Hemodialysis International 2015; 19:60–65

Weekly high-dose ergocalciferol to correct vitamin D deficiency/insufficiency in hemodialysis patients: A pilot trial Elisa DEL VALLE,1 Armando L. NEGRI,1 Erich FRADINGER,2 Manuel CANALIS,3 Pablo BEVIONE,3 Maria CURCELEGUI,3 Marina BRAVO,3 Marcelo PUDDU,3 Alicia MARINI,3 Jaime RYBA,3 Patricia PERI,3 Guillermo ROSA DIEZ,3 Luis SINTADO,3 Eduardo GOTTLIEB3 Departments of 1Nephrology and 2Biochemistry, Instituto de Investigaciones Metabólicas, Buenos Aires, Argentina; 3Department of Nephrology, Fresenius Medical Care, Buenos Aires, Argentina

Abstract Controversy exists on which vitamin D (D2 or D3) and which dosage scheme is the best to obtain and maintain adequate 25 OH D levels in dialysis patients safely. We tried to determine whether high-dose vitamin D2 supplementation could obtain optimal vitamin D status without inducing hypercalcemia. We studied 82 patients on dialysis not taking active vitamin D therapy and supplemented them with oral vitamin D2 72,000 IU/week for 12 weeks followed by 24,000 IU/week as maintenance therapy during 36 weeks. By week 12, serum 25(OH)D increased from 15.2 ± 5.4 to 42.5 ± 13.2 ng/mL (P < 0.01) at week 12 and remained optimal (34.7 ± 12.0); 84.8% of the patients reached values ≥30 ng/mL. iPTH and alkaline phosphatase did not change at 48 weeks compared with baseline, but bone alkaline phosphatase decreased significantly (54.3 ± 46.0 to 44.3 ± 25.0; P = 0.02). Uncorrected serum Ca increased significantly at the end of follow-up (9.03 ± 0.42 to 9.14 ± 0.62; P = 0.04); hypercalcemia was presented in two patients in the first control visit (week 12), in one patient in the second control (week 30), and in one patient in the third control (week 48). In 222 serum calcium determinations during follow-up, hypercalcemia was observed in only 1.8% of cases. This vitamin D2 oral regimen with initial high doses was safe and sufficient to obtain and maintain optimal serum 25(OH)D concentrations and prevent vitamin D insufficiency in chronic kidney disease patients on dialysis. Key words: High-dose ergocalciferol, vitamin D deficiency, hemodialysis, controlled trial

INTRODUCTION The prevalence of vitamin D deficiency (25(OH)D) in the general population ranges from 20% to 50% with race, age, sunlight exposure, and comorbid conditions such as diabetes and obesity accounting for the variation in prevaCorrespondence to: A. L. Negri, MD, Department of Nephrology, Instituto de Investigaciones Metabólicas, Libertad 836 1 Piso, Buenos Aires 1012, Argentina. E-mail: [email protected]

lence rates.1–3 Vitamin D deficiency prevalence is reported to be even higher in the chronic kidney disease (CKD) population, especially on dialysis, with estimates as high as 97%.4 In our own dialysis, population prevalence was 76.1% at the end of winter.5 Circulating 1,25(OH)2D generated from the kidney appears to drive most endocrine functions of vitamin D, such as its effects on calcium transport and mineral metabolism. Additional tissues, including prostate, breast, colon, testes, myocardium, pancreas, parathyroid glands, and components of the immune system, also

© 2014 International Society for Hemodialysis DOI:10.1111/hdi.12209

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express 1-alpha-hydroxylase, and Vitamin D receptor (VHD) is expressed ubiquitously.6–8 Local production of 1,25(OH)2D from 25(OH)D is likely necessary for additional autocrine or paracrine functions. In these scenarios, adequate circulating levels of 25(OH)D (derived from sun exposure or nutritional sources) rather than 1,25(OH)2D may be essential. Clinical practice guidelines provided by the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI) have recommend measuring 25(OH)D in patients with stage 3 and 4 CKD with associated secondary hyperparathyroidism, and if levels are 18 years old) chronic HD (>3 months) patients from five Fresenius Medical Care centers in the Buenos Aires Metropolitan area were screened for 25(OH)D serum levels. From this population, patients with serum 25(OH) vitamin D levels ≤20 ng/mL were selected (Figure 1); patients should also have intact parathyroid hormone (iPTH) levels between two and nine times the upper normal limit for the method, serum phosphorus levels ≤6.5 mg/dL, and serum calcium ≤10.2 mg/dL. Patients with previous parathyroidectomy, those receiving treatment with bisphosphonates and/or corticosteroids, Vitamin D derivatives during the three months prior to the study, and patients with chronic liver disease were excluded from the study. The study was approved by the Institutional Review Board (IRB) of the

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Figure 1 Flowchart of the study.

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normalization of serum 25(OH) was accompanied by changes in PTH and bone turnover markers; 1,25(OH)2D3 and BALP serum levels were evaluated at baseline and at the end of the maintenance therapy. All measurements were done in a centralized laboratory. Blood samples were performed in the second dialysis session of the week. We considered adequate 25(OH)D levels above 30 ng/mL, insufficiency values between 30 and 15 ng/mL, and deficiency below 15 ng/mL. Our main goal was to assess if the administered dose of ergocalciferol during the first 12 weeks was able to increase 25(OH)D levels >30 ng/mL in 80% of patients and if the maintenance dose selected was able to maintain levels of 25 OH vitamin D levels >30 ng/mL in the long term.

Methods The 25(OH)D (D2 + D3) serum levels were measured by radioimmunoassay (RIA; Diasorin Inc, Stillwater, MN, USA). Serum calcium was measured with ion-selective electrode (ISE) method (Synchron CX9 ALX, Beckman) and phosphorus by ultraviolet (UV) method (Synchron CX9 ALX). Intact PTH was measured using a secondgeneration assay (Roche Cobas e411 electrochemiluminescence immunoassay, Manheim, Germany). Specific BALP was measured using EIA KIT (Quidel Corporation, San Diego, CA, USA). Total alkaline phosphatase was measured with p-nitrophenyl phosphate assay (Roche). 1.25(OH)2D was measured using RIA with previous purification with C18 cartridges.

Statistics Continuous data are reported as mean ± SD. Frequency counts were calculated for categorical variables. One-way analysis of variance (ANOVA) was used for the statistical analysis of 25 OH D, calcium, phosphate, and TALP serum levels. For post-hoc comparison of means, Tukey test (honest significant difference) was applied. Nonparametric bivariate correlation analysis (Spearman) was performed for selected variables. Statistical analysis was performed using CSS: Statistica software (StatSoft, Inc, Tulsa, OK, USA).

RESULTS Baseline data of the 82 patients included are presented in Table 1. Median dialysis vintage was 29.5 months (range 5–168 months). Seventy-nine patients completed the 12-week high-dose correction face of the study.

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Table 1. Baseline characteristic of the patients Parameter Age (years) Dry Weight (Kg) BMI (Kg/m2) Gender (Male/Female) 25 (OH)D (ng/ml) 1.25 (OH)2D (pg/ml) Serum calcium (mg%) Serum Phosphate (mg%) Intact PTH (pg/ml) Total Alkaline Phosphatase (U/L) Bone Alkaline Phosphatase

64.6 ± 15.2 69.0 ± 16.1 25.6 ± 5.1 48/34 15.23 ± 5.4 3.1 ± 4.84 9.03 ± 0.49 4.9 ± 1.2 360 ± 143 286 ± 163 54.3 ± 46.0

Ergocalciferol supplementation was associated with a highly significant increase in plasma 25(OH)D levels (baseline: 15.2 ± 5.4; at 12 weeks: 42.5 ± 13.2 ng/mL; P < 0.01) Mean increase in calcidiol levels was 32.7 ± 16.8 ng/mL; 84.8% of the patients reached values greater than 30 ng/mL. Calcidiol remained optimal (34.7 ± 12.0) at the end of the maintenance therapy (Figure 2). Twelve patients did not achieve target levels of vitamin D. These patients took the medication irregularly: in nine cases with hospitalizations, one patient with impregnation syndrome, one patient with a feeding disorder, and one patient with digestive intolerance which was solved after taking the medication with meals. Intact PTH did not change along the study (baseline: 360 ± 143 pg/mL; at 48 weeks: 362 ± 193 pg/mL; P = 0.16) the same as TALP (baseline: 286 ± 163 IU/L; at 48 weeks: 263 ± 108 IU/L; P = 0.08). We observed a significant decrease in BALP at the end of follow-up (Figure 3). Uncorrected serum calcium was 9.03 ± 0.42 at baseline but had a significant increase at the end of follow-up (9.14 ± 0.62; P = 0.049). Hypercalcemia was presented in two patients in the first control visit (week 12), in one patient in the second control (week 30), and in one patient in the third control (week 48). Hypercalcemia was observed in only 0.42% of 936 monthly determinations of serum calcium during follow-up. Serum phosphorus remained unchanged during the follow-up (basal 4.9 ± 1.2; final 4.7 ± 1.1). We were able to determine 1,25(OH)2D serum levels in 47 of the patients at baseline; mean values were 3.1 ± 4.84 pg/mL (in 32 patients, levels were not detectable); at week 48, serum levels increased to 15.92 ± 8.32 pg/mL (not detectable in only three patients) (Figure 4). Ten patients showed levels of 1.25(OH)2D ≥ 20 pg/mL and two of them greater than 30 pg/mL. A good positive correlation was found between 25 OH D and 1,25(OH)D serum levels (P < 0001).

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High-dose ergocalciferol in hemodialysis

Figure 2 Changes in calcidiol serum levels after ergocalciferol supplementation.

DISCUSSION This study shows that oral high-dose supplementation with ergocalciferol (72,000 IU/week) increased serum

Figure 3 Bone alkaline phosphatase serum levels before and at the end of ergocalciferol treatment.

Figure 4 Change in serum 1,25-dihydroxycholecalciferol after 48 wk of ergocalciferol treatment.

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25(OH)D levels greater than 30 ng/mL in 84.8% of dialysis patients with baseline levels below 20 ng/mL. Calcidiol levels remained optimal (34.7 ± 12.0) at the end of the maintenance therapy following a maintenance dose of 24,000 IU/week during 36 weeks. Hypercalcemia was observed in only 1.8% of 222 serum calcium determinations during follow-up and in very few patients. Furthermore, ergocalciferol supplementation caused a significant increase in 1,25(OH)2D serum levels. Current treatment guidelines for CKD patients recommend that hypovitaminosis D should be corrected.9 However, there are limited data behind these recommendations. There have been several studies in predialysis patients treated with ergocalciferol.15–17 Qunibi et al. have argued that treatment with ergocalciferol as recommended by KDOQI guidelines is inadequate for correcting vitamin D deficiency/insufficiency.18 Few studies have used vitamin D2 in dialysis patients. Blair et al.19 observed in a retrospective study conducted at five dialysis centers in Western Massachusetts that ergocalciferol supplementation (50,000 IU/week × 24) was associated with significant improvements in serum 25(OH)D from baseline (18.4 ± 9.0 ng/mL) to 6 months (42.0 ± 24.7 ng/mL). More recently, Porter et al.20 conducted a retrospective study of 96 HD patients at a single center dialysis unit with Vitamin D insufficiency or deficiency. Oral ergocalciferol replacement was given according to KDOQI guidelines for CKD stages III–IV (patients with 25(OH)D levels 30 ng/mL, and none >100 ng/mL. No hypercalcemia could be attributed to supplementation. In our study, we have found similar results with higher initial doses and lower maintenance doses of ergocalciferol. Previous studies with vitamin D2 or D3 supplementation in HD patients have been inconsistent with PTH responses: Some studies reported significant declines12,13 whereas others had no significant change.11,22 Our results show no significant change in PTH. Despite this, a significant decrease in BALP was observed at the end of follow-up. This could be due to a decrease in bone turnover or improvement in bone mineralization. Although studies have highlighted the profound deficiency of vitamin D among patients with kidney disease, it is unclear if vitamin D deficiency is in itself linked with adverse outcomes. Pilz et al. have done a systematic review and meta-analysis of prospective observational studies, observing that higher 25(OH)D levels are associated with significantly improved survival in patients with CKD with and without dialysis. An increase in 10 ng/mL 25(OH)D led to a significant decrease of 14% in mortality risk (RR 0.86; 95% CI 0.82–0.91).23 Zheng et al. have recently performed a meta-analysis of 20 studies in which patients with CKD not requiring dialysis and patients with end stage renal disease (ESRD) requiring dialysis receiving vitamin D receptor activators had lower mortality compared with those with no treatment,24 although these findings have not been confirmed in prospective randomized trials. Another important question that requires further studies is whether nutritional vitamin D supplementation will improve outcomes in the same patients. Interventional studies with nutritional vitamin D in patients with CKD and ESRD have shown that after supplementation, there were lower levels of proinflammatory cytokines, IL-8, IL-6, and TNF and differences in circulating monocyte proteins.25 They also observed a significant reduction in left ventricular mass index at the end of supplementation.26 Finally, another interesting aspect of our study was that 1,25(OH)2D serum levels increased from undetectable levels to low levels at the end of the supplementation period with ergocalciferol in an important fraction of the patients. This corroborates previous studies that have shown persistent probably extra-renal production of 1,25(OH)2D in HD patients after several months of

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25(OH)D(3) administration.27 In 12 of the patients, 1,25 serum levels reached normal values (20–60 pg/mL) suggesting important local conversion of 25 OH D to 1,25 in macrophage/monocytes, breast, colon, prostate, and other tissues that could produce significant nonclassical biological effects of vitamin D as immune modulation, inhibition of angiogenesis, or induction of apoptosis. Our study has limitations. First, it was a single-armed unblinded and uncontrolled study. Second, we did not study any of the biochemical and pleiotropic effects that have been attributed to vitamin D deficiency/insufficiency correction. In summary, this vitamin D2 oral regimen was safe and sufficient to obtain and maintain optimal serum 25(OH)D concentrations and prevent vitamin D insufficiency in CKD patients on dialysis. Manuscript received April 2014; revised July 2014.

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10 Kidney Disease Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical guidelines for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease mineral and bone disorder (CKDMBD). Kidney Int Suppl. 2009; 113:S1–S130. 11 Tokmak F, Quack I, Schieren G, et al. High-dose cholecalciferol to correct vitamin D deficiency in hemodialysis patients. Nephrol Dial Transplant. 2008; 23:4016–4020. 12 Jean G, Souberbielle J, Chazot C. Monthly cholecalciferol administration in hemodialysis patients: A simple and efficient strategy for vitamin D supplementation. Nephrol Dial Transplant. 2009; 24:3799–3805. 13 Matias PJ, Jorge C, Ferreira C, et al. Cholecalciferol supplementation in hemodialysis patients: Effects on mineral metabolism, inflammation, and cardiac dimension parameters. Clin J Am Soc Nephrol. 2010; 5:905–911. 14 Marckmann P, Agerskov H, Thienshkumar S, et al. Randomized controlled trial of cholecalciferol supplementation in chronic kidney disease patients with hypovitaminosis D. Nephrol Dial Transplant. 2012; 27:3523–3531. 15 DeVille J, Thorp ML, Tobin L, Gray E, Johnson ES, Smith DH. Effect of ergocalciferol supplementation on serum parathyroid hormone and serum 25-hydroxyvitamin D in chronic kidney disease. Nephrology (Carlton). 2006; 11:555–559. 16 Zisman AL, Hristova M, Ho LT, Sprague SM. Impact of ergocalciferol treatment of vitamin D deficiency on serum parathyroid hormone concentrations in chronic kidney disease. Am J Nephrol. 2007; 27:36–43. 17 Al-Aly Z, Qazi RA, González EA, Zeringue A, Martin KJ. Changes in serum 25-hydroxyvitamin D and plasma intact PTH levels following treatment with ergocalciferol in patients with CKD. Am J Kidney Dis. 2007; 50:59–68. 18 Qunibi WY, Abdellatif A, Sankar S, et al. Treatment of vitamin D deficiency in CKD patients with ergocalciferol: Are current K/DOQI treatment guidelines adequate? Clin Nephrol. 2010; 73:276–285. 19 Blair D, Byham-Gray L, Lewis E, McCaffrey S. Prevalence of vitamin D [25(OH)D] deficiency and effects of supplementation with ergocalciferol (vitamin D2) in stage 5

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insufficiency in hemodialysis patients: a pilot trial.

Controversy exists on which vitamin D (D2 or D3) and which dosage scheme is the best to obtain and maintain adequate 25 OH D levels in dialysis patien...
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