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Vitamin D deficiency is common among patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) and is associated with secondary hyperparathyroidism, anaemia, erythropoietin resistance, impaired immune response[4, 5] and increased morbidity and mortality. In contrast, little is known about vitamin D deficiency or its association with outcomes among patients with acute kidney injury (AKI).
Deficiencies of both 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] have been reported in small studies in rats, dogs and humans with AKI.[9, 10] Larger studies among critically ill patients have shown strong associations between 25(OH)D deficiency and adverse outcomes, including increased length of stay, infection and mortality.[11-14] However, these studies were focused on critical illness and did not specifically evaluate the association between vitamin D deficiency and AKI. Patients with AKI may be particularly at risk of having low levels of 1,25(OH)2D due to diminished renal synthesis. Most studies of vitamin D among hospitalized patients, however, only measured 25(OH)D and did not simultaneously measure levels of other vitamin D metabolites, vitamin D binding protein and other hormones that regulate mineral metabolism, such as parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23). Accordingly, the metabolism, pathophysiology and clinical relevance of dysregulated mineral metabolism among patients with AKI remain largely unknown.
We tested the hypotheses that AKI is associated with decreased levels of 25(OH)D, 1,25(OH)2D and bioavailable 25(OH)D (the sum of free- and albumin-bound 25(OH)D) and that decreased levels of these vitamin D metabolites are associated with greater severity of sepsis and greater risk of death among patients with AKI.
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The principal findings are that levels of bioavailable 25(OH)D were strongly and inversely associated with severity of sepsis in the overall sample and, unlike other vitamin D metabolites, inversely associated with hospital mortality among participants with AKI. In addition, we found that participants with AKI had lower levels of 1,25(OH)2D and VDBP, a trend towards lower levels of 25(OH)D and similar levels of bioavailable 25(OH)D and bioavailable 1,25(OH)2D compared to controls. Cumulatively, these findings suggest a complex interplay between AKI, vitamin D and adverse outcomes.
These findings are consistent with and extend those from prior reports in both animals[7, 8] and humans.[9, 10, 20] In one study, patients with AKI requiring haemodialysis were found to have low levels of both 25(OH)D and 1,25(OH)2D. However, the sample size was limited to eight patients, the control group consisted of healthy volunteers rather than more comparable hospitalized patients without AKI, and other mineral metabolites such as VDBP were not measured. In contrast, strengths of the current study included a larger sample size, an inpatient control group, a comprehensive evaluation of mineral metabolites and their association with clinical outcomes.
We found lower levels of 1,25(OH)2D among participants with AKI; however, the precise mechanisms could not be discerned. Reduced levels of circulating 25(OH)D, severely reduced GFR or global nephron dysfunction may have contributed to diminished delivery of 25(OH)D substrate available for activation by renal 1α-hydroxylase. Alternatively, elevated levels of FGF23, through inhibition of 1α-hydroxylase and/or stimulation of the catabolic 24-hydroxylase, may have resulted in diminished conversion of 25(OH)D to 1,25(OH)2D.[21, 22] However, we measured 24R,25(OH)2D3, the major metabolite of 25(OH)D, and found that levels were not elevated in AKI. Accordingly, we did not find evidence that enhanced catabolism of 25(OH)D is the primary mechanism of reduced 1,25(OH)2D in AKI. These findings are consistent with a study of rats with acute tubular necrosis, which found that lower levels of 1,25(OH)2D resulted from decreased production and not enhanced catabolism of the hormone.
We also found that levels of bioavailable 25(OH)D were inversely associated with severity of sepsis in the overall sample and with hospital mortality among participants with AKI. These outcomes were more tightly associated with bioavailable 25(OH)D than with other mineral metabolites, findings which are consistent with previous studies in both normal healthy individuals and in haemodialysis patients demonstrating bioavailable 25(OH)D to be more closely linked to mineral metabolism than total 25(OH)D. However, unlike these previous studies, we did not observe bioavailable 25(OH)D to be more tightly associated with other mineral metabolites than total 25(OH)D, perhaps reflecting the role of bioavailable 25(OH)D as a global severity of illness marker rather than a marker of mineral metabolism. Alternatively, our findings of a stronger association between bioavailable vs total 25(OH)D levels and severity of sepsis may be related to selective uptake of bioavailable 25(OH)D by macrophages and other nontraditional target organs. These sites may be more dependent on adequate bioavailable 25(OH)D than the renal proximal tubules, which take up VDBP-25(OH)D via megalin-dependent endocytosis.
The greater prognostic value of bioavailable 25(OH)D compared to other mineral metabolites may be partially attributable to a confounding effect from albumin or VDBP, both of which are variables in the equations used to estimate bioavailable 25(OH)D. In univariate analyses, neither albumin nor VDBP showed a significant association with mortality, unlike bioavailable 25(OH)D. Nonetheless, potential residual confounding cannot be excluded, particularly because multiple studies have shown albumin and VDBP levels[25, 26] to be negative predictors of adverse outcomes among hospitalized patients.
Our observations of bioavailable 25(OH)D and mortality are consistent with previous reports of total 25(OH)D levels and risk of mortality among critically ill patients.[11-14] While the exact mechanism of this association is unknown, vitamin D plays a critical role in host defence, both by stimulating innate immunity and by inhibiting adaptive immunity. Specifically, the antimicrobial peptide cathelicidin (LL-37) is regulated by the vitamin D receptor and can be increased in vitro by administration of 1,25(OH)2D. LL-37 levels correlate positively with 25(OH)D levels in both healthy adults and in critically ill patients and are inversely associated with risk of infectious disease mortality among patients undergoing haemodialysis. Markers of systemic inflammation, on the other hand, such as interleukin-6, are elevated among vitamin D deficient patients and can be significantly decreased by vitamin D supplementation, suggesting that vitamin D also plays a role in limiting an exaggerated inflammatory response. Randomized controlled studies will be needed to determine whether vitamin D supplementation can beneficially influence host defence parameters and ultimately improve outcomes among patients with AKI, critical illness or both. One such study is currently underway (NCT01130181).
These findings must be interpreted in the context of the study design, including modest sample size, single-centre, a maximum of only two data points per participant, relatively short duration of follow-up (until hospital discharge) and observational design. We did not have vitamin D levels prior to the onset of acute illness and therefore cannot exclude the possibility of reverse causality. Levels of bioavailable 25(OH)D and bioavailable 1,25(OH)2D were estimated using equations which were not developed and validated in AKI. Consequently, estimated values for these vitamin D metabolites should be viewed as preliminary and in need of validation. The AKI group had a disproportionate number of diabetics compared to the control group, which may have resulted in bias. However, the groups were similar with regard to other baseline demographics and comorbidities, and analyses between mineral metabolites and mortality were restricted to the AKI group. We did not have data available on body mass index, a potential source of residual confounding as 25(OH)D levels have been shown to be inversely associated with obesity. Additionally, surrogate informed consent was not approved for this study, which precluded enrolment of critically ill patients lacking decisional capacity due to sedation, intubation or other acute processes affecting consciousness or cognition. However, given our observations that the lowest levels of vitamin D metabolites tended to occur among participants with the most severe critical illness, it is likely that the above limitation would have, if anything, biased our results towards the null. Future studies should aim to include the full spectrum of patients with and without AKI, including those who are most critically ill.
Additional studies will be needed to further define the pathophysiology and prognostic importance of vitamin D deficiency among patients with AKI and critical illness. Our data suggest that bioavailable 25(OH)D could have a role as a biomarker of adverse outcomes among those with established AKI and perhaps hospitalized patients in general. Whether low levels of bioavailable 25(OH)D may be directly linked to adverse outcomes through an effect on nontraditional targets, such as the innate immune response, is an intriguing possibility that will require interventional studies of vitamin D supplementation. Future studies should aim to validate the equations used to estimate levels of bioavailable 25(OH)D in AKI patients through actual measurement of the free- and albumin-bound vitamin D concentrations and should continue to assess whether bioavailable levels, compared with total levels, are a more meaningful marker of vitamin D status.