Effects of vitamin D supplementation on the calcium–phosphate balance in renal transplant patients
2008; Elsevier BV; Volume: 75; Issue: 6 Linguagem: Inglês
10.1038/ki.2008.549
ISSN1523-1755
AutoresMarie Courbebaisse, Éric Thervet, J.-C. Souberbielle, Julien Zuber, Dominique Eladari, Frank Martinez, Marie‐France Mamzer, Pablo Ureña, Christophe Legendre, Gérard Friedlander, Dominique Prié,
Tópico(s)Electrolyte and hormonal disorders
ResumoLow serum levels of 25-hydroxy vitamin D frequently occur after renal transplantation, but few studies have evaluated the effects of normalizing this on serum parathyroid hormone and calcium levels or urinary calcium excretion. To determine this we compared the outcomes of 94 renal transplant patients with low 25-hydroxy vitamin D and normal serum calcium levels who were either treated or not with cholecalciferol every 2 weeks for 2 months (intensive phase) followed by an every other month maintenance phase. The biological characteristics of the two equally divided patient groups did not differ before treatment. After the intensive phase, serum 25-hydroxy vitamin D levels were normalized in all but 3 patients and the serum parathyroid hormone decreased and calcium levels increased with no severe adverse effects. During the maintenance phase, the serum 25-hydroxy vitamin D level decreased but remained significantly higher than in controls. In the control group, the serum 25-hydroxy vitamin D concentration increased slightly but became normal in only three patients. Serum 25-hydroxy vitamin D levels were significantly higher and parathyroid hormone levels were lower in treated patients compared to controls one year following transplant. Hence, cholecalciferol treatment significantly increased serum 25-hydroxy vitamin D and decreased parathyroid hormone levels with no adverse effects in 25-hydroxy vitamin D–deficient renal transplant patients. Low serum levels of 25-hydroxy vitamin D frequently occur after renal transplantation, but few studies have evaluated the effects of normalizing this on serum parathyroid hormone and calcium levels or urinary calcium excretion. To determine this we compared the outcomes of 94 renal transplant patients with low 25-hydroxy vitamin D and normal serum calcium levels who were either treated or not with cholecalciferol every 2 weeks for 2 months (intensive phase) followed by an every other month maintenance phase. The biological characteristics of the two equally divided patient groups did not differ before treatment. After the intensive phase, serum 25-hydroxy vitamin D levels were normalized in all but 3 patients and the serum parathyroid hormone decreased and calcium levels increased with no severe adverse effects. During the maintenance phase, the serum 25-hydroxy vitamin D level decreased but remained significantly higher than in controls. In the control group, the serum 25-hydroxy vitamin D concentration increased slightly but became normal in only three patients. Serum 25-hydroxy vitamin D levels were significantly higher and parathyroid hormone levels were lower in treated patients compared to controls one year following transplant. Hence, cholecalciferol treatment significantly increased serum 25-hydroxy vitamin D and decreased parathyroid hormone levels with no adverse effects in 25-hydroxy vitamin D–deficient renal transplant patients. Low serum 25-hydroxyvitamin (25-OH) vitamin D concentration is a frequent finding in renal transplant recipients (RTRs)1.Querings K. Girndt M. Geisel J. et al.25-Hydroxyvitamin D deficiency in renal transplant recipients.J Clin Endocrinol Metab. 2006; 91: 526-529Crossref PubMed Scopus (123) Google Scholar, 2.Sadlier D.M. Magee C.C. Prevalence of 25(OH) vitamin D (calcidiol) deficiency at time of renal transplantation: a prospective study.Clin Transplant. 2007; 21: 683-688PubMed Google Scholar, 3.Stavroulopoulos A. Cassidy M.J. Porter C.J. et al.Vitamin D status in renal transplant recipients.Am J Transplant. 2007; 7: 2546-2552Crossref PubMed Scopus (133) Google Scholar that can generate secondary hyperparathyroidism.4.Boudville N.C. Hodsman A.B. Renal function and 25-hydroxyvitamin D concentrations predict parathyroid hormone levels in renal transplant patients.Nephrol Dial Transplant. 2006; 21: 2621-2624Crossref PubMed Scopus (56) Google Scholar, 5.Lomonte C. Antonelli M. Vernaglione L. et al.Are low plasma levels of 25-(OH)vitamin D a major risk factor for hyperparathyroidism independent of calcitriol in renal transplant patients?.J Nephrol. 2005; 18: 96-101PubMed Google Scholar Several studies suggest that in non-renal transplant subjects, serum 25-OH vitamin D concentration should be maintained above 30 ng/ml6.Dawson-Hughes B. Heaney R.P. Holick M.F. et al.Estimates of optimal vitamin D status.Osteoporos Int. 2005; 16: 713-716Crossref PubMed Scopus (1512) Google Scholar, 7.Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10618) Google Scholar, 8.Malabanan A. Veronikis I.E. Holick M.F. Redefining vitamin D insufficiency.Lancet. 1998; 351: 805-806Abstract Full Text Full Text PDF PubMed Scopus (939) Google Scholar, 9.Vieth R. Why the optimal requirement for Vitamin D3 is probably much higher than what is officially recommended for adults.J Steroid Biochem Mol Biol. 2004; 89–90: 575-579Crossref PubMed Scopus (243) Google Scholar to prevent serum parathormone (PTH) levels from increasing. In most RTRs, serum 25-OH vitamin D concentration is below this value in the months or years following transplantation.1.Querings K. Girndt M. Geisel J. et al.25-Hydroxyvitamin D deficiency in renal transplant recipients.J Clin Endocrinol Metab. 2006; 91: 526-529Crossref PubMed Scopus (123) Google Scholar, 2.Sadlier D.M. Magee C.C. Prevalence of 25(OH) vitamin D (calcidiol) deficiency at time of renal transplantation: a prospective study.Clin Transplant. 2007; 21: 683-688PubMed Google Scholar, 3.Stavroulopoulos A. Cassidy M.J. Porter C.J. et al.Vitamin D status in renal transplant recipients.Am J Transplant. 2007; 7: 2546-2552Crossref PubMed Scopus (133) Google Scholar This may be because of various causes: (1) insufficient vitamin D supplementation in dialysis and after transplantation, (2) reduced sun exposure recommended to RTR to prevent skin cancers, and (3) increased 25-OH vitamin D catabolism induced by immunosuppressive drugs and increased fibroblast growth factor-23 secretion, which is a common finding in RTR.10.Bhan I. Shah A. Holmes J. et al.Post-transplant hypophosphatemia: tertiary ‘hyper-phosphatoninism’?.Kidney Int. 2006; 70: 1486-1494Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar, 11.Pande S. Ritter C.S. Rothstein M. et al.FGF-23 and sFRP-4 in chronic kidney disease and post-renal transplantation.Nephron Physiol. 2006; 104: p23-p32Crossref PubMed Scopus (78) Google Scholar Indeed, in rats, fibroblast growth factor-23 stimulates 24 hydroxylase enzyme activity, increases 25-OH vitamin D conversion into 24,25-(OH)2 vitamin D, and decreases serum 25-OH vitamin D concentration.12.Saito H. Kusano K. Kinosaki M. et al.Human fibroblast growth factor-23 mutants suppress Na+-dependent phosphate co-transport activity and 1alpha,25-dihydroxyvitamin D3 production.J Biol Chem. 2003; 278: 2206-2211Crossref PubMed Scopus (347) Google Scholar In RTR, as in nontransplant populations, low 25-OH vitamin D levels may be associated with osteomalacia, osteoporosis, and may increase the risks of fractures,13.Chapuy M.C. Arlot M.E. Duboeuf F. et al.Vitamin D3 and calcium to prevent hip fractures in the elderly women.N Engl J Med. 1992; 327: 1637-1642Crossref PubMed Scopus (2656) Google Scholar cancers,7.Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10618) Google Scholar autoimmune,7.Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10618) Google Scholar and cardiovascular diseases.14.Zittermann A. Vitamin D and disease prevention with special reference to cardiovascular disease.Prog Biophys Mol Biol. 2006; 92: 39-48Crossref PubMed Scopus (366) Google Scholar, 15.Zittermann A. Schleithoff S.S. Tenderich G. et al.Low vitamin D status: a contributing factor in the pathogenesis of congestive heart failure?.J Am Coll Cardiol. 2003; 41: 105-112Abstract Full Text Full Text PDF PubMed Scopus (488) Google Scholar The National Kidney Foundation/Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) guidelines recommend vitamin D supplementation when serum 25-OH vitamin D concentration is lower than 30 ng/ml in patients with chronic kidney disease stage 3 or 4. According to these guidelines, RTRs should be managed as non-transplant chronic kidney disease patients with similar glomerular filtration rate (GFR) for bone and mineral metabolism.16.National Kidney Foundation K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease.Am J Kidney Dis. 2003; 42: S1-S201PubMed Google Scholar Despite these recommendations, most RTRs do not receive vitamin D supplementation for at least two reasons: first, it is unknown if vitamin D supplements at the doses required to achieve 25-OH vitamin D concentrations above 30 ng/ml could induce hypercalcemia, hypercalciuria, or hyperphosphatemia, all disorders that could have adverse outcomes on renal function and patient survival. Second, it is uncertain if increasing serum 25-OH vitamin D concentration above 30 ng/ml will reduce serum PTH concentration in RTR. In our department, until 2006 RTRs were not treated with 25-OH vitamin D during the first year following renal transplantation. From May 2006 vitamin D supplements were given in the absence of hypercalcemia in all renal transplants with serum 25-OH vitamin D concentration below 30 ng/ml 3 months after renal transplantation. In this study we evaluated the effects of the treatment by cholecalciferol, a precursor of 25-OH vitamin D, on serum 25-OH vitamin D, PTH levels, and on calcium–phosphate balance in 47 patients and compared these results with those obtained in another group of 47 RTRs who did not receive vitamin D supplementation. Patient clinical characteristics are presented in Table 1. Among the patients who received a renal transplant in our department since May 2006, 49 had normal or low serum calcium concentrations and 25-OH vitamin D levels below 30 ng/ml at M3 and were consequently treated with cholecalciferol according to the regimen described in ‘Materials and Methods’. Two patients were excluded from the analyses because of the lack of compliance to treatment. A total of 47 patients transplanted from May 2005 to December 2005 met the criteria described above and were not supplemented with vitamin D. These 47 untreated patients were considered as a control group for the statistical analyses. Treated and untreated patients did not statistically differ for age, gender immunosuppressive treatment, initial nephropathy, and number of acute rejection (Table 1).Table 1Demographic and treatment characteristicsTreated patientsUntreated patientsPRecipient age46.82±2.1845.30±2.18NSRecipient gender (M/F)29/1828/19NSImmunosuppressive regimenNS Biological induction (D0)98%100%NS Cyclosporine (M3/M12) (n, %)13 (28)/16 (35)22 (47)/15 (32)NS Tacrolimus (M3/M12) (n, %)30 (65)/30 (65)24 (51)/29 (62)NS Steroid dose (M3/M12) (mg)9.8±7.5/5.9±4.010.7±7.9/7.8±3.7NSAcute rejection incidence20%25.5%NSInitial nephropathy Chronic glomerulonephritis2212NS Polycystic disease58 Chronic interstitial nephritis35 Uropathy64 Diabetic nephropathy25 Vascular nephropathy26 NA77F, female; M, male; NA, not available; NS, not significant. Open table in a new tab F, female; M, male; NA, not available; NS, not significant. At M3 biological characteristics of treated and untreated patients were similar as shown in Table 2.Table 2Biochemical parameters at month 3, before cholecalciferol therapy was initiated in the treated groupTreated group (n=47)Untreated group (n=47)PMonth 3 Serum Ca (mmol/l)2.29 (2.08–2.51)2.30 (2.05–2.52)NS Serum phosphate (mmol/l)0.78 (0.56–1.30)0.76 (0.37–1.13)NS PTH (pg/ml)68 (19–668)78 (24–346)NS 25-OH vitamin D (ng/ml)14 (5–30)12 (4–28)NS Urinary Ca/Creat (mmol/mmol)0.09 (0.003–1.09)0.08 (0.006–0.52)NS GFR (ml/min)58 (24–106)59 (25–92)NSGFR, glomerular filtration rate; NS, not significant; PTH, parathormone. All differences were nonsignificant. Open table in a new tab GFR, glomerular filtration rate; NS, not significant; PTH, parathormone. All differences were nonsignificant. From month 4 (M4) to month 6 (M6) the treated patients received cholecalciferol 100,000 IU every 2 weeks (intensive phase). As shown in Figure 1, median serum 25-OH vitamin D concentration increased significantly at M6 compared to M3 (M3: median 14 ng/ml, range 5–30; M6: median 43, range 16–72; P<0.0001; Figure 1a) and reached values above 30 ng/ml in all but three patients. This was associated with a significant decrease in serum PTH concentration between M3 and M6 (M3: median 76 pg/ml, range 19–668; M6: median 63, range 14–364; P=0.028; Figure 1b). Serum calcium concentration increased significantly from M3 to M6 (M3: median 2.29, range 2.08–2.51 mmol/l; M6: median 2.42, range 2.18–2.71 mmol/l; P<0.001; Figure 1c) but remained within the normal range, below 2.70 mmol/l, in all but one patient. Serum phosphate levels moderately rose from 0.78 mmol/l (range 0.56–1.30) to 1.04 mmol/l (range 0.71–1.53) (P<0.0001; Figure 1d). We observed no case of hypercalciuria induced by the cholecalciferol treatment. At M3 one patient exhibited fasting hypercalciuria that persisted at M6. Median fasting urinary calcium excretion did not change significantly between M3 and M6 (M3: median 0.09, range 0.003–1.09 mmol/l; M6: median 0.12, range 0.01–1.22 mmol/l; Figure 1e). After M6, the treated patients received cholecalciferol 100,000 IU every other month (maintenance phase). In this group serum 25-OH vitamin D concentration significantly decreased from M6 to M12 but remained above M3 values (Figure 1a). At M12 25-OH vitamin D concentration remained above 30 ng/ml in only 24 treated subjects (51%). The decrease in serum 25-OH vitamin D concentration between M6 and M12 (Figure 1a) was associated with a significant decrease in mean serum calcium (Figure 1c) and phosphate (Figure 1e) concentrations whereas median serum PTH concentration (Figure 1b) and urinary Ca/creatinine ratio (Figure 1e) did not change significantly. At M12 all treated patients had serum calcium concentration below 2.70 mmol/l, and normal urinary calcium excretion. GFR did not significantly vary between M3 and M12 (M3: median 58 ml/min, range 24–106; M12: median 56 ml/min, range 19–93, P=0.104). Serum 25-OH vitamin D concentration slightly but significantly increased between M3 and M12 in the patients who did not received cholecalciferol supplementation (M3: median 12 ng/ml, range 4–28; M12 median 14 ng/ml, range 4–46, P=0.0043, Wilcoxon matched-pairs test). This slight increase in 25-OH vitamin D concentration in untreated patients was not accompanied by significant changes of serum PTH (Figure 2b), calcium or phosphate concentrations (Figure 2c), or urinary calcium excretion (Figure 2d) between M3 and M12. GFR remained stable (M3: median 59 ml/min, range 25–92; M12: median 59 ml/min, range 27–101, P=0.946). At M3 the two groups of patients did not differ. The numbers of patients with serum PTH concentration within the values recommended by the NKF-KDOQI guidelines were not statistically different between the two groups (Table 3). At M12 serum 25-OH vitamin D concentrations were significantly higher in treated than in untreated patients (Figure 3a, P<0.0001, Mann–Whitney test). Serum PTH concentration was significantly lower and serum calcium concentration was significantly higher in treated patients than in untreated subjects (Figure 3b and c), and the number of patients with serum PTH concentration within the NKF-KDOQI recommended values was significantly higher in the treated group (Table 3). Serum phosphate concentration and urinary calcium excretion did not differ between the two groups at M12 (Figure 3d and e). At M12 the number of patients with 25-OH vitamin D concentration above 30 ng/ml was significantly higher in the group who received cholecalciferol (24/47 versus 3/47, P<0.0001, χ2-test). GFR was not different between the two groups (treated median 56 ml/min, range 19–93 ml/min; untreated median 59 ml/min, range 27–101, P=0.267).Table 3Number of cholecalciferol-treated or nontreated patients with serum PTH concentration within (KDOQI+) or not (KDOQI-) KDOQI recommended values according to their GFR at M3 and M12M3M12Treated groupControl groupTreated groupControl groupKDOQI+24193418KDOQI-23281329KDOQI, Kidney Disease Outcomes Quality Initiative. At M3 the number of patients with serum PTH concentration within KDOQI recommended value was not different between the two groups (χ2, P=0.41). At M12 the number of patients with serum PTH concentration within recommended KDOQI range was significantly higher in the treated group (χ2, P=0.002). Open table in a new tab KDOQI, Kidney Disease Outcomes Quality Initiative. At M3 the number of patients with serum PTH concentration within KDOQI recommended value was not different between the two groups (χ2, P=0.41). At M12 the number of patients with serum PTH concentration within recommended KDOQI range was significantly higher in the treated group (χ2, P=0.002). This study shows that treating RTRs with four doses of 100,000 IU cholecalciferol from M4 to M6 after transplantation increases serum 25-OH vitamin D concentration above 30 ng/ml in almost all patients, decreases serum PTH levels, and has no adverse effects on calcium and phosphate concentrations. This study also indicates that the dose of cholecalciferol used during the maintenance phase was insufficient to maintain serum 25-OH vitamin D concentration above 30 ng/ml in half of the patients. In the absence of cholecalciferol supplementation, serum 25-OH vitamin D concentration slightly increased within the first year following renal transplantation. However only three patients of the control group had 25-OH vitamin D levels above 30 ng/ml at M12 and serum calcium and PTH levels remained below those of RTR of the treated group. This confirms that common diets do not bring enough vitamin D to normalize vitamin D status in RTRs. The threshold of 30 ng/ml for serum 25-OH vitamin D concentration was chosen on the basis of data showing that increasing serum 25-OH vitamin D concentration above such levels results in a decrease in serum PTH levels in non-RTR.7.Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10618) Google Scholar, 13.Chapuy M.C. Arlot M.E. Duboeuf F. et al.Vitamin D3 and calcium to prevent hip fractures in the elderly women.N Engl J Med. 1992; 327: 1637-1642Crossref PubMed Scopus (2656) Google Scholar, 17.Holick M.F. Siris E.S. Binkley N. et al.Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy.J Clin Endocrinol Metab. 2005; 90: 3215-3224Crossref PubMed Scopus (740) Google Scholar, 18.Thomas M.K. Lloyd-Jones D.M. Thadhani R.I. et al.Hypovitaminosis D in medical inpatients.N Engl J Med. 1998; 338: 777-783Crossref PubMed Scopus (1272) Google Scholar Our data indicate that this threshold is relevant in RTR, as the increase in serum 25-OH vitamin D concentration at M6 was associated with a decrease in serum PTH levels and an increase in calcium concentration. The decrease in serum PTH concentration may be due to an increase in 1,25(OH)2 vitamin D production in the kidney or in the parathyroid glands. This may also result from a direct effect of 25-OH vitamin D on PTH synthesis. Indeed Ritter et al.19.Ritter C.S. Armbrecht H.J. Slatopolsky E. et al.25-Hydroxyvitamin D(3) suppresses PTH synthesis and secretion by bovine parathyroid cells.Kidney Int. 2006; 70: 654-659Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar reported that 25-OH vitamin D repressed PTH gene transcription and PTH secretion by activating vitamin D receptor in bovine parathyroid cells. Several studies report associations between low 25-OH vitamin D plasma concentrations and cardiovascular disease or cancer incidence and a decrease in the frequencies of these disorders in subjects treated with vitamin D.20.Autier P. Gandini S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials.Arch Intern Med. 2007; 167: 1730-1737Crossref PubMed Scopus (984) Google Scholar, 21.Giovannucci E. The epidemiology of vitamin D and cancer incidence and mortality: a review (United States).Cancer Causes Control. 2005; 16: 83-95Crossref PubMed Scopus (542) Google Scholar, 22.Giovannucci E. Vitamin D and cancer incidence in the Harvard cohorts.Ann Epidemiol. 2008Google Scholar, 23.Wang T.J. Pencina M.J. Booth S.L. et al.Vitamin D deficiency and risk of cardiovascular disease.Circulation. 2008; 117: 503-511Crossref PubMed Scopus (1927) Google Scholar The impact of the improvement of 25-OH vitamin D plasma concentrations on the risks of bone fracture, muscle strength, cardiovascular morbidity or mortality, and cancer occurrences in RTR remains to be established in larger studies with longer follow-up. In most RTRs, GFR and proximal tubule functions are often altered, which may hamper 25-OH vitamin D hydroxylation into calcitriol. Consequently, the threshold for suitable 25-OH vitamin D concentration may be higher than that recommended for healthy subjects. We cannot determine from our data whether increasing serum 25-OH vitamin D concentration above this threshold would result in a further decrease in serum PTH concentration in renal recipients. The achievement of the 25-OH vitamin D concentration threshold required high doses of cholecalciferol. We used the vitamin D doses recommended by Holick7.Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10618) Google Scholar to treat vitamin D deficiency in patients with chronic kidney disease. With similar doses Adewoye et al.24.Adewoye A.H. Chen T.C. Ma Q. et al.Sickle cell bone disease: response to vitamin D and calcium.Am J Hematol. 2008; 83: 271-274Crossref PubMed Scopus (51) Google Scholar corrected vitamin D deficiency in patients with sickle cell disease. The use of lower doses of cholecalciferol (25,000 IU once a month) as reported by Wissing et al.25.Wissing K.M. Broeders N. Moreno-Reyes R. et al.A controlled study of vitamin D3 to prevent bone loss in renal-transplant patients receiving low doses of steroids.Transplantation. 2005; 79: 108-115Crossref PubMed Scopus (91) Google Scholar failed to correct 25-OH vitamin D insufficiency in renal transplants. During the maintenance treatment phase, from M6 to M12, we reduced the doses of cholecalciferol supplementation. Although serum 25-OH vitamin D concentration was above 30 ng/ml in almost all patients at M6, the dosage of cholecalciferol used from M6 to M12 was insufficient to maintain 25-OH vitamin D concentration above the target in 49% of patients, resulting in a significant decrease in serum calcium levels. This finding suggests that RTRs have important needs of vitamin D to maintain calcium–phosphate balance. In a recent review Holick7.Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10618) Google Scholar suggested a maintenance dose of 100,000 IU/month of cholecalciferol in patients with chronic kidney diseases, our data support this recommendation. Further studies are needed to determine the optimal cholecalciferol dosage required to maintain serum 25-OH vitamin D concentration above 30 ng/ml in these patients. However, our data suggest that measurements of serum 25-OH vitamin D concentrations should be performed at least three times in the first year following renal transplantation to adjust cholecalciferol treatment to achieve the targeted 25-OH vitamin D concentration. Generally, GFR is below normal values in most of RTRs, and inappropriate vitamin D supplementation might induce hypercalcemia, hyperphosphatemia, or hypercalciuria. Our results indicate that our treatment procedure to reverse vitamin D insufficiency does not induce those adverse effects. Dosages similar to those used in the present study and associated with oral calcium supplementation in some subjects did not induce adverse effects in non-renal transplant patients.26.Adams J.S. Kantorovich V. Wu C. et al.Resolution of vitamin D insufficiency in osteopenic patients results in rapid recovery of bone mineral density.J Clin Endocrinol Metab. 1999; 84: 2729-2730Crossref PubMed Scopus (97) Google Scholar, 27.Kimball S.M. Ursell M.R. O’Connor P. et al.Safety of vitamin D3 in adults with multiple sclerosis.Am J Clin Nutr. 2007; 86: 645-651PubMed Google Scholar, 28.Wu F. Staykova T. Horne A. et al.Efficacy of an oral, 10-day course of high-dose calciferol in correcting vitamin D deficiency.NZ Med J. 2003; 116: U536PubMed Google Scholar Recent studies indicate that toxicity occurs for serum 25-OH vitamin D concentration beyond 200 ng/ml, the maximal serum 25-OH vitamin D concentration reached in our study was far below that value.29.Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety.Am J Clin Nutr. 1999; 69: 842-856Crossref PubMed Scopus (1194) Google Scholar, 30.Vieth R. Critique of the considerations for establishing the tolerable upper intake level for vitamin D: critical need for revision upwards.J Nutr. 2006; 136: 1117-1122PubMed Scopus (104) Google Scholar In summary, we show that vitamin D deficiency persists 1 year after renal transplantation in the absence of treatment and that the increase in serum 25-OH vitamin D concentration above 30 ng/ml requires high dose of cholecalciferol and improves secondary hyperparathyroidism in renal transplant. This goal can be reached without adverse effects. From May 2006 to December 2006, 49 adult patients were transplanted in our department and received cholecalciferol treatment according to a regimen detailed below, because they had serum 25-OH vitamin D levels below 30 ng/ml 3 months after transplantation. None of these patients were hypercalcemic (serum calcium concentration <2.70 mmol/l) when cholecalciferol treatment was started. From May 2005 to December 2005, 47 adult patients had a renal transplantation in our department, and 25-OH vitamin D levels below 30 ng/ml in the absence of hypercalcemia and did not receive vitamin D supplementation. These latter patients were considered as a control group to compare the effects of cholecalciferol on calcium–phosphate balance and serum PTH concentration. The group of vitamin D-treated RTRs received four oral doses of 100,000 IU cholecalciferol, once every 2 weeks from M4 to M6 after renal transplantation (intensive phase), then every 2 months until M12 (maintenance phase). The group of RTRs who had no vitamin D supplementation had the same follow up at M3 and M12 but did not receive cholecalciferol treatment. At M3 and M12, all patients had similar investigation including GFR measurement by iohexol clearance, serum calcium concentration, serum phosphate, PTH, 25-OH vitamin D, calcitriol levels, and urinary calcium excretion expressed as urinary calcium/creatinine ratio. At M6, which corresponds to the end of the intensive treatment period for treated patients, we measured in all treated patients serum calcium, phosphate, 25-OH vitamin D and PTH levels, and urinary calcium excretion (calcium/creatinine ratio). These measurements were performed 2 weeks after the last dose of cholecalciferol. Patient compliance to treatment was assessed by questioning. Calcium, phosphate, and creatinine concentrations were measured using standard methods. Serum PTH level was measured with immunochemiluminescent assays performed on the Elecsys analyzer (Roche Diagnostics, Meylan, France). 25-OH vitamin D concentration was measured by radioimmunoassay (DiaSorin, Stillwater, MN, USA). Results are expressed as median and range for quantitative variables. Quantitative variables were compared using nonparametric tests. Multiple paired comparisons were performed with the use of Friedman test and Wilcoxon matched-pairs test as post hoc test. To compare two paired values we performed Wilcoxon matched-pairs test. We used Mann–Whitney test to compare values of two unpaired groups. Categorical variables were compared using χ2-test. Type 1 error α<0.05 was considered as statistically significant. All comparisons were performed with the use of GraphPad InStat software for Macintosh.
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