vitamin-d-2 and Renal-Insufficiency

Calcitriol controls parathyroid gland (PTG) growth and suppresses the synthesis and secretion of PTH. However, because of its potent effects on intestinal calcium and phosphorus absorption and bone mobilization, calcitriol treatment can induce hypercalcemia and hyperphosphatemia often precluding its use at therapeutic doses. In the past decade, several vitamin D analogs have been developed. These analogs retain the action on the PTG while having less effect on calcium and phosphorus. Most of these analogs for the treatment of secondary hyperparathyroidism (SH) have a modification on the side chain of calcitriol. In the USA, two vitamin D analogs 19-nor 1,25(OH)(2)D(2) and 1 alpha(OH)D(2) are currently used for the treatment of SH. Studies in animals demonstrated that 19-nor-1,25(OH)(2)D(2) is less calcemic and phosphatemic than 1 alpha(OH)D(2). The lower Ca x P product in 19-nor-1,25(OH)(2)D(2)-treated rats may be an important consideration in patient therapy. Further studies in patients are necessary to define these differences.

Topics: Animals; Calcium; Ergocalciferols; Humans; Hyperparathyroidism; Phosphorus; Rats; Renal Insufficiency; Vitamin D

The skeletal disorders associated with renal insufficiency result from alterations in calcium, phosphorus, and vitamin D metabolism. Each requires intervention to prevent and control the problem. Hyperparathyroidism and its treatment can also result in extraskeletal complications. To prevent the development of parathyroid hyperplasia and the skeletal complications of chronic kidney disease, it is desirable to initiate interventions early in the course of kidney disease; however, many patients present with established hyperparathyroidism and additional strategies are necessary to suppress hyperparathyroidism. Mainstays of this approach are the control of phosphorus and the use of vitamin D analogs. Phosphorus control requires the use of phosphate binders, preferably non-calcium-containing binders, to prevent intestinal phosphorus absorption. Vitamin D analogs are used to suppress hyperparathyroidism and have the potential to have lesser toxicity than calcitriol. Paricalcitol is the most widely used vitamin D analog in this country and it effectively suppresses hyperparathyroidism with only minimal effects on calcium and phosphorus. A substantial body of data in experimental animals supports the use of paricalcitol as a preferential therapeutic agent. Recently, an additional vitamin D sterol, doxercalciferol, has been introduced, which is metabolized to 1,25-dihydroxyvitamin D(2). Although initially thought to have lesser toxicity than its vitamin D(3) counterpart, recent studies have not provided support for a major difference in this regard. Doxercalciferol is also effective in lowering parathyroid hormone (PTH), though hypercalcemia in hyperphosphatemic episodes occurred relatively frequently during the clinical studies. As these therapeutic strategies are undertaken, it is important not to oversuppress PTH and decrease bone turnover to abnormally low levels because of the risk for adynamic renal bone disease. It is possible that when bone turnover is abnormally low, the extraskeletal deposition of calcium in blood vessels and other tissues is enhanced. Accordingly, constant monitoring is required during treatment, with emphasis on minimizing the calcium load, and, if monitored correctly, a satisfactory control of hyperparathyroidism may be achieved with the agents currently available.

Topics: Animals; Calcium; Chronic Kidney Disease-Mineral and Bone Disorder; Ergocalciferols; Humans; Hyperparathyroidism; Osteoporosis; Parathyroid Hormone; Phosphorus; Renal Dialysis; Renal Insufficiency; Vitamin D

Proteinuria after kidney transplantation is accompanied by an increased risk of graft failure. In this single-center, placebo-controlled, double-blind trial we studied whether vitamin D receptor activator paricalcitol might reduce proteinuria. Patients with urinary protein-to-creatinine ratio (UPCR) ≥20 mg/mmol despite optimization of the renin angiotensin aldosterone system (RAAS) blockade were randomly assigned to receive 24 weeks' treatment with 2 μg/day paricalcitol or placebo. Primary endpoint was change in UPCR, and main secondary endpoints were change in urinary albumin-to-creatinine ratio (UACR) and 24-h proteinuria. Analysis was by intention to treat. One hundred and sixty-eight patients undergo randomization, and 83 were allocated to paricalcitol, and 85 to placebo. Compared with baseline, UPCR declined in the paricalcitol group (-39%, 95% CI -45 to -31) but not in the placebo group (21%, 95% CI 9 to 35), with a between group difference of -49% (95% CI -57 to -41; P < 0.001). UACR and 24-h proteinuria decreased only on paricalcitol therapy and significantly differed between groups at end-of-treatment (P < 0.001). Paricalcitol was well tolerated but incidence of mild hypercalcemia was higher than in placebo. In conclusion, addition of 2 μg/day paricalcitol lowers residual proteinuria in kidney transplant recipients. Long-term studies are needed to determine if the reduction in proteinuria improves transplant outcomes (ClinicalTrials.gov, number NCT01436747).

Topics: Adult; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Bone Density Conservation Agents; Cohort Studies; Creatinine; Double-Blind Method; Ergocalciferols; Female; Graft Survival; Humans; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Phenotype; Proteinuria; Renal Insufficiency; Renin-Angiotensin System; Treatment Outcome

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

Options for chronic treatment of hypoparathyroidism include calcitriol, recombinant human parathyroid hormone, and high-dose vitamin D (D2). D2 is used in a minority of patients because of fear of prolonged hypercalcemia and renal toxicity. There is a paucity of recent data about D2 use in hypoparathyroidism.. Compare renal function, hypercalcemia, and hypocalcemia in patients with hypoparathyroidism treated chronically with either D2 (D2 group) or calcitriol.. A retrospective study of patients with hypoparathyroidism treated at the University of Maryland Hospital. Participants were identified by a billing record search with diagnosis confirmed by chart review. Thirty patients were identified; 16 were treated chronically with D2, 14 with calcitriol. Data were extracted from medical records.. Serum creatinine and calcium, hospitalizations, and emergency department (ED) visits for hypercalcemia and hypocalcemia.. D2 and calcitriol groups were similar in age (58.9 ± 16.7 vs 50.9 ± 22.6 years, P = 0.28), sex, and treatment duration (17.8 ± 14.2 vs 8.5 ± 4.4 years, P = 0.076). Hospitalization or ED visits for hypocalcemia occurred in none of the D2 group vs four of 14 in the calcitriol group (P = 0.03); three in the calcitriol group had multiple ED visits. There were no differences between D2 and calcitriol groups in hospitalizations or ED visits for hypercalcemia, serum creatinine or calcium, or kidney stones.. We found less morbidity from hypocalcemia in hypoparathyroid patients treated chronically with D2 compared with calcitriol and found no difference in renal function or morbidity from hypercalcemia. Treatment with D2 should be considered in patients with hypoparathyroidism, particularly in those who experience recurrent hypocalcemia.

Topics: Adult; Aged; Calcitriol; Calcium; Creatinine; Emergency Service, Hospital; Ergocalciferols; Female; Hospitalization; Humans; Hypercalcemia; Hypocalcemia; Hypoparathyroidism; Kidney Calculi; Male; Middle Aged; Nephrocalcinosis; Renal Insufficiency; Retrospective Studies; Vitamins

Etelcalcetide, a novel peptide agonist of the calcium-sensing receptor, prevents vascular calcification in a rat model of renal insufficiency with secondary hyperparathyroidism. Vascular calcification occurs frequently in patients with chronic kidney disease (CKD) and is a consequence of impaired mineral homeostasis and secondary hyperparathyroidism (SHPT). Etelcalcetide substantially lowers parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23) levels in SHPT patients on hemodialysis. This study compared the effects of etelcalcetide and paricalcitol on vascular calcification in rats with adenine-induced CKD and SHPT. Uremia and SHPT were induced in male Wistar rats fed a diet supplemented with 0.75% adenine for 4 weeks. Rats were injected with vehicle, etelcalcetide, or paricalcitol for 4 weeks from the beginning of adenine diet. Rats fed an adenine-free diet were included as nonuremic controls. Similar reductions in plasma PTH and parathyroid chief cell proliferation were observed in both etelcalcetide- and paricalcitol-treated rats. Serum calcium and phosphorus were significantly lower in etelcalcetide-treated uremic rats and was unchanged in paricalcitol-treated rats. Both serum FGF23 and aortic calcium content were significantly lower in etelcalcetide-treated uremic rats compared with either vehicle- or paricalcitol-treated uremic rats. The degree of aortic calcium content for etelcalcetide-treated rats was similar to that in nonuremic controls and corroborated findings of lack of histologic aortic mineralization in those groups. In conclusion, etelcalcetide and paricalcitol similarly attenuated progression of SHPT in an adenine rat model of CKD. However, etelcalcetide differentially prevented vascular calcification, at least in part, due to reductions in serum FGF23, calcium, and phosphorus levels.

Topics: Animals; Disease Models, Animal; Ergocalciferols; Hyperparathyroidism, Secondary; Male; Peptides; Rats; Rats, Wistar; Renal Insufficiency; Vascular Calcification

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

Cardiovascular diseases are the most important cause of death in patients with impaired kidney function. Left ventricular hypertrophy (LVH), cardiac interstitial fibrosis and cardiovascular calcifications are characteristic of chronic renal insufficiency (CRI). Periostin is a fibrogenesis- and calcification-related matricellular protein re-expressed in adult tissues undergoing remodelling in response to pathological stimuli. The role of periostin in CRI-induced LVH is unknown.. Rats were 5/6-nephrectomized (NX), and after 15 weeks of disease progression high-calcium, high-phosphate or paricalcitol treatment was given for 12 weeks. Cardiac tissue and blood samples were taken to study periostin gene expression and to determine factors contributing to its reactivation, respectively. Left ventricular (LV) periostin expression was also examined in response to angiotensin II or arginine(8)-vasopressin (AVP)-induced pressure overload and in spontaneously hypertensive rats.. CRI resulted in a 6.5-fold increase in LV periostin messenger RNA (mRNA) levels. Positive extracellular immunostaining for periostin was detected in areas of infiltrated inflammatory cells and fibrotic lesions. There was a significant correlation between LV periostin mRNA levels and plasma biomarkers of impaired kidney function, LVH, fibrogenesis-related proteins osteopontin and osteoactivin, and anti-calcific matrix Gla protein. Moreover, LV periostin gene expression in CRI correlated positively with systolic blood pressure (BP) and was activated rapidly in response to angiotensin II or AVP infusions.. Periostin is involved in fibrotic cardiac remodelling in CRI. The re-expression of periostin is localized to the fibrotic and inflammatory lesions and is most likely the consequence of elevated BP.

Topics: Animals; Biomarkers; Blotting, Western; Bone Density Conservation Agents; Calcinosis; Cell Adhesion Molecules; Disease Models, Animal; Ergocalciferols; Fibrosis; Gene Expression; Heart Ventricles; Hypertension; Immunoenzyme Techniques; Kidney Function Tests; Myocardial Infarction; Nephrectomy; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Renal Insufficiency; RNA, Messenger

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

To examine whether treatment of secondary hyperparathyroidism with paricalcitol provides benefits to arteries in uremic rats.. 5/6-nephrectomized rats were treated (NX+Pari) or not treated (NX) with paricalcitol (200 ng/kg, thrice weekly) for 12 weeks. Aortic histology and isolated segments of the main and 2nd-order mesenteric arterial branches were studied.. Creatinine clearance was reduced by 54-61%, plasma phosphate increased 2.1- to 2.5-fold, and blood pressure by 40 mm Hg in both NX groups. PTH increased 13-fold in NX and 5-fold in NX+Pari rats. Calcification in aortic cross-sections increased from 2.1 to 7.1% after paricalcitol. In the large mesenteric artery, vasoconstriction to noradrenaline was reduced in NX+Pari rats. In the large and small arteries, vasorelaxation to acetylcholine was impaired in NX rats and unaffected by paricalcitol. In the small artery, paricalcitol increased nitric oxide synthase inhibition-resistant relaxation to acetylcholine, and maximal relaxation to levcromakalim. The small arteries of NX rats featured increased wall cross-sectional area, while paricalcitol further increased wall thickness and the wall:lumen ratio.. Paricalcitol treatment showed both benefits and harmful effects in uremic rats: in the large artery vasoconstriction was reduced but calcification increased, while in the small artery vasorelaxation via potassium channels was moderately improved but hypertrophic remodeling was aggravated.

Topics: Animals; Arteries; Ergocalciferols; Male; Rats; Rats, Sprague-Dawley; Renal Insufficiency

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

Cardiovascular complications are a major problem in chronic renal failure. We examined the effects of plasma calcium, phosphate, parathyroid hormone (PTH), and calcitriol on cardiac morphology in 5/6 nephrectomized rats. Fifteen weeks after nephrectomy rats were given a control diet, high-calcium or -phosphorus diet, or given paricalcitol treatment for 12 weeks. Sham-operated rats were on a control diet. Blood pressure, plasma phosphate, and PTH were increased, while the creatinine clearance was reduced in remnant kidney rats. Phosphate and PTH were further elevated by the high-phosphate diet but suppressed by the high-calcium diet, while paricalcitol reduced PTH without influencing phosphate or calcium. The high-calcium diet increased, while the high-phosphate diet reduced plasma calcium. Plasma calcitriol was significantly reduced in other remnant kidney groups, but further decreased after paricalcitol. Cardiac perivascular fibrosis and connective tissue growth factor were significantly increased in the remnant kidney groups, and further increased in paricalcitol-treated rats. Hence, regardless of the calcium, phosphate, or PTH levels, cardiac perivascular fibrosis and connective tissue growth factor increase in rats with renal insufficiency in association with low calcitriol. Possible explanations are that aggravated perivascular fibrosis after paricalcitol in renal insufficiency may be due to further suppression of calcitriol, or to a direct effect of the vitamin D analog.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Calcitriol; Calcium; Cardiovascular System; Chronic Disease; Creatinine; Ergocalciferols; Fibrosis; Male; Nephrectomy; Parathyroid Hormone; Peptidyl-Dipeptidase A; Phosphorus; Rats; Rats, Sprague-Dawley; Renal Insufficiency; Renin

Topics: Arthritis; Calcinosis; Ergocalciferols; Humans; Kidney; Renal Insufficiency