In a large, general-population cohort, 25(OH)D deficiency was common and independently associated with prevalent albuminuria. The association between serum 25(OH)D and albuminuria was most pronounced in those with a 25(OH)D level in the lowest quartile (<47
nmol/L) and remained significant in the multivariate model. Our study did not demonstrate a significant association between 25(OH)D deficiency and an impaired eGFR.
The association between 25(OH)D deficiency and albuminuria was also described in the NHANES III cohort[16
]. Both this study and ours are similar in that they are general population based surveys with a low prevalence of advanced CKD. Nevertheless the NHANES III cohort differs to our study population, with a lower prevalence of 25(OH)D deficiency (22.2% versus 30.7), a higher prevalence of albuminuria (11.6% versus 6.9%), and hypertension (30.9% versus 22.5%), and greater ethnic diversity (non-Caucasians, 54.1% versus 87.3), The consistency of this finding in two, large cohorts highlights the robust nature of this association. This association was also demonstrated in a CKD cohort from the SEEK (Study of Early Evaluation of Chronic Kidney Disease) study [19
], where 25(OH)D deficiency was independently associated with prevalent albuminuria.
Plausible mechanistic links exist between serum 25(OH)D deficiency and albuminuria. Activation of the Wnt/β-catenin signaling pathway induces podocyte injury in animal models [32
], and this pathway can be blocked by paricalcitol administration [33
]. A number of experimental studies demonstrate the reno-protective effects of vitamin D, likely mediated through the RAS and NF-κB [34
]. Mice lacking the vitamin D receptor or α-hydroxylase (required for vitamin D activation), constitutively over-express renin and develop hypertension [35
]. In animal models of renal injury, vitamin D analogues have been shown to attenuate interstitial fibrosis [36
], glomerulosclerosis [37
] and CKD progression [38
]. Vitamin D is known to decrease renin gene transcription[9
], and administration of vitamin D analogues resulted in decreased renin expression and consequently reduced Angiotensin II expression [39
]. As Angiotensin II is a key mediator of proteinuria and kidney damage through haemodynamic (vasoconstriction) and non-haemodynamic (cell proliferation, fibrosis, oxidative stress) means [40
], this is one likely mechanism of the protection afforded by vitamin D.
NF-κB is involved in the regulation of inflammatory cytokines and may promote inflammation and fibrogenesis in experimental and clinical kidney disease [41
]. Fibroblasts derived from mice lacking the vitamin D receptor have intrinsic activation of NF-κB [10
]. This appears relevant to kidney disease as administration of paricalcitol to mice with experimental obstructive nephropathy was found to block NF-κB and attenuate tubule-interstitial inflammation [36
]. Inflammatory cytokines such as transforming growth factor-β and monocyte chemo-attractant protein-1 have been implicated in the pathogenesis of nephropathy [42
]. In a study of CKD patients, low levels of vitamin D metabolites were associated with increased inflammatory parameters [44
Clinical studies have examined the effects of vitamin D on proteinuria in CKD. Calcitriol and paricalcitol administration reduced proteinuria in patients with IgA [45
] and diabetic nephropathy [46
], already on RAS blockade. In a recent study high dose cholecalciferol, showed a reduction in proteinuria in patients with diabetic nephropathy on RAS blockade [42
]. The significant increase in serum calcitriol level observed also highlight the important role of paracrine calcitriol synthesis in mediating the “non-classical” effects of vitamin D. Interestingly proteinuria can also contribute to 25(OH)D deficiency through a decrease in the megalin-mediated reuptake of 25(OH)D in the proximal tubule [47
], however this is only likely to be of clinical significance in cases of heavy proteinuria.
In our study cohort with a low prevalence of severe renal impairment, we did not demonstrate a significant relationship between serum 25(OH)D levels and impaired eGFR in the multivariate models, which is consistent with the NHANES III data [48
]. Our study did show an association between 25(OH)D deficiency and an eGFR <30, however this was lost upon multivariate adjustment. Longitudinal studies demonstrate an association between 25(OH)D deficiency and progression to ESKD. In 13,328 participants from NHANES III, 25(OH)D levels <15
nmol/L) were significantly more likely to progress to ESKD over a median follow-up of 9.1
]. In 1705 participants aged 65
years and older, 25(OH)D <15
ng/ml were associated with more rapid GFR loss [18
]. In a smaller study of mild-moderate CKD, low 25(OH)D levels were associated with increased likelihood of CKD progression [20
The association between low serum 25(OH)D levels and CKD progression, but not prevalence of low eGFR may be important. It is clear that many among the general community with stage 3 CKD do not progress [49
]. As low serum 25(OH)D is associated with albuminuria and renal inflammation – two key predictors of CKD progression, it may well be that low serum 25(OH)D may be a useful marker of risk progression amongst those with a lower eGFR. It is possible that GFR derived with new equations that use cystatin C alone, or in combination with creatinine, may allow for better stratification of patients [50
], and help to delineate any potential associations. Given the generally slow rate of CKD progression, it is possible that longitudinal analysis may differentiate between stable and progressive CKD and better delineate this association.
The strengths of this study include the recruitment of a large, national, population-based cohort, a standardized interview and examination process, and all biochemical measurements being performed in a central laboratory. In contrast to previous population-based studies, the prevalence of impaired renal function is more likely to reflect clinically significant renal impairment given the use of the CKD-EPI equation and calibrated enzymatic serum creatinine. However, there are also several limitations. The cross-sectional design does not infer causality and the associations described may be confounded by unknown and unmeasured factors. The baseline 25(OH)D levels may not be an accurate reflection of lifetime 25(OH)D levels, however one recent study suggests that vitamin D status tends to remain stable over time [51
]. Calcitriol levels and additional markers of mineral metabolism (phosphate, parathyroid hormone and fibroblast growth factor-23) were not measured and these may confound the relationship between 25(OH)D levels and CKD progression. Similarly biochemical markers of the RAS, such as plasma renin levels were also not recorded. Serum creatinine and albuminuria were recorded with a single measurement, introducing the potential for misclassification bias. Calcitriol use and vitamin D supplementation were not recorded. It is likely that calcitriol use would be negligible given the low prevalence of CKD and local prescribing guidelines. Similarly any prolonged use of vitamin D or multi-vitamin supplements should be reflected in the serum 25(OH)D levels. Medications known to affect CKD progression, in particular ACE-inhibitors and angiotensin receptor blockers were also not recorded. These medications are likely to confer a protective benefit over and above that of blood pressure control, and their use may therefore decrease any positive effect of vitamin D observed.