydroxyvitamin D (1,25(OH)(2)D); measured by enzyme immunoassay. For the assessment, we selected 85 postmenopausal women, based on low (0.14-0.39 microg/L) or high (0.66-2.1 microg/L) urinary cadmium, within a cross-sectional population-based women's health survey in Southern Sweden. We also measured 25-hydroxy vitamin D, cadmium in blood, bone mineral density and several markers of bone remodeling and kidney effects. Although there were clear differences in both kidney and bone effect markers between women with low and high cadmium exposure, the 1,25(OH)(2)D concentrations were not significantly different (median, 111 pmol/L (5-95th percentile, 67-170 pmol/L) in low- and 125 pmol/L (66-200 pmol/L) in high-cadmium groups; p=0.08). Also, there was no association between 1,25(OH)(2)D and markers of bone or kidney effects. It is concluded that the low levels of cadmium exposure present in the studied women, although high enough to be associated with lower bone mineral density and increased bone resorption, were not associated with lower serum concentrations of 1,25(OH)(2)D. Hence, decreased circulating levels of 1,25(OH)(2)D are unlikely to be the proposed link between cadmium-induced effects on kidney and bone.

Topics: Bone and Bones; Bone Density; Bone Diseases; Cadmium; Cross-Sectional Studies; Environmental Exposure; Female; Humans; Kidney; Kidney Diseases; Menopause; Middle Aged; Osteoporosis; Population Surveillance; Risk Assessment; Risk Factors; Sweden; Vitamin D

1. Accumulating evidence suggests that vitamin D and its analogues are renoprotective. However, the precise mechanisms and the molecular targets by which active vitamin D exerts its beneficial effects remain obscure. The objective of the present study was to evaluate the effect of active vitamin D on rats with puromycin aminonucleoside (PAN) nephropathy, a model that is characterized by predominant podocyte injury. 2. The PAN nephropathy rats were created by a single intravenous injection of 100 mg/kg PAN. Changes in renal pathology and podocyte numbers were observed. Real-time polymerase chain reaction (PCR) was performed to examine mRNA expression of nephrin, transforming growth factor (TGF)-beta1 and bone morphogenetic protein (BMP)-7. Protein expression of nephrin, TGF-beta1, BMP-7 and p-Smad2/3 and p-Smad1/5/8 was examined by immunofluorescence, immunohistochemistry and western blotting, respectively. Rats were treated with 1,25(OH)(2)D(3) by gastric gavage at a dose of 2.5 microg/kg per day, starting 2 days before PAN injection and continuing throughout the experiment. 3. A single injection of PAN induced massive proteinuria and elevated serum creatinine on Day 7, both of which were significantly suppressed by 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)). Immunofluorescence and real-time PCR of the podocyte-associated protein nephrin revealed reduced and discontinuous staining and this change was reversed by 1,25(OH)(2)D(3). In PAN nephropathy rats, TGF-beta1 and p-Smad2/3 expression was upregulated, whereas that of BMP-7 and p-Smad1/5/8 was downregulated. Treatment with 1,25(OH)(2)D(3) significantly restored BMP-7/Smad signalling while suppressing TGF-beta1/Smad signalling. 4. In conclusion, 1,25(OH)(2)D(3) can ameliorate podocyte damage and proteinuria induced by PAN. The beneficial effects of 1,25(OH)(2)D(3) on podocytes may be attributable, in part, to direct modulation of TGF-beta1/BMP-7 signalling.

Topics: Animals; Bone Morphogenetic Protein 7; Kidney Diseases; Male; Podocytes; Puromycin Aminonucleoside; Rats; Rats, Sprague-Dawley; Signal Transduction; Transforming Growth Factor beta1; Vitamin D

Institutionalized older people have a high risk of bone fractures due to osteoporosis. In addition, chronic kidney disease (CKD) is highly prevalent in older people living in residential homes. Secondary hyperparathyroidism, poor calcium intake and deficiency of 1,25-dihydroxyvitamin D may lead to decreased bone mass in people with CKD. The present cross-sectional study assessed the relationship between markers of bone mineral metabolism and kidney function in a residential care home population.. Older subjects were recruited from residential care homes and kidney function stratified by the estimated glomerular filtration rate (GFR). Parathyroid hormone (PTH), 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were measured in 188 residents not receiving vitamin D/calcium treatment [mean age 85 (range 68- 100) years, 75% female] and in 52 residents receiving vitamin D/calcium supplementation.. Amongst those not receiving vitamin D/calcium, median PTH increased with declining GFR (P < 0.0001), particularly as GFR (mL/min/1.73 m(2)) fell below 45. PTH concentration was suppressed by increasing 25-hydroxyvitamin D (P < 0.0001), but not 1,25-dihydroxyvitamin D (P > 0.05) concentration. Nearly all residents (92%) had 25-hydroxyvitamin D deficiency or insufficiency and this was uninfluenced by kidney function (P > 0.05). Concentration of 1,25-dihydroxyvitamin D declined with worsening renal function (P < 0.0004) but 1,25-dihydroxyvitamin D deficiency was prevalent at all stages of kidney disease, including amongst residents receiving vitamin D/calcium supplementation.. Vitamin D deficiency and secondary hyperparathyroidism are common in this population irrespective of renal function. However, as GFR falls below 45, the prevalence of secondary hyperparathyroidism and 1,25-dihydroxyvitamin D deficiency increases. Unidentified CKD appears to exacerbate secondary hyperparathyroidism in this at risk population.

Topics: Aged; Aged, 80 and over; Bone and Bones; Bone Density; Chronic Disease; Cross-Sectional Studies; Dietary Supplements; Female; Glomerular Filtration Rate; Humans; Hyperparathyroidism, Secondary; Kidney Diseases; Male; Parathyroid Hormone; Residential Facilities; Vitamin D; Vitamin D Deficiency

Disturbances in bone and mineral metabolism are common in chronic kidney disease (CKD) patients. Most studies have been performed in hemodialysis and there is less information on non-dialysis patients, on the coexistence of other risk factors and on the achievement of more recent and stringent guidelines. Cross sectional study of analytical mineral and bone parameters in 125 incident patients (creatinine clearance <60 ml/min) in a monographic CKD clinic. Evaluation after one year of follow-up in 69 patients. Progression of CKD was associated with significant increased levels of phosphate, calcium x phosphate and iPTH and decreased calcium and 1,25 dihydroxyvitamin D. Levels of 25-hydroxyvitamin D were unchanged, but lower than recommended. Phosphate correlated negatively with 1,25-dihydroxivitamin D and creatinine clearance, and positively with iPTH. At every stage of CKD, most patients had PTH values outside recommended limits. More than 69% CKD 3 and CKD 4 patients had higher than recommended PTH levels. Above recommended phosphate levels were present in 25% of CKD 4 and 47% of CKD 5 patients. Most of these had associated high LDL-cholesterol. Higher than recommended calcium levels were more prevalent than low calcium and there was a high prevalence (31%) of vascular calcification. One year of intervention improved the percentage of patients with controlled calcium or iPTH, but not phosphate.. In incident CKD patients there is a high prevalence of out-of-target mineral and bone analytical parameters. The currently authorized therapeutic arsenal for these patients may not be adequate to deal with the problem.

Topics: Adult; Aged; Aged, 80 and over; Calcium; Chronic Disease; Cohort Studies; Creatinine; Cross-Sectional Studies; Female; Follow-Up Studies; Humans; Hyperparathyroidism; Hyperphosphatemia; Kidney Diseases; Male; Middle Aged; Parathyroid Hormone; Phosphates; Prevalence; Vitamin D

Dialysis Outcomes and Practice Patterns Study has shown that the proportion of haemodialysis patients with adequate mineral metabolism parameters according to the Kidney Disease Outcome Quality Initiative (K/DOQI) guidelines is very low. The adequacy of such parameters in relation to the recommended ranges in patients with different chronic kidney disease (CKD) stages has not been reported. The objective of this study is to provide an in-depth description of mineral metabolism in the early stages of CKD in a European population, and to compare it with current recommendations for stages 3-5 (K/DOQI guidelines).. A total of 1836 patients were classified into stages 1-5 according to K/DOQI guidelines. The following clinical and biochemical data were recorded: age, gender, CKD aetiology, presence of diabetes, serum creatinine, creatinine clearance, serum phosphate, calcium, CaxP product and intact parathyroid hormone (PTH).. A decrease in 1,25-dihydroxyvitamin D and an increase in PTH are the earliest mineral metabolism alterations in CKD, while serum calcium and phosphate are altered later in the course of CKD. The percentages of patients with serum levels within the recommended K/DOQI guidelines for stages 3, 4 and 5 were as follows: serum calcium: 90.7, 85.6 and 55; serum phosphate: 90.9, 77.1 and 70.3; iPTH 42.4, 24.6 and 46.8 and Ca x P product 99.9, 99.6 and 83.8, respectively. The percentages of patients who had all four parameters within the recommended ranges were 34.9, 18.4 and 21.6 for stages 3, 4 and 5, respectively.. Mineral metabolism disturbances start early in the course of CKD. The first alterations to take place are a 1,25-dihydroxyvitamin D decrease, a 24 h urine phosphate decrease and a PTH elevation, which show significant level variation when the glomerular filtration rate falls below 60 ml/min. K/DOQI recommended levels for mineral metabolism parameters are difficult to accomplish, in particular for PTH levels.

Topics: Adult; Aged; Aged, 80 and over; Calcium; Chronic Disease; Creatinine; Cross-Sectional Studies; Europe; Female; Humans; Kidney Diseases; Male; Middle Aged; Minerals; Outcome Assessment, Health Care; Parathyroid Hormone; Phosphates; Practice Guidelines as Topic; Reference Values; Renal Dialysis; Vitamin D

Active vitamin D compounds repress parathyroid hormone (PTH) gene transcription and block chief cell hyperplasia, making them integral tools in the treatment of secondary hyperparathyroidism in patients with chronic kidney disease. Recently, human parathyroid glands have been shown to express 25-hydroxyvitamin D 1alpha-hydroxylase (1alphaOHase), but documentation of the 1alphaOHase activity in parathyroid cells and its potential role in activating 25-hydroxyvitamin D(3) (25(OH)D(3)) to 1,25-dihydroxyvitamin D(3) (1,25(OH)2D3) have not been reported. The relative potencies of 25(OH)D(3) and 1,25(OH)(2)D(3) in reducing PTH secretion and mRNA were determined in primary cultures of bovine parathyroid cells (bPTC). The effects of blocking 1alphaOHase activity on suppression of PTH mRNA and induction of 24-hydroxylase mRNA were examined. Vitamin D receptor (VDR) affinities were estimated by intact cell competitive binding assay. Metabolism of 25(OH)D(3) by bPTC was assessed using a radioimmunoassay that measures all 1-hydroxylated metabolites of vitamin D. 25(OH)D(3) suppressed PTH secretion and mRNA (ED(50)=2 nM), but was several hundred times less potent than 1,25(OH)(2)D(3). The lower potency of 25(OH)D(3) correlated with its lower VDR affinity. bPTCs converted 25(OH)D(3) to 1-hydroxylated metabolites, but the rate of conversion was low. Inhibition of 1alphaOHase with the cytochrome P450 inhibitor clotrimazole did not block 25(OH)D(3)-mediated suppression of PTH. Clotrimazole enhanced 24-hydroxylase mRNA induction, presumably by inhibiting catabolism of 25(OH)D(3). In conclusion, 25(OH)D(3) suppresses PTH synthesis by parathyroid cells, possibly by direct activation of the VDR.

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Animals; Calcifediol; Cattle; Cells, Cultured; Clotrimazole; Cytochrome P-450 Enzyme Inhibitors; Gene Expression Regulation; Gene Expression Regulation, Enzymologic; Hyperparathyroidism, Secondary; Kidney Diseases; Parathyroid Glands; Parathyroid Hormone; Protein Binding; Receptors, Calcitriol; RNA, Messenger; Steroid Hydroxylases; Vitamin D; Vitamin D3 24-Hydroxylase

We describe a familial syndrome in two brothers who were investigated after the casual discovery of tubular proteinuria in their 1st month of life. During a follow-up of 20 and 11 years, respectively, the two children grew well and were asymptomatic, but developed the same biochemical abnormalities, i.e., tubular proteinuria and hyperphosphaturia, progressive decrease in serum phosphorus below the normal values for age, and an increase in serum 1,25-dihydroxyvitamin D levels over normal values. Moreover, hyperabsorptive hypercalciuria and systemic osteopenia developed and progressively worsened. In both children, at a different age, medullary nephrocalcinosis appeared. The oldest boy suffered a progressive decrease in urinary concentration ability and in glomerular filtration rate. Oral phosphate supplementation led to reversal of all biochemical abnormalities, with the exception of decreased phosphate tubular reabsorption and tubular proteinuria. With long-term phosphate supplementation, a normal bone mass was reached, while progression of nephrocalcinosis was arrested and impairment of renal function was slowed down. In a family study (siblings and parents), the only detectable abnormality was microglobinuria in the mother, thus suggesting a X-linked inheritance of this disorder. In the two probands a mutation within the renal chloride channel gene (CLCN5) was discovered.

Topics: Child; Child, Preschool; Chloride Channels; Female; Genetic Linkage; Glomerular Filtration Rate; Humans; Infant, Newborn; Kidney Concentrating Ability; Kidney Diseases; Male; Mutation; Syndrome; Vitamin D; X Chromosome