vitamin-d-2 and Uremia

The fields for clinical employment of vitamin D analogs are growing and under active evaluation in different medical specialties, ranging from dermatology to immunology and oncology. In this review we provide a brief description of the drugs that have been developed more specifically for the treatment of secondary hyperparathyroidism (SH) associated with uremia.

Topics: Calcitriol; Dihydroxycholecalciferols; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Uremia; Vitamin D

Intestinal malabsorption of calcium and the development of osteomalacia in conservatively treated renal failure is explained by a quantitative deficiency of 1,25-dihydroxycholecalciferol, which also contributes to the development of hypocalcaemia. Excess of 25-hydroxycholecalciferol can substitute for this deficiency. The presence and healing of azotaemic osteomalacia is unrelated to the prevailing plasma [Ca] x [P] product. The data suggest that "vitamin D" acts directly on bone mineralisation, but the claim that this apparent effect is normally due to 25-hydroxycholecalciferol is considered unproven. Most of the phenomena of azotaemic osteodystrophy are encountered in simple vitamin D deficiency; as in that condition, deficiency of 1,25-dihydroxycholecalciferol may be of primary significance in causing secondary hyperparathyroidism in renal failure.

Topics: Bone Resorption; Calcium; Dihydroxycholecalciferols; Drug Resistance; Ergocalciferols; Humans; Hypoparathyroidism; Kidney Failure, Chronic; Phosphates; Pseudohypoparathyroidism; Uremia; Vitamin D

Pruritus is a common problem among hemodialyzed patients. Its causes are poorly understood, and, as a result, itching is often attributed to elevated serum phosphorus and other disorders of bone and minerals. The primary purpose of this study was to analyze the relationship between pruritus and common tests of bone and mineral disease.. This study was a post hoc analysis of data from a randomized controlled trial of 3 months of ergocalciferol versus placebo treatment in 50 hemodialysis patients with uremic pruritus. A pruritus survey was administered at baseline and then every 2 weeks for 12 weeks. Concurrent serum phosphorus, intact parathyroid hormone (PTH), serum calcium, and calcium-phosphate product were measured.. Pruritus score was not found to be associated or correlated with serum phosphate, intact PTH, serum calcium, or calcium-phosphate product at each time interval or over time. Likewise, when analyzed by original study group (placebo or ergocalciferol), no association or correlation between the mineral and bone indicators and itching were found.. Neither serum phosphate nor other tests of bone and mineral status were found to be significant predictors of pruritus at any point in time or over time.

Topics: Aged; Aged, 80 and over; Calcium; Double-Blind Method; Ergocalciferols; Female; Humans; Male; Middle Aged; Parathyroid Hormone; Phosphates; Phosphorus; Placebos; Pruritus; Renal Dialysis; Uremia

Endothelial dysfunction and vitamin D deficiency are prevalent in patients with cardiovascular disease (CVD) and chronic kidney disease (CKD). Both are risk factors for cardiovascular events in patients with CKD. No studies have investigated the effect of nutritional forms of vitamin D on endothelial function in earlier stages of CKD, when vascular endothelium may be more amenable to this therapy. We studied the effect of ergocalciferol in a pre-clinical model of mild uraemia. Male Wistar rats underwent either a 5/6th nephrectomy or sham surgery. Four weeks after the final stage of the surgery, these two groups were randomly allocated to placebo or an oral dose of 1000 iu of ergocalcfierol at day 7 and 2 pre sacrifice. Vascular responses to acetylcholine, Spermine NONOate and phenylephrine were determined in aortic rings. Blood pressure, calcium, phosphate and parathyroid hormone were measured in all groups. Ergocalciferol significantly improved the endothelium-dependent responses to acetylcholine and overcame the blunting of the contractile response to phenylephrine seen in uraemic animals. Ergocalciferol improved the contractile response to potassium chloride in uraemic, but not sham animals. All effects occurred independently of changes to calcium, phosphate, parathyroid hormone and systolic blood pressure. There were no differences in endothelium-independent relaxation to Spermine NONOate. In summary, in a model of mild uraemia, ergocalciferol improved vasodilator and vasoconstrictor tone independently of blood pressure and bone mineral parameters suggesting a direct effect of ergocalciferol on the endothelium.

Topics: Animals; Aorta; Disease Models, Animal; Endothelial Cells; Endothelium, Vascular; Ergocalciferols; Humans; Parathyroid Hormone; Rats; Renal Insufficiency; Renal Insufficiency, Chronic; Uremia; Vasoconstrictor Agents; Vasodilation; Vitamin D; Vitamin D Deficiency

In uremic animals, vitamin D receptor (VDR) agonists like paricalcitol (Pc) attenuate cardiac hypertrophy, but this effect has not been replicated consistently in humans with chronic kidney disease. Elevated fibroblast growth factor 23 (FGF23) levels cause cardiac hypertrophy with activation of the myocardial calcineurin/nuclear factor of activated T cell (NFAT) axis and may antagonize the cardioprotective effects of VDR agonist therapy. We hypothesized that the effectiveness of Pc may depend on the prevailing circulating levels of FGF23 and could be potentiated by the combined administration of a pan-FGF23 receptor (FGFR) blocker agent (PD173074).. In rats with 5/6 nephrectomy treated with Pc or PD173074 or both agents concurrently, myocardial mRNA expression of renin-angiotensin system, VDR, FGFR4, and calcineurin/NFAT target genes was determined. In adolescents on hemodialysis, we analyzed sequential echocardiograms, blood pressures and serial FGF23 measurements, and their relations to the cumulative administered dose of parenteral Pc.. The ratio of Pc dose/plasma levels of FGF23 correlated inversely (P < 0.005) with the cardiac mass in uremic rats and in hemodialysis patients, independently of hypertension. Despite persistently elevated FGF23 levels and myocardial FGFR4 activation, Pc suppressed upregulated myocardial calcineurin/NFAT target genes, and the effects were amplified by coadministration of PD173074.. The beneficial effects of Pc on uremic cardiac hypertrophy are counterbalanced by the increased FGF23 levels. Blockade of FGF23-mediated signaling increased the Pc-induced suppression of the myocardial calcineurin/NFAT system. Higher doses of Pc should be considered in the treatment of patients with uremic cardiomyopathy.

Topics: Adolescent; Animals; Cardio-Renal Syndrome; Cardiomyopathies; Child; Disease Models, Animal; Drug Therapy, Combination; Ergocalciferols; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Heart Ventricles; Humans; Kidney Failure, Chronic; Male; Pyrimidines; Rats, Sprague-Dawley; Receptor, Fibroblast Growth Factor, Type 4; Receptors, Calcitriol; Retrospective Studies; Signal Transduction; Uremia; Ventricular Function, Left; Ventricular Remodeling

Topics: Arterioles; Breast Diseases; Calcinosis; Ergocalciferols; Female; Humans; Kidney Failure, Chronic; Middle Aged; Skin Ulcer; Thiosulfates; Uremia

Background Dysfunctional endothelium may contribute to the development of cardiovascular complications in chronic kidney disease ( CKD ). Supplementation with active vitamin D has been proposed to have vasoprotective potential in CKD , not only by direct effects on the endothelium but also by an increment of α-Klotho. Here, we explored the capacity of the active vitamin D analogue paricalcitol to protect against uremia-induced endothelial damage and the extent to which this was dependent on increased α-Klotho concentrations. Methods and Results In a combined rat model of CKD with vitamin D deficiency, renal failure induced vascular permeability and endothelial-gap formation in thoracic aorta irrespective of baseline vitamin D, and this was attenuated by paricalcitol. Downregulation of renal and serum α-Klotho was found in the CKD model, which was not restored by paricalcitol. By measuring the real-time changes of the human endothelial barrier function, we found that paricalcitol effectively improved the recovery of endothelial integrity following the addition of the pro-permeability factor thrombin and the induction of a wound. Furthermore, immunofluorescence staining revealed that paricalcitol promoted vascular endothelial-cadherin-based cell-cell junctions and diminished F-actin stress fiber organization, preventing the formation of endothelial intracellular gaps. Conclusions Our results demonstrate that paricalcitol attenuates the CKD -induced endothelial damage in the thoracic aorta and directly mediates endothelial stability in vitro by enforcing cell-cell interactions.

Topics: Actins; Animals; Aorta, Thoracic; Cadherins; Capillary Permeability; Disease Models, Animal; Endothelium, Vascular; Ergocalciferols; Glucuronidase; Human Umbilical Vein Endothelial Cells; Humans; Intercellular Junctions; Klotho Proteins; Rats; Renal Insufficiency, Chronic; Stress Fibers; Uremia; Vitamin D Deficiency

Uraemic cardiomyopathy, a process mainly associated with increased myocardial fibrosis, is the leading cause of death in chronic kidney disease patients and can be prevented by vitamin D receptor activators (VDRAs). Since some microRNAs (miRNAs) have emerged as regulators of the fibrotic process, we aimed to analyse the role of specific miRNAs in VDRA prevention of myocardial fibrosis as well as their potential use as biomarkers.. Wistar rats were nephrectomized and treated intraperitoneally with equivalent doses of two VDRAs: calcitriol and paricalcitol. Biochemical parameters, cardiac fibrosis, miRNA (miR-29b, miR-30c and miR-133b) levels in the heart and serum and expression of their target genes collagen I (COL1A1), matrix metalloproteinase 2 (MMP-2) and connective tissue growth factor (CTGF) in the heart were evaluated.. Both VDRAs attenuated cardiac fibrosis, achieving a statistically significant difference in the paricalcitol-treated group. Increases in RNA and protein levels of COL1A1, MMP-2 and CTGF and reduced expression of miR-29b and miR-30c, known regulators of these pro-fibrotic genes, were observed in the heart of chronic renal failure (CRF) rats and were attenuated by both VDRAs. In serum, significant increases in miR-29b, miR-30c and miR-133b levels were observed in CRF rats, which were prevented by VDRA use. Moreover, vitamin D response elements were identified in the three miRNA promoters.. VDRAs, particularly paricalcitol, attenuated cardiac fibrosis acting on COL1A1, MMP-2 and CTGF expression, partly through regulation of miR-29b and miR-30c. These miRNAs and miR-133b could be useful serum biomarkers for cardiac fibrosis and also potential new therapeutic targets.

Topics: Animals; Biomarkers; Calcitriol; Cardiomyopathies; Collagen Type I; Connective Tissue Growth Factor; Ergocalciferols; Fibrosis; Gene Expression Regulation; Kidney Failure, Chronic; Male; Matrix Metalloproteinase 2; MicroRNAs; Myocardium; Rats; Rats, Wistar; Receptors, Calcitriol; Signal Transduction; Uremia

The parathyroid oxyphil cell content increases in patients with chronic kidney disease (CKD), and even more in patients treated with the calcimimetic cinacalcet and/or calcitriol for hyperparathyroidism. Oxyphil cells have significantly more calcium-sensing receptors than chief cells, suggesting that the calcium-sensing receptor and calcimimetics are involved in the transdifferentiation of a chief cell to an oxyphil cell type. Here, we compared the effect of the vitamin D analog paricalcitol (a less calcemic analog of calcitriol) and/or cinacalcet on the oxyphil cell content in patients with CKD to further investigate the genesis of these cells. Parathyroid tissue from four normal individuals and 27 patients with CKD who underwent parathyroidectomy for secondary hyperparathyroidism were analyzed. Prior to parathyroidectomy, patients had received the following treatment: seven with no treatment, seven with cinacalcet only, eight with paricalcitol only, or cinacalcet plus paricalcitol in five. Oxyphilic areas of parathyroid tissue, reported as the mean percent of total tissue area per patient, were normal, 1.03; no treatment, 5.3; cinacalcet, 26.7 (significant vs. no treatment); paricalcitol, 6.9 (significant vs. cinacalcet; not significant vs. no treatment); and cinacalcet plus paricalcitol, 12.7. Cinacalcet treatment leads to a significant increase in parathyroid oxyphil cell content but paricalcitol does not, reinforcing a role for the calcium-sensing receptor activation in the transdifferentiation of chief-to-oxyphil cell type. Thus, two conventional treatments for hyperparathyroidism have disparate effects on parathyroid composition, and perhaps function. This finding is provocative and may be useful when evaluating future drugs for hyperparathyroidism.

Topics: Adult; Calcimimetic Agents; Calcitriol; Cell Transdifferentiation; Cinacalcet; Drug Therapy, Combination; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Male; Middle Aged; Oxyphil Cells; Parathyroid Glands; Parathyroidectomy; Receptors, Calcium-Sensing; Renal Insufficiency, Chronic; Uremia; Vitamin D

Vitamin D receptor (VDR) modulators (VDRMs) are commonly used to control secondary hyperparathyroidism (SHPT) associated with chronic kidney disease, and are associated with beneficial outcomes in cardiovascular disease. In this study, we compared the cardiac effect of VS-105, a novel VDRM, with that of paricalcitol in 5/6 nephrectomized uremic rats. Male Sprague-Dawley rats were 5/6 nephrectomized, fed a standard diet for 4 weeks to establish uremia, and then treated (intraperitoneally, 3 times/week) with vehicle (propylene glycol), paricalcitol (0.025 and 0.15μg/kg), or VS-105 (0.05 and 0.3μg/kg) for 4 weeks. In uremic rats, neither VDRM (low and high doses) altered serum creatinine and phosphorus levels. Serum calcium was significantly higher with high dose paricalcitol compared to sham rats. PTH levels were significantly decreased with low dose paricalcitol and VS-105, and were further reduced in the high dose groups. Interestingly, serum FGF23 was significantly higher with high dose paricalcitol compared to sham rats, whereas VS-105 had no significant effect on FGF23 levels. Left ventricle (LV) weight and LV mass index determined by echocardiography were significantly suppressed in both high dose VDRM groups. This suppression was more evident with VS-105. Western blotting showed significant decreases in a fibrosis marker TGF-β1 in both high dose VDRM groups (vs. vehicle) and Masson trichrome staining showed significant decreases in cardiac fibrosis in these groups. These results suggest that VS-105 is less hypercalcemic than paricalcitol and has favorable effects on SHPT and cardiac parameters that are similar to those of paricalcitol in uremic rats. The cardioprotective effect is a noteworthy characteristic of VS-105.

Topics: Animals; Calcitriol; Calcium; Cardiotonic Agents; Creatinine; Echocardiography; Ergocalciferols; Fibroblast Growth Factors; Gene Expression; Heart Ventricles; Injections, Intraperitoneal; Male; Nephrectomy; Parathyroid Hormone; Rats; Rats, Sprague-Dawley; Receptors, Calcitriol; Renal Insufficiency; Transforming Growth Factor beta1; Uremia; Ventricular Remodeling

Klotho plays an important role in the pathogenesis of cardiovascular disease in chronic kidney disease (CKD). Klotho is highly expressed in the kidney and parathyroid glands, but its presence in the vasculature is debated. Renal Klotho is decreased in CKD, but the effect of uremia on Klotho in other tissues is not defined. The effect of vitamin D receptor activator therapy in CKD on the expression of Klotho in various tissues is also in debate. In uremic rats (surgical 5/6th nephrectomy model), we compared 3 months of treatment with and without paricalcitol on Klotho immunostaining in the kidney, parathyroid glands, and aorta. With uremia, Klotho was unchanged in the parathyroid, significantly decreased in the kidney (66%) and the intimal-medial area of the aorta (69%), and significantly increased in the adventitial area of the aorta (67%) compared with controls. Paricalcitol prevented the decrease of Klotho in the kidney, increased expression in the parathyroid (31%), had no effect in the aortic media, but blunted the increase of Klotho in the aortic adventitia. We propose that fibroblasts are responsible for the expression of Klotho in the adventitia. In hyperplastic human parathyroid tissue from uremic patients, Klotho was higher in oxyphil compared with chief cells. Thus, under our conditions of moderate CKD and mild-to-moderate hyperphosphatemia in rats, the differential expression of Klotho and its regulation by paricalcitol in uremia is tissue-dependent.

Topics: Adventitia; Animals; Aorta; Bone Density Conservation Agents; Disease Models, Animal; Ergocalciferols; Female; Fibroblasts; Glucuronidase; Humans; Hyperparathyroidism, Secondary; Hyperphosphatemia; Kidney; Klotho Proteins; Nephrectomy; Oxyphil Cells; Parathyroid Glands; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Tunica Intima; Uremia

Klotho is an evolutionarily highly conserved protein related to longevity. Increasing evidence of a vascular protecting effect of the Klotho protein has emerged and might be important for future treatments of uremic vascular calcification. It is still disputed whether Klotho is locally expressed in the vasculature or whether its vascular effects arise uniquely from its presence in the circulation.

Topics: Animals; Aorta; Bone Density Conservation Agents; Ergocalciferols; Female; Glucuronidase; Humans; Kidney; Parathyroid Glands; Uremia

Vitamin D attenuates uremic cardiac hypertrophy, possibly by suppressing the myocardial renin-angiotensin system (RAS) and fibroblast growth factors (FGFs). We compared the suppression of cardiac hypertrophy and myocardial expression of RAS and FGF receptor genes offered by the vitamin D analog paricalcitol (Pc) or the angiotensin-converting enzyme inhibitor enalapril (E) in experimental uremia.. Rats with 5/6 nephrectomy received Pc or E for 8 weeks. Renal function, systolic blood pressure, and cardiac hypertrophy were evaluated. Myocardial expression of RAS genes, brain natriuretic peptide (BNP), and FGF receptor-1 (FGFR-1) were determined using quantitative reverse-transcription (pRT)-PCR.. Blood pressure, proteinuria, and serum creatinine were significantly higher in untreated uremic animals. Hypertension was significantly reduced by E but only modestly by Pc; however, cardiac hypertrophy in the untreated group was similarly attenuated by Pc or E. Upregulation of myocardial expressions of renin, angiotensinogen, FGFR-1, and BNP in untreated uremic animals was reduced similarly by Pc and E, while the angiotensin II type 1 receptor was downregulated only by E.. Uremic cardiac hypertrophy is associated with activation of the myocardial RAS and the FGFR-1. Downregulation of these genes induced by Pc and E results in similar amelioration of left ventricular hypertrophy despite the different antihypertensive effects of these drugs.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Cardiomegaly; Disease Models, Animal; Down-Regulation; Enalapril; Ergocalciferols; Fibroblast Growth Factors; Hypertension; Male; Myocardium; Nephrectomy; Rats, Sprague-Dawley; Receptor, Fibroblast Growth Factor, Type 1; Renin-Angiotensin System; RNA, Messenger; Uremia

The search for new therapies providing cardiorenal protection in chronic kidney disease (CKD) has led to treatments that combine conventional renin-angiotensin-aldosterone-system inhibitors with other drugs that exhibit potential in disease management.. In rats made uremic by renal ablation, we examined the effects of addition of the endothelin-A receptor antagonist atrasentan to a previously examined combination of enalapril (angiotensin converting enzyme inhibitor) and paricalcitol (vitamin D receptor activator) on cardiac and renal parameters. The effects of the individual and combined drugs were examined after a 3-month treatment.. A decrease in systolic blood pressure, serum creatinine and proteinuria, and improvement of renal histology in uremic rats were attributed to enalapril and/or paricalcitol treatment; atrasentan alone had no effect. In heart tissue, individual treatment with the drugs blunted the increase in cardiomyocyte size, and combined treatment additively decreased cardiomyocyte size to normal levels. Perivascular fibrosis was blunted in uremic control rats with atrasentan or enalapril treatment.. We found distinct cardiac and renal effects of atrasentan. Combination treatment with atrasentan, enalapril and paricalcitol provided positive effects on cardiac remodeling in uremic rats, whereas combination treatment did not offer further protective effects on blood pressure, proteinuria or renal histology.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrasentan; Bone Density Conservation Agents; Drug Therapy, Combination; Enalapril; Endothelin Receptor Antagonists; Ergocalciferols; Female; Glomerulosclerosis, Focal Segmental; Heart; Kidney; Kidney Function Tests; Myocardium; Nephrectomy; Nephritis; Pyrrolidines; Rats; Rats, Sprague-Dawley; Survival Analysis; Uremia

To investigate whether the frequency of monitoring paricalcitol's impact on serum calcium (Ca), phosphorus and PTH in current clinical practice is sufficient by mapping the time-dependent effects of paricalcitol on these parameters.. The 5/6 nephrectomized (NX) male, Sprague-Dawley rats with established uremia were treated with vehicle or paricalcitol (0.16 μg/kg, i.p., 3×/week). On Day 0 (before treatment), Days 12 and 13 after treatment, and also at 0, 1, 4, 8, 16, 24 h after the last dosing, blood and small intestine samples were collected.. Serum creatinine and blood urea nitrogen levels were significantly elevated in 5/6 NX rats. Significant increases were observed in serum Ca while PTH decreased by >90% when the parameters were determined at 12 or 13 days after paricalcitol dosing. Paricalcitol caused a step-wise increase in serum Ca levels at 1-24 h following dosing, reduced serum PTH levels with PTH values ranging from 1.06±0.06 to 26.7±25.7 pg/ml (vs. 152±15 pg/ml in Sham rats), but did not affect serum phosphorus in a time-dependent manner. Consistent with the serum Ca data, paricalcitol significantly induced the intestinal expression of Calb3 and TRPV6, genes involved in intestinal Ca transport, and also significantly induced the intestinal calcium absorption.. Our results suggest that the frequency of monitoring paricalcitol's effect on serum Ca, phosphorus and PTH in current clinical practice seems adequate. Additional clinical trials may be needed to resolve the inconsistent clinical observations about the impact of paricalcitol on serum Ca.

Topics: Animals; Blood Urea Nitrogen; Calcium; Creatinine; Ergocalciferols; Male; Nephrectomy; Parathyroid Hormone; Phosphorus; Rats; Rats, Sprague-Dawley; Time Factors; Uremia

Angiotensin-converting enzyme (ACE) inhibitors ameliorate the progression of renal disease. In combination with vitamin D receptor activators, they provide additional benefits. In the present study, uremic (U) rats were treated as follows: U+vehicle (UC), U+enalapril (UE; 25 mg/l in drinking water), U+paricalcitol (UP; 0.8 μg/kg ip, 3 × wk), or U+enalapril+paricalcitol (UEP). Despite hypertension in UP rats, proteinuria decreased by 32% vs. UC rats. Enalapril alone, or in combination with paricalcitol, further decreased proteinuria (≈70%). Glomerulosclerosis and interstitial infiltration increased in UC rats. Paricalcitol and enalapril inhibited this. The increase in cardiac atrial natriuretic peptide (ANP) seen in UC rats was significantly decreased by paricalcitol. Enalapril produced a more dramatic reduction in ANP. Renal oxidative stress plays a critical role in inflammation and progression of sclerosis. The marked increase in p22(phox), a subunit of NADPH oxidase, and decrease in endothelial nitric oxide synthase were inhibited in all treated groups. Cotreatment with both compounds inhibited the uremia-induced increase in proinflammatory inducible nitric oxide synthase (iNOS) and glutathione peroxidase activity better than either compound alone. Glutathione reductase was also increased in UE and UP rats vs. UC. Kidney 4-hydroxynonenal was significantly increased in the UC group compared with the normal group. Combined treatment with both compounds significantly blunted this increase, P < 0.05, while either compound alone had no effect. Additionally, the expression of Mn-SOD was increased and CuZn-SOD decreased by uremia. This was ameliorated in all treatment groups. Cotreatment with enalapril and paricalcitol had an additive effect in increasing CuZn-SOD expression. In conclusion, like enalapril, paricalcitol alone can improve proteinuria, glomerulosclerosis, and interstitial infiltration and reduce renal oxidative stress. The effects of paricalcitol may be amplified when an ACE inhibitor is added since cotreatment with both compounds seems to have an additive effect on ameliorating uremia-induced changes in iNOS and CuZn-SOD expression, peroxidase activity, and renal histomorphometry.

Topics: Aldehydes; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Enalapril; Ergocalciferols; Female; Glomerulonephritis; Kidney; NADPH Oxidases; Nitric Oxide Synthase Type II; Oxidative Stress; Proteinuria; Rats; Receptors, Calcitriol; Superoxide Dismutase; Uremia

Vitamin D sterols may modulate vascular response to inflammation and vascular calcification (VC).. Rat aortic rings (RARs) and human vascular smooth muscle cells (HVSMCs) were treated in vitro with phosphate (P), tumour necrosis factor alpha (TNF-α), calcitriol (CTR) and paricalcitol (PCT). Rats having undergone subtotal nephrectomy (Nx) (n = 66) on a high-phosphorus diet were treated with Escherichia coli lipopolysacharide (LPS) (40-400 μg/kg/day) or LPS plus CTR (80 ng/kg/48 h) or LPS plus PCT (240 ng/kg/48 h) for 14 days.. In vitro, the addition of TNF-α to the medium increased the mineral content of RAR and HVSMC. Treatment with both vitamin D analogues decreased bone morphogenetic protein 2 but did not modify Runx-2. Calcification was prevented only by PCT. In vivo, treatment with LPS increased plasma levels of TNF-α, monocyte chemotactic protein-1 and interleukin-1alfa and induced calcification. The concomitant administration of LPS with either CTR or PCT led to a significant decrease in cytokine plasma levels and the decrease was more accentuated after treatment with PCT than with CTR. Rats treated with CTR showed an elevation in aortic Ca and marked Von Kossa staining; however, rats treated with PCT did not increase aortic Ca and did not show Von Kossa staining.. Treatment with PCT resulted in more marked anti-inflammatory effect than treatment with CTR and, as opposed to CTR, PCT prevented VC.

Topics: Animals; Aorta; Blood Pressure; Blotting, Western; Bone Density Conservation Agents; Calcinosis; Calcitriol; Calcium; Cells, Cultured; Cytokines; Ergocalciferols; Female; Humans; Inflammation; Lipopolysaccharides; Muscle, Smooth, Vascular; Nephrectomy; Phosphorus; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Necrosis Factor-alpha; Uremia; Vascular Diseases

Kidney disease patients experience declining calcitriol levels and develop secondary hyperparathyroidism (SHPT). Animal models of uremia based on 5/6 nephrectomy (NTX) do not consistently reproduce this calcitriol deficiency. We developed an animal model, the NTX Cyp27b1-null mouse, which completely lacks endogenous calcitriol, and examined the suitability of this model for evaluation of treatment with vitamin D analogs in uremia.. NTX was performed at 2 months of age. One week post-NTX, animals were treated for 4 weeks with vehicle; doxercalciferol at 30, 100 or 300 pg/g body weight (b.w.); or paricalcitol at 100, 300 or 1,000 pg/g b.w. by gavage 3 times per week.. Serum blood urea nitrogen and creatinine were elevated. Vehicle-treated NTX null mice had hypocalcemia and SHPT. Doxercalciferol at 100 or 300 pg/g b.w. normalized serum calcium and parathyroid hormone (PTH) levels. Paricalcitol at 300 or 1,000 pg/g normalized serum calcium, but PTH levels remained elevated. Osteomalacia was corrected by 100 pg/g b.w. of doxercalciferol or 1,000 pg/g b.w. of paricalcitol. The highest dose of doxercalciferol, but not of paricalcitol, significantly reduced osteitis fibrosa.. Our results reveal the differential efficacy of doxercalciferol and paricalcitol in this novel animal model incorporating both calcitriol deficiency and renal insufficiency.

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Administration, Oral; Animals; Calcitriol; Calcium; Disease Models, Animal; Dose-Response Relationship, Drug; Ergocalciferols; Mice; Mice, Knockout; Osteitis; Osteomalacia; Parathyroid Hormone; Uremia

Calcific uremic arteriolopathy, or calciphylaxis, is a serious and life-threatening complication of end-stage renal disease. Its pathogenesis is not yet fully elucidated and treatment is controversial. In the presence of severe hyperparathyroidism, parathyroidectomy should be considered. We report a case of a woman on maintenance hemodialysis therapy with calciphylaxis and parathyroid adenoma who refused to undergo parathyroidectomy. She was treated successfully with a combination of noncalcium phosphate binders, cinacalcet, and paricalcitol. Subcutaneous plaques disappeared, and the necrotic lesion was healed. Discontinuation of paricalcitol led to an increase in serum parathyroid hormone levels and reappearance of the patient's symptoms, whereas its reintroduction resulted in complete remission of the clinical picture. Paricalcitol, a less calcemic vitamin D analogue, is also a selective vitamin D receptor activator with a number of nonclassic actions (such as inhibition of inflammation and ossification-calcification) that could prove beneficial in cases of calciphylaxis.

Topics: Adenoma; Arterial Occlusive Diseases; Arterioles; Biopsy; Bone Density Conservation Agents; Calcinosis; Ergocalciferols; Female; Follow-Up Studies; Humans; Middle Aged; Parathyroid Neoplasms; Positron-Emission Tomography; Uremia

Calcimimetics activate the calcium-sensing receptor (CaR) and reduce parathyroid hormone (PTH) by increasing the sensitivity of the parathyroid CaR to ambient calcium. The calcimimetic, cinacalcet, is effective in treating secondary hyperparathyroidism in dialysis patients [chronic kidney disease (CKD 5)], but little is known about its effects on stage 3-4 CKD patients. We compared cinacalcet and paricalcitol in uremic rats with creatinine clearances "equivalent" to patients with CKD 3-4. Uremia was induced in anesthetized rats using the 5/6th nephrectomy model. Groups were 1) uremic control, 2) uremic + cinacalcet (U+Cin; 15 mg x kg(-1) x day(-1) po for 6 wk), 3) uremic + paricalcitol (U+Par; 0.16 microg/kg, 3 x wk, ip for 6 wk), and 4) normal. Unlike U+Par animals, cinacalcet promoted hypocalcemia and marked hyperphosphatemia. The Ca x P in U+Cin rats was twice that of U+Par rats. Both compounds suppressed PTH. Serum 1,25-(OH)(2)D(3) was decreased in both U+Par and U+Cin rats. Serum FGF-23 was increased in U+Par but not in U+Cin, where it tended to decrease. Analysis of tibiae showed that U+Cin, but not U+Par, rats had reduced bone volume. U+Cin rats had similar bone formation and reduced osteoid surface, but higher bone resorption. Hypocalcemia, hyperphosphatemia, low 1,25-(OH)(2)D(3), and cinacalcet itself may play a role in the detrimental effects on bone seen in U+Cin rats. This requires further investigation. In conclusion, due to its effects on bone and to the hypocalcemia and severe hyperphosphatemia it induces, we believe that cinacalcet should not be used in patients with CKD without further detailed studies.

Topics: Animals; Biomarkers; Bone Resorption; Calcitriol; Calcium; Cinacalcet; Creatinine; Disease Models, Animal; Ergocalciferols; Female; Fibroblast Growth Factors; Hyperparathyroidism; Hyperphosphatemia; Hypocalcemia; Naphthalenes; Nephrectomy; Parathyroid Hormone; Phosphorus; Rats; Rats, Sprague-Dawley; Receptors, Calcium-Sensing; Renal Insufficiency, Chronic; Severity of Illness Index; Tibia; Uremia

Topics: Animals; Biomarkers; Bone Remodeling; Bone Resorption; Calcitriol; Cinacalcet; Ergocalciferols; Fibroblast Growth Factors; Humans; Hyperparathyroidism; Hyperphosphatemia; Hypocalcemia; Naphthalenes; Parathyroid Hormone; Rats; Renal Insufficiency, Chronic; Severity of Illness Index; Tibia; Treatment Outcome; Uremia

This study investigated the protective effect of the angiotensin-converting enzyme inhibitor, enalapril, and the vitamin D analog, paricalcitol, alone or in combination, on cardiac oxidative stress in uremic rats.. Rats were made uremic by 5/6 nephrectomy and treated for 4 months as follows: (1) uremic + vehicle (n = 11); (2) uremic + enalapril (30 mg/l in drinking water, n = 13); (3) uremic + paricalcitol (200 ng 3x week, n = 6); (4) uremic + enalapril + paricalcitol (n = 14), and (5) controls (n = 6).. Cardiac NADPH oxidase activity increased by 300% in uremic rats compared to normal controls. Treatment with enalapril, paricalcitol or the combination of the two protected uremic rats from cardiac oxidative stress by inhibiting enzyme activity. Cardiac malondialdehyde (MDA) levels were significantly increased in uremic rats compared to normal controls. Only the combination therapy inhibited the increase in MDA levels in uremic rats. Cardiac glutathione was significantly reduced in uremic rats compared to normal controls. Enalapril, paricalcitol or the two in combination all protected against this reduction in glutathione. Cardiac copper/zinc superoxide dismutase (CuZn-SOD) activity decreased whereas manganese (Mn-SOD) activity increased in uremic rats compared to controls. Both mono and combination therapies ameliorated the alterations in cardiac SOD activity seen in uremic rats.. Enalapril, paricalcitol and their combined therapy afford protection against cardiac oxidative stress in uremia.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antioxidants; Drug Therapy, Combination; Enalapril; Ergocalciferols; Female; Heart Diseases; Malondialdehyde; NADPH Oxidases; Oxidative Stress; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Uremia

Vascular calcification is associated with an increase in cardiovascular mortality in stage 5 chronic kidney disease. To determine if vitamin D receptor activators (VDRAs) have differential effects in the pathogenesis of aortic calcification, we assessed the effects of paricalcitol and doxercalciferol in vivo using 5/6 nephrectomized (NX) rats. To quantify the functional consequences of vascular calcification, pulse wave velocity (PWV), an aortic compliance index, was measured.. NX rats were fed a diet containing 0.9% phosphorous and 0.6% calcium 4 weeks prior to and throughout the study. On Day 0, rats received vehicle or VDRA (0.083, 0.167 and 0.333 microg/kg, i.p.) three times per week for 6 weeks. At Day 0 and Weeks 2 and 6, blood was drawn and PWV was measured by Doppler ultrasound.. VDRAs (0.167 and 0.333 microg/kg) consistently lowered PTH at Weeks 2 and 6. All doses of paricalcitol increased serum calcium at Week 6 but not at Week 2, while the two higher doses of doxercalciferol increased serum calcium at both Weeks 2 and 6. Treatment with paricalcitol (0.333 microg/kg) increased serum phosphorus at Weeks 2 and 6; these changes were not different from those observed in 5/6 NX rats. All doses of doxercalciferol increased serum phosphorus at Week 6. Paricalcitol had no effect on Ca x P; however, the two highest doses of doxercalciferol increased Ca x P at Weeks 2 and 6 above that observed in the 5/6 NX vehicle-treated group. There were no differences in aortic calcium and phosphorus contents at the end of 6 weeks among SHAM-, 5/6 NX- and paricalcitol-treated rats. However, treatment with the two higher doses of doxercalciferol caused a significant elevation in aortic calcium and phosphorus contents. Measurements of PWV demonstrated differential effects of VDRAs on vascular compliance. Paricalcitol produced no effects on PWV, while the two highest doses of doxercalciferol increased PWV at Week 6.. In uraemic rats with established secondary hyperparathyroidism, we demonstrate differential effects of paricalcitol and doxercalciferol on aortic calcification and PWV, independent of serum Ca, P and Ca x P, suggesting different mechanisms of action between VDRAs.

Topics: Animals; Aorta; Blood Flow Velocity; Calcinosis; Calcium; Ergocalciferols; Hyperparathyroidism, Secondary; Male; Nephrectomy; Parathyroid Hormone; Phosphorus; Rats; Rats, Sprague-Dawley; Receptors, Calcitriol; Renal Insufficiency, Chronic; Uremia; Vascular Resistance

Vitamin D derivatives and calcimimetics are used to treat secondary hyperparathyroidism in patients with chronic renal failure. We investigated the effect of calcitriol, paricalcitol, and the calcimimetic AMG 641 on soft-tissue calcification in uremic rats with secondary hyperparathyroidism. Control and uremic rats were treated with vehicle, calcitriol, paricalcitol, AMG 641, or a combination of AMG 641 plus calcitriol or paricalcitol. Parathyroid hormone levels were reduced by all treatments but were better controlled by the combination of paricalcitol and AMG 641. The calcimimetic alone did not induce extraosseous calcification but co-administration of AMG 641 reduced soft-tissue calcification and aortic mineralization in both calcitriol- and paricalcitol-treated rats. Survival was significantly reduced in rats treated with calcitriol and this mortality was attenuated by co-treatment with AMG 641. Our study shows that extraskeletal calcification was present in animals treated with calcitriol and paricalcitol but not with AMG 641. When used in combination with paricalcitol, AMG 641 provided excellent control of secondary hyperparathyroidism and prevented mortality associated with the use of vitamin D derivatives without causing tissue calcification.

Topics: Animals; Aorta; Calcinosis; Calcitriol; Calcium; Calcium Channel Agonists; Ergocalciferols; Hyperparathyroidism, Secondary; Male; Phosphorus; Rats; Rats, Wistar; Uremia

Monotherapy with angiotensin-converting enzyme inhibitors has been shown to be beneficial in suppressing the progression of experimentally induced kidney diseases. Whether such therapy provides additional benefits when combined with vitamin D or an analog of vitamin D has not been established. Rats were made uremic by 5/6 nephrectomy and treated as follows: Uremic + vehicle (UC), uremic + enalapril (30 mg/L in drinking water; E), uremic + paricalcitol (19-nor; 0.8 microg/kg, three times a week), and uremic + enalapril + paricalcitol (E + 19-nor). A group of normal rats served as control (NC). BP was significantly elevated in the UC and 19-nor groups compared with the NC group but was indistinguishable from normal in the E and E + 19-nor groups. The decrease in creatinine clearance and the increase in the excretion of urinary protein that were observed in the UC group were ameliorated by the use of E alone or by E + 19-nor (P < 0.05 versus UC). The glomerulosclerotic index was significantly decreased in both the 19-nor (P < 0.01) and E + 19-nor groups (P < 0.01) compared with the UC group. Tubulointerstitial volume was significantly decreased in both the E (P < 0.05) and E + 19-nor groups (P < 0.01) compared with the UC group. Both macrophage infiltration (ED-1-positive cells) and production of the chemokine monocyte chemoattractant protein-1 were significantly blunted in E + 19-nor compared with E group. TGF-beta1 mRNA and protein expression were increased in the UC group (mRNA: 23.7-fold; protein: 29.1-fold versus NC). These increases were significantly blunted in the 19-nor group (mRNA: 7.1-fold; protein: 8.0-fold versus NC) and virtually normalized in the E + 19-nor group (protein: 0.8-fold versus NC). Phosphorylation of Smad2 was also elevated in the UC group (7.6-fold versus NC) but less so in the 19-nor-treated rats (5.5-fold versus NC). When rats were treated with E + 19-nor, the phosphorylation of Smad2 was normal (1.1-fold versus NC). Thus, 19-nor can suppress the progression of renal insufficiency via mediation of the TGF-beta signaling pathway, and this effect is amplified when BP is controlled via renin-angiotensin system blockade.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Disease Models, Animal; Disease Progression; Drug Therapy, Combination; Enalapril; Ergocalciferols; Female; Macrophages; Nephrectomy; Parathyroid Hormone; Proteinuria; Rats; Rats, Sprague-Dawley; Renal Insufficiency; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta1; Uremia; Vitamin D

Vascular calcification is associated with cardiovascular disease, the most common cause of death in chronic kidney disease (CKD). Patients with CKD are treated with vitamin D receptor activators (VDRAs); therefore, we determined if this treatment affects vascular calcification. Uremic rats were given vehicle, calcitriol, paricalcitol, or doxercalciferol three times a week for 1 month. Calcitriol significantly increased the serum calcium-phosphate product and aortic calcium content. Paricalcitol had no effect but the same dose of doxercalciferol significantly increased the calcium-phosphate product and the aortic calcium content, the latter being confirmed by von Kossa staining. To see if the increased aortic calcium was due to an increased serum calcium-phosphate product or to a differential effect of the two VDRAs, we lowered the dose of doxercalciferol and increased the dose of paricalcitol. A lower doxercalciferol did not increase the calcium-phosphate product but increased the aortic calcium content. A higher dose of paricalcitol still had no effect. Doxercalciferol treatment increased the mRNA and protein expression of the bone-related markers Runx2 and osteocalcin in the aorta, whereas paricalcitol did not. Hence, different VDRAs have different effects on vascular calcification in uremic rats. The effects are independent of the serum calcium-phosphate product suggesting independent mechanisms.

Topics: Animals; Aorta; Aortic Diseases; Bone Density Conservation Agents; Calcinosis; Calcitriol; Calcium; Ergocalciferols; Female; Parathyroid Hormone; Phosphates; Rats; Rats, Sprague-Dawley; Receptors, Calcitriol; Uremia

The control of parathyroid hyperplasia and high circulating parathyroid hormone (PTH) levels is crucial in preventing secondary hyperparathyroidism (SH) in renal failure. Parathyroid gland enlargement and elevated levels of PTH are major contributors to increase bone resorption, a feature of renal osteodystrophy.. These studies assessed the efficacy of the 1,25(OH)2D3 analog, 19-Nor-1,25(OH)2D2 (19-Nor), in the prevention (protocol I) and treatment (protocol II) of SH and renal osteodystrophy in uremic rats. In protocol I, normal and uremic rats were fed a high phosphorus diet for 2 months; uremic rats were administered intraperitoneal injections of either vehicle or 19-Nor (200 ng three times a week). In protocol II, normal and uremic rats were fed a high phosphorus diet for 4 months; 2 months after the onset of uremia, rats were administered either intraperitoneal vehicle or 19-Nor (200 ng three times a week). Serum PTH and bone histology were used to assess the degree of SH.. 19-Nor was effective in preventing (protocol I) and suppressing (protocol II) the significant SH induced by uremia and further enhanced by a high phosphorus diet. In protocol I, bone histology in uremic controls showed a threefold increase in the cancellous bone mass compared to normal rats. This expansion in unmineralized bone was accompanied by 5-, 1.5-, and 7-fold increases in eroded surface, mineralization lag time (MLT), and bone formation rate (BFR/BS), respectively. Moreover, cortical bone porosity in untreated uremic rats increased 267-fold compared to normal animals. 19-Nor ameliorated these changes in cancellous and cortical bone. In protocol II, the reported indices worsened even further. In contrast, 2 months of 19-Nor treatment improved bone histology by reducing cortical bone porosity, woven bone formation, MLT, and BFR/BS.. In an experimental model of chronic renal failure (CRF), 19-Nor prevents SH and ameliorates the histomorphometric changes induced by uremia and high phosphorus diet. In addition, 19-Nor suppresses serum PTH and improves bone histology in uremic rats with established severe SH. Further studies in patients with CRF are necessary to define the clinical applicability of 19-Nor on bone histology in humans.

Topics: Animals; Bone Diseases; Ergocalciferols; Female; Hyperparathyroidism; Kidney Failure, Chronic; Parathyroid Hormone; Phosphorus, Dietary; Rats; Rats, Sprague-Dawley; Uremia

Calcitriol, 1,25-(OH)(2)D(3) (1,25D), the most active metabolite of vitamin D, has been used in the treatment of secondary hyperparathyroidism (SH) because it controls parathyroid gland growth and suppresses parathyroid hormone (PTH) synthesis and secretion. Due to the calcemic and phosphatemic actions of 1,25D, two analogs with potentially less side effects, 19-nor-1,25-(OH)(2)D(2) (19-nor) and 1alpha(OH)D(2) (1alphaD(2)) are currently being used in the treatment of SH.. This study compares the effects of these two analogs on calcium (Ca) and phosphorus (P) metabolism in normal, uremic, and parathyroidectomized (PTX) rats. Using doses of 50 to 250 ng of 19-nor or 1alphaD(2), experiments were conducted in normal and uremic rats.. In uremic rats, 19-nor did not increase plasma Ca or P while 1alphaD2 caused a dose-dependent increase in both. In addition, while the Ca x P product remained unchanged in 19-nor-treated rats, it increased progressively with 1alphaD(2)administration. In metabolic studies in normal rats treated with vehicle, 10 ng of 1,25D, 100 ng of 19-nor or 100 ng 1alphaD(2), intestinal calcium absorption and urinary calcium excretion were significantly higher in 1alphaD(2)-treated rats compared to those receiving 19-nor. Similar results were seen for intestinal phosphorus absorption and urinary phosphorus excretion. Finally, the skeletal response to these two analogs was tested in PTX rats fed a calcium-deficient diet and treated daily with 100 ng of 19-nor or 1alphaD(2). The increase in plasma calcium in 1alphaD2-treated rats was markedly higher than in those receiving 19-nor. Similar results were seen in plasma phosphorus when these studies were repeated using a phosphorus-deficient diet.. These studies demonstrate that when given in large doses to rats 19-nor is less calcemic and phosphatemic than 1alphaD(2). The lower Ca x P product in 19-nor treated rats may be an important consideration in patient therapy. Further studies in patients are necessary to define the clinical applicability of these differences.

Topics: Animals; Calcium; Ergocalciferols; Female; Male; Parathyroidectomy; Phosphorus; Rats; Rats, Sprague-Dawley; Uremia

High dietary phosphorus (P) worsens uremia-induced parathyroid (PT) hyperplasia through increases in the growth promoter transforming growth factor-alpha (TGF-alpha). In contrast, P restriction prevents PT hyperplasia by inducing the cell cycle inhibitor p21. Since 1,25(OH)2D3-antiproliferative action in various cell types involve increases in p21, we studied whether induction of p21 by 1,25(OH)2D3 or the vitamin D analog, 19-Nor-1,25(OH)2D2, could counteract the PT hyperplasia induced by high dietary P in early uremia.. Normal (N) and uremic (U; 5/6 nephrectomized) female Sprague-Dawley rats were fed high P (HP), low P (LP) or high Ca (HCa) diets and administered intraperitoneally (IP) either vehicle or vitamin D metabolites for seven days, as follows: N-HP; U-HP + vehicle; U-HP + 1,25(OH)2D3 (4 ng/day); U-HP + 19-Nor-1,25(OH)2D2 (30 ng/day); U-LP; U-HCa. Serum PTH and PT gland weight assessed secondary hyperparathyroidism. Immunohistochemical quantitation of two markers of mitotic activity, Ki67 and PCNA measured PT hyperplasia. Immunohistochemical expression of PT p21 and TGF-alpha addressed potential mechanisms regulating PT cell growth.. 1,25(OH)2D3 and 19-Nor-1,25(OH)2D2 were effective in suppressing both PTH secretion and PT hyperplasia induced by uremia and high dietary P independent of increases in ionized Ca. Both vitamin D compounds enhanced PT p21 expression and prevented high P-induced increases in PT TGF-alpha content. Induction of PT p21 and reduction of TGF-alpha content also occurred when uremia-induced PT hyperplasia was suppressed by high dietary Ca.. In early uremia, vitamin D suppression of high P-induced PT hyperplasia and high dietary Ca arrest of PT growth involve induction of PT p21 and prevention of increases in TGF-alpha.

Topics: Animals; Blood; Calcium, Dietary; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Dose-Response Relationship, Drug; Ergocalciferols; Female; Hyperplasia; Parathyroid Glands; Parathyroid Hormone; Phosphorus, Dietary; Rats; Rats, Sprague-Dawley; Transforming Growth Factor alpha; Uremia; Vitamin D

The use of calcitriol in the treatment of uremic hyperparathyroidism and renal osteodystrophy is limited in many patients by hypercalcemic side-effects. New less calcemic analogues of calcitriol are being developed, and some are under clinical evaluation. To investigate whether these compounds possess important differences in their action on bone cells, we have studied their effects [with and without parathyroid hormone (PTH)] on the release and synthesis of the resorptive osteotropic cytokine, interleukin-6 (IL-6).. MG 63 and SaOS-2 human osteoblastic cell lines were cultured for 6 or 24 hours in media containing calcitriol, the sterols of interest, or 1-34 synthetic PTH. IL-6 release was assayed by commercially available enzyme-linked immunosorbent assay. IL-6 mRNA levels were assessed by reverse transcriptase-polymerase chain reaction.. We found that calcitriol and paricalcitol behaved in a similar fashion, resulting in increased IL-6 release only at higher concentrations (10(-7) to 10(-9) M). In contrast, 22-oxacalcitriol and 1,25-dihydroxydihydrotachysterol2 stimulated release to a similar extent but at concentrations three to four orders of magnitude lower (10(-11) to 10(-13) M), despite being less potent as suppressers of parathyroid function than calcitriol. Studies of IL-6 mRNA showed a similar pattern of concentration and cell line-dependent transcription.. Compounds stimulating IL-6 release at concentrations achievable during the treatment of uremic hyperparathyroidism might favor continuing linked bone formation and resorption and thereby avoid adynamic bone disease while still allowing profound suppression of PTH.

Topics: Bone Diseases; Calcitriol; Cell Line; Dihydrotachysterol; Ergocalciferols; Humans; Interleukin-1; Osteoblasts; Parathyroid Hormone; RNA, Messenger; Uremia; Vitamin D

The active metabolite of vitamin D, calcitriol [1,25(OH)2D3] suppresses parathyroid hormone (PTH) gene transcription and PTH secretion. Although 1,25(OH)2D3 is effective in suppressing secondary hyperparathyroidism in uremic patients, the mandatory use of large amounts of calcium salts to control serum phosphorus may preclude in some patients the use of ideal therapeutic doses of 1,25(OH)2D3 because of hypercalcemia. We have studied a new analogue of calcitriol,19-nor-1,25(OH)2D2 that possesses low calcemic and phosphatemic activity. We have clearly demonstrated that this analogue of calcitriol can suppress secondary hyperparathyroidism without inducing hypercalcemia or hyperphosphatemia in uremic rats. In addition, this analogue of vitamin D supresses pre-pro PTH messenger RNA in a similar fashion to that of 1,25(OH)2D3. Contrary to the effect of 1,25(OH)2D3 that increases the intestinal vitamin D receptor, this analogue of vitamin D suppresses the intestinal vitamin D receptor. This finding may be critical for the lack of calcemic activity of 19-nor-1,25(OH)2D2 seen in these studies. One of the explanations for the lack of an increasing intestinal VDR is the fact that 19-nor-1,25(OH)2D2 decreases endogenous levels of 1,25(OH)2D3. In summary, we have shown that 19-nor-1,25(OH)2D2, a new analogue of calcitriol is effective in suppressing PTH in uremic rats with secondary hyperparathyroidism. In addition, there is a significant decrease in the VDR in the intestine, which may explain in part the less calcemic and hyperphosphatemic effect of this analogue.

Topics: Animals; Calcitriol; Calcium; Cattle; Cells, Cultured; Dose-Response Relationship, Drug; Ergocalciferols; Female; Hyperparathyroidism, Secondary; Intestine, Small; Parathyroid Glands; Parathyroid Hormone; Phosphorus; Rats; Rats, Sprague-Dawley; Receptors, Calcitriol; Uremia

We have previously reported that 19-nor-1,25-(OH)2D2, a new analog of 1,25-(OH)2D3, suppresses parathyroid hormone (PTH) secretion in uremic rats in the absence of hypercalcemia or hyperphosphatemia. In the current study, we examined the effect of 19-nor-1,25-(OH)2D2 on parathyroid gland growth and intestinal vitamin D receptor (VDR) content. After induction of uremia by 5/6 nephrectomy, rats were divided into five experimental groups and received intraperitoneal injections of vehicle, 1,25-(OH)2D3 (2 or 6 ng/rat), or 19-nor-1,25-(OH)2D2 (25 or 100 ng/rat) three times a week for 8 weeks. Twelve normal rats received vehicle and served as the normal control group. During the course of the study, rats were maintained on a 1.0% calcium and 0.8% phosphorus diet. The higher dose of 1,25-(OH)2D3, 6 ng, significantly decreased PTH from 52.7 +/- 10.2 pg/mL in the uremic control group to 25.7 +/- 6.7 pg/mL (P < 0.01). This dose of 1,25-(OH)2D3, however, increased serum levels of both ionized calcium (4.71 +/- 0.05 to 4.85 +/- 0.06 mg/dL; P < 0.05) and phosphorus (4.34 +/- 0.30 to 6.67 +/- 0.63 mg/dL; P < 0.01). Both doses of 19-nor-1,25-(OH)2D2 decreased serum PTH as effectively as 1,25-(OH)2D3 without changes in serum calcium or phosphorus. The 100-ng dose of 19-nor-1,25-(OH)2D2 decreased PTH to 20.7 +/- 3.1 pg/mL (P < 0.01) and suppressed parathyroid gland growth by more than 50%. Both doses of 19-nor-1,25-(OH)2D2 also decreased endogenous 1,25-(OH)2D3 levels compared with uremic control rats (25 ng:30.4 +/- 2.0, P < 0.05, and 100 ng:27.9 +/- 3.2, P < 0.01, v 48.4 +/- 6.6 pg/mL). The 6-ng dose of 1,25-(OH)2D3 elevated intestinal VDR content (138.5 +/- 20.0 fmol/mg protein) compared with animals receiving both doses of 19-nor-1,25-(OH)2D2 (25 ng:84.0 +/- 11.9, P < 0.05, and 100 ng:78.4 +/- 10.9, P < 0.01). This was probably attributable to the marked decrease in endogenous 1,25-(OH)2D3 levels caused by both doses of 19-nor-1,25-(OH)2D2 because intestinal VDR correlated directly with serum 1,25-(OH)2D3 (r = 0.963; P = 0.008). Thus, 19-nor-1,25-(OH)2D2 appears to exert a selective action on the parathyroid glands compared with the intestine. Its low calcemic and phosphatemic properties may result from the decreased endogenous 1,25-(OH)2D3 levels that lead to a reduction in intestinal VDR. This selectivity makes this analog ideal for the treatment of secondary hyperparathyroidism.

Topics: Animals; Calcium; Ergocalciferols; Female; Intestinal Mucosa; Intestines; Nephrectomy; Parathyroid Glands; Parathyroid Hormone; Phosphorus; Rats; Rats, Sprague-Dawley; Receptors, Calcitriol; Uremia

Nephrocalcinosis (NC) detected by ultrasound is a recognized abnormality for some patients with X-linked hypophosphatemia (XLH) who received vitamin D2 and inorganic phosphate therapy, but is commonly observed in XLH patients treated with 1,25-dihydroxyvitamin D3 and inorganic phosphate supplementation. Nevertheless, long-term follow-up of kidney function in XLH patients with NC detected ultrasonographically has not been reported. We investigated two women with XLH, ages 31 (patient 1) and 39 (patient 2) years, each of whom had suffered at least one documented episode of vitamin D2-induced hypercalcemia and renal azotemia during childhood. Patient 2 had also been treated with inorganic phosphate. No medications for XLH had been taken during adulthood. Renal ultrasonography at our institution demonstrated marked bilateral medullary NC in both women. No other explanation was found for their NC that apparently occurred several decades earlier from medical therapy for XLH. Detailed studies (including creatinine clearance, beta2-microglobulin excretion, and fasting urinary osmolality and acidification) revealed no impairment of kidney function in either patient. Our findings indicate that subradiographic medullary NC acquired during medical therapy for XLH may persist for decades, but with no adverse renal sequelae. Definitive (long-term) assessment of kidney function in the XLH population with NC, however, will be necessary to fully understand the risk of current medical treatment for this most common heritable form of rickets.

Topics: Adult; Ergocalciferols; Family Health; Female; Humans; Hypophosphatemia, Familial; Kidney; Kidney Diseases; Kidney Medulla; Nephrocalcinosis; Time Factors; Uremia

Glucocorticoids are often used to treat hypercalcemia due to vitamin D overdosage. We measured the effect of 1.5 mg/day of prednisolone on the amount of calcium deposited in the kidney of rats dosed with either 500 ng/d or 2000 ng/day of 1-alpha OHD2 or 1-alpha OHD3. The rats were given a diet containing 0.3% calcium and 0.5% phosphate. A second group of rats received 2000 ng/d of the vitamin D analogs and a diet which contained only 0.02% calcium. After 6 weeks, rats given the vitamin D analogs had two to six times more calcium in the kidney compared with the controls (0.096-0.276 mg vs. 0.240-1.064 mg). When a pharmacological dose of prednisolone was added to treatment, calcium in renal tissue increased to 0.305-3.083 mg. The urinary output of calcium seemed to be increased by prednisolone whereas the serum calcium was lowered. It appears that glucocorticoids given at the same time as vitamin D compounds increases the risk for nephrocalcinosis possibly due to increased amounts of calcium in the urine.

Topics: Animals; Calcinosis; Calcitriol; Calcium, Dietary; Disease Models, Animal; Ergocalciferols; Hypercalcemia; Kidney; Male; Prednisolone; Rats; Rats, Inbred Strains; Uremia

The initial step in cholecalciferol (vitamin D3) metabolism is the photo-conversion of 7-dehydrocholesterol to previtamin D3. This reaction occurs in the epidermis and requires ultraviolet light. We measured the circulating concentration of vitamin D (ergocalciferol and cholecalciferol), 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in 14 normal white, 9 normal black subjects, and in 9 white and 17 black hemodialysis patients. The mean plasma vitamin D in normal white subjects was greater than in normal black subjects, 4.01 +/- 1.02 ng/ml versus 0.96 +/- 0.30 ng/ml, respectively (P less than 0.05). Plasma 25-hydroxyvitamin D in normal blacks was also less than in normal whites, 17.7 +/- 1.5 ng/ml versus 31.3 +/- 3.0 ng/ml, respectively (P less than 0.01). In uremic white subjects, plasma vitamin D, 6.7 +/- 2.6 ng/ml, was similar to normal white subjects. However, vitamin D was not detectable in 12 of 17 uremic black subjects and was depressed in the remainder of the group. Following exposure to a single minimal erythema dose of ultraviolet-B irradiation, the maximal increase in plasma vitamin D was depressed in white dialysis patients as compared to healthy white subjects, 6.3 +/- 1.9 ng/ml versus 21.3 +/- 2.8 ng/ml, respectively (P less than 0.02). 7-Dehydrocholesterol content was similar in epidermis from site-matched skin of fresh cadavers and white hemodialysis patients, 131 +/- 23 ng/mg versus 124 +/- 14 ng/mg skin, respectively. It is concluded that chronic hemodialysis patients exhibit defective photoproduction of cholecalciferol, despite normal epidermal content of substrate, 7-dehydrocholesterol.

Topics: Adult; Cholecalciferol; Dehydrocholesterols; Epidermis; Ergocalciferols; Humans; Male; Renal Dialysis; Ultraviolet Rays; Uremia

Topics: Adult; Bone and Bones; Calcium; Calcium Metabolism Disorders; Chronic Disease; Decalcification, Pathologic; Ergocalciferols; Female; Glomerulonephritis; Humans; Hypercalcemia; Male; Middle Aged; Osteoporosis; Paralysis; Phosphates; Polycystic Kidney Diseases; Pyelonephritis; Radiography; Renal Dialysis; Uremia

Topics: Cholecalciferol; Ergocalciferols; Humans; Hydroxycholecalciferols; Hydroxylation; Kidney; Liver; Uremia; Vitamin D

Topics: Adult; Biological Transport; Bone and Bones; Calcium; Cell Membrane Permeability; Diabetic Retinopathy; Ergocalciferols; Female; Heart Failure; Humans; Hypercalcemia; Peritoneal Dialysis; Peritoneum; Phosphorus; Solutions; Uremia