Christiansen C, Rodbro, P, Christensen M S, Hartnack B. Is 1,25-Dihydroxy-Cholecalciferol Harmful to renal Function in Patients with Chronic Renal Failure? Clin Endocrinol 1981; 15:229-236.
Abstract/Summary
Seventeen undialysed adult patients with chronic renal failure took part in a controlled study of the effects of 1,25(OH)2D3 and D3. After a 6-month observation period the patients were allocated at random to two groups for 6 months of treatment with either 1,25(OH)2D3 (mean dose 0.5 µg daily) or D3 (dose 100 µg daily). Treatment was then discontinued and the patients were studied for a further 6 months.
Serum iPTH was decreased in both groups but most markedly in the 1,25(OH)2D3 group in which the iPTH values became normal. Serum creatinine increased during treatment in both groups. In the group receiving 1,25(OH)2D3 this was coupled to an increase in serum calcium within the normal range.
Our data demonstrate that 1,25(OH)2D3 treatment in patients with chronic renal failure leads to a further reduction in renal function, which may be partially reversible. Physicians should therefore be reluctant to give vitamin D analogues to patients with chronic renal failure unless they have severe symptomatic renal osteodystrophy.
Tougaard L, Sorensen E, Brochner-Mortensen J, Christiansen MS, Rodero P, Sorensen AWS. Controlled Trial of 1 alpha-Hydroxycholecalciferol in Chronic Renal Failure. The Lancet, 1976; May 15 edition, 1044-1047.
Abstract/Summary
24 patients with chronic renal failure (glomerular filtration-rate [G.F.R.] 5-25 ml/min) participated in a double-blind placebo-controlled trial of the effects of 1 alpha-H.C.C.) 1 µg daily for eleven weeks. This treatment induced significant increases in the intestinal absorption of calcium and in plasma-calcium which reached normal levels within two weeks. It also induced a significant reduction of the raised serum levels of parathyroid hormone. No significant changes were induced in plasma-phosphorus, plasma-alkaline-phosphatase, or in the degree of bone mineralization as measured by the phosphorus/hydroxyproline ratio in bone. The bone mineral content in the forearm measured by photon absorptiometry decreased to the same extent in the 1 alpha-H.C.C. groups and in the placebo group. The fall in G.F.R. over eleven weeks was 2.5 times greated in the 1 alpha-H.C.C. group than in the placebo group, but this difference was not significant. It is concluded that 1 alpha-H.C.C. treatment in chronic renal failure does not affect the progressive loss of calcium from bone despite normalization of plasma-calcium.
Baker LRI, Abrams SML, Roe AJ, Faugere M-C, Fanti P, Subayti Y, Malluche HH. 1,25(OH)2D3 administration in moderate renal failure: A prospective double-blind trial. Kidney Int 1989; 35:661-669.
Abstract/Summary
This study represents the first randomized prospective, double-blind, placebo-controlled trial of the efficacy of 1,25(OH)2D3 on bone histology and serum biochemistry in patients with mild to moderate renal failure. Sixteen patients with chronic renal impairment (creatinine clearance 20 to 59 ml per min) received either 1,25(OH)2D3 at a dose of 0.25 to 0.5 µg daily (eight patients), or placebo. Transilliac crest bone biopsies were performed before entrance into the study and after 12 months of experimental observation. None of the patients were symptomatic or had radiological evidence of bone disease. Of the thirteen patients who completed the study, initial serum 1,25(OH)2D3 levels were low in seven patients and parathyroid hormone levels were elevated in seven patients. Bone histology was abnormal in all patients. 1,25(OH)2D3 treatment was associated with a significant fall in serum phosphorus and alkaline phosphatase concentrations as well as with histological evidence of an amelioration of hyperparathyroid changes. In contrast to previous reports, no deterioriation of renal function attributable to the treatment occurred, perhaps because a modest dose of 1,25(OH)2D3 was employed combined with meticulous monitoring. Further investigation is required to determine whether alternative therapeutic strategies (smaller doses or intermittent therapy) may avoid the potential for suppressing bone turnover to abnormally low levels in the long term.
Nielsen HE, Romer FK, Melsen F, Christensen MS, Hansen HE. 1 alpha-hydroxy vitamin D3 treatment of non-dialyzed patients with chronic renal failure. Effects on bone, mineral metabolism and kidney function. Clin Nephrol 1980; 13(3):103-108.
Abstract/Summary
Nine non-dialyzed patients with creatinine clearance below 20 ml/min and histological and biochemical signs of renal osteodystrophy received 1 alpha-hydroxy vitamin D3 for 6 months in a mean daily dosage of 0.9 µg. The serum concentrations of calcium and phosphate increased, and the serum concentrations of alkaline phosphatase and parathyroid hormone decreased during treatment. Quantitative histological examination of iliac crest bone biopsies showed a marked improvement of uremic bone changes, including normalization of the initial low mineralization rates evaluated by tetracycline uptake in bone. No significant change was seen in bone mineral content in the forearm measured by photon absorptiometry. An accelerated loss of kidney function was observed during the treatment period with 1,25(OH)2D3 as compared with control periods before and after the treatment.
Christiansen C, Rodero P, Christensen MS, Hartnack B, Transbol I. Deterioriation of Renal Function During Treatment of Chronic Renal Failure with 1,25-Dihydroxycholecalciferol. The Lancet, 1978; September 30th edition, 700-703.
Abstract/Summary
A controlled study of the effects of the potent vitamin-D metabolite, 1,25-dihydroxycholecalciferol (1,25(OH)2D3), and vitamin D3 was done in 18 non-dialysed patients with chronic renal failure (C.R.F.). Patients with a creatinine clearance below 35 ml/min and mild renal osteodystrophy were selected. After 6 months’ observation of the spontaneous course, the patients were randomly allocated to 6 months’ oral treatment with either 1,25(OH)2D3 or vitamin D3, in initial daily doses of 1 µg and 4000 i.u., respectively, combined with 0.5 g calcium. 1,25(OH)2D3 quickly corrected hypocalcaemia, reduced serum-alkaline-phosphatases and serum-immunoreactive-parathyroid-hormone, and more than doubled the urinary excretion rate of calcium. D3 had similar, but less pronounced effects. 7 out of 8 patients on 1,25(OH)2D3 developed hypercalcaemia which necessitated a reduction in dosage. None of the patients on D3 treatment developed hypercalcaemia. The percentage fall in creatinine clearance was greater during treatment than before treatment in all patients on 1,25(OH)2D3 (p<0.01) and in 7 of 9 patients on vitamin D3 treatment (though the group change here was not significant). Deterioration of renal function is a major limitation of the clinical use of 1,25(OH)2D3 and D3, in non-dialysed patients with C.R.F. In fact, the decreased formation of 1,25(OH)2D3 seen in C.R.F. might protect renal function at the expense of abnormalities in mineral metabolism.
Goodman WG, Coburn JW. The Use of 1,25-Dihydroxyvitamin D3 in Early Renal Failure. Annu Rev Med 1992: 43:227-237.
Abstract/Summary
Alterations in renal calcitriol synthesis are important in the pathogenesis of secondary hyperparathyroidism in patients with progressive renal failure. Many of the manifestations of secondary hyperparathyroidism can be reversed by treatment with 1alpha-hydroxyvitamin D3, but some studies suggest that such treatment accelerates the rate of progression of renal disease in patients with mild to moderate renal failure. Thus, calcitriol and 1alpha-hydroxyvitamin D3 have been used infrequently in this group of patients. A review of more than 20 clinical reports indicates that the use of calcitriol or 1alpha-hydroxyvitamin D3, in daily doses of 0.25 – 0.5 µg, is rarely associated with hypercalcemia, hyperphosphatemia, or impairment in renal function. If such complications arise, they are usually reversible when treatment with vitamin D sterols is withdrawn and serum calcium levels return to pretreatment values. There is evidence that calcitriol impairs creatinine secretion by the renal tubule; thus, serum creatinine levels may increase and measurements of creatinine clearance may fall during calcitriol therapy in patients with mild to moderate renal failure without any change in true glomerular filtration rate. Daily oral doses of 0.25-0.50 µg of calcitriol or 1alpha-hydroxyvitamin D3 are well tolerated, and they can reverse the biochemical and histologic features of secondary hyperparathyroidism. Calcitriol therapy may be particularly valuable in patients recognized to be at higher risk of developing progressive secondary hyperparathyroidism as their renal failure slowly advances.
Paterson CR. Vitamin-D Poisoning: Survey of Causes in 21 Patients with Hypercalcaemia. The Lancet, 1980; May 31st issue, p. 1164-1165.
Abstract/Summary
Hypercalcaemia developed in 21 patients due to vitamin-D poisoning; 2 were poisoned twice and 2 were poisoned three times. All patients had taken milligram doses of vitamin D, which for 5 patients was inappropriate. For the other 15 patients (mainly with hypoparathyroidism) milligram doses of vitamin D were appropriate; the patients were poisoned either early in therapy, trying to correct the plasma-calcium too quickly, or, later, because of failure to follow up patients properly. 2 patients died as a result of their intoxication. Constant vigilance is essential when patients are taking large doses of vitamin D.
Kanis JA, Cundy T, Earnshaw M, Henderson RG, Heynen G, Naik R, Russell RGG, Smith R, and Woods CG. Treatment of Renal Bone Disease with 1alpha-Hydroxylated Derivatives of Vitamin D3. Quarterly J of Med, New Series XLVIII, 1979; No. 190, p. 289-322.
Abstract/Summary
Forty patients with severe bone disease and chronic renal failure were treated with 1alpha-hydroxycholecalciferol (1alpha-OHD3) or 1,25-dihydroxycholecalciferol (1,25(OH)2D3) for 7-49 months (total = 738 patient months). There were symptomatic, biochemical and radiographic improvements in the majority of patients (>70 percent). Paired bone biopsies, taken before and during treatment in 26 patients, showed no change in bone matrix area, whereas matrix area decreased in a control group of 26 patients over the same period. There were small but consistent decreases in bone marrow fibrosis and in bone cell (osteoblast and osteoclast) counts in treated patients but not in controls. However, the proportion of patients who showed histological ‘cure’, in the sense of complete reversal of marrow fibrosis or excess osteoid was no greater in the treated than in the control group. In terms of the overall response, there were significant correlations between the improvement noted in symptoms, radiographs and plasma biochemistry, and these in turn were related to the smaller improvement in bone histology.
The major detectable factors before treatment which adversely influence its outcome were a high plasma level of calcium associated with high levels of parathyroid hormone, and the presence of marked osteomalacia without osteitis fibrosa. Other factors examined, which included the dose of agent used, initial plasma levels of phosphate and alkaline phosphatase, and dietary supplements of calcium, did not greatly influence the response. During the course of treatment, the dose of 1alpha-OHD3 or 1,25(OH)2D3 tolerated progressively decreased. In patients with poor histological response, hypercalcaemia occurred commonly at the start of treatment, whereas it occurred later in good responders when biochemical improvement was nearly complete. Hypercalcaemia could be rapidly corrected by stopping treatment. The rapid onset and reversal of action of 1alpha-OHD3 and 1,25(OH)2D3 confer therapeutic advantages over vitamin D. However, because these drugs do not invariably reverse bone disease and may give rise to unwanted effects, they should not be used indiscriminately in all renal patients. Their use demands adequate clinical, biochemical and radiographic supervision.
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