Association of Oral Calcitriol with Improved Survival in Nondialyzed CKD

Abstract

Parenteral vitamin D is associated with improved survival among long-term hemodialysis patients. Among nondialyzed patients with chronic kidney disease (CKD), oral activated vitamin D reduces parathyroid hormone levels, but the impact on clinical outcomes is unknown. We evaluated associations of oral calcitriol use with mortality and dialysis dependence in 1418 nondialysis patients with CKD and hyperparathyroidism in the Veterans' Affairs Consumer Health Information and Performance Sets database. Incident calcitriol users and nonusers were selected on the basis of stages 3 to 4 CKD, hyperparathyroidism, and the absence of hypercalcemia before calcitriol use and then were matched by age and estimated kidney function. During a median follow-up of 1.9 yr, 408 (29%) patients died and 217 (16%) initiated long-term dialysis. After adjustment for demographics; comorbidities; estimated kidney function; medications; and baseline levels of parathyroid hormone, calcium, and phosphorous, oral calcitriol use was associated with a 26% lower risk for death (95% confidence interval 5 to 42% lower; P ϭ 0.016) and a 20% lower risk for death or dialysis (95% confidence interval 1 to 35% lower; P ϭ 0.038). The association of calcitriol with improved survival was not statistically different across baseline parathyroid hormone levels. Calcitriol use was associated with a greater risk for hypercalcemia. In conclusion, oral calcitriol use is associated with lower mortality in nondialysis patients with CKD. Chronic kidney disease (CKD) affects Ͼ10% of American adults and leads to disturbances in vitamin D and mineral metabolism. [1][2][3][4] The kidneys play an important role in converting 25-hydroxyvitamin D to calcitriol, the most biologically potent vitamin D metabolite, under regulation by parathyroid hormone (PTH) and phosphate. 5,6 A decline in calcitriol levels and a rise in serum PTH levels are among the first detectable mineral metabolism disturbances in CKD. 2,7,8 In clinical trials of predialysis patients with CKD, oral calcitriol or its analogues lowered serum PTH levels. 9 -11 A body of evidence suggests potential health benefits of vitamin D beyond reducing PTH levels. 12 Activated vitamin D binds to the vitamin D receptor to influence a diverse genetic response. 13 In renal and nonrenal populations, lower 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels have been associated with cardiovascular risk factors, including higher renin levels, inflammation, albuminuria, and glucose intolerance. 14 -17 In observational studies of long-term hemodialysis patients, intravenous vitamin D treatment has been associated with improved survival. 18 -21 Given biologic plausibility for an effect of oral calcitriol on survival and lack of clinical outcome data pertaining to this commonly prescribed CKD medication, we evaluated associations of oral calcitriol use with mortality and dialysis dependence in 1418 patients with stages 3 to 4 CKD and hyperparathyroidism.

A Randomized Multicenter Trial of Paricalcitol versus Calcitriol for Secondary Hyperparathyroidism in Stages 3–4 CKD

“…On the basis of observational and preclinical data, hypotheses have been generated that hyperphosphatemia, hypercalcemia, and calcitriol deficiency contribute to cardiovascular events and deaths in patients with CKD (24)(25)(26). Use of calcitriol in patients with stages 3-4 CKD is associated with improved survival; paricalcitol was shown in blinded trials to reduce proteinuria, but failed to alter left ventricular remodeling (27)(28)(29). However, proteinuria and left ventricular remodeling are intermediate outcomes, and no randomized trials have assessed mortality during use of VDRAs.…”

Daily Variability in Mineral Metabolites in CKD and Effects of Dietary Calcium and Calcitriol

“…This novel finding provides a potential explanation for seemingly conflicting findings from previous studies. Calcitriol has been associated with improved survival among patients with CKD (28). However, calcitriol raises FGF23 levels (23), and elevated FGF23 is an independent risk factor for death (4).…”

Associação entre fatores de risco clínicos e laboratoriais e progressão da doença renal crônica pré-dialítica

“…3 Sesso et al and Fernandes et al showed that most patients who start on RRT in our country is referred to nephrology services very late, and most are on stage 4 (47.3%), which contrasts with data in international literature, in which most patients are on stage 3. [3][4][5][6][7][8][9][10][11][12][13][14][15] Besides the expected contribution of age and CKD staging, the correlation of proteinuria with the progression of the renal disease, even if eased by the renoprotection by ACEI and ARB, is demonstrated in many studies. [16][17][18] This phenomenon is clearly observed in patients with type II DM, in which ¼ of the patients presents with renal compromise after ten years of disease.…”

“…Considering these facts, it is interesting to observe the results are in accordance with prior studies, which clearly showed the important benefits of vitamin D for CKD. 8,26 In the beginning of the study, the observation that SAP and DAP were inadequate and were not associated to the outcomes represented by the need for RRT and death deserves some attention, even though it was not the only observation. The fact that pressure levels were higher than recommended in the base period of the study does not necessarily means that they stayed this way during follow-up.…”

“…6 It has recently been demonstrated that the correction of vitamin D deficiency, hyperuricemia and metabolic acidosis also lead to the decrease of GFR in patients with predialytic CKD. [7][8][9][10] This study aimed to assess the impact of demographic, clinical and laboratory variables that were present at admission and let to the outcomes death or renal replacement therapy (RRT) in patients with stages 3-5 CKD on conservative treatment.…”