Oral active vitamin D is associated with improved survival in hemodialysis patients

Injection of active vitamin D is associated with better survival of patients receiving chronic hemodialysis. Since in many countries oral active vitamin D administration is the most common form of treatment for secondary hyperparathyroidism we determined the survival benefit of oral active vitamin D in hemodialysis patients from six Latin America countries (FME Register® as part of the CORES study) followed for a median of 16 months. Time-dependent Cox regression models, after adjustment for potential confounders, showed that the 7,203 patients who received oral active vitamin D had significant reductions in overall, cardiovascular, infectious and neoplastic mortality compared to the 8,801 patients that had not received vitamin D. Stratified analyses found a survival advantage in the group that had received oral active vitamin D in 36 of the 37 strata studied including that with the highest levels of serum calcium, phosphorus and parathyroid hormone. The survival benefit of oral active vitamin D was seen in those patients receiving mean daily doses of less than 1 μg with the highest reduction associated with the lowest dose. Our study shows that hemodialysis patients receiving oral active vitamin D had a survival advantage inversely related to the vitamin dose. Injection of active vitamin D is associated with better survival of patients receiving chronic hemodialysis. Since in many countries oral active vitamin D administration is the most common form of treatment for secondary hyperparathyroidism we determined the survival benefit of oral active vitamin D in hemodialysis patients from six Latin America countries (FME Register® as part of the CORES study) followed for a median of 16 months. Time-dependent Cox regression models, after adjustment for potential confounders, showed that the 7,203 patients who received oral active vitamin D had significant reductions in overall, cardiovascular, infectious and neoplastic mortality compared to the 8,801 patients that had not received vitamin D. Stratified analyses found a survival advantage in the group that had received oral active vitamin D in 36 of the 37 strata studied including that with the highest levels of serum calcium, phosphorus and parathyroid hormone. The survival benefit of oral active vitamin D was seen in those patients receiving mean daily doses of less than 1 μg with the highest reduction associated with the lowest dose. Our study shows that hemodialysis patients receiving oral active vitamin D had a survival advantage inversely related to the vitamin dose. Calcitriol deficiency is a common medical condition among patients with chronic kidney disease.1.Llach F. Yudd M. Pathogenic, clinical, and therapeutic aspects of secondary hyperparathyroidism in chronic renal failure.Am J Kidney Dis. 1998; 32: S3-S12PubMed Google Scholar,2.Slatopolsky E. Brown A. Dusso A. Pathogenesis of secondary hyperparathyroidism.Kidney Int Suppl. 1999; 73: S14-S19Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar Calcitriol, the most active form of vitamin D, increases intestinal calcium absorption, effectively suppresses parathyroid hormone (PTH) secretion, prevents skeletal complications, and it has been the standard therapy for secondary hyperparathyroidism for more than two decades.3.Ishimura E. Nishizawa Y. Inaba M. et al.Serum levels of 1,25-dihydroxyvitamin D, 24,25-dihydroxyvitamin D, and 25-hydroxyvitamin D in nondialyzed patients with chronic renal failure.Kidney Int. 1999; 55: 1019-1027Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar Calcitriol administration may also result in an elevation of serum calcium and phosphorus levels, which may facilitate vascular calcification and death.4.Salusky I.B. Goodman W.G. Cardiovascular calcification in end-stage renal disease.Nephrol Dial Transplant. 2002; 17: 336-339Crossref PubMed Scopus (79) Google Scholar Conversely, other studies have shown that the use of calcitriol and other forms of vitamin D derivatives is associated with improved survival in patients with cancer or infections.5.Grant W.B. Ecologic studies of solar UV-B radiation and cancer mortality rates.Recent Results Cancer Res. 2003; 164: 371-377Crossref PubMed Scopus (140) Google Scholar,6.Tangpricha V. Flanagan J.N. Whitlatch L.W. et al.25-hydroxyvitamin D-1alpha-hydroxylase in normal and malignant colon tissue.Lancet. 2001; 357: 1673-1674Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar,7.Haug C. Muller F. Aukrust P. et al.Subnormal serum concentration of 1,25-vitamin D in human immunodeficiency virus infection: correlation with degree of immune deficiency and survival.J Infect Dis. 1994; 169: 889-893Crossref PubMed Scopus (139) Google Scholar More recently, a large historical cohort study has demonstrated a significant survival advantage of 20% in chronic hemodialysis patients receiving injectable active vitamin D.8.Teng M. Wolf M. Ofsthun M.N. et al.Activated injectable vitamin D and hemodialysis survival: a historical cohort study.J Am Soc Nephrol. 2005; 16: 1115-1125Crossref PubMed Scopus (713) Google Scholar In many countries, the most common form of administration of active vitamin D as treatment for secondary hyperparathyroidism is the oral route instead of the injectable form. Accordingly, this study examined the potential survival effect of oral active vitamin D in a large cohort of hemodialysis patients. Baseline characteristics of the group that received oral active vitamin D (n=7203) and the group that did not receive it (n=8801) are shown in Table 1. Baseline serum levels of phosphorus and calcium-phosphorus product were significantly lower, whereas PTH was higher in the oral active vitamin D users. Patients who did not receive oral active vitamin D were older; and there were more diabetics. Throughout the whole follow-up there were 3110 deaths and 1792 lost to follow-up due to: renal transplantation (39.0%), switch to peritoneal dialysis (29.5%), voluntary withdrawal from therapy (16.1%), recovery of renal function (9.6%), unknown circumstances (3.7%), and transfer to a non-Fresenius dialysis unit (2.1%).Table 1Baseline data before the oral active vitamin D treatmentaBaseline laboratory values represent the mean and standard deviation value over the 3 months before 90 days after initiating dialysis for the non-vitamin D group and the 3 months before initiating vitamin D therapy in the vitamin D group. The mean and standard deviation of baseline parathyroid hormone was obtained over 6 months.CharacteristicsWithout Vitamin DWith Vitamin DP-value(N=8801)(N=7203)Age (year)55.6 (16.0)53.9 (15.9)<0.001Male patients (%)58.458.30.81Cause of renal failure (% of patients)<0.001 Diabetes28.724.5 Nephroangioesclerosis15.820.9 Glomerulonephritis9.912.6 Other45.642.0Vascular access (% of patients)<0.001 Catheter25.922.0 Fistula27.850.0 Graft3.35.8 Unknown43.022.2Weekly hours on dialysis (hour)11.8 (0.9)11.9 (0.7)<0.001Time on dialysis (year)0.9 (2.4)1.5 (3.3)<0.001Time on dialysis (year)bBaseline time on dialysis, parathyroid hormone and ferritin represent the median and interquartile range. In the case of the parathyroid hormone, the median and interquartile range were obtained over 6 months. A Mann–Whitney U-test has been made for comparison between groups.0 (0–0.3)0 (0–1.1)<0.001Dialysate calcium (mEq/l)3.1 (0.4)3.1 (0.6)0.61Weight (kg)63.8 (14.3)64.2 (14.2)0.10Calcium (mg per 100 ml)9.1 (0.9)9.1 (0.9)<0.001Body mass index (kg/m2)23.7 (4.7)23.8 (4.6)0.11Phosphorus (mg per 100 ml)5.0 (1.5)4.9 (1.3)<0.001Calcium-Phosphorus product (mg2 per (100 ml)2)45.6 (14.4)44.6 (13.2)<0.001Parathyroid hormone (pg/ml)213 (284)421 (393)<0.001Parathyroid hormone (pg/ml)bBaseline time on dialysis, parathyroid hormone and ferritin represent the median and interquartile range. In the case of the parathyroid hormone, the median and interquartile range were obtained over 6 months. A Mann–Whitney U-test has been made for comparison between groups.123 (57–247)324 (169–534)<0.001Albumin (g per 100 ml)3.7 (0.6)3.7 (0.5)<0.001Total cholesterol (mg per 100 ml)185 (53)185 (50)0.93Hemoglobin (g per 100 ml)9.1 (1.8)9.6 (1.8)<0.001Ferritin (ng/ml)433 (389)449 (383)0.044Ferritin (ng/ml)bBaseline time on dialysis, parathyroid hormone and ferritin represent the median and interquartile range. In the case of the parathyroid hormone, the median and interquartile range were obtained over 6 months. A Mann–Whitney U-test has been made for comparison between groups.320 (159–590)340 (164–619)0.019Creatinine (mg per 100 ml)7.8 (2.98)8.2 (2.8)<0.001Kt/VcDelivered Kt/V=-ln (R-0.008 × t)+(4-3.5R) × UF/W, where R=post dialysis/pre dialysis blood urea nitrogen, t=dialysis hours, UF=pre dialysis-post dialysis weight change, and W=post dialysis weight.1.37 (0.3)1.3 (0.3)<0.001Calcium acetate (g)66.3 (428.1)81.7 (410.3)0.48Calcium acetate (g)dCalcium acetate, calcium bicarbonate, and aluminum hydroxide binders represent the median and interquartile range. A Mann–Whitney U-test has been made for comparison between groups. Calcium acetate and calcium bicarbonate as non-aluminic phosphate binders data were available in 4560 patients and aluminum hydroxide binders were available in 338 patients.25 (12–54)32 (12–64)<0.005Calcium carbonate (g)210 (1,454)195 (1,324)0.72Calcium carbonate (g)dCalcium acetate, calcium bicarbonate, and aluminum hydroxide binders represent the median and interquartile range. A Mann–Whitney U-test has been made for comparison between groups. Calcium acetate and calcium bicarbonate as non-aluminic phosphate binders data were available in 4560 patients and aluminum hydroxide binders were available in 338 patients.30 (12–65)49 (22–100)<0.001Aluminum hydroxide binders (g)4.6 (9.6)4.5 (7.0)0.91Aluminum hydroxide binders (g)dCalcium acetate, calcium bicarbonate, and aluminum hydroxide binders represent the median and interquartile range. A Mann–Whitney U-test has been made for comparison between groups. Calcium acetate and calcium bicarbonate as non-aluminic phosphate binders data were available in 4560 patients and aluminum hydroxide binders were available in 338 patients.1.0 (0.02–6)1.0 (0.01–5)0.73a Baseline laboratory values represent the mean and standard deviation value over the 3 months before 90 days after initiating dialysis for the non-vitamin D group and the 3 months before initiating vitamin D therapy in the vitamin D group. The mean and standard deviation of baseline parathyroid hormone was obtained over 6 months.b Baseline time on dialysis, parathyroid hormone and ferritin represent the median and interquartile range. In the case of the parathyroid hormone, the median and interquartile range were obtained over 6 months. A Mann–Whitney U-test has been made for comparison between groups.c Delivered Kt/V=-ln (R-0.008 × t)+(4-3.5R) × UF/W, where R=post dialysis/pre dialysis blood urea nitrogen, t=dialysis hours, UF=pre dialysis-post dialysis weight change, and W=post dialysis weight.d Calcium acetate, calcium bicarbonate, and aluminum hydroxide binders represent the median and interquartile range. A Mann–Whitney U-test has been made for comparison between groups. Calcium acetate and calcium bicarbonate as non-aluminic phosphate binders data were available in 4560 patients and aluminum hydroxide binders were available in 338 patients. Open table in a new tab The overall mortality rate was 19.4%; Venezuela (25.4%), Argentina (22.7%), Mexico (16.2%), Brazil (15.7%), Chile (14.6%); and Colombia (13.8%). The crude analysis using the Kaplan–Meier curve showed significant reduction of mortality risk in patients who received oral active vitamin D within 1 year compared to these who did not receive it (P<0.001, Figure 1). As the Figure 2 shows, the association of oral active vitamin D use with mortality reduction did not vary by country, including countries with both high and low overall death rates.Figure 2Hazard ratios for mortality risk associated with oral active vitamin D treatment stratified by exposure characteristic. Each result reflects a multivariable adjusted model (age, gender, diabetes status, weekly hours on dialysis, Kt/V, center, baseline laboratory values, and comorbidity) according to Table 2. Percentage represents fraction of deaths within each stratum, circles represent the point estimates, and horizontal lines represent 95% confidence intervals. Reference category for each analysis is the corresponding group that did not receive oral active vitamin D.View Large Image Figure ViewerDownload (PPT) As primary exposure was time dependent and the Kaplan–Meier curve might have overestimated the survival benefit, additional analyses (models 2–5 in Table 2) were carried out after adjustment for potential confounders. There were no differences between the adjusted and unadjusted mortality risk among those patients who did and did not receive vitamin D therapy. Multivariable adjusted analyses revealed that patients who received oral active vitamin D had a significant 45% (hazard ratio, 0.55; 95% confidence interval (CI), 0.49–0.63) lower overall mortality risk compared to patients who did not receive oral active vitamin D (Table 2). Furthermore, cardiovascular, infectious, and neoplastic mortality risk were 45 (hazard ratio, 0.55; CI, 0.45–0.67), 48 (hazard ratio, 0.52; CI, 0.39–0.68), and 47% (hazard ratio, 0.53; CI, 0.34–0.82) lower, respectively, in patients on oral active vitamin D.Table 2Cox proportional hazard analysis of mortality with oral vitamin DModelCovariatesNo. of patientsHazard ratio95% confidence interval1Unadjusted16,0040.580.54–0.632Age, gender, diabetes status, and time on dialysis15,6480.600.56–0.653Model 2 plus Kt/V, and country11,0820.520.47–0.584Model 3 plus vascular access, baseline values, and time-varying variablesaThe baseline values quoted were weight, albumin, creatinine, and hemoglobin.61360.580.51–0.655Model 4 plus comorbidities61360.550.49–0.63Time-varying variables were serum calcium, phosphorus, and parathyroid hormone.a The baseline values quoted were weight, albumin, creatinine, and hemoglobin. Open table in a new tab Time-varying variables were serum calcium, phosphorus, and parathyroid hormone. Similar results were observed when center instead of country was used as covariate in the multivariate analysis. As once the patient was withdrawn from hemodialysis, no additional information about mortality was obtained, a sensitivity analysis was carried out to examine the potential impact of the censored patients. The sensitive analysis revealed that censored patients (hazard ratio, 0.58; CI, 0.51–0.67) did not differ from those who were not censored (hazard ratio, 0.55; CI, 0.49–0.63) and the association of vitamin D with reduced mortality did not differ when participants were considered to have died at the time of censoring (hazard ratio, 0.58; CI, 0.53–0.65). The 244 patients censored, because they switched from oral active vitamin D to injectable active vitamin D, also showed a survival benefit (hazard ratio, 0.63; CI, 0.42–0.93). The analysis of prevalent and incident hemodialysis patients showed also a significant reduction in the mortality risk rates in both groups. Overall mortality (hazard ratio, prevalent: 0.51; CI, 0.40–0.66 and hazard ratio, incident: 0.57; CI, 0.50–0.67), cardiovascular mortality (hazard ratio, prevalent: 0.59; CI, 0.40–0.88 and hazard ratio, incident: 0.53; CI, 0.42–0.67), infectious mortality (hazard ratio, prevalent: 0.61; CI, 0.37–1.02 and hazard ratio, incident: 0.50; CI, 0.38–0.75), and neoplastic mortality (hazard ratio, prevalent: 0.33, CI, 0.13–0.84 and hazard ratio, incident: 0.56; CI, 0.34–0.75). The association of vitamin D with reduced mortality was not altered when socioeconomic status was added to analyses in a subset of participants with available data (n=6961 from Argentina). As it has been mentioned, certain baseline characteristics differed between the two groups (Table 1). Patients who received oral active vitamin D treatment were 1.7 years younger with a 4.2% lower prevalence of diabetes. Other baseline characteristics such as body weight, serum creatinine, serum albumin, and serum hemoglobin levels were higher in patients who received oral active vitamin D treatment. In order to minimize the confounding effect of these baseline differences, we performed stratified analyses (Figure 2). Within each level of the stratified variables, the analysis was multivariable adjusted for all the potential confounders included in the final model shown in Table 2. In 36 of the 37 strata studied, we observed a significant survival advantage in the group that had received oral active vitamin D, including the stratum of patients with the highest serum calcium (tertile 3: >9.37 mg per 100 ml), phosphorus (tertile 3: >5.33 mg per 100 ml), and PTH levels (tertile 3: >326 pg/ml). The stratification of the propensity score in tertiles confirmed a significant survival advantage in the group that had received oral active vitamin D (tertile 1—hazard ratio: 0.65, CI: 0.51–0.83; tertile 2—hazard ratio: 0.51, CI: 0.41–0.65; tertile 3—hazard ratio: 0.44, CI: 0.35–0.55). To further examine the effect of different doses of oral active vitamin D, we analyzed the results of the four preestablished categories using unadjusted and adjusted analyses, using as covariates all those included in model 5 in Table 2. Patients who received oral active vitamin D in a mean daily dose lower than 0.25 μg, between 0.25–0.50 μg, and 0.51–1 μg showed a mortality reduction of 54% (hazard ratio, 0.46; CI, 0.39–0.54), 42% (hazard ratio, 0.58; CI, 0.49–0.70), and 36% (hazard ratio, 0.64; CI, 0.50–0.83), respectively. However, no significant reduction in mortality was observed with a mean daily dose higher than 1 μg (hazard ratio, 0.83; CI, 0.58–1.19; Figure 3). In the lower dose group (<0.25 μg) the cumulative dose was 78 μg and the duration of treatment was 540 days, meanwhile in the highest dose group (>1 μg) the cumulative dose was nine times higher (686 μg) and the duration of treatment shorter (314 days). We also performed independent analyses in those patients whom the current clinical practice K/DOQI guidelines recommended the use of active vitamin D metabolites (baseline intact PTH >300 pg/ml and Calcium-Phosphorus product <55 mg2 per (100 ml)2).9.National Kidney Foundation K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease.Am J Kidney Dis. 2003; 42: S1-S201Crossref PubMed Scopus (648) Google Scholar A mean daily dose lower than 0.25 μg (mean 0.15 μg) and also a dose between 0.25 and 0.50 μg (mean 0.34 μg) significantly reduced the mortality risk rate by 55% (hazard ratio, 0.45; CI, 0.31–0.65) and by 60% (hazard ratio, 0.40; CI, 0.27–0.60), respectively, compared to oral active vitamin D nonusers. No significant reduction in mortality risk was found in patients receiving either a mean daily dose between 0.51 and 1 μg (mean 0.67; hazard ratio, 0.77; CI, 0.49–1.23) or a dose of more than 1 μg (mean 1.69; hazard ratio, 1.14; CI, 0.56–2.33). The analyses of prevalent and incident patients showed similar patterns; however, patients who started oral active vitamin D treatment within the first 90 days showed a slightly better results than patients who started the treatment later (hazard ratio, 0.57; CI, 0.48–0.68 vs hazard ratio, 0.74; CI, 0.62–0.87, respectively). In the past few years, the detrimental or beneficial effect of active vitamin D treatment on the cardiovascular system and the risk of mortality has been a controversial issue. The concern about the harmful effect of vitamin D derivatives is mainly based on the fact that in experimental models high doses of vitamin D metabolites have shown to increase vascular calcifications10.Henley C. Colloton M. Cattley R.C. et al.1,25-Dihydroxyvitamin D3 but not cinacalcet HCl (Sensipar/Mimpara) treatment mediates aortic calcification in a rat model of secondary hyperparathyroidism.Nephrol Dial Transplant. 2005; 20: 1370-1377Crossref PubMed Scopus (125) Google Scholar,11.Lopez I. Aguilera-Tejero E. Mendoza F.J. et al.Calcimimetic R-568 decreases extraosseous calcifications in uremic rats treated with calcitriol.J Am Soc Nephrol. 2006; 17: 795-804Crossref PubMed Scopus (126) Google Scholar and some human data also support this notion.12.Mallick N.P. Berlyne G.M. Arterial calcification after vitamin-D therapy in hyperphosphatemic renal failure.Lancet. 1968; 2: 1316-1320Abstract PubMed Google Scholar On the other hand, experimental studies have shown that low and more physiological dose of active vitamin D may have a cardioprotective effect.13.Wu J. Garami M. Cheng T. et al.1,25(OH)2 vitamin D3, and retinoic acid antagonize endothelin-stimulated hypertrophy of neonatal rat cardiac myocytes.J Clin Invest. 1996; 97: 1577-1588Crossref PubMed Scopus (215) Google Scholar,14.O'Connell T.D. Berry J.E. Jarvis A.K. et al.1,25-Dihydroxyvitamin D3 regulation of cardiac myocyte proliferation and hypertrophy.Am J Physiol. 1997; 272: H1751-H1758PubMed Google Scholar Observational studies in patients on dialysis have also demonstrated morbidity15.Dobrez D.G. Mathes A. Amdahl M. et al.Paricalcitol-treated patients experience improved hospitalization outcomes compared with calcitriol-treated patients in real-world clinical settings.Nephrol Dial Transplant. 2004; 19: 1174-1181Crossref PubMed Scopus (106) Google Scholar and a cardiovascular16.Shoji T. Shinohara K. Kimoto E. et al.Lower risk for cardiovascular mortality in oral 1alpha-hydroxy vitamin D3 users in a haemodialysis population.Nephrol Dial Transplant. 2004; 19: 179-184Crossref PubMed Scopus (332) Google Scholar or overall mortality advantage8.Teng M. Wolf M. Ofsthun M.N. et al.Activated injectable vitamin D and hemodialysis survival: a historical cohort study.J Am Soc Nephrol. 2005; 16: 1115-1125Crossref PubMed Scopus (713) Google Scholar,17.Kalantar-Zadeh K. Kuwae N. Regidor D.L. et al.Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients.Kidney Int. 2006; 70: 771-780Abstract Full Text Full Text PDF PubMed Scopus (750) Google Scholar,18.Tentori F. Hunt W.C. Stidley C.A. et al.Mortality risk among hemodialysis patients receiving different vitamin D analogs.Kidney Int. 2006; 70: 1858-1865Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar for patients who are treated with active vitamin D derivatives vs those without treatment. In addition, one epidemiological study reported a survival advantage when patients receiving new vitamin D analogs were compared to patients receiving an injectable calcitriol formulation.19.Teng M. Wolf M. Lowrie E. et al.Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy.N Engl J Med. 2003; 349: 446-456Crossref PubMed Scopus (851) Google Scholar However, this effect was less pronounced in a recent paper.18.Tentori F. Hunt W.C. Stidley C.A. et al.Mortality risk among hemodialysis patients receiving different vitamin D analogs.Kidney Int. 2006; 70: 1858-1865Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar It was speculated that the potential survival advantage was mediated by the described less calcemic and phosphatemic effects of the new analogs, but the survival benefit was sustained for almost all levels of phosphorus and calcium.18.Tentori F. Hunt W.C. Stidley C.A. et al.Mortality risk among hemodialysis patients receiving different vitamin D analogs.Kidney Int. 2006; 70: 1858-1865Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar,19.Teng M. Wolf M. Lowrie E. et al.Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy.N Engl J Med. 2003; 349: 446-456Crossref PubMed Scopus (851) Google Scholar Although oral active vitamin D treatment is widely used, till date there is only one paper investigating survival using oral active vitamin D in a small cohort of patients.16.Shoji T. Shinohara K. Kimoto E. et al.Lower risk for cardiovascular mortality in oral 1alpha-hydroxy vitamin D3 users in a haemodialysis population.Nephrol Dial Transplant. 2004; 19: 179-184Crossref PubMed Scopus (332) Google Scholar The results of our study show for the first time a significant survival advantage of oral active vitamin D in a larger cohort of chronic hemodialysis patients. Similarly to others,8.Teng M. Wolf M. Ofsthun M.N. et al.Activated injectable vitamin D and hemodialysis survival: a historical cohort study.J Am Soc Nephrol. 2005; 16: 1115-1125Crossref PubMed Scopus (713) Google Scholar this advantage of oral active vitamin D appeared to be independent of other potential risk factors and confounders. In fact, the reduction in mortality risk was observed in 36 of the 37 multivariate strata analyzed, including baseline serum calcium, phosphorus, and PTH levels. The only stratum which did not achieve statistical significance was the one related to the use of grafts as vascular access, possibly due to the low number of patients. Despite the potentially higher bioavailability of the injectable form of vitamin D compared to the oral form, our data show a higher reduction in the overall mortality risk compared to the results obtained with injectable active vitamin D.8.Teng M. Wolf M. Ofsthun M.N. et al.Activated injectable vitamin D and hemodialysis survival: a historical cohort study.J Am Soc Nephrol. 2005; 16: 1115-1125Crossref PubMed Scopus (713) Google Scholar The biological significance on survival benefit for oral active vitamin D users merits a detailed analysis. The positive results in all causes of mortality suggest that the beneficial effect of active vitamin D is beyond its effect on calcium-phosphorus metabolism. In recent years, several experimental studies have demonstrated, among other actions, an important role of active vitamin D in the suppression of cell growth and regulation of immune response.20.Dusso A.S. Brown A.J. Slatopolsky E. Vitamin D.Am J Physiol Renal Physiol. 2005; 289: F8-F28Crossref PubMed Scopus (995) Google Scholar,21.Tangpricha V. Spina C. Yao M. et al.Vitamin D deficiency enhances the growth of MC-26 colon cancer xenografts in Balb/c Mice.J Nutr. 2005; 135: 2350-2354PubMed Google Scholar Moreover, nutritional and epidemiological evidence has linked abnormalities in the vitamin D system to susceptibility to infections, autoimmune diseases, and cancer.22.Zittermann A. Vitamin D in preventive medicine: are we ignoring the evidence?.Br J Nutr. 2003; 89: 552-572Crossref PubMed Scopus (683) Google Scholar,23.Garland C. Shekelle R.B. Barrett-Connor E. et al.Dietary vitamin D and calcium and risk of colorectal cancer: a 19-year prospective study in men.Lancet. 1985; 1: 307-309Abstract PubMed Scopus (628) Google Scholar,24.Kumagai T. O'Kelly J. Said J.W. et al.Vitamin D2 analog 19-nor-1,25-dihydroxyvitamin D2: antitumor activity against leukemia, myeloma, and colon cancer cells.J Natl Cancer Inst. 2003; 95: 896-905Crossref PubMed Scopus (101) Google Scholar Similarly in our study, neoplastic and infectious mortality were significantly reduced (47 and 48%, respectively) in patients receiving oral active vitamin D. Moreover, for neoplastic mortality risk this effect was more marked in patients who spent more time on dialysis (prevalent hemodialysis patients, 67%; incident hemodialysis patients, 44%), suggesting a long-term benefit of active oral vitamin D. Besides these positive survival effects, the benefit of oral active vitamin D for the cardiovascular system is a controversial issue. It is well known that high doses of active vitamin D increase serum calcium and serum phosphorus, and also suppress serum PTH favoring through different mechanisms vascular calcification and mortality.10.Henley C. Colloton M. Cattley R.C. et al.1,25-Dihydroxyvitamin D3 but not cinacalcet HCl (Sensipar/Mimpara) treatment mediates aortic calcification in a rat model of secondary hyperparathyroidism.Nephrol Dial Transplant. 2005; 20: 1370-1377Crossref PubMed Scopus (125) Google Scholar,11.Lopez I. Aguilera-Tejero E. Mendoza F.J. et al.Calcimimetic R-568 decreases extraosseous calcifications in uremic rats treated with calcitriol.J Am Soc Nephrol. 2006; 17: 795-804Crossref PubMed Scopus (126) Google Scholar,12.Mallick N.P. Berlyne G.M. Arterial calcification after vitamin-D therapy in hyperphosphatemic renal failure.Lancet. 1968; 2: 1316-1320Abstract PubMed Google Scholar,25.Goodman W.G. Goldin J. Kuizon B.D. et al.Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis.N Engl J Med. 2000; 342: 1478-1483Crossref PubMed Scopus (2331) Google Scholar,26.Qunibi W.Y. Nolan C.A. Ayus J.C. Cardiovascular calcification in patients with end-stage renal disease: a century-old phenomenon.Kidney Int Suppl. 2002; 82: 73-80Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar Conversely, physiological doses of active vitamin D have shown protective cardiovascular effects reducing the inflammatory response to cardiovascular injury, the myocardial cell hypertrophy and proliferation, and the renin-angiotensin system activation.27.Levin A. Li Y.C. Vitamin D and its analogues: do they protect against cardiovascular disease in patients with kidney disease?.Kidney Int. 2005; 68: 1973-1981Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar As it has been said, part of these paradoxical effects of vitamin D can be explained by the different dose of active vitamin D used. High pharmacological doses may favor and precipitate vascular calcifications whereas more physiological doses may have protective effects. Our study shows that mean daily doses of oral active vitamin D lower than 1 μg showed a significant benefit in survival rate. Interestingly, the reduction in morta