Editorial Breaking Down the Vitamin D–GFR Relationship Related Article, p. 187

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s glomerular filtration rate (GFR) decreases, there is a corresponding decline in activity of the renal 1a-hydroxylase enzyme. This change limits the conversion of 25-hydroxyvitamin D (25[OH]D, or calcifediol), the predominant circulating form of the vitamin, to 1,25-dihydroxyvitamin D (1,25[OH]2D, or calcitriol), generally considered to be the active form.1 Consequently, progressive kidney disease is associated with a decline in 1,25(OH)2D, leading to wellrecognized downstream effects, such as secondary hyperparathyroidism and associated deleterious changes in bone structure and turnover. Much of the therapeutic focus in chronic kidney disease (CKD)associated mineral and bone disease (MBD) has been on using 1,25(OH)2D or its analogues to bypass this enzymatic impairment.2 Much attention in recent years has been paid to the potential importance of 25(OH)D levels in patients with CKD.3 Insufficient 25(OH)D is common in patients with chronic kidney failure and earlier stages of CKD and appears to increase in prevalence as GFR declines.4,5 Low 25(OH)D levels have been associated with increased mortality in a range of populations, and many believe that some of the nontraditional actions of vitamin D (such as its immunologic effects) may require adequate 25(OH)D levels to allow for regional conversion to 1,25(OH)2D in target tissues. The biological underpinnings of 25(OH)D deficiency in CKD are less clear than 1,25(OH)2D deficiency, in which reduced 1a-hydroxylase activity plays a central role. While mechanisms such as reduced sunlight exposure and urinary loss of vitamin D–binding protein have been postulated to play a role in CKD-associated 25(OH)D insufficiency,6 one consideration has been increased catabolism by CYP24A1, the 24a-hydroxylase enzyme, to 24,25-dihydroxyvitamin D (24,25(OH)2D). This enzyme also can convert 1,25(OH)2D to 1,24,25trihydroxyvitamin D (1,24,25(OH)3D), and both 24-hydroxylated compounds generally are considered to be inactive metabolites. If CKD were associated with increased catabolism of the major vitamin D compounds, it might provide a novel biological explanation of why 25(OH)D and 1,25(OH)2D levels are low in Address correspondence to Ishir Bhan, MD, MPH, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114. E-mail: [email protected] Ó 2014 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2014.05.004 168

CKD. Furthermore, it might provide an attractive therapeutic target for managing low vitamin D levels in CKD. In this issue of AJKD, de Boer et al7 assess 24,25(OH)2D levels across diverse populations by analyzing samples from 3 observational cohort studies (the Multi-Ethnic Study of Atherosclerosis [MESA], the Cardiovascular Health Study [CHS], and the Seattle Kidney Study [SKS]) and 2 randomized trials (the Diabetes Control and Complications Trial [DCCT] and the Hemodialysis [HEMO] Study). This is not the authors’ first attempt to clarify the effects of GFR on 24,25(OH)2D level. An earlier study using only the SKS cohort (n 5 278) found that both 1,25(OH)2D and 24,25(OH)2D levels correlated with GFR, which led the authors to suspect that CKD could be viewed as a state of “stagnant” vitamin D metabolism.8 Other groups similarly have observed lower 24,25(OH)2D levels in both animal models and humans with CKD.9 In the present study, the authors provide a considerably more robust investigation, examining not just 24,25(OH)2D levels but also whether estimated GFR modifies the relationship between 25(OH)D and 24,25(OH)2D levels, opening a window into the activity of CYP24A1, the enzyme that converts between these 2 forms. In this study, de Boer et al7 examine the nature of the correlation between 25(OH)D and 24,25(OH)2D. When addressing the correlation between 2 factors in an observational study, 2 aspects of the relationship can be considered. The first is the strength of the correlation, that is, how reliably one value can be predicted from the other. 25(OH)D became a weaker predictor of 24,25(OH)2D in individuals with more severely decreased kidney function; in other words, there was more variability in 24,25(OH)2D levels at a given value of 25(OH)D at lower GFRs than at higher GFRs. The second aspect to consider is the “slope” of the relationship: how much does one factor differ for a given difference in the other factor? The slope of the relationship between 25(OH)D and 24,25(OH)2D became less steep at lower estimated GFRs, suggesting that a change in 25(OH)D levels in a state of low GFR would not be expected to alter 24,25(OH)D as much as it would if GFR were higher. These features suggest that factors other than availability of the substrate became more important drivers of 24,25(OH)2D production in advanced CKD. Variability in 24,25(OH)2D levels might be due to changes in the effects of other hormones (eg, parathyroid hormone and fibroblast growth factor 23 [FGF-23]),10 though the authors attempted to adjust for these variables when they could. Individual differences in 24,25(OH)D clearance and distribution also could play a role. Am J Kidney Dis. 2014;64(2):168-170

Editorial

An important strength of this study over previous attempts to untangle these relationships is that the authors drew samples from several large studies that span diverse populations and clinical characteristics. In total, 9,596 individual participants are analyzed, an impressive cohort for studying a previously underinvestigated compound. Measuring 24,25(OH)2D remains a technical challenge, and the authors do their best to refine their assay over time and compensate for nonspecificity of older versions of the assay. It is essential that these assays be replicated and refined by other groups to provide support to the validity of these findings. Why should we care about 24,25(OH)2D? CYP24A1, the enzyme responsible for its generation, is present in a wide range of target tissues, including seemingly most (if not all) tissues with a vitamin D receptor.10 Because 1,25(OH)2D can induce CYP24A1,11 one model is that CYP24A1 essentially has a classic negative-feedback role, inhibiting 1,25(OH)2D action in states of excess and thus limiting toxicity at the tissue level. In children, loss-of-function mutations in CYP24A1 are associated with hypercalcemia and nephrolithiasis.12 Studying vitamin D levels in this population may give us an assessment of systemic vitamin D catabolism, potentially shaping clinical repletion strategies. However, 24,25(OH)2D levels may have significance beyond their use as a marker of vitamin D catabolism. Animal studies have suggested that CYP24A1 activity and production of

24,25(OH)2D may have an active role in facilitating fracture repair.13 Understanding the factors that control its production is the first step to promoting a hormonal milieu that optimizes bone health. One implication of the findings in the study by de Boer et al7 is that treatment with 25(OH)D would be less likely to induce CYP24A1 in advanced CKD. Because this enzyme also is capable of metabolizing active vitamin D agents (including paricalcitol, doxercalciferol, 22-oxacalcitriol, and calcitriol), this is potentially reassuring news for advocates of nutritional vitamin D treatment in late-stage kidney disease. However, because many factors might affect 25(OH)D, prospective studies are needed to determine definitively the effect of ergocalciferol or cholecalciferol supplementation on 24,25(OH)2D production. Additionally, we cannot tell from association studies whether it is the progressive decline in GFR that impairs CYP24A1 activity or that individuals with impaired CYP24A1 activity are at greater risk for progression of CKD. An additional paradox that remains unsolved is that CKDassociated factors such as FGF-23 appear to stimulate CYP24A1 transcription while reducing 24,25(OH)2D levels.9 Thus, 24,25(OH)2D levels do not appear to be a direct reflection of CYP24A1 production. Because 1,25(OH)2D is thought to be a major regulator of CYP24A1, it is important that future studies take administration of its analogues into account. As these analogues (eg, paricalcitol and doxercalciferol)

Figure 1. The major circulating form of vitamin D (25D) can be converted to active vitamin D (1,25D) by the renal 1a-hydroxylase enzyme (CYP27B1) or to the inactive form (24,25D) by the 24a-hydroxylase enzyme (CYP24A1). The findings of de Boer et al7 suggest that low glomerular filtration rate (GFR), like high parathyroid hormone (PTH) level, suppresses CYP24A1 activity and thus reduces 24,25D production. Others have found that fibroblast growth factor 23 (FGF-23) similarly seems to suppress 24,25D production despite increasing CYP24A1 transcription. Levels of the catabolite of active vitamin D (1,24,25D) are not assessed directly in this study. Am J Kidney Dis. 2014;64(2):168-170

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Ishir Bhan

are used increasingly widely as CKD progresses, they may be important confounders of the relationship between GFR and 24,25(OH)2D in advanced CKD. It may be that any effect of GFR in suppressing CYP24A1 is even more profound than it appears from this analysis if patients with lower GFRs are more likely to be treated with the CYP24A1-inducing active vitamin D compounds. That said, in at least one study, the association of low GFR with reduced 24,25(OH)2D level persisted despite adjustment for calcitriol use.8 Defining the nature of the active vitamin D treatment on CYP24A1 potentially is more central to CKD management. It may not be surprising that CYP24A1 activity is linked less strongly to 25(OH)D levels in CKD if such a relationship requires activation to 1,25(OH)2D (Fig 1); this weakened relationship may reflect, at least in part, reduced 1a-hydroxylase activity associated with CKD. Aside from recent studies highlighting the potential additional value of 25(OH)D augmentation, most vitamin D management is focused on using active agents. CYP24A1 can catabolize 1,25(OH)2D into 1,24,25(OH)3D, but the current assays available to these authors were unable to assess this metabolite. This effect of catabolism of active vitamin D compounds and the factors that modify this catabolism will be key in optimizing the management of CKD-MBD. Although the overall CKD-associated reduction in CYP24A1 activity suggested by this study would cast doubt on the value of the emerging inhibitors of this enzyme, prospective studies will be essential to test their real-world effects, particularly if 24-hydroxylated vitamin D compounds have important biological roles beyond being mere markers of catabolism. Additional studies also will need to explore the potential importance of genetic polymorphisms of CYP24A1, several of which have been identified.10 Given the recent interest in the role of vitamin D– binding protein,14 it also will be important to identify how levels and polymorphisms of this binding protein affect the production of 24-hydroxylated compounds and, potentially, their biological action. For a field in which altering the vitamin D axis is so central to disease management, the study by de Boer et al7 is an exciting next step in shedding light on a previously underappreciated catabolic pathway and working toward more optimal management of CKD-MBD. However, it is important to temper this enthusiasm appropriately. There still is much uncertainty about vitamin D catabolism and the factors that control it, and there is no clear clinical role for testing 24,25(OH)2D at this time.

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Ishir Bhan, MD, MPH Massachusetts General Hospital Boston, Massachusetts

ACKNOWLEDGEMENTS Support: None. Financial Disclosure: The author declares that he has no relevant financial interests.

REFERENCES 1. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3): 266-281. 2. Kidney Disease: Improving Global Outcomes CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2009;113:S1-S130. 3. Nigwekar SU, Bhan I, Thadhani R. Nutritional vitamin D in dialysis patients: what to D-iscern? Nephrol Dial Transplant. 2011;26(3):764-766. 4. Levin A, Bakris GL, Molitch M, et al. Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease. Kidney Int. 2007;71(1):31-38. 5. Wolf M, Shah A, Gutierrez O, et al. Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int. 2007;72(8):1004-1013. 6. Bhan I, Burnett-Bowie SA, Ye J, Tonelli M, Thadhani R. Clinical measures identify vitamin D deficiency in dialysis. Clin J Am Soc Nephrol. 2010;5(3):460-467. 7. de Boer IH, Sachs MC, Chonchol M, et al. Estimated GFR and circulating 24,25-dihydroxyvitamin D3 concentration: a participant-level analysis of 5 cohort studies and clinical trials. Am J Kidney Dis. 2014;64(2):187-197. 8. Bosworth CR, Levin G, Robinson-Cohen C, et al. The serum 24,25-dihydroxyvitamin D concentration, a marker of vitamin D catabolism, is reduced in chronic kidney disease. Kidney Int. 2012;82(6):693-700. 9. Dai B, David V, Alshayeb HM, et al. Assessment of 24, 25(OH)2D levels does not support FGF23-mediated catabolism of vitamin D metabolites. Kidney Int. 2012;82(10):1061-1070. 10. Jones G, Prosser DE, Kaufmann M. 25-Hydroxyvitamin D-24-hydroxylase (CYP24A1): its important role in the degradation of vitamin D. Arch Biochem Biophys. 2012;523(1):9-18. 11. Makin G, Lohnes D, Byford V, Ray R, Jones G. Target cell metabolism of 1,25-dihydroxyvitamin D3 to calcitroic acid. Evidence for a pathway in kidney and bone involving 24-oxidation. Biochem J. 1989;262(1):173-180. 12. Colussi G, Ganon L, Penco S, et al. Chronic hypercalcaemia from inactivating mutations of vitamin D 24-hydroxylase (CYP24A1): implications for mineral metabolism changes in chronic renal failure. Nephrol Dial Transplant. 2014;29(3):636-643. 13. St-Arnaud R. CYP24A1-deficient mice as a tool to uncover a biological activity for vitamin D metabolites hydroxylated at position 24. J Steroid Biochem Mol Biol. 2010;121(1-2):254-256. 14. Powe CE, Evans MK, Wenger J, et al. Vitamin D-binding protein and vitamin D status of black Americans and white Americans. N Engl J Med. 2013;369(21):1991-2000.

Am J Kidney Dis. 2014;64(2):168-170

Breaking down the vitamin D-GFR relationship.

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