Is Vitamin D3 Bad for the Kidney?

Carsten A. Wagner

Disclosures

Nephrol Dial Transplant. 2018;33(12):2071-2072. 

Active vitamin D3 {1,25-dihydroxyvitamin D3 [1,25(OH)2D3], calcitriol} is a hormone best known for its role in modulating mineral balance. Its synthesis involves several steps, including a hepatic hydroxylation to calcidiol {25-hydroxyvitamin D [25(OH)D3]}, requiring the cytochrome P450 enzyme CYP2R1, and final activation in the kidney by CYP27B1, mostly expressed in proximal tubules. Also, the degradation of calcitriol and calcidiol is performed by CYP24A1 in the proximal tubule.[1] Importantly, only 1,25(OH)2D3 exerts significant biological activity, all other forms of vitamin D3 (i.e. intermediate metabolites of synthesis and degradation) are thought to have minimal or no biologic activity.[1,2] As expected for a hormone that has many functions in controlling mineral homeostasis, the synthesis and degradation of calcitriol is tightly regulated by many calci- and phosphatotropic factors, including parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), calcium and phosphate. In addition, immune cytokines modulate calcitriol levels.[1,3,4]

Genetic studies of humans with rare inherited disorders have demonstrated important roles of the vitamin D receptor (VDR) and CYP24A1 enzyme, as well as of genes involved in controlling FGF23, PTH and calcium and phosphate levels. However, much less is known about the genetics underlying vitamin D3 metabolism in the general population. Only a few genome-wide association studies (GWASs) have been reported, with a remarkably low number of gene loci associated with 25(OH)D3, whereas no data have been published for GWASs for 1,25(OH)2D3.[5–7]

In patients with chronic kidney disease (CKD), the decline of circulating calcitriol levels is part of the complex endocrine dysregulation.[3,8] Calcitriol is a controversial part of the armamentarium to treat patients with CKD.[9] Animal and in vitro experiments have provided evidence that calcitriol could have many beneficial effects on vascular integrity and function, on cell proliferation and cancer, on the immune system, on neuronal functions and on aging in general.[1] Studies in humans have shown a less clear picture.[1,10,11]

So, one could assume, having higher levels of calcitriol should be a good thing. Well, the jury is still out, but an article in this issue of NDT adds another piece to this complex picture.[12] Teumer et al.[12] examined the association between calcidiol and kidney function in terms of estimated GFR (eGFR) and urinary albumin:creatinine ratio (UACR) in several large cohorts that include a total of >200 000 individuals. An inherent problem of many epidemiological studies, including GWASs, is that they can establish associations but not causal links. To study causality, prospective studies are required, which are logistically challenging and costly. The problem of proving causality can be partly overcome by using Mendelian randomization. This approach is based on the identification of certain single-nucleotide polymorphisms (SNPs) in the general population (through previous GWASs) that associate with specific traits, such as in this study, where SNPs in CYP24A1 (degrading calcitriol and calcidiol) associate with the levels of calcidiol. Since the inheritance of these SNPs in the population occurs mostly independent from the phenotypical confounders, this randomization reduces the impact of confounding factors (unless dependent on the same SNPs).[13,14] Here the authors selected SNPs associated previously with the levels of 25(OH)D3 [these SNPs were located near to or in a vitamin D3 binding protein and the enzymes DHCR7 and CYP2R1 involved in 25(OH)D3 synthesis) and then tested for the potential impact of 25(OH)D3 on kidney function. Whereas no effect on UACR was found, a negative impact of increasing levels of 25(OH)D3 on eGFR was detected.

An important question is, how relevant is an association between the inactive calcidiol and a biological function or disease risk? In clinical practice, 25(OH)D3 is often measured to assess the overall vitamin D3 status and is taken as a surrogate marker for 1,25(OH)2D3. However, this assumption may not be always be correct, certainly not in patients with CKD where the step in the activation of calcitriol is impaired, resulting in low calcitriol levels despite normal calcidiol. But there are also doubts in other subgroups of the general population about how tight the correlation between calcidiol and calcitriol is.[2,15] The authors addressed this issue by including another sample of >20 000 participants pooled from several studies in which they had calcidiol and calcitriol measurements and eGFR was calculated. Similar to calcidiol, increasing calcitriol negatively influenced eGFR. Unfortunately, the authors excluded another potentially interesting SNP located close to CYP24A1, the enzyme directly degrading 25(OH)D3 and 1,25(OH)2D3. Inactivating mutations in this gene cause idiopathic infantile hypercalcaemia with highly elevated levels of calcitriol, which can cause massive nephrocalcinosis and subsequent loss of kidney function.[16] SNPs close to CYP24A1 were directly associated with lower eGFR, thereby potentially confounding the effect of calcidiol and calcitriol on eGFR. While methodologically correct, this SNP and the well-known biology behind its gene, as well as the strong effect of the gene on calcidiol and calcitriol (assuming that there might be an effect of this SNP on enzyme activity), may have provided a case where an association or even a causal link could be brought together with some existing mechanistic understanding.

The relevance of calcitriol (and calcidiol) on human health and kidney disease is controversial. Epidemiological studies have generated conflicting results, with positive, no or negative effects (in the case of kidney disease), and well-controlled interventional studies are scarce. Teumer et al.[12] addressed this question by performing a subgroup analysis with stratifying individuals in two groups with eGFR greater than or less than 60 mL/min/1.73 m2, rationalizing that lower kidney function causes a decrease in calcitriol that could confound positive or negative associations between calcidiol or calcitriol and kidney function. Participant numbers were much lower, with 18 029 non-CKD individuals and 1109 CKD individuals for the calcidiol analysis and 7371 non-CKD and 448 CKD individuals for the calcitriol analysis. The effect of calcitriol on kidney function was positive for both subgroups, whereas calcidiol had a negative effect in the non-CKD population but a positive association with kidney function in the CKD individuals. Thus previous controversial results may simply arise from mixed population samples with participants having various degrees of renal impairment.

Of course, these results will need replication in other populations. Nevertheless, the question of how higher levels of calcidiol could negatively impact on kidney function has arisen. First, calcidiol is thought to not be biologically active. Thus effects should depend on the conversion rate of calcidiol to calcitriol and the activity of calcitriol. Obviously the levels of calcitriol are tightly regulated and are only loosely associated with calcidiol levels. Kidney function itself is a determinant of the activation of calcitriol, as the proximal tubule is the main site of CYP27B1 activity (the enzyme converting calcidiol to calcitriol). Teumer et al.[12] also speculate that this, via reverse causation, may mask an effect of calcitriol on kidney function. The mechanism by which calcidiol is taken up by proximal tubules is shared with the reuptake of filtered low molecular weight proteins and albumin. In their study, Teumer et al.[12] did not find an association between UACR and calcidiol/calcitriol and possibly low molecular weight proteinuria would be the more sensitive marker for proximal tubule function than albuminuria, which is a composite marker of glomerular and proximal tubular function. Second, calcidiol has been associated with a number of conditions that can affect kidney function, including diabetes, body mass index (BMI) and blood pressure.[17,18] However, in most cases, lower calcidiol levels are associated with higher risk, higher blood pressure or higher BMI and in most cases we do not know how tight the association is for calcitriol.

The findings presented by Teumer et al.[12] are interesting and have to be replicated in independent study cohorts. Mechanistic studies are required to understand the basis of any possible positive or negative impact of vitamin D3 on kidney function (and any other disease risk associated with vitamin D3). Most importantly, these studies should be performed for the biologically active calcitriol, even though measurements of this hormone are technically a bit more challenging and less frequently performed in clinical routine.

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