Several health outcomes and co-morbidities that present in the early stages of CKD, including those related to bone and mineral disturbances, as well as cardiometabolic risk factors, have been linked to vitamin D deficiency,46
which is highly prevalent in patients with CKD.19
Moreover, vitamin D deficiency has been shown to be a predictor of CKD progression and death in this population in clinical and epidemiologic studies.6,27,47-49
We conducted a systematic review of the published literature to investigate the effects of vitamin D supplementation (in the form of cholecalciferol or ergocalciferol) in patients with pre-dialysis stage CKD. The studies reviewed varied widely in the form of vitamin D, dosage and protocol. The reported outcomes primarily reflected bone and mineral outcomes, such as changes in 25(OH)D and PTH. There was limited data available with respect to extra-skeletal outcomes.
The National Kidney Foundation recommends an optimal serum/plasma 25(OH)D of greater than or equal to 30 ng/mL to define optimal vitamin D status in patients with CKD.2
Although all studies reviewed noted a significant improvement in 25(OH)D concentrations, a mean optimal vitamin D concentration was not achieved by all and may be due to several reasons including an insufficient dose of vitamin D and/or use of a less effective form of vitamin D (ergocalciferol, as opposed to cholecalciferol). In general the studies supplementing with the equivalent of 700 to 1,000 IU vitamin D per day34,36
did not achieve mean optimal vitamin D status. In a dosage comparison study, Okša et al.36
found that 20,000 IU cholecalciferol/wk (~2,857 IU/day), but not 5,000 IU/wk (~714 IU/day) was sufficient to achieve optimal status in CKD patients. Collectively, studies in this review suggest daily doses of vitamin D > 2,000 IU/day (or weekly/monthly equivalents) are required to achieve optimal vitamin D status.
The KDOQI guidelines recommend the use of ergocalciferol with a specific dosing strategy to treat vitamin D deficiency/insufficiency2
; however, several studies in healthy participants have shown cholecalciferol to be more effective in raising and maintaining 25(OH)D concentrations than ergocalciferol.50-52
No study has compared the effectiveness of cholecalciferol vs. ergocalciferol in a head-to-head trial in raising 25(OH)D concentrations in patients with CKD. However, a comparison of the placebo-controlled cholecalciferol trial in CKD by Chandra et al.29
to ergocalciferol trials with similar baseline serum 25(OH)D values and dosing strategies31,42,44
supports the hypothesis that cholecalciferol is more effective than ergocalciferol in CKD. Taken together, these data suggest KDOQI guidelines may need to be updated to recommend the use of cholecalciferol as opposed to ergocalciferol. Further study is needed to establish effective vitamin D dosing protocols specific to patients with CKD to achieve and maintain optimal serum 25(OH)D concentrations.
Alleviation of secondary hyperparathyroidism is a major target for CKD management2
and the most commonly investigated outcome for vitamin D supplementation in early CKD, as indicated by this review. Vitamin D is a known regulator of PTH secretion2
; however the effective amount and form needed to manage or prevent secondary hyperparathyroidism in early CKD are not known. The 2003 KDOQI guidelines made opinion-based recommendations to assess serum 25(OH)D concentrations and treat vitamin D insufficiency with ergocalciferol in patients with CKD Stages 3 and 4 only if PTH concentrations are elevated.2
Several studies identified in this review used modified vitamin D dosing strategies modeled after KDOQI and found varying effects on PTH. The sole study published following the exact 2003 KDOQI protocol did not find a PTH-lowering effect of ergocalciferol treatment.44
Kandula et al.53
performed a meta-analysis on the PTH lowering effects of any form of vitamin D (including calcitriol) or vitamin D analog and reported a significant decrease in PTH in early CKD patients. A 30% decrease in PTH has been cited as being clinically effective.42
In the only randomized, double-blind, placebo-controlled trial of vitamin D adults with early CKD, serum PTH decreased ~30% after 12 weeks of cholecalciferol treatment, although the sample size may have not been large enough to detect a statistically significant change in PTH.29
Given the wide variability in the design of published vitamin D supplementation trials and the corresponding variability in PTH lowering effects, it is clear that further randomized, placebo-controlled trials are necessary to establish an optimal treatment strategy with vitamin D to manage secondary hyperparathyroidism.
CKD severity plays a role in the effectiveness of vitamin D in reducing serum PTH. Two studies reported a reduction in serum PTH in patients with Stage 3 but not Stage 4 CKD.40,42
These data suggest that vitamin D is most beneficial in lowering serum PTH when 1α-hydroxylase is more active.8,9
In this regard, it may be prudent to test and correct 25(OH)D concentrations prior to elevations in serum PTH among early stage CKD patients, despite current KDOQI guidelines.2
Indeed, ergocalciferol treatment in children with CKD stage 2–4 delayed the onset of secondary hyperparathyroidism compared with placebo,30
suggesting that optimization of vitamin D status may be especially important during early CKD. This remains to be examined in adult CKD patients.
Only two studies have investigated the use of active vitamin D analogs vs. supplemental vitamin D in CKD. One clinical trial showed paricalcitol more effectively suppressed PTH.31
The other suggested doxercalciferol may be better at reducing PTH but did not significantly differ from cholecalciferol.32
It is hypothesized that supplemental vitamin D may be a better choice given its lower cost, fewer side effects and potential extra-renal benefits that require adequate serum 25(OH)D as a substrate for conversion to 1,25(OH)2
D to act as a paracrine/autocrine hormone in local tissue.17
Studies have not investigated differences between vitamin D forms on other outcomes in this regard. Vitamin D analogs have been hypothesized to interfere with local paracrine/autocrine VDR activation and effects by inhibiting local 1-α hydroxylase or promoting 24-hydroxylase expression thereby suppressing local calcitriol production.8,54
Furthermore, adequate serum 25(OH)D is able to suppress PTH synthesis and secretion in parathyroid cells.55
These reasons underscore the importance of maintaining adequate serum 25(OH)D levels in CKD.
The presence of proteinuria in CKD is an independent predictor for disease progression to ESRD and mortality.56,57
Cross-sectional studies indicate inverse relationships between circulating 25(OH)D and albuminuria in patients with CKD.58,59
Experimental evidence suggests that vitamin D may protect against or reduce proteinuria via its inhibitory effects on renin gene transcription and subsequent angiotensin II production;60
via inhibition of renal TNFα converting enzyme expression;8,61,62
via direct upregulation of nephrin;60,63
and/or via upregulation of renal megalin expression.22,64
Paricalcitol has been shown to significantly decrease proteinuria in clinical trials of patients with CKD,65-68
and may have anabolic effects, as indicated by increases in serum creatinine and blood urea nitrogen.65,69
eGFR is highly influenced by serum creatinine which may explain the reported decreases in eGFR identified in the review after cholecalciferol supplementation.34,36
Only one clinical trial of vitamin D supplementation identified by this review reported albuminuria as an outcome, albeit secondary, and did not observe a significant reduction in albuminuria.32
Given the possibility that proteinuria may promote vitamin D deficiency through urinary loss of VDBP,21
future clinical trials aimed at raising serum 25(OH)D concentrations with cholecalciferol and using proteinuria as a primary outcome are warranted. As accelerated protein energy wasting occurs with progressive CKD,70
the implications for a vitamin D protective effect on muscle integrity in this population should also be further explored.
Low circulating 25(OH)D concentrations predict increased all-cause mortality risk in pre-dialysis CKD patients in large cohort studies.6,27,47,49
Mortality was reduced by 26% in early CKD patients who received calcitriol, and this was independent of PTH and other risk factors.71
The mechanisms mediating a reduced mortality risk with higher vitamin D status are yet unknown; however vitamin D may play a role in infection-associated morbidity and mortality, which is significantly greater among patients with CKD.72
Calcitriol promotes upregulation of antimicrobial defenses by the immune system,5,73-75
and a higher rate of infection-associated mortality has been linked to severe vitamin D deficiency in ESRD.76
No studies have investigated the relationship between vitamin D status and infection in early chronic kidney disease.
The cardioprotective effects of vitamin D may also mediate the associations between better vitamin D status and reduced mortality in CKD. Vitamin D deficiency in ESRD patients is associated with an increased risk of CVD events.77
In contrast, a meta-analysis did not find a benefit of vitamin D analogs on cardiovascular outcomes.78
We identified only one study to-date examining the effect of vitamin D supplementation on CVD events in CKD. In a retrospective data review, Lishmanov et al.41
reported a reduced incidence of CVD events (albeit not statistically significant), as well as lower all-cause and CVD-related mortality, in early CKD patients successfully treated with ergocalciferol. Findings were independent of changes in PTH, suggesting other mechanisms mediated the reduced cardiovascular risk. Long-term, prospective, randomized-controlled trials of vitamin D supplementation are required to confirm effects in patients with early CKD.
Adequate vitamin D status may be important for regulation of several predictors of CVD risk that are relevant in patients with CKD, such as hypertension and left ventricular hypertrophy,79-81
insulin resistance/glucose intolerance,82
and oxidative stress.85
A reduction in these CVD risk indicators with cholecalciferol and/or active vitamin D analog treatment has been shown in ESRD patients.79,85-93
Only two trials, as indicated in this review, have investigated effects of vitamin D supplementation on such measures of CVD risk with suggestive, but not significant, results, and not as primary outcomes.31,32
No study has specifically investigated if vitamin D supplementation improves glucose homeostasis in early CKD. Given the scarcity of data available, conclusions cannot be made regarding specific effects of vitamin D supplementation on CVD risk in early stage CKD. Prospective clinical trials are required to identify the best measure of cardioprotective effects of vitamin D supplementation in early stage CKD, as well as the optimal vitamin D formulation.