Background and objectives Serum calcification propensity is a novel functional test that quantifies the functionality of the humeral system of calcification control. Low serum calcification propensity is associated with higher risk of cardiovascular events and death in patients with ESKD. Increasing magnesium in serum increases (i.e., improves) serum calcification propensity in vitro, but so far, no clinical trials have investigated whether increasing serum magnesium increases serum calcification propensity in subjects with ESKD.Design, setting, participants, & measurements We conducted a single-center, randomized, double-blinded, parallel group, controlled clinical trial, in which we examined the effect of increasing dialysate magnesium from 1.0 to 2.0 mEq/L for 28 days compared with maintaining dialysate magnesium at 1.0 mEq/L on serum calcification propensity in subjects undergoing hemodialysis for ESKD. The primary end point was the value of calcification propensity, measured by T50, at the end of the intervention.Results Fifty-nine subjects were enrolled in the trial, and of these, 57 completed the intervention and were analyzed for the primary outcome. In the standard dialysate magnesium group, serum calcification propensity was 233681 minutes (mean6SD) at baseline (mean of days 27 and 0) and 229693 minutes at follow-up (mean of days 21 and 28), whereas in the high dialysate magnesium group, serum calcification propensity was 247669 minutes at baseline and 302666 minutes at follow-up. The difference in serum calcification propensity between the two groups at follow-up (primary analysis) was 73 minutes (between-group difference; 95% confidence interval, 30 to 116; P,0.001), and the between-group difference in serum magnesium was 0.88 mg/dl (95% confidence interval, 0.66 to 1.10; P=0.001).Conclusions Increasing dialysate magnesium increases serum calcification propensity in subjects undergoing maintenance hemodialysis.
IntroductionChronic kidney disease (CKD) is associated with high cardiovascular morbidity and mortality. Recent evidence suggests that increases in both serum and intracellular magnesium (Mg) can slow or even prevent the development of vascular calcification seen in CKD. Serum calcification propensity (T50) is a novel functional test, which is associated with all-cause mortality in CKD and measures the ability of serum to delay the formation of crystalline nanoparticles. Theoretically, increasing serum Mg should improve T50 and thereby reduce the propensity towards ectopic calcification.MethodsWe conducted a randomized placebo-controlled double-blinded clinical trial to investigate the safety of 2 different doses of oral Mg supplementation in subjects with CKD stages 3 and 4 as well as their effects on intracellular Mg and T50. Thirty-six subjects with CKD stages 3 and 4 were randomized to one of 3 groups (placebo, elemental Mg 15 mmol/d or elemental Mg 30 mmol/d) given as slow-release Mg hydroxide and followed for 8 weeks.ResultsThirty-four subjects completed the trial. Intracellular Mg remained stable throughout the trial despite significant increases in both serum and urine Mg. T50 increased significantly by 40 min from 256 ± 60 (mean ± SD) to 296 ± 64 minutes (95% confidence interval, 11–70, P < 0.05) in the Mg 30 mmol/d group after 8 weeks. No serious adverse events related to the study medication were reported during the study.DiscussionOral Mg supplementation was safe and well tolerated in CKD stages 3 and 4 and improved T50, but did not increase intracellular Mg. Further studies are needed to investigate the long-term effects of Mg supplementation in CKD stage 3 and 4 and whether improvement in calcification propensity is related to clinical endpoints.
Background and objectives The calcimimetic cinacalcet reduced the risk of death or cardiovascular (CV) events in older, but not younger, patients with moderate to severe secondary hyperparathyroidism (HPT) who were receiving hemodialysis. To determine whether the lower risk in younger patients might be due to lower baseline CV risk and more frequent use of cointerventions that reduce parathyroid hormone (kidney transplantation, parathyroidectomy, and commercial cinacalcet use), this study examined the effects of cinacalcet in older ($65 years, n=1005) and younger (,65 years, n=2878) patients.Design, setting, participants, & measurements Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) was a global, multicenter, randomized placebo-controlled trial in 3883 prevalent patients on hemodialysis, whose outcomes included death, major CV events, and development of severe unremitting HPT. The age subgroup analysis was prespecified.Results Older patients had higher baseline prevalence of diabetes mellitus and CV comorbidity. Annualized rates of kidney transplantation and parathyroidectomy were .3-fold higher in younger relative to older patients and were more frequent in patients randomized to placebo. In older patients, the adjusted relative hazard (95% confidence interval) for the primary composite (CV) end point (cinacalcet versus placebo) was 0.70 (0.60 to 0.81); in younger patients, the relative hazard was 0.97 (0.86 to 1.09). Corresponding adjusted relative hazards for mortality were 0.68 (0.51 to 0.81) and 0.99 (0.86 to 1.13). Reduction in the risk of severe unremitting HPT was similar in both groups. ConclusionsIn the EVOLVE trial, cinacalcet decreased the risk of death and of major CV events in older, but not younger, patients with moderate to severe HPT who were receiving hemodialysis. Effect modification by age may be partly explained by differences in underlying CV risk and differential application of cointerventions that reduce parathyroid hormone.
Alfacalcidol and paricalcitol are vitamin D analogs used for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease, but have known dose-dependent side effects that cause hypercalcemia and hyperphosphatemia. In this investigator-initiated multicenter randomized clinical trial, we originally intended two crossover study periods with a washout interval in 86 chronic hemodialysis patients. These patients received increasing intravenous doses of either alfacalcidol or paricalcitol for 16 weeks, until parathyroid hormone was adequately suppressed or calcium or phosphate levels reached an upper threshold. Unfortunately, due to a period effect, only the initial 16-week intervention period for 80 patients was statistically analyzed. The proportion of patients achieving a 30% decrease in parathyroid hormone levels over the last four weeks of study was statistically indistinguishable between the two groups. Paricalcitol was more efficient at correcting low than high baseline parathyroid hormone levels, whereas alfacalcidol was equally effective at all levels. There were no differences in the incidence of hypercalcemia and hyperphosphatemia. Thus, alfacalcidol and paricalcitol were equally effective in the suppression of secondary hyperparathyroidism in hemodialysis patients while calcium and phosphorus were kept in the desired range.
The present study found a 57% lower metabolic clearance rate of 1,25(OH)(2)D(3) in uraemic patients, as compared with that of healthy volunteers (P<0.03). The bioavailability of 1,25(OH)(2)D(3) following administration of 1alpha(OH)D(3) i.v. and orally in both healthy volunteers and uraemic patients was markedly lower than after administration of oral 1,25(OH)(2)D(3) (P<0.03). In spite of lower plasma-1,25(OH)(2)D(3) levels after administration of 1alpha(OH)D(3), no significant difference was observed on the suppressive effect of 4 microg i.v. of either 1,25(OH)(2)D(3) or 1alpha(OH)D(3) on the plasma-PTH levels in the uraemic patients. This might suggest the existence of an effect of 1alpha(OH)D(3) on the parathyroid glands which is independent of the plasma-1,25(OH)(2)D(3) levels, that are achieved after oral or i.v. administration of 1alpha(OH)D(3).
Summary: CBP was measured in 15 patients on chronic hemodialytic treatment. CBP was measured with xenon-133 inhalation using single photon emission tomography. In addition, computerized tomography (CT) and a neuro logical examination were done prior to hemodialysis. Mean CBP was 66.2 ± 17.3 (SD) ml 100 g-I min-I, which was significantly higher (t-test, p < 0.05) than for an age-matched control group (54.7 ± 10.2 ml 100 g-I min -I). However, the hematocrit for the patients was considerably lower, 0.30 ± 0.07, as compared to 0.43 ± 0.03 in the controls. A significant negative correlation was observed between CBP and the hematocrit (y = -1.79x + 120.7, r = -0.71, p < 0.01). Calculating CBP from this equation in the dialyzed patients using a hematAs focal or diffuse brain tissue damage is invari ably followed by a reduction in CBF, there are rea sons to expect a CBF decrease in patients on long term hemodialytic treatment. First, the renal dis ease itself may cause uremic encephalopathy (Olsen, 1961;Tyler, 1968), although today most pa tients will receive hemodialysis early in the course of their disease to prevent long-standing severe ure mia. Second, a severe progressive neurological syn drome called dialysis dementia evolves in a number of patients regularly treated with hemodialysis. The etiology of this syndrome was originally found to relate to a high aluminum content in the dialysate (Alfrey et aI., 1976;Alfrey, 1987). Lately, it has Received November 22, 1991; final revision received March 18, 1992; accepted March 18, 1992. Address correspondence and reprint requests to Dr. Sissel Vorstrup, Department of Neurology, Rigshospitalet, 9, Blegdamsvej, 2100 Copenhagen, Denmark.Abbreviations used: CT, computed tomography; CM, can thomeatal (plane); Hct, hematocrit; PET, positron emission to mography. 745ocrit of 0.43 yielded a mean CBP value of 43.7 mlloo g-I min -I, i.e., 20% below the expected. Two patients showed a focal CBP decrease. CT showed central or cor tical atrophy in five patients, and two had small hypo dense lesions. The neurological examination revealed slight to moderate dementia in seven cases. Although mean CBP was found to be increased by 21% as com pared to the control group, an even higher CBP level would have been expected to outweigh the decreased ox ygen carrying capacity of the blood. The findings suggest a lowered metabolic demand of the brain tissue, probably due to subtle brain damage. Key Words: Anemia-CBP Hemodialysis.been suggested that even the moderately increased aluminum levels in the blood, often seen in these patients because of a high daily intake of aluminum containing phosphate-binding gels, may cause de mentia (Altmann et aI., 1989). Third, hypotensive episodes, arterial hypoxemia, and fluctuations in electrolytes and cerebral water content may occur during hemodialysis and cause subtle subclinical brain tissue damage (Savazzi et aI., 1985). Finally, the underlying process for the renal disease could cause brain damage and thereby decrease CBF. We therefore studied the in...
Alfacalcidol and paricalcitol increase the plasma levels of FGF23 equally and substantially in haemodialysis patients.
The long-term effects of high dose steroid treatment with either prednisone (PDN) or deflazacort (DFZ) were examined on various parts of the skeleton in 29 patients with nephrotic syndrome. All had normal skeleton at the start of the steroid treatment. At the beginning, PDN was given as 80 mg/day and tapered down to 20 mg/day for 1 year and DFZ was given in an equipotent dosage. Twenty-three patients completed 6 months of treatment, and 18 patients completed 12 months of treatment. Beside laboratory parameters to ensure the effect of treatment on the nephrotic syndrome, all had measurements of the bone mineral content (BMC) at 0, 6, and 12 months of treatment. BMC was measured by single photon absorptiometry of both forearms and by dual photon absorptiometry of the mandible, forearms, and lumbar spine. The effect of DFZ was compared to that of PDN due to a potential "calcium sparing" effect of DFZ. The therapeutical effects on the nephrotic syndrome were not different between the two drugs. Urinary 24-hour protein decreased from 9.9 to 1.1 g in the DFZ-treated patients and from 8.0 to 1.4 g in the PDN-treated patients. Plasma albumin concentration normalized in both groups. Both groups of steroid-treated patients had a significant reduction of the BMC levels in all parts of the skeleton. However, the bone decay rates per month were significantly different between different bone regions and between different drug regimes. In the forearm, the bone decay rate was 5.3%/year in the PDN group and 2.0%/year in the DFZ group (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
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