Lower risk for cardiovascular mortality in oral 1 -hydroxy vitamin D3 users in a haemodialysis population

Elevated calcium and phosphorus levels after therapy with injectable vitamin D for secondary hyperparathyroidism may accelerate vascular disease and hasten death in patients undergoing long-term hemodialysis. Paricalcitol, a new vitamin D analogue, appears to lessen the elevations in serum calcium and phosphorus levels, as compared with calcitriol, the standard form of injectable vitamin D. We conducted a historical cohort study to compare the 36-month survival rate among patients undergoing long-term hemodialysis who started to receive treatment with paricalcitol (29,021 patients) or calcitriol (38,378 patients) between 1999 and 2001. Crude and adjusted survival rates were calculated and stratified analyses were performed. A subgroup of 16,483 patients who switched regimens was also evaluated. The mortality rate among patients receiving paricalcitol was 3417 per 19,031 person-years (0.180 per person-year), as compared with 6805 per 30,471 person-years (0.223 per person-year) among those receiving calcitriol (P<0.001). The difference in survival was significant at 12 months and increased with time (P<0.001). In the adjusted analysis, the mortality rate was 16 percent lower (95 percent confidence interval, 10 to 21 percent) among paricalcitol-treated patients than among calcitriol-treated patients. A significant survival benefit was evident in 28 of 42 strata examined, and in no stratum was calcitriol favored. At 12 months, calcium and phosphorus levels had increased by 6.7 and 11.9 percent, respectively, in the paricalcitol group, as compared with 8.2 and 13.9 percent, respectively, in the calcitriol group (P<0.001). The two-year survival rate among patients who switched from calcitriol to paricalcitol was 73 percent, as compared with 64 percent among those who switched from paricalcitol to calcitriol (P=0.04). Patients who receive paricalcitol while undergoing long-term hemodialysis appear to have a significant survival advantage over those who receive calcitriol. A prospective, randomized study is critical to confirm these findings. Copyright 2003 Massachusetts Medical Society

Parathyroid hormone and vitamin D have been shown to influence cardiac and vascular growth and function experimentally in human subjects with normal renal function. Because of the increased prevalence of hyperparathyroidism and altered vitamin D status in chronic renal failure, these alterations have been considered to contribute to the increased prevalence of cardiovascular disease and hypertension seen in this patient population. Methods and Results. In this article, we review experimental and clinical literature on the cardiovascular effects of parathyroid hormone and vitamin D and relate them to the development of cardiac and vascular dysfunction in uremia, such as: cardiomyopathy, myocardial hypertrophy, and fibrosis, as well as to myocardial ischemia; uremic glucose intolerance, dyslipidemia, and atherosclerosis; hypertension; and vascular and cardiac calcifications. The hyperparathyroid state and altered vitamin D status found in uremia contribute to the cardiovascular pathology seen clinically in uremia and also to the excess mortality from cardiovascular causes found in this patient group. The therapeutic implications of these observations are also discussed.

1,25(OH)2 Vitamin D3 (VD3) and retinoic acid (RA) function as ligands for nuclear receptors which regulate transcription. Though the cardiovascular system is not thought to represent a classical target for these ligands, it is clear that both cardiac myocytes and vascular smooth muscle cells respond to these agents with changes in growth characteristics and gene expression. In this study we demonstrate that each of these ligands suppresses many of the phenotypic correlates of endothelin-induced hypertrophy in a cultured neonatal rat cardiac ventriculocyte model. Each of these agents reduced endothelin-stimulated ANP secretion in a dose-dependent fashion and the two in combination proved to be more effective than either agent used alone (VD3: 49%; RA:52%; VD3 + RA:80% inhibition). RA, at concentrations known to activate the retinoid X receptor, and, to a lesser extent, VD3 effected a reduction in atrial natriuretic peptide, brain natriuretic peptide, and alpha-skeletal actin mRNA levels. Similar inhibition (VD3:30%; RA:33%; VD3 + RA:59% inhibition) was demonstrated when cells transfected with reporter constructs harboring the relevant promoter sequences were treated with VD3 and/or RA for 48 h. These effects were not accompanied by alterations in endothelin-induced c-fos, c-jun, or c-myc gene expression, suggesting either that the inhibitory locus responsible for the reduction in the mRNA levels lies distal to the activation of the immediate early gene response or that the two are not mechanistically coupled. Both VD3 and RA also reduced [3H]leucine incorporation (VD3:30%; RA:33%; VD3 + RA:45% inhibition) in endothelin-stimulated ventriculocytes and, once again, the combination of the two was more effective than either agent used in isolation. Finally, 1,25(OH)2 vitamin D3 abrogated the increase in cell size seen after endothelin treatment. These findings suggest that the liganded vitamin D and retinoid receptors are capable of modulating the hypertrophic process in vitro and that agents acting through these or similar signaling pathways may be of value in probing the molecular mechanisms underlying hypertrophy.