Use of active vitamin D sterols in patients with chronic kidney disease, stages 3 and 4
2003; Elsevier BV; Volume: 63; Linguagem: Inglês
10.1046/j.1523-1755.63.s85.12.x
ISSN1523-1755
Autores Tópico(s)Pharmacological Effects and Toxicity Studies
ResumoUse of active vitamin D sterols in patients with chronic kidney disease, stages 3 and 4. This paper reviews randomized controlled trials and other reported data on the use of the active vitamin D sterols, such as calcitriol, alfacalcidol, and doxercalciferol, in the management of secondary hyperparathyroidism in patients with mild-to-moderate renal insufficiency (stage 3 or 4 chronic kidney disease). Data on potential benefits, including improved histologic abnormalities of bone from secondary hyperparathyroidism, increased bone mineral density, and a reduction of elevated parathyroid hormone levels, are documented. Consideration is given to the risks of such therapy, which include the production of hypercalcemia, more rapid progression of renal insufficiency, the induction of adynamic bone "disease," and accelerated vascular and soft tissue calcification. The low therapeutic index, or "benefit/risk ratio" of calcitriol and alfacalcidol, the sterols currently licensed for such treatment, is recognized. It is recommended that phosphate-restricted diets, phosphate-binding agents, and oral calcium supplements be given adequate trials before starting calcitriol or alfacalcidol. If PTH levels cannot be controlled by these measures, initial doses of these sterols and the proper surveillance during treatment are given. It is emphasized that the risks of hypercalcemia are likely to increase as the degree of kidney failure worsens. Further research using the "less calcemic" vitamin D sterols is clearly needed. Use of active vitamin D sterols in patients with chronic kidney disease, stages 3 and 4. This paper reviews randomized controlled trials and other reported data on the use of the active vitamin D sterols, such as calcitriol, alfacalcidol, and doxercalciferol, in the management of secondary hyperparathyroidism in patients with mild-to-moderate renal insufficiency (stage 3 or 4 chronic kidney disease). Data on potential benefits, including improved histologic abnormalities of bone from secondary hyperparathyroidism, increased bone mineral density, and a reduction of elevated parathyroid hormone levels, are documented. Consideration is given to the risks of such therapy, which include the production of hypercalcemia, more rapid progression of renal insufficiency, the induction of adynamic bone "disease," and accelerated vascular and soft tissue calcification. The low therapeutic index, or "benefit/risk ratio" of calcitriol and alfacalcidol, the sterols currently licensed for such treatment, is recognized. It is recommended that phosphate-restricted diets, phosphate-binding agents, and oral calcium supplements be given adequate trials before starting calcitriol or alfacalcidol. If PTH levels cannot be controlled by these measures, initial doses of these sterols and the proper surveillance during treatment are given. It is emphasized that the risks of hypercalcemia are likely to increase as the degree of kidney failure worsens. Further research using the "less calcemic" vitamin D sterols is clearly needed. Secondary hyperparathyroidism appears and advances with progressive deterioration of renal function that is common with chronic kidney disease (CKD). There is evidence, which is reviewed elsewhere in this issue, that the renal synthesis of calcitriol is impaired as kidney function is reduced, and this contributes to the development of secondary hyperparathyroidism. Also, in patients with CKD, both inadequate dermal synthesis and reduced intake of vitamin D per se, as evidenced by suboptimal plasma 25(OH)-vitamin D levels is common; this "vitamin D insufficiency" predisposes such patients to the development of secondary hyperparathyroidism. With current interest in various pharmacologic and nutritional approaches aimed at slowing the progression of CKD toward end-stage renal disease (ESRD), attention toward the management of secondary hyperparathyroidism is indicated to minimize the development of progressive bone disease. This review considers the benefits and potential pitfalls of therapy of secondary hyperparathyroidism with the active vitamin D sterols. The nomenclature used is that recommended by the National Kidney Foundation1.National Kidney Foundation K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification and stratification.Am J Kidney Dis. 2002; 39: S1-S266PubMed Google Scholar. We focus on patients with CKD, stage 3: glomerular filtration rate (GFR) 30 to 59 mL/min/1.73m2; and stage 4: GFR, 15 to 29 mL/min/1.73m2. The treatment of patients with stage 5 CKD (those with a GFR <15 mL/min/1.73m2 or undergoing dialysis) is not included. Calcitriol and alfacalcidol have been in use for more than three decades, and several "new" active analogs of vitamin D are now available2.Steddon S.J. Schroeder N.J. Cunningham J. Vitamin D analogues: How do they differ and what is their clinical use.Nephrol Dial Transplant. 2001; 16: 1965-1967Crossref PubMed Scopus (25) Google Scholar. A recommendation will be made when patients with CKD should be considered for treatment with an active vitamin D sterol, with recommendations on initial dosages. In this review, more weight will be given to randomized controlled trials (RCT), but lessons learned from open-label experiences will also be considered. There are reports on the use of active vitamin D sterols in patients with stage 3 or 4 CKD in 8 RCTs3.Massry S.G. et al.Assessment of 1,25(OH2D3 in the correction and prevention of renal osteodystrophy in patients with mild to moderate renal failure.in: Norman A.W. Schaefer K. Grigoleit H-G. Vitamin D: A Chemical, Biochemical and Clinical Update. de Gruyter, Berlin1985: 935-937Google Scholar, 4.Nordal K.P. Dahl E. Low dose calcitriol versus placebo in patients with predialysis chronic renal failure.J Clin Endocrinol Metab. 1988; 67: 929-936Crossref PubMed Scopus (108) Google Scholar, 5.Baker L.R.I. Abrams S.M.L. Roe C.J. et al.1,25(OH)2D3 administration in moderate renal failure: A prospective double-blind trial.Kidney Int. 1989; 35: 661-669Abstract Full Text PDF PubMed Scopus (164) Google Scholar, 6.Przedlacki J. Manelius J. Huttunen K. Bone mineral density evaluated by dual-energy X-ray absorptiometry after one-year treatment with calcitriol started in the predialysis phase of chronic renal failure.Nephron. 1995; 69: 433-437Crossref PubMed Scopus (45) Google Scholar, 7.Ritz E. Küster S. Schmidt-Gayk H. et al.Low-dose calcitriol prevents the rise in 1,84 iPTH without affecting serum calcium and phosphate in patients with moderate renal failure (prospective placebo-controlled multicentre trial).Nephrol Dial Transplant. 1995; 10: 2228-2234PubMed Google Scholar, 8.Hamdy N.A.T. Kanis J.A. Beneton M.N.C. et al.Effect of alfacalcidol on natural course of bone disease in mild to moderate renal failure.BMJ. 1995; 310: 358-363Crossref PubMed Scopus (283) Google Scholar, 9.Rix M. Metabolic bone disease in patients with predialysis chronic renal failure. University of Copenhagen, Copenhagen1999: 1-84Google Scholar, 10.Coburn J.W. Sprague S.M. Lindberg J.S. 1αD2 Study Group A comparison of controlled trials of doxercalciferol (1αD2) versus alfacalcidol (1αD3) for 2° hyperparathyroidism in chronic kidney disease (CKD).Nephrol Dial Transplant. 2002; 17: 7Google Scholar and several controlled open-label trials11.Coen G. Mazzaferro S. Bonucci E. et al.Treatment of secondary hyperparathyroidism of pre-dialysis chronic renal failure with low doses of 1,25(OH)2D3: Humoral and histomorphometric results.Miner Electrolyte Metab. 1986; 12: 375-382PubMed Google Scholar, 12.Bianchi M.L. Colantonio G. Campanini F. et al.Calcitriol and calcium carbonate therapy in early chronic renal failure.Nephrol Dial Transplant. 1994; 9: 1595-1599PubMed Google Scholar, 13.Bertoli M. Luisetto G. Ruffatti A. et al.Renal function during calcitriol therapy in chronic renal failure.Clin Nephrol. 1990; 33: 98-102PubMed Google Scholar, 14.Nordal K.P. Dahl E. Halse J. et al.Long-term low-dose calcitriol in predialysis chronic renal failure: Can it prevent hyperparathyroid bone disease?.Nephrol Dial Transplant. 1995; 10: 203-206PubMed Google Scholar, 15.Panichi V. Andreini B. De Pietro S. et al.Calcitriol oral therapy for the prevention of secondary hyperparathyroidism in patients with predialytic renal failure.Clin Nephrol. 1998; 49: 245-250PubMed Google Scholar. Three of the earliest studies reported that calcitriol led to substantial improvement of skeletal histomorphometry from the pre- to posttreatment bone biopsies3.Massry S.G. et al.Assessment of 1,25(OH2D3 in the correction and prevention of renal osteodystrophy in patients with mild to moderate renal failure.in: Norman A.W. Schaefer K. Grigoleit H-G. Vitamin D: A Chemical, Biochemical and Clinical Update. de Gruyter, Berlin1985: 935-937Google Scholar, 4.Nordal K.P. Dahl E. Low dose calcitriol versus placebo in patients with predialysis chronic renal failure.J Clin Endocrinol Metab. 1988; 67: 929-936Crossref PubMed Scopus (108) Google Scholar, 5.Baker L.R.I. Abrams S.M.L. Roe C.J. et al.1,25(OH)2D3 administration in moderate renal failure: A prospective double-blind trial.Kidney Int. 1989; 35: 661-669Abstract Full Text PDF PubMed Scopus (164) Google Scholar; however, the PTH measurements used immunoassays that cannot be readily compared with the widely used "second generation" intact PTH assay. Moreover, most CKD patients entered these trials independent of the PTH level. Bianchi et al12.Bianchi M.L. Colantonio G. Campanini F. et al.Calcitriol and calcium carbonate therapy in early chronic renal failure.Nephrol Dial Transplant. 1994; 9: 1595-1599PubMed Google Scholar did find skeletal histomorphometric features of significant secondary hyperparathyroidism in their CKD patients who had "second generation" intact PTH levels that were only modestly elevated, with a mean value of about twice the upper normal limit. Creatinine clearances ranged from 36 to 64 mL/min, indicating that most patients had stage 3 CKD. The second bone biopsies, done after two years of treatment with calcitriol 0.25 μg/day, showed significant improvement. This study12.Bianchi M.L. Colantonio G. Campanini F. et al.Calcitriol and calcium carbonate therapy in early chronic renal failure.Nephrol Dial Transplant. 1994; 9: 1595-1599PubMed Google Scholar is of note in that there was little or no histologic evidence for "skeletal resistance" to PTH action, as was found in bone biopsies from hemodialysis patients16.Quarles L.D. Lobaugh B. Murphy G. Intact parathyroid hormone overestimates the presence and severity of parathyroid-mediated osseous abnormalities in uremia.J Clin Endocrinol Metab. 1992; 75: 145-150Crossref PubMed Scopus (232) Google Scholar,17.Sherrard D.J. Hercz G. Pei Y. et al.The spectrum of bone disease in end-stage renal failure—An evolving disorder.Kidney Int. 1993; 43: 436-442Abstract Full Text PDF PubMed Scopus (637) Google Scholar, and in those with stage 5 CKD who had not yet initiated dialysis18.Hernandez D. Concepcion M.T. Lorenzo V. et al.Adynamic bone disease with negative aluminum staining in predialysis patients: Prevalence and evolution after maintenance dialysis.Nephrol Dial Transplant. 1994; 9: 517-523PubMed Google Scholar. In the large RCT of Hamdy et al8.Hamdy N.A.T. Kanis J.A. Beneton M.N.C. et al.Effect of alfacalcidol on natural course of bone disease in mild to moderate renal failure.BMJ. 1995; 310: 358-363Crossref PubMed Scopus (283) Google Scholar, abnormal bone histology was found in 73% and 76% of patients with mean entry intact PTH levels of 68 and 109 pg/mL in placebo and alfacalcidol groups, respectively. Of the alfacalcidol-treated patients with abnormal bone histology on the entry bone biopsy, 42% were normalized after two years of treatment, compared to only 4% of patients assigned to placebo. Another benefit of active vitamin D treatment has been improvement of bone mineral density (BMD)6.Przedlacki J. Manelius J. Huttunen K. Bone mineral density evaluated by dual-energy X-ray absorptiometry after one-year treatment with calcitriol started in the predialysis phase of chronic renal failure.Nephron. 1995; 69: 433-437Crossref PubMed Scopus (45) Google Scholar, 9.Rix M. Metabolic bone disease in patients with predialysis chronic renal failure. University of Copenhagen, Copenhagen1999: 1-84Google Scholar, 12.Bianchi M.L. Colantonio G. Campanini F. et al.Calcitriol and calcium carbonate therapy in early chronic renal failure.Nephrol Dial Transplant. 1994; 9: 1595-1599PubMed Google Scholar. Compared to changes in BMD measurements over six months prior to treatment, Bianchi et al12.Bianchi M.L. Colantonio G. Campanini F. et al.Calcitriol and calcium carbonate therapy in early chronic renal failure.Nephrol Dial Transplant. 1994; 9: 1595-1599PubMed Google Scholar found slowing of bone loss in the forearm and spine following 24 months of calcitriol treatment 0.25 μg/day. In an RCT, Przedlacki et al6.Przedlacki J. Manelius J. Huttunen K. Bone mineral density evaluated by dual-energy X-ray absorptiometry after one-year treatment with calcitriol started in the predialysis phase of chronic renal failure.Nephron. 1995; 69: 433-437Crossref PubMed Scopus (45) Google Scholar found significant improvement of BMD of the lumbar spine and femoral neck after treatment for one year with calcitriol, 0.25 μg/day, compared to the placebo group. In an 18-month placebo-controlled trial, Rix9.Rix M. Metabolic bone disease in patients with predialysis chronic renal failure. University of Copenhagen, Copenhagen1999: 1-84Google Scholar found improved BMD of the spine and femur in CKD patients given alfacalcidol compared to the placebo group; the alfacalidol dose averaged 0.44 μg/day. Another finding during treatment with an active vitamin D sterol is a significant reduction of elevated PTH levels in comparison to those receiving placebo6.Przedlacki J. Manelius J. Huttunen K. Bone mineral density evaluated by dual-energy X-ray absorptiometry after one-year treatment with calcitriol started in the predialysis phase of chronic renal failure.Nephron. 1995; 69: 433-437Crossref PubMed Scopus (45) Google Scholar, 7.Ritz E. Küster S. Schmidt-Gayk H. et al.Low-dose calcitriol prevents the rise in 1,84 iPTH without affecting serum calcium and phosphate in patients with moderate renal failure (prospective placebo-controlled multicentre trial).Nephrol Dial Transplant. 1995; 10: 2228-2234PubMed Google Scholar, 8.Hamdy N.A.T. Kanis J.A. Beneton M.N.C. et al.Effect of alfacalcidol on natural course of bone disease in mild to moderate renal failure.BMJ. 1995; 310: 358-363Crossref PubMed Scopus (283) Google Scholar, 9.Rix M. Metabolic bone disease in patients with predialysis chronic renal failure. University of Copenhagen, Copenhagen1999: 1-84Google Scholar, 10.Coburn J.W. Sprague S.M. Lindberg J.S. 1αD2 Study Group A comparison of controlled trials of doxercalciferol (1αD2) versus alfacalcidol (1αD3) for 2° hyperparathyroidism in chronic kidney disease (CKD).Nephrol Dial Transplant. 2002; 17: 7Google Scholar, 12.Bianchi M.L. Colantonio G. Campanini F. et al.Calcitriol and calcium carbonate therapy in early chronic renal failure.Nephrol Dial Transplant. 1994; 9: 1595-1599PubMed Google Scholar. The degree of reduction of PTH differed depending on the dosages used, the duration of treatment, and the changes of serum calcium. Hamdy et al8.Hamdy N.A.T. Kanis J.A. Beneton M.N.C. et al.Effect of alfacalcidol on natural course of bone disease in mild to moderate renal failure.BMJ. 1995; 310: 358-363Crossref PubMed Scopus (283) Google Scholar gave alfacalcidol at a starting dose of 0.25 μg/day and increased the dose if serum Ca did not increase "slightly" within the normal range; they noted a maximum reduction of intact PTH at six months, followed by a slow increase to baseline at the end of two years of treatment with a mean alfacalcidol dose of 0.42 μg/day. In contrast, intact PTH levels rose progressively in the placebo-treated patients over two years. The mean serum Ca level rose by approximately 0.4 mg/dL with alfacalcidol and was unchanged with placebo8.Hamdy N.A.T. Kanis J.A. Beneton M.N.C. et al.Effect of alfacalcidol on natural course of bone disease in mild to moderate renal failure.BMJ. 1995; 310: 358-363Crossref PubMed Scopus (283) Google Scholar. With calcitriol 0.25 μg/day, combined with supplemental calcium carbonate providing calcium 400 mg/day, Bianchi et al12.Bianchi M.L. Colantonio G. Campanini F. et al.Calcitriol and calcium carbonate therapy in early chronic renal failure.Nephrol Dial Transplant. 1994; 9: 1595-1599PubMed Google Scholar noted mean reductions of intact PTH by 35% and 42% after 12 and 24 months, respectively. These changes of intact PTH occurred in association with significant increments of mean serum Ca of 0.8 and 1.4 mg/dL at these periods, respectively. In an RCT, Ritz et al7.Ritz E. Küster S. Schmidt-Gayk H. et al.Low-dose calcitriol prevents the rise in 1,84 iPTH without affecting serum calcium and phosphate in patients with moderate renal failure (prospective placebo-controlled multicentre trial).Nephrol Dial Transplant. 1995; 10: 2228-2234PubMed Google Scholar gave calcitriol in a dose of only 0.125 μg/day for one year to patients with serum creatinine levels of 1.4 to 6.5 mg/dL. Serum Ca and P levels were unchanged with calcitriol treatment, and intact PTH levels did not fall. However, intact PTH levels rose in the placebo-treated patients. The changes of intact PTH during treatment with calcitriol versus placebo were most evident in patients with higher entry serum creatinine levels (≥3.0 mg/dL). In an RCT using doxercalciferol (1αD2), the initial dose of 1.0 μg/day was increased at intervals if the intact PTH was not lowered by 30%, and provided the serum calcium was below 9.6 mg/dL and serum P below 4.6 mg/dL10.Coburn J.W. Sprague S.M. Lindberg J.S. 1αD2 Study Group A comparison of controlled trials of doxercalciferol (1αD2) versus alfacalcidol (1αD3) for 2° hyperparathyroidism in chronic kidney disease (CKD).Nephrol Dial Transplant. 2002; 17: 7Google Scholar. During the six-month RCT, mean intact PTH fell by 46% in 1αD2-treated patients who exhibited a maximum increase of mean serum calcium of 0.4 mg/dL. Levels of intact PTH were unchanged in the placebo group; also, serum Ca and P did not differ significantly between the placebo and doxercalciferol groups. The average dose of 1αD2 was 1.6 μg/day at the end of the six- month trial. A major concern about the use of active vitamin D sterols is the occurrence of hypercalcemia. In the early trials with calcitriol, daily dosages were increased from 0.25 to 0.50 μg4.Nordal K.P. Dahl E. Low dose calcitriol versus placebo in patients with predialysis chronic renal failure.J Clin Endocrinol Metab. 1988; 67: 929-936Crossref PubMed Scopus (108) Google Scholar,5.Baker L.R.I. Abrams S.M.L. Roe C.J. et al.1,25(OH)2D3 administration in moderate renal failure: A prospective double-blind trial.Kidney Int. 1989; 35: 661-669Abstract Full Text PDF PubMed Scopus (164) Google Scholar, or even to 0.75 μg3.Massry S.G. et al.Assessment of 1,25(OH2D3 in the correction and prevention of renal osteodystrophy in patients with mild to moderate renal failure.in: Norman A.W. Schaefer K. Grigoleit H-G. Vitamin D: A Chemical, Biochemical and Clinical Update. de Gruyter, Berlin1985: 935-937Google Scholar; the higher doses led to unacceptable rises of serum Ca that necessitated a dose reduction in most patients. In subsequent RCTs and in open-label studies, hypercalcemia was unusual with the use of calcitriol in doses that did not exceed 0.25 μg/day6.Przedlacki J. Manelius J. Huttunen K. Bone mineral density evaluated by dual-energy X-ray absorptiometry after one-year treatment with calcitriol started in the predialysis phase of chronic renal failure.Nephron. 1995; 69: 433-437Crossref PubMed Scopus (45) Google Scholar, 11.Coen G. Mazzaferro S. Bonucci E. et al.Treatment of secondary hyperparathyroidism of pre-dialysis chronic renal failure with low doses of 1,25(OH)2D3: Humoral and histomorphometric results.Miner Electrolyte Metab. 1986; 12: 375-382PubMed Google Scholar, 12.Bianchi M.L. Colantonio G. Campanini F. et al.Calcitriol and calcium carbonate therapy in early chronic renal failure.Nephrol Dial Transplant. 1994; 9: 1595-1599PubMed Google Scholar, and with alfacalcidol in doses of 0.25 to 0.5 μg/day8.Hamdy N.A.T. Kanis J.A. Beneton M.N.C. et al.Effect of alfacalcidol on natural course of bone disease in mild to moderate renal failure.BMJ. 1995; 310: 358-363Crossref PubMed Scopus (283) Google Scholar. In the two-year study of Hamdy et al8.Hamdy N.A.T. Kanis J.A. Beneton M.N.C. et al.Effect of alfacalcidol on natural course of bone disease in mild to moderate renal failure.BMJ. 1995; 310: 358-363Crossref PubMed Scopus (283) Google Scholar that included 89 alfacalcidol-treated patients, serum Ca exceeded 12.0 mg/dL in four patients and reached 10.5 to 12.0 mg/dL in 10 alfacalcidol patients, compared to three of 87 placebo patients. Bianchi et al12.Bianchi M.L. Colantonio G. Campanini F. et al.Calcitriol and calcium carbonate therapy in early chronic renal failure.Nephrol Dial Transplant. 1994; 9: 1595-1599PubMed Google Scholar found mean serum Ca 8.5 ± 0.3 (SE) at baseline and 9.3 ± 0.2 and 9.9 ± 0.2 mg/dL after treatment for 12 and 24 months, respectively; the incidence of hypercalcemia was not reported. A risk of hypercalcemia would most likely be greater in patients given vitamin D sterols in the less structured follow-up of clinical practice. The occurrence of hypercalcemia would be more common as renal function decreases and there is less ability of the diseased kidney to excrete additional calcium. In the placebo-controlled trials, serum P levels were either unchanged or rose slightly with time in the studies of longer duration, as renal function decreased in both treated and placebo patients8.Hamdy N.A.T. Kanis J.A. Beneton M.N.C. et al.Effect of alfacalcidol on natural course of bone disease in mild to moderate renal failure.BMJ. 1995; 310: 358-363Crossref PubMed Scopus (283) Google Scholar,19.Coen G. Mazzaferro S. Manni M. et al.Treatment with small doses of 1,25-dihydroxyvitamin D3 in predialysis chronic renal failure may lower the rate of decline of renal function.Ital J Miner Electrolyte Metab. 1994; 8: 117-121Google Scholar. There were no differences between those receiving placebo or the active vitamin D sterol. Another potentially adverse event would be the conversion of bone disease to adynamic, or low-turnover bone "disease." In the RCT of Baker et al5.Baker L.R.I. Abrams S.M.L. Roe C.J. et al.1,25(OH)2D3 administration in moderate renal failure: A prospective double-blind trial.Kidney Int. 1989; 35: 661-669Abstract Full Text PDF PubMed Scopus (164) Google Scholar that utilized calcitriol in seven patients at doses up to 0.50 μg/day, there was concern about the risk of excessive reduction of bone formation leading to adynamic bone (H. Malluche, personal communication, 2002). Bianchi et al did not find adynamic bone after 24 months of treatment with calcitriol 0.25 μg/day. In the Hamdy study8.Hamdy N.A.T. Kanis J.A. Beneton M.N.C. et al.Effect of alfacalcidol on natural course of bone disease in mild to moderate renal failure.BMJ. 1995; 310: 358-363Crossref PubMed Scopus (283) Google Scholar, nine patients had adynamic bone on the initial biopsy before treatment; this disorder resolved in four of six alfacalcidol-treated patients and two of three placebo patients. After two years of treatment, eight of 72 alfacalcidol-treated patients had developed adynamic bone, compared to four of 62 placebo-treated patients. In contrast to the rarity of low bone turnover, adynamic bone was found in 32% of 92 stage 5 CKD predialysis patients who had bone biopsies at the time of vascular access surgery18.Hernandez D. Concepcion M.T. Lorenzo V. et al.Adynamic bone disease with negative aluminum staining in predialysis patients: Prevalence and evolution after maintenance dialysis.Nephrol Dial Transplant. 1994; 9: 517-523PubMed Google Scholar; these patients never received active vitamin D sterols, indicating no relation between the development of this lesion and vitamin D treatment. Thus, a risk of developing adynamic bone seems small in stage 3 and 4 CKD patients when there are only small increments of serum calcium. Another concern is whether treatment with an active vitamin D sterol can cause impairment of renal function. With the use of calcitriol in doses of 0.5 μg/day for four months in 10 CKD patients, Bertoli et al13.Bertoli M. Luisetto G. Ruffatti A. et al.Renal function during calcitriol therapy in chronic renal failure.Clin Nephrol. 1990; 33: 98-102PubMed Google Scholar observed increments of serum creatinine and reductions of creatinine clearance; however, GFR measured by inulin clearance did not change. Two months after calcitriol was stopped, serum creatinine levels returned to baseline. Calcitriol can raise serum creatinine levels in individuals with normal renal function, as well. Thus, small but significant increments of serum creatinine were noted in both healthy, elderly women given calcitriol 0.5 μg/day for 12 months20.Jensen G.F. Christiansen C. Transbol I. 1,25(OH)2D3 and renal function.Acta Med Scand. 1982; 211: 51-54Crossref PubMed Scopus (10) Google Scholar, and in psoriatic patients given calcitriol 1.5 to 4.0 μg each night21.Perez A. Raab R. Chen T.C. et al.Safety and efficacy of oral calcitriol (1,25-dihydroxyvitamin D3) for the treatment of psoriasis.Br J Derm. 1996; 134: 1070-1078Crossref PubMed Scopus (135) Google Scholar. In eight CKD and psoriatic patients, inulin and creatinine clearances were measured before and after six months of treatment; creatinine clearance fell by 24%, but there was no change in GFR as measured by inulin clearance21.Perez A. Raab R. Chen T.C. et al.Safety and efficacy of oral calcitriol (1,25-dihydroxyvitamin D3) for the treatment of psoriasis.Br J Derm. 1996; 134: 1070-1078Crossref PubMed Scopus (135) Google Scholar. These observations are consistent with calcitriol in doses of 0.5 μg/day and above, reducing the renal tubular secretion of creatinine, but without affecting GFR. The retrospective observations of Coen et al19.Coen G. Mazzaferro S. Manni M. et al.Treatment with small doses of 1,25-dihydroxyvitamin D3 in predialysis chronic renal failure may lower the rate of decline of renal function.Ital J Miner Electrolyte Metab. 1994; 8: 117-121Google Scholar, who evaluated changes of renal function utilizing the slope of 1/serum creatinine, indicate a reduced rate of progression of CKD in a significant fraction of patients given calcitriol 0.25 μg/day, compared to CKD patients not given the vitamin D sterol; such data suggest that calcitriol, given in a dose of 0.25 μg/day, may not affect the tubular secretion of creatinine. Another concern is whether treatment with an active vitamin D sterol might enhance the development of vascular calcification, thus making such patients more likely to have significant vascular disease by the time they reach ESRD. There is evidence that small increments of serum calcium associated with use of calcium-based phosphate binders can accelerate the deposition of calcium in coronary arteries of ESRD patients22.Chertow G.M. Burke S.K. Raggi P. Treat to Goal Working Group Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients.Kidney Int. 2002; 62: 245-252Abstract Full Text Full Text PDF PubMed Scopus (1269) Google Scholar, but such data are not available in those with stage 3 and 4 CKD. Nonetheless, these data raise concern about any treatment that would cause a rise of serum calcium into the upper range of normal. On the basis of available information, general guidelines for the use of active vitamin D sterols in patients with stage 3 and 4 CKD are given in Tables 1 and 2. These recommendations are similar to those considered by the Work Group for the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI). Many of the RCTs and certain clinical trials have recruited all compliant patients with stage 3 or 4 CKD independent of the entry PTH levels. However, the recommendations are to limit such treatment to patients with more severe secondary hyperparathyroidism compared to those in the reported trials. These guidelines are intended to provide optimal safety (particularly to prevent overt hypercalcemia), to avoid more rapid deterioration of renal function, and to avoid the acceleration of soft tissue calcification and/or vascular calcifications. As noted elsewhere in this paper, it is recommended that "vitamin D insufficiency," as indicated by suboptimal levels of 25(OH)-vitamin D, be treated appropriately before resorting to the use of the highly potent active vitamin D sterols. The "ideal" or target serum calcium is recommended to be in the lower range of normal, and active vitamin D treatment is not recommended when serum calcium, corrected for albumin, exceeds 9.5 mg/dL, or the serum phosphorus is greater than 4.5 mg/dL. It is also recommended that such CKD patients first be treated with phosphate-restricted diets and the addition of phosphate-binding agents combined with appropriate supplemental calcium intake. If iPTH levels fall into the desirable range, treatment with an active vitamin D sterol would not be necessary. The low therapeutic index of these potent active vitamin D sterols must be recognized, and adequate follow-up of patients entered into such treatment is essential. Further data are needed to identify whether the "newer" vitamin D sterols may be safer than calcitriol or alfacalcidol.Table 1Recommendations for therapy with active vitamin D sterol in CKD, stage 3aIf serum 25(OH)-vitamin D level <30 ng/mL, give supplemental vitamin D2 or D3Measure intact PTH If <70 pg/mL, monitor patient and maintain S-Ca 8.8 to 9.5 mg/dL and S-P 3.0 to 4.6 mg/dL If ≥70 pg/mL, follow next guideline If S-Ca ≤9.5 mg/dL despite supplemental Ca and S-P 9.5 mg/dL, lower Ca-based P-binder dose or vitamin D dose S-P ≥4.6 mg/dL, reduce P intake and/or raise P-binder dose If S-P remains ≥4.6 mg/dL, reduce or stop vitamin DFollow intact PTH levels quarterly If PTH>70 pg/mL, maintain and/or resumecAfter vitamin D is stopped for high S-P or S-Ca, or low PTH, the dose should be reduced active vitamin D If PTH ≤35 pg/mL, stop active vitamin D If PTH>35 to ≤50 pg/mL, reduce active vitamin D doseFollow S-Ca, S-P, and PTH Manage using same parameters noted abovea If serum 25(OH)-vitamin D level <30 ng/mL, give supplemental vitamin D2 or D3b Vitamin D sterols approved for treating secondary hyperparathyroidism in CKD, stages 3 and 4c After vitamin D is stopped for high S-P or S-Ca, or low PTH, the dose should be reduced Open table in a new tab Table 2Recommendations for therapy with active vitamin D sterol in CKD, stage 4aIf serum 25(OH)-vitamin D level <30 ng/mL, give supplemental vitamin D2 or D3Measure intact PTH If <110 pg/mL, monitor patient: maintain S-Ca 8.8 to 9.5 mg/dL and S-P 3.0 to 4.6 mg/dL If ≥110 pg/mL, follow next guideline If S-Ca ≤9.5 mg/dL despite supplemental Ca and S-P 9.5 mg/dL, lower Ca-based P-binder dose or vitamin D dose S-P ≥4.6 mg/dL, reduce P intake and/or raise P-binder dose If S-P remains ≥4.6 mg/dL, reduce or stop active vitamin DFollow intact PTH levels quarterly If PTH>85 pg/mL, maintain and/or resumecAfter vitamin D is stopped for high S-P or S-Ca, or low PTH, the dose should be reduced active level vitamin D If PTH ≤70 pg/mL, stop active vitamin D If PTH>70 to ≤85 pg/mL, reduce active vitamin D dosea If serum 25(OH)-vitamin D level <30 ng/mL, give supplemental vitamin D2 or D3b Vitamin D sterols approved for treating secondary hyperparathyroidism in CKD, stages 3 and 4c After vitamin D is stopped for high S-P or S-Ca, or low PTH, the dose should be reduced Open table in a new tab
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