1,25-Dihydroxyvitamin D3 but not cinacalcet HCl (Sensipar/Mimpara) treatment mediates aortic calcification in a rat model of secondary hyperparathyroidism.

BACKGROUND: Calcitriol treatment of secondary hyperparathyroidism (HPT) in chronic kidney disease (CKD) patients can lead to increased serum calcium and phosphorus, which have been associated as risk factors for vascular calcification. Cinacalcet HCl (Sensipar/Mimpara) {(alphaR)-(-)-alpha-methyl-N-[3-[3-(trifluoromethylphenyl)propyl]-1-napthalenemethanamine hydrochloride} lowers serum parathyroid hormone (PTH), calcium, phosphorus and calcium-phosphorous (CaxP) product in stage 5 CKD dialysis patients; however, its effects on vascular calcification are unknown. METHODS: Cinacalcet HCl (10 or 1 mg/kg, p.o. gavage), 1,25-dihydroxyvitamin D(3) (0.1 microg, s.c, calcitriol) or the combination was administered daily for 26 days in a rat model of secondary HPT [5/6 nephrectomy]. After dosing, aortic calcification was determined using the von Kossa staining method. Serum PTH and blood chemistries were determined on days 0, 26 and 0, 14, 26, respectively, prior to and after dosing. RESULTS: Calcitriol-treated rats had moderate to marked aortic calcification, whereas no significant calcification was observed in vehicle- or cinacalcet HCl-only treated groups. Co-administration of cinacalcet HCl with calcitriol did not attenuate the calcitriol-mediated increase in CaxP product or calcitriol-mediated aortic calcification. Both calcitriol and cinacalcet HCl therapy significantly reduced serum PTH levels. Calcitriol significantly elevated serum calcium, serum phosphorous and CaxP product above pretreatment levels, or those seen with vehicle or cinacalcet HCl. Cinacalcet HCl (10 or 1 mg/kg) decreased serum ionized calcium and decreased calcitriol-induced hypercalcaemia. CONCLUSION: Cinacalcet HCl and calcitriol both effectively reduce PTH, albeit via different mechanisms, but unlike calcitriol, cinacalcet HCl did not produce hypercalcaemia, an increased CaxP product or vascular calcification.     

Calcimimetic R-568 decreases extraosseous calcifications in uremic rats treated with calcitriol

Calcimimetics decrease parathyroid hormone (PTH) levels in uremic patients with secondary hyperparathyroidism without increasing serum calcium (Ca). The aim of this study was to evaluate the effect of calcimimetic R-568 alone or in combination with calcitriol on vascular and other soft tissue calcifications in uremic rats with secondary hyperparathyroidism. Sham-operated and 5/6 nephrectomized Wistar rats were studied. 5/6 Nephrectomized rats were treated with vehicle, calcitriol (80 ng/kg every other day), R-568 (1.5 and 3 mg/kg per d), and both calcitriol and R-568 1.5 mg/kg, as above. Rats were killed after 14 or 56 d of treatment. Blood was drawn for biochemical measurements. Aortic, heart, kidney, lung, and stomach tissue samples were processed for histopathology and measurement of tissue Ca and phosphorus content. PTH concentrations were significantly reduced by all treatments. Treatment with calcitriol induced significant vascular calcification (aortic Ca increased to 4.2+/-1.2 mg/g at day 14 and to 11.4+/-0.7 mg/g at day 56; P<0.05 versus vehicle). Treatment with R-568 did not induce vascular calcification. Concurrent administration of R-568 with calcitriol reduced the aortic Ca (1.9+/-0.2 mg/g at day 14 and 7.5+/-1.4 mg/g at day 56) in relation to calcitriol alone. Soft tissue calcifications mirrored aortic mineralizations. Survival was significantly (P<0.001) reduced in calcitriol-treated rats, and mortality was attenuated (P=0.01) by concurrent treatment with R-568. In uremic rats, R-568 reduces elevated PTH levels without inducing vascular calcification, prevents calcitriol-induced vascular calcification, and decreases mortality.     

Oral Calcitriol Use,Vertebral Fractures,and Vitamin K in Hemodialysis Patients: A Cross-Sectional Study

Fractures and vascular calcifications (VCs) are common in patients with chronic kidney disease (CKD). They are related to abnormalities in vitamin D metabolism, calcium, phosphorus, parathyroid hormone, and fibroblast growth factor 23 (FGF23)/Klotho that occur with CKD. Impaired vitamin D metabolism and abnormal levels of calcium, phosphate, parathyroid hormone (PTH), and FGF23/Klotho drive bone and vascular changes in CKD. It is unclear if oral calcitriol safely mitigates fracture risk without increasing the burden of calcifications. Therefore, we investigated whether treatment with calcitriol affected the prevalence of fractures and VC progression in hemodialysis (HD) patients. This report is a secondary analysis of the Vitamin K Italian (VIKI) study, a cross-sectional study involving 387 HD patients. We assessed vitamin 25(OH)D, alkaline phosphatase, PTH, calcium, phosphate, osteocalcin or bone Gla protein, matrix Gla protein, and vitamin K levels. Vertebral fractures (VFs) and VCs were determined by spine radiograph. A reduction of >20% of vertebral body height was considered a VF. VCs were quantified by the length of calcific lesions along the arteries. The patients treated with oral calcitriol were 177 of 387 patients (45.7%). The prevalence of VF was lower in patients receiving oral calcitriol than in those untreated (48.6% versus 61.0%, p  =  0.015), whereas the presence of aortic and iliac calcifications was similar (aortic: 81.9% versus 79.5%, respectively, p = 0.552; iliac: 52.0% and 59.5%, respectively, p = 0.167). In multivariable logistic regression analysis, oral calcitriol was associated with a 40.2% reduced odds of fracture (OR 0.598; 95% confidence interval [CI], 0.363–0.985; p = 0.043). In conclusion, we found a significant association between oral calcitriol and lower VF in HD patients without an increase in the burden of VC. Further prospective and interventional studies are needed to confirm these findings. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Vitamin D metabolism in rats with adjuvant-induced arthritis

Adjuvant-induced arthritis in rats shares many of the features of humans with rheumatoid arthritis, including the development of osteopenia in areas distal to erosive joint disease. We established adjuvant arthritis in male and female Sherman strain rats and then studied external calcium balances and vitamin D metabolism during the period of acute active clinical, serologic, and pathologic arthritis and osteopenia and in the preclinical period. While ingesting a calcium-sufficient vitamin D-replete diet (0.6% calcium, 0.65% phosphorus, and 2.2 IU D3 per g food), female rats with arthritis demonstrated reduced calcium balance (arthritic, 36 +/- 8 versus control, 169 +/- 13 mg per 6 days, p less than 0.02) because of inefficient gastrointestinal absorption of calcium (arthritic 9.7% versus control 37%). This was associated with calcitriol deficiency (arthritic 52 +/- 7 versus control 70 +/- 10 pg/ml) and reduced osteocalcin levels. Male rats with arthritis demonstrated an inability to raise serum calcitriol levels to the same degree as control rats (200 +/- 30 versus 440 +/- 70, respectively) while ingesting a calcium-deficient diet (0.002% calcium, 0.34% phosphorus, and 2.2 IU D3 per g food) and also had reduced balance (59 +/- 7 versus 85 +/- 10 mg per 6 days, respectively) due in part to decreased efficiency of absorption (55 versus 67%). No abnormalities in calcium balance or in serum calcitriol levels on the sufficient diet were present in the preclinical period. Physiologic calcitriol replacement to arthritic female rats increased osteoid available for mineralization and increased mineral apposition rates.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of estrogen on daylong circulating calcium, phosphorus, 1,25-dihydroxyvitamin D, and parathyroid hormone in postmenopausal women

We studied the effects of estrogen on daylong circulating levels of calcium, inorganic phosphorus, parathyroid hormone (PTH), and 1,25-(OH)2D3 (calcitriol) in a group of 10 postmenopausal women (68.5 +/- 1.4 years, mean +/- SEM). The study was conducted under strict dietary control, with mean calcium and phosphorus intakes of 845 and 970 mg. After treatment with conjugated equine estrogens, 1.25 mg/day, for 1 month, significant decreases in fasting (0800 h) serum levels were observed for calcium (9.09 +/- 0.08 versus 9.46 +/- 0.10 mg/dl, p less than 0.01) and phosphorus (3.38 +/- 0.10 versus 3.73 +/- 0.08 mg/dl, p less than 0.01). On the 0800 h fasting specimen, midmolecule PTH concentrations were higher (44.0 +/- 7.9 versus 34 +/- 8.2 pg/ml, p less than 0.05), but intact PTH was unchanged (28.6 +/- 2.7 versus 29.1 +/- 1.7 pg/ml) and a rise in circulating calcitriol (39.8 +/- 4.3 versus 31.6 +/- 2.1 pg/ml) was marginally significant (p = 0.07). When data represented multiple samples averaged over 7 and 15 h, significant estrogen-related reductions in serum calcium and phosphorus concentrations were observed. In addition, estrogen was associated with a significant rise in the daylong (15 h) level of calcitriol (39.4 +/- 4 versus 30.5 +/- 2.4 pg/ml, p less than 0.01). Daylong mid- and intact PTH concentrations were unchanged on estrogen compared to baseline values. No significant correlations were observed between changes in fasting calcitriol level and changes in fasting concentrations of calcium, phosphorus, or PTH. Further, the rise in daylong calcitriol concentration did not correlate significantly with changes in fasting or integrated values of calcium or PTH.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of calcitriol in the control of plasma calcium after parathyroidectomy. A placebo-controlled, double-blind study in chronic hemodialysis patients

Severe, prolonged hypocalcemia in observed in some, but not all, hemodialysis patients after parathyroidectomy performed because of uncontrolled hyperparathyroidism. The aim of the present study was to investigate whether calcitriol and calcium supplementation in the immediate period after parathyroidectomy (days 1-14) was of more help in the control of plasma calcium than calcium supplementation alone. Fourteen hemodialysis patients were enrolled in a prospective, randomized, double-blind and placebo-controlled study. From the day after parathyroidectomy, 7 patients received calcitriol and the remaining 7 a placebo using incremental doses adjusted to the degree of hypocalcemia (up to 4 micrograms/day for calcitriol). Plasma calcium, phosphorus, alkaline phosphatase and immunoreactive parathyroid hormone levels before parathyroidectomy were comparable in both patients groups, as was the lowest plasma calcium achieved after parathyroidectomy. The decrease in plasma calcium after parathyroidectomy was related to plasma alkaline phosphatase and to the number of osteoclasts and osteoblasts on bone biopsy surface before parathyroidectomy. The mean decrement of plasma calcium (days 3-9) as compared to that before parathyroidectomy was less pronounced in calcitriol-treated than in placebo-treated patients (0.25 +/- 0.06 versus 0.45 +/- 0.05 mM, mean +/- SEM, p less than 0.025). Treatment with placebo was interrupted before day 14 because of persistent severe hypocalcemia in 4 of 7 patients, whereas calcitriol treatment was continued in all 7 patients up to 14 days. Patients on calcitriol treatment required less mean calcium supplements (days 1-9) than patients receiving placebo (37.4 +/- 3.2 versus 49.4 +/- 3.7 g, p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Heart valve calcifications in patients with end-stage renal disease: analysis for risk factors

BACKGROUND: The prevalence of valve calcification (VC) in end-stage renal disease patients is high and information regarding risk factors is scarce. Our aims were to determine the prevalence of VC in our maintenance haemodialysis (HD) population and to examine some possible aetiologic factors for its occurrence. METHODS: We studied 90 patients (47 women) on maintenance HD for more than 12 months. An M-mode two-dimensional echocardiogram was carried out to evaluate mitral, aortic VC and ventricular geometry. We calculated mean daily calcium intake for the phosphate intestinal chelaing in the previous year to echocardiogram date and also mean values from previous year of Ca, PO4, Ca x PO4, parathyroid hormone, lipide profile, nutritional and inflammatory marquers. Finally consumption of calcium and alfacalcidol was also noted. RESULTS: Thirty-six patients (40%) presented with VC. Patients with VC were older and showed higher levels of serum calcium (92.00 +/- 7.54 vs 89.27 +/- 6.86 mg/L, P = 0.04), phosphorus (69.70 +/- 18.33 vs 44.90 +/- 12.43 mg/L, P < 0.0001), Ca x P product (6164.97 +/- 1797.64 vs 4024.70 +/- 1066.40 mg(2)/L(2), P < 0.0001) and poor ventricular geometry, as compared with patients without VC. Moreover, they required higher doses of alfacalcidol for treating secondary hyperparathyroidism (0.43 +/- 0.60 vs 0.11 +/- 0.46 microg/day, P < 0.0001). CONCLUSION: Findings of the present study are consistent with a role of altered calcium and phosphate metabolism in the pathogenesis of VC in HD patients.     

Calcemic response to parathyroid hormone in renal failure: role of calcitriol and the effect of parathyroidectomy.

Hyperparathyroidism due to renal failure begins in the early stages of renal insufficiency and is in part secondary to skeletal resistance to the calcemic action of parathyroid hormone (PTH). Factors which have been reported to reduce the calcemic response to PTH include: decreased calcitriol levels, hyperphosphatemia and down regulation of PTH receptors in bone. While hyperphosphatemia may directly decrease the calcemic response to PTH, it may also act indirectly by a suppression of calcitriol synthesis. In this study, the effect of calcitriol on the calcemic response to PTH was evaluated in normal rats and in rats with moderate and advanced renal failure. To determine the combined effect of calcitriol and phosphorus on the calcemic response to PTH, rats receiving calcitriol were fed either a high (1.0%) or low (0.2%) phosphorus diet during a 48-hour PTH infusion. In advanced renal failure, calcitriol administration increased the calcemic response to PTH independent of the dietary phosphorus intake. During ingestion of a low phosphorus diet, a 48 hour PTH infusion resulted in a serum calcium level of 13.7 +/- 0.5 and 12.1 +/- 0.2 mg/dl (P less than 0.02) with and without calcitriol administration, respectively. In normal rats and in rats with moderate renal failure, calcitriol administration improved the calcemic response only during a high phosphorus intake. After a 48-hour PTH infusion in normal rats, the serum calcium levels with and without calcitriol were 16.1 +/- 0.9 and 14.8 +/- 0.6 mg/dl, P less than 0.01 respectively; in rats with moderate renal failure, calcitriol administration increased serum calcium, 13.2 +/- 0.5 versus 11.2 +/- 0.4 mg/dl, P less than 0.01.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiac valve calcifications and left ventricular hypertrophy in hemodialysis patients

Cardiac valve calcification (VC) is a common finding in end-stage renal disease patients. It was shown recently that VC is an independent predictor for all-cause and cardiovascular mortality in peritoneal dialysis patients. In hemodialysis (HD) patients, VC was associated with all-cause and cardiovascular mortality, but after adjusting for other cardiovascular risk factors and complications, as well as left ventricular mass index (LVMI), it lost significance. The aim of the study was to assess the relationship between VC and left ventricular hypertrophy in hemodialysis patients. Echocardiographic examination with mitral and aortic valves assessment and LVMI calculation was performed in 65 HD patients ages 49+/-12, with duration of HD therapy 38+/-32 months. VC were found in 32 of 65 patients (49%)-Group VC(+), mitral valve calcifications (MVC) in 10, aortic valve calcifications (AVC) in 9, and both valves calcifications (MVC+AVC) in 13 patients. Patients with VC were older, on HD therapy were longer, had higher systolic and pulse pressure, and had higher LVMI. Patients with both VCs had the highest LVMI. No significant differences were found with respect to Ca, P, PTH, and mean Ca x P product, but the incidence of Ca x P product above 4.43 mmol2/L2 was higher in VC(+) compared with those without VCs. VC coexists with left ventricular hypertrophy, particularly when both valves are calcified. Even short-lasting incidents of increased Ca x P product may lead to cardiac VC.     

Safety and efficacy of long-term treatment of secondary hyperparathyroidism by low-dose intravenous calcitriol.

To assess the safety and efficacy of low-dose intravenous (IV) calcitriol therapy for the treatment of secondary hyperparathyroidism, 21 hemodialysis patients with amino-terminal parathyroid hormone (N-PTH) levels greater than 4 times normal were treated for 12 to 24 months in a prospective trial. The initial dose was 0.50 microgram, which was titrated every 3 months thereafter, as dictated by predialysis calcium, phosphorus, and N-PTH concentration. Dialysate calcium concentration was 1.5 mmol/L. Low-dose IV calcitriol decreased the N-PTH concentration to 48 +/- 6% and 29 +/- 5% of baseline following 12 and 24 months of therapy, respectively. The maximum dose of calcitriol was 0.92 +/- 0.11 microgram (0.50 to 2.25 micrograms). After 12 months of therapy, serum calcium increased from 2.22 +/- 0.04 to 2.41 +/- 0.03 mmol/L (8.9 +/- 0.2 to 9.7 +/- 0.1 mg/dL) without change thereafter. Baseline serum phosphorus was 1.44 +/- 0.09 mmol/L (4.5 +/- 0.3 mg/dL), and was unaltered by calcitriol therapy. Control of serum phosphorus was achieved with calcium-containing phosphate binders, except in three patients who were subsequently withdrawn from the study after 12 months because of persistent hyperphosphatemia due to noncompliance. We conclude that long-term, low-dose IV calcitriol is a safe and effective therapy for most hemodialysis patients with secondary hyperparathyroidism. In contrast to conventional dosing regimens, low-dose IV therapy does not necessitate the use of aluminum-containing phosphate binders and/or a low-calcium dialysate bath.     

Calcemic response to parathyroid hormone in renal failure: role of phosphorus and its effect on calcitriol.

The calcemic response to parathyroid hormone (PTH) is decreased in renal failure. The reduction of hyperphosphatemia improves the calcemic response to PTH in animals with advanced renal failure. However, since low calcitriol levels in renal failure may also contribute to the decreased calcemic response to PTH, the improved calcemic response observed during the reduction of serum phosphorus may be partially mediated by an increase in serum calcitriol levels. The present study evaluated the calcemic response to PTH in rats with moderate and advanced renal failure and how this response was modified by a high and a low phosphorus diet. In addition, the effect of a change in dietary phosphorus on calcitriol levels was also evaluated. A 48-hour continuous infusion of 1-34 rat PTH increased the serum calcium level to 18.2 +/- 0.4 mg/dl in normal rats, versus 13.7 +/- 0.9 and 12.1 +/- 0.2 mg/dl in rats with moderate and advanced renal failure, respectively. During the PTH infusion, a high phosphorus diet increased the serum phosphorus and resulted in a reduced calcemic response to PTH at each level of renal function; respective serum calcium levels were 13.8 +/- 0.6 mg/dl in normals, 11.2 +/- 0.2 mg/dl in moderate renal failure and 9.6 +/- 0.5 mg/dl in advanced renal failure. In normal rats and in rats with moderate renal failure, dietary phosphorus restriction during the PTH infusion increased serum calcitriol levels. In rats with advanced renal failure, serum calcitriol levels were lower than in the other two groups and were not affected by changes in dietary phosphorus.(ABSTRACT TRUNCATED AT 250 WORDS)     

Osteoprotegerin and progression of coronary and aortic calcifications in chronic kidney disease

Vascular calcifications (VCs) are important predictors of cardiovascular mortality in patients with chronic kidney disease (CKD). We have shown previously that osteoprotegerin (OPG), a potential early biomarker for VC, was an independent predictor of mortality in CKD patients. The aim of our study was to follow longitudinally coronary and aortic VCs. VCs were measured using Siemens 16 detector CT in a group of predialysis and hemodialyzed patients before and after a follow-up of 4 years. Some of these patients were transplanted in the meantime. Renal function, calcium, phosphate, iPTH, hs-CRP (high sensitive protein C reactive), and OPG serum levels were also compared. VCs progressed in predialysis, hemodialyzed, and transplanted patients but the progression was not the same in all arterial beds. A progression of coronary calcifications was observed in predialysis and transplanted patients, while aortic calcifications worsened significantly only in hemodialyzed patients. OPG serum levels and hs-CRP were significantly lower among transplanted patients. We concluded that VC depends on the severity of the kidney disease. Transplanted patients are not protected from VC, yet their OPG serum levels were significantly lower, suggesting that there is no link between between OPG levels and severity of VC. Longer follow-up of these patients would be necessary to assess whether a decline in OPG correlates with better survival.     

Vascular calcifications and renal osteodystrophy in chronic hemodialysis patients: what is the relationship between them?

Introduction

Vascular calcifications (VCs) and renal osteodystrophy (ROD) are frequently seen together and represent the major causes of morbidity and mortality in hemodialysis (HD) patients. Some studies suggest a pathogenic link between them, but there is no consensus as yet regarding this issue. The main objective of our study was to establish whether there is any relation between VCs and ROD in our HD patients. We evaluated the prevalence of VCs and ROD and the relationship between VCs and some clinical and biochemical characteristics of HD patients.

Methods

We examined radiological signs of VCs and ROD on hands and pelvis bone radiographs in 81 chronic HD patients, and we calculated a VC score on this basis.

Results

We found a significant relation between radiological signs of ROD and those of VC (P?=?0.019). The patients with ROD had a higher mean VC score (P?=?0.02). By linear regression, the VC score correlated directly with serum calcium (Ca), phosphorus (P), intact parathyroid hormone (iPTH) and CaxP product and inversely with serum albumin. The logistic regression model revealed that ROD, male gender and treatment with calcium salts were predictive of VCs development. There were no associations between VCs and age, HD vintage, diabetes, dialysate Ca concentration, vitamin D treatment, spKt/V, URR and C-reactive protein (CRP) levels.

Conclusion

There seems to be a pathogenetic link between bone and artery diseases in chronic HD patients. Both VCs and ROD have a high prevalence. ROD, male gender and treatment with calcium salts are risk factors for VCs.     

Effect of calcitriol treatment and withdrawal on hyperparathyroidism in haemodialysis patients with hypocalcaemia.

BACKGROUND: Calcitriol is used to treat secondary hyperparathyroidism in dialysis patients. For similarly elevated parathyroid hormone (PTH) levels, the PTH response to calcitriol treatment is believed to be better in hypocalcaemic dialysis patients than in dialysis patients with higher serum calcium values. Furthermore, few studies have evaluated the rapidity of the rebound in serum PTH values after prolonged treatment with calcitriol. Our goal was to evaluate (i) the PTH response to calcitriol treatment in hypocalcaemic haemodialysis patients, (ii) the rapidity of rebound in PTH after calcitriol treatment was stopped, and (iii) whether the effect of calcitriol treatment on PTH levels could be separated from those produced by changes in serum calcium and phosphate values. METHODS: Eight haemodialysis patients (29+/-3 years) with hypocalcaemia and hyperparathyroidism were treated thrice weekly with 2 microg of intravenous calcitriol and were dialysed with a 3.5 mEq/l calcium dialysate. Parathyroid function (PTH-calcium curve) was determined before and after 30 weeks of calcitriol treatment and 15 weeks after calcitriol treatment was stopped. RESULTS: Pretreatment PTH and ionized calcium values were 907+/-127 pg/ml and 3.89+/-0.12 mg/dl (normal, 4.52+/-0.07 mg/dl). During calcitriol treatment, one patient did not respond, but basal (predialysis) PTH values in the other seven patients decreased from 846+/-129 to 72+/-12 pg/ml, P<0.001 and in all seven patients, the decrease exceeded 85%. During the 15 weeks after calcitriol treatment was stopped, a slow rebound in basal PTH values in the seven patients was observed, 72+/-12 to 375+/-44 pg/ml. Covariance analysis was used to evaluate the three tests of parathyroid function (0, 30, and 45 weeks), and showed that calcitriol treatment was associated with reductions in maximal PTH values while reductions in basal PTH were affected by ionized calcium and serum phosphate. The basal/maximal PTH ratio and the set point of calcium were associated with changes in ionized calcium. CONCLUSIONS: In haemodialysis patients with hypocalcaemia, (i) moderate to severe hyperparathyroidism responded well to treatment with calcitriol, (ii) reductions in maximal PTH were calcitriol dependent while reductions in basal PTH were affected by the ionized calcium and serum phosphate concentrations, (iii) changes in the basal/maximal PTH ratio and the set point of calcium were calcium dependent, and (iv) the delayed rebound in basal PTH levels after withdrawal of calcitriol treatment may have been due to the long duration of treatment and the marked PTH suppression during treatment.     

Pulse oral calcitriol for the treatment of hyperparathyroidism in patients on continuous ambulatory peritoneal dialysis: preliminary observations.

A direct effect of calcitriol on the regulation of the secretion of parathyroid hormone (PTH) has been shown in vitro and in vivo. In patients with renal failure on maintenance hemodialysis, it has been shown that intravenous (IV) administration of calcitriol appears to be superior to continuous oral administration. This may be due to the higher levels of calcitriol obtained in blood with consequent improved delivery of calcitriol to peripheral target tissues including the parathyroid glands. However, IV administration of calcitriol, is not practical for patients with end-stage renal disease (ESRD) who are maintained on continuous ambulatory peritoneal dialysis (CAPD). The present studies were designed to investigate whether intermittent administration of large doses of calcitriol orally ("pulse therapy") could mimic the effects of IV calcitriol in hemodialysis patients and achieve suppression of PTH secretion. Studies were performed in five patients who had been maintained on CAPD for more than 6 months. After basal determinations of calcium, phosphorus, and PTH, therapy was begun with calcitriol administered orally in a dose of 5 micrograms given twice per week. Calcium carbonate was continued as a phosphate binder. Dialysate calcium concentration was 1.75 mmol/L (3.5 mEq/L). With this therapy, PTH levels decreased rapidly, and, after 4 to 6 weeks of therapy, reached values 60% lower than pretreatment values. Mean values for serum calcium did not change significantly (2.29 +/- 0.12 mmol/L [9.6 +/- 0.5 mg/dL] before treatment compared with 2.32 +/- 0.08 mmol/L [9.7 +/- 0.25 mg/dL] after therapy). Mean serum phosphorus was also unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Efficacy and safety of long-term treatment with calcium carbonate as a phosphate binder

The efficacy and safety of calcium carbonate as a phosphate binder was evaluated in 20 patients on chronic hemodialysis who had previously received aluminum hydroxide. During the control period the patients were on aluminum hydroxide and calcitriol therapy and had plasma phosphorus levels less than 6 mg/dL (4.95 +/- 0.8 mg/dL). Aluminum hydroxide was then discontinued and no phosphate binder was prescribed for 1 month. Every patient developed hyperphosphatemia so that calcium carbonate treatment was begun and calcitriol dose was adjusted in relation to plasma calcium changes. After 24 months of calcium carbonate therapy, plasma phosphorus was 4.85 +/- 0.7 mg/dL, using a daily dose of calcium carbonate of 2.57 +/- 1.3 g (range, 1 to 6 g). The daily dose per patient of calcitriol was not different from that prescribed during the control period, but in five patients calcitriol was permanently withdrawn for hypercalcemia. At the end of the study plasma calcium, magnesium, bicarbonate, alkaline phosphatase, and parathyroid hormone values were unchanged in comparison with the control period, whereas a significant reduction in plasma aluminum and plasma aluminum increase induced by deferoxamine infusion was observed. The frequency of hypercalcemic and hyperphosphatemic episodes during the last 12 months of calcium carbonate therapy (6.2% and 16.6%, respectively) was not different from that observed during the 12 months on aluminum hydroxide therapy preceding the control period (4.5% and 14.7%, respectively). It was concluded that calcium carbonate is effective in the control of hyperphosphatemia and secondary hyperparathyroidism in patients on chronic hemodialysis and that the incidence of hypercalcemia is low when the daily dosage is less than 6 g.     

Local calcitriol injections as a suppressive treatment of secondary hyperparathyroidism in chronic dialysis patients

AIM: A prospective study was made of the effectiveness of repeatable local calcitriol injections therapy to suppress secondary hyperparathyroidism resistant to conventional therapy in chronic dialysis patients. METHODS: Under ultrasonographic guidance, six injections at an interval of two days were performed in 14 chronic dialysis patients. The total amount of calcitriol to be injected each time was estimated as 100% of the calculated gland volume. Calcitriol was given in doses 1 mug of medicine per 1 cubic cm (as measured by USG) of parathyroid tissue. Parathormone concentration, total calcium, ionized calcium, phosphate, and alkaline phosphatase levels were assessed on the first and last day of the treatment period. RESULTS: Prior to therapy, the mean gland volumes were 0.62 (0.15-3.0) ml, and they increased to 0.85 (0.2-3.9) after 14 days (NS). Seven patients were found to have decreased their PTH levels to 909 +/- 387 pg/mL after 14 days of treatment when compared with the first day mean values of 1588 +/- 440 pg/mL (p < 0.05). After completion of the therapy, four patients were reported to be free from any clinical symptoms of ostalgia or arthralgia. Others reported an alleviation of pain. CONCLUSIONS: Parathyroid adenoma injection is an alternative method of treatment for some patients resistant to treatment by means of vitamin D3 pulses or intravenous administration of calcitriol. The success of treatment is to a great extent determined by proper selection of patients and the taking of decisions when the period of secondary hyperparathyroidism is not very advanced.     

Calcitriol synthesis is decreased in spontaneously hypertensive rats

To investigate the mechanisms of abnormal calcium metabolism, such as hypocalcemia, decreased intestinal calcium absorption and hypercalciuria in spontaneously hypertensive rats (SHR), we have measured the plasma concentration of calcitriol and its synthesis in 5-, 8-, 12-, 16-, and 20-week-old normotensive Wistar Kyoto rats (WKY) and SHR. Metabolic clearance rate (MCR) and production rate (PR) of calcitriol were measured by the constant isotope infusion method. Plasma concentration of calcitriol and PR of calcitriol were decreased in SHR after 12 weeks of age. MCR of calcitriol, however, was not different between WKY and SHR in any age group. Therefore, the decreased synthesis of calcitriol accounts for the lower plasma level of calcitriol in SHR after 12 weeks of age. Metabolic acidosis or decreased renal function could not account for the decreased synthesis of calcitriol, since the blood pH and pCO2 and creatinine clearance were similar between WKY and SHR at times when the calcitriol synthesis was reduced in SHR. Plasma concentration of ionized calcium was also lower in SHR after 12 weeks of age. Plasma concentration of calcitonin was significantly higher in 16-week-old SHR (41.6 +/- 1.5 pg/ml) than in age-matched WKY (30.5 +/- 1.7, P less than 0.001). The values, however, were not different between 8- and 12-week-old WKY and SHR. We believe that the decreased synthesis of calcitriol could be the pathogenetic factor for the development of abnormal calcium metabolism in SHR. Age of animals should be considered when studying the calcium metabolism in SHR.