Editorial
Vitamin D Deficiency: Consequence or Cause of CKD? Ian H. de Boer* and Ravi Thadhani†
Clin J Am Soc Nephrol 8: 1844–1846, 2013. doi: 10.2215/CJN.09480913
Pioneering studies in the 1970s demonstrated that CKD leads to substantial perturbations in the vitamin D endocrine system and, as a result, bone loss (1–4). In particular, in CKD, renal production of 1,25-dihydroxyvitamin D (1,25(OH) 2 D) from 25hydroxyvitamin D (25(OH)D) is markedly reduced, leading to low circulating 1,25(OH) 2 D concentrations. Insufficient 1,25(OH) 2D contributes to the development of secondary hyperparathyroidism and osteitis fibrosa. Moreover, 1,25(OH)2D treatment lowers circulating parathyroid hormone (PTH) concentrations and reigns in excessively high bone turnover (5,6). More recently, it has become clear that insufficient 1,25(OH)2D may contribute to a wide variety of nonbone health problems. The vitamin D receptor (VDR) is present in virtually all cells. 1,25(OH)2D complexes with the VDR and coreceptors to regulate transcription by binding to vitamin D response elements, which are present in the promoter region of hundreds of human genes. Through this mechanism, 1,25(OH)2D regulates cell proliferation and differentiation, immune cell function, and a number of tissue-specific processes. Interestingly, the effect of 1,25(OH)2D may be greatest on the organ that produces it in greatest quantity— the kidney. In animals, 1,25(OH) 2 D and its analogs potently suppress the transcription of renin in the juxtaglomerular apparatus and exert direct prosurvival effects on podocytes, preventing damage and apoptosis (7–13). In diverse kidney injury models, 1,25(OH)2D and its analogs reduce albuminuria, glomerulosclerosis, and loss of GFR (7–9). Importantly, these effects appear to be synergistic with those of renin-angiotensin inhibitors, suggesting that 1,25(OH)2D may offer a useful addition to standard CKD care (9). Still unknown is the degree to which 1,25(OH)2D deficiency affects the human kidney in vivo and— more importantly—whether vitamin D–related treatments can improve kidney health. Short-duration clinical trials have consistently demonstrated that treatment with 1,25(OH)2D or an analog reduces urine albumin excretion (14,15). Over the short term, treatment with 1,25(OH)2D or an analog also lowers estimated GFR. In the PRIMO (Paricalcitol Capsule Benefits in Renal Failure–Induced Cardiac Morbidity) trial, this effect, combined with an imbalance of baseline GFR, may have contributed to an excess progression to ESRD (six patients versus one patient over 48 weeks) (16). Whether continued treatment with 1,25(OH)2D or an analog leads to progressive 1844
Copyright © 2013 by the American Society of Nephrology
GFR loss or long-term renoprotection, as with reninangiotensin system inhibitors, remains to be determined. “Nutritional” forms of vitamin D, such as cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2), are an interesting and promising alternative treatment to 1,25(OH)2D. These agents require metabolism to 25(OH)D and then 1,25(OH)2D to tightly bind the VDR. Because the conversion of 25(OH)D to 1,25(OH)2D is tightly regulated, nutritional vitamin D supplementation leads less to toxicity, particularly hypercalcemia, than does 1,25(OH)2D treatment. Moreover, tissuespecific production of 1,25(OH) 2 D from 25(OH)D may most effectively enhance beneficial paracrine effects of 1,25(OH)2D. Observational studies of circulating 25(OH)D offer an important tool to gauge the degree to which nutritional vitamin D supplementation may affect health. Circulating 25(OH)D concentration largely reflects the total intake of cholecalciferol and ergocalciferol through cutaneous synthesis and dietary consumption. In this issue of CJASN, Fernández-Juárez et al. report a cohort study testing associations of circulating 25(OH)D concentration with CKD progression and death among 103 people with type 2 diabetes and a urine albumin/creatinine ratio $300 mg/g (17). The authors report that 25(OH)D ,15 ng/ml was associated with substantial increases in the risk of the primary composite outcome (.50% increase in serum creatinine, ESRD, or death; adjusted hazard ratio, 2.88; 95% confidence interval, 1.84 to 7.67) and the risk of a more limited renal outcome (.50% increase in serum creatinine or ESRD; adjusted hazard ratio, 3.79; 95% confidence interval, 1.20 to 12.02), compared with 25(OH)D $15 ng/ml. A remarkable feature of the report is the magnitude of association, which is substantially larger than that observed in prior studies of 25(OH)D and CKD progression, which have observed smaller (18,19) or null associations (20,21). Together, these studies suggest a large range of potential renal benefit from vitamin D supplementation. The study by Fernández-Juárez et al. has important strengths, including the measurement of 25(OH)D at three time points near study baseline to improve ascertainment of long-term 25(OH)D exposure, frequent regular follow-up for the primary study outcome, a reasonably long median follow-up of 32 months, and a large number of events observed. Of course, as with other studies in the field, this study also has limitations that must be considered when interpreting
*Division of Nephrology, and Kidney Research Institute, Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington; and † Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts Correspondence: Dr. Ian H. de Boer, Division of Nephrology and Kidney Research Institute, Departments of Medicine and Epidemiology, University of Washington, Box 359606, 325 Ninth Avenue, Seattle, WA 98104. Email: deboer@ u.washington.edu
www.cjasn.org Vol 8 November, 2013
Clin J Am Soc Nephrol 8: 1844–1846, November, 2013
and applying results. These include the focus on a single biomarker, limits to external validity, and potential confounding due to the observational design. Circulating 25(OH)D is a valuable biomarker because it largely reflects cholecalciferol and ergocalciferol intake, is modifiable with supplementation, and has favorable measurement characteristics, including relatively high circulating concentrations and a long circulating t1/2 of approximately 4 weeks. However, 25(OH)D is also affected by genetic factors (22), regulatory hormones including PTH and fibroblast growth factor-23 (FGF-23), and common CKD treatments. For example, in stage 3–4 CKD, treatment with VDR agonists substantially reduces 25(OH)D concentration by inducing its catabolism (23). Biomarkers of vitamin D metabolism are therefore interrelated. Fernández-Juárez et al. did not measure FGF-23 or 1,25(OH)2D, and it is possible that these biomarkers, PTH, or vitamin D treatments partially explain the observed association of low 25(OH)D with study outcomes. More importantly, it should be recognized that supplementation with cholecalciferol and ergocalciferol is likely to affect more than just 25(OH)D. The study from Fernández-Juárez et al. derives from a multicenter clinical trial in Spain. Similarities between participants due to geographic proximity may help reduce bias and increase internal validity, which can help identify important relationships. As a trade-off, homogeneity also limits external validity. In community-based populations, associations of 25(OH)D with nonrenal clinical outcomes have been reported to vary by race/ethnicity and by polymorphisms in the VDR gene (24,25). Results may therefore not necessarily extrapolate to more geographically or racially diverse populations. In addition, 25(OH)D assays vary in quality and calibration. Without careful calibration to an accepted standard, such as that provided by the National Institute of Standards and Technology, and without careful statistical analyses focused on identifying a suitable 25(OH)D threshold associated with disease risk, readers should not assume that the 25(OH)D threshold used in this study (15 ng/ml) is a proven therapeutic target. Like the observational studies that preceded it, the most important limitation of the study by Fernández-Juárez et al. is its observational design, which can lead to confounding. Physical inactivity, diets low in dairy and oily fish, adiposity, heavy proteinuria, and other unfavorable health habits and conditions lead to low 25(OH)D concentrations. It could be these characteristics, rather than insufficient 25(OH)D itself, that adversely affect the kidney. Observational studies of 25(OH)D are therefore insufficient on their own to change practice. Clinical trials are necessary to determine the effects of vitamin D supplementation on CKD and other health outcomes. As with 1,25(OH)2D trials, trials of vitamin D supplementation to date have been of short duration. In addition, these trials have mostly focused on vitamin D– and bonerelated outcomes, such as circulating 25(OH)D and PTH concentrations, and most have been small in size. Larger, longer trials are needed. Observational studies are critical to designing such trials. For example, observational studies, including that by Fernández-Juárez et al., suggest that the association of circulating 25(OH)D with CKD progression may be largest among people with diabetes, who tend to have greater urine albumin excretion and a
Editorial: Vitamin D and CKD, de Boer and Thadhani
1845
faster rate of GFR loss (17,19).On the basis of this observation and others, one ongoing clinical trial (NCT01684722) has enrolled 1320 participants with type 2 diabetes to test the effects of cholecalciferol on urine albumin excretion and estimated GFR over at least 2 years of follow-up. It is important to note that a single clinical trial rarely answers an important scientific question. Any given trial has a limited target population, a limited nature or dose of intervention(s), and a discrete primary outcome. Given the compelling evidence now supporting potential beneficial effects of vitamin D–related interventions on the kidney and other health outcomes, additional trials in this field are warranted (26). How should the expanding literature on circulating 25 (OH)D concentration, including the article by FernándezJuárez et al., affect clinical practice? It is quite reasonable to be excited about the prospects of vitamin D as a potential new tool to improve kidney health. However, it remains premature to measure 25(OH)D concentrations or prescribe vitamin D–related therapies for the purpose of improving kidney or other nonbone outcomes. Instead, vitamin D–related therapies should be guided by our knowledge of how CKD affects the vitamin D endocrine system and bone health. In the future, the table may turn, with focus directed instead on the effect of the vitamin D endocrine system on CKD. Acknowledgments I.H.d.B. is supported by National Institutes of Health (NIH) Grants DK088762, DK087726, and HL096875. R.T. is supported by NIH grants DK094872, DK094486, and HL112746. Disclosures I.H.d.B. and R.T. have each received a research grant from Abbott Laboratories to perform a randomized trial with a vitamin D analogue. References 1. Kodicek E, Lawson DE, Wilson PW: Biological activity of a polar metabolite of vitamin D. Nature 228: 763–764, 1970 2. Omdahl J, Holick M, Suda T, Tanaka Y, DeLuca HF: Biological activity of 1,25-dihydroxycholecalciferol. Biochemistry 10: 2935–2940, 1971 3. Lawson DE, Fraser DR, Kodicek E, Morris HR, Williams DH: Identification of 1,25-dihydroxycholecalciferol, a new kidney hormone controlling calcium metabolism. Nature 230: 228– 230, 1971 4. Brickman AS, Coburn JW, Norman AW: Action of 1,25dihydroxycholecalciferol, a potent, kidney-produced metabolite of vitamin D, in uremic man. N Engl J Med 287: 891–895, 1972 5. Slatopolsky E, Weerts C, Thielan J, Horst R, Harter H, Martin KJ: Marked suppression of secondary hyperparathyroidism by intravenous administration of 1,25-dihydroxy-cholecalciferol in uremic patients. J Clin Invest 74: 2136–2143, 1984 6. Andress DL, Norris KC, Coburn JW, Slatopolsky EA, Sherrard DJ: Intravenous calcitriol in the treatment of refractory osteitis fibrosa of chronic renal failure. N Engl J Med 321: 274–279, 1989 7. Schwarz U, Amann K, Orth SR, Simonaviciene A, Wessels S, Ritz E: Effect of 1,25 (OH)2 vitamin D3 on glomerulosclerosis in subtotally nephrectomized rats. Kidney Int 53: 1696–1705, 1998 8. Kuhlmann A, Haas CS, Gross ML, Reulbach U, Holzinger M, Schwarz U, Ritz E, Amann K: 1,25-Dihydroxyvitamin D3 decreases podocyte loss and podocyte hypertrophy in the subtotally nephrectomized rat. Am J Physiol Renal Physiol 286: F526–F533, 2004 9. Zhang Z, Zhang Y, Ning G, Deb DK, Kong J, Li YC: Combination therapy with AT1 blocker and vitamin D analog markedly
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13.
14.
15.
16.
17.
18. 19.
20.
Clinical Journal of the American Society of Nephrology
ameliorates diabetic nephropathy: Blockade of compensatory renin increase. Proc Natl Acad Sci U S A 105: 15896–15901, 2008 Branisteanu DD, Leenaerts P, van Damme B, Bouillon R: Partial prevention of active Heymann nephritis by 1 alpha, 25 dihydroxyvitamin D3. Clin Exp Immunol 94: 412–417, 1993 Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP: 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 110: 229–238, 2002 Hirata M, Makibayashi K, Katsumata K, Kusano K, Watanabe T, Fukushima N, Doi T: 22-Oxacalcitriol prevents progressive glomerulosclerosis without adversely affecting calcium and phosphorus metabolism in subtotally nephrectomized rats. Nephrol Dial Transplant 17: 2132–2137, 2002 Wang Y, Deb DK, Zhang Z, Sun T, Liu W, Yoon D, Kong J, Chen Y, Chang A, Li YC: Vitamin D receptor signaling in podocytes protects against diabetic nephropathy. J Am Soc Nephrol 23: 1977–1986, 2012 de Zeeuw D, Agarwal R, Amdahl M, Audhya P, Coyne D, Garimella T, Parving HH, Pritchett Y, Remuzzi G, Ritz E, Andress D: Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): A randomised controlled trial. Lancet 376: 1543–1551, 2010 de Borst MH, Hajhosseiny R, Tamez H, Wenger J, Thadhani R, Goldsmith DJ: Active vitamin D treatment for reduction of residual proteinuria: A systematic review [published online ahead of print August 8, 2013]. J Am Soc Nephrol doi:10.1681/ASN.2013030203 Thadhani R, Appelbaum E, Pritchett Y, Chang Y, Wenger J, Tamez H, Bhan I, Agarwal R, Zoccali C, Wanner C, Lloyd-Jones D, Cannata J, Thompson BT, Andress D, Zhang W, Packham D, Singh B, Zehnder D, Shah A, Pachika A, Manning WJ, Solomon SD: Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: The PRIMO randomized controlled trial. JAMA 307: 674–684, 2012 Ferna´ndez-Jua´rez G, Lun˜o J, Vicente Barrio V, Garcı´a de Vinuesa S, Praga M, Goicoechea M, Lahera V, Casas L, Oliva J; on behalf of the PRONEDI Study Group: 25(OH) vitamin D levels and renal disease progression in patients with type 2 diabetic nephropathy and blockade of the renin-angiotensin system. Clin J Am Soc Nephrol 8: 1870–1876, 2013 Ravani P, Malberti F, Tripepi G, Pecchini P, Cutrupi S, Pizzini P, Mallamaci F, Zoccali C: Vitamin D levels and patient outcome in chronic kidney disease. Kidney Int 75: 88–95, 2009 de Boer IH, Katz R, Chonchol M, Ix JH, Sarnak MJ, Shlipak MG, Siscovick DS, Kestenbaum B: Serum 25-hydroxyvitamin D and change in estimated glomerular filtration rate. Clin J Am Soc Nephrol 6: 2141–2149, 2011 Kendrick J, Cheung AK, Kaufman JS, Greene T, Roberts WL, Smits G, Chonchol M; HOST (Homocysteinemia in Kidney and End Stage Renal Disease) Study Investigators: Associations of plasma
21.
22.
23.
24.
25.
26.
25-hydroxyvitamin D and 1,25-dihydroxyvitamin D concentrations with death and progression to maintenance dialysis in patients with advanced kidney disease. Am J Kidney Dis 60: 567– 575, 2012 de Boer IH, Sachs MC, Cleary PA, Hoofnagle AN, Lachin JM, Molitch ME, Steffes MW, Sun W, Zinman B, Brunzell JD; Diabetes Control and Complication Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group: Circulating vitamin D metabolites and kidney disease in type 1 diabetes. J Clin Endocrinol Metab 97: 4780–4788, 2012 Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D, Kiel DP, Streeten EA, Ohlsson C, Koller DL, Peltonen L, Cooper JD, O’Reilly PF, Houston DK, Glazer NL, Vandenput L, Peacock M, Shi J, Rivadeneira F, McCarthy MI, Anneli P, de Boer IH, Mangino M, Kato B, Smyth DJ, Booth SL, Jacques PF, Burke GL, Goodarzi M, Cheung CL, Wolf M, Rice K, Goltzman D, Hidiroglou N, Ladouceur M, Wareham NJ, Hocking LJ, Hart D, Arden NK, Cooper C, Malik S, Fraser WD, Hartikainen AL, Zhai G, Macdonald HM, Forouhi NG, Loos RJ, Reid DM, Hakim A, Dennison E, Liu Y, Power C, Stevens HE, Jaana L, Vasan RS, Soranzo N, Bojunga J, Psaty BM, Lorentzon M, Foroud T, Harris TB, Hofman A, Jansson JO, Cauley JA, Uitterlinden AG, Gibson Q, Ja¨rvelin MR, Karasik D, Siscovick DS, Econs MJ, Kritchevsky SB, Florez JC, Todd JA, Dupuis J, Hyppo¨nen E, Spector TD: Common genetic determinants of vitamin D insufficiency: A genome-wide association study. Lancet 376: 180–188, 2010 de Boer IH, Sachs M, Hoofnagle AN, Utzschneider KM, Kahn SE, Kestenbaum B, Himmelfarb J: Paricalcitol does not improve glucose metabolism in patients with stage 3-4 chronic kidney disease. Kidney Int 83: 323–330, 2013 Robinson-Cohen C, Hoofnagle AN, Ix JH, Sachs MC, Tracy RP, Siscovick DS, Kestenbaum BR, de Boer IH: Racial differences in the association of serum 25-hydroxyvitamin D concentration with coronary heart disease events. JAMA 310: 179–188, 2013 Levin GP, Robinson-Cohen C, de Boer IH, Houston DK, Lohman K, Liu Y, Kritchevsky SB, Cauley JA, Tanaka T, Ferrucci L, Bandinelli S, Patel KV, Hagstro¨m E, Michae¨lsson K, Melhus H, Wang T, Wolf M, Psaty BM, Siscovick D, Kestenbaum B: Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes. JAMA 308: 1898– 1905, 2012 de Boer IH, Kestenbaum B: Vitamin D in chronic kidney disease: Is the jury in? Kidney Int 74: 985–987, 2008
Published online ahead of print. Publication date available at www. cjasn.org. See related article, “25 (OH) Vitamin D Levels and Renal Disease Progression in Patients with Type 2 Diabetic Nephropathy and Blockade of the Renin-Angiotensin System,” on pages 1870–1876.
Vitamin D Deficiency: Consequence or Cause of CKD? Ian H. de Boer* and Ravi Thadhani†
Clin J Am Soc Nephrol 8: 1844–1846, 2013. doi: 10.2215/CJN.09480913
Pioneering studies in the 1970s demonstrated that CKD leads to substantial perturbations in the vitamin D endocrine system and, as a result, bone loss (1–4). In particular, in CKD, renal production of 1,25-dihydroxyvitamin D (1,25(OH) 2 D) from 25hydroxyvitamin D (25(OH)D) is markedly reduced, leading to low circulating 1,25(OH) 2 D concentrations. Insufficient 1,25(OH) 2D contributes to the development of secondary hyperparathyroidism and osteitis fibrosa. Moreover, 1,25(OH)2D treatment lowers circulating parathyroid hormone (PTH) concentrations and reigns in excessively high bone turnover (5,6). More recently, it has become clear that insufficient 1,25(OH)2D may contribute to a wide variety of nonbone health problems. The vitamin D receptor (VDR) is present in virtually all cells. 1,25(OH)2D complexes with the VDR and coreceptors to regulate transcription by binding to vitamin D response elements, which are present in the promoter region of hundreds of human genes. Through this mechanism, 1,25(OH)2D regulates cell proliferation and differentiation, immune cell function, and a number of tissue-specific processes. Interestingly, the effect of 1,25(OH)2D may be greatest on the organ that produces it in greatest quantity— the kidney. In animals, 1,25(OH) 2 D and its analogs potently suppress the transcription of renin in the juxtaglomerular apparatus and exert direct prosurvival effects on podocytes, preventing damage and apoptosis (7–13). In diverse kidney injury models, 1,25(OH)2D and its analogs reduce albuminuria, glomerulosclerosis, and loss of GFR (7–9). Importantly, these effects appear to be synergistic with those of renin-angiotensin inhibitors, suggesting that 1,25(OH)2D may offer a useful addition to standard CKD care (9). Still unknown is the degree to which 1,25(OH)2D deficiency affects the human kidney in vivo and— more importantly—whether vitamin D–related treatments can improve kidney health. Short-duration clinical trials have consistently demonstrated that treatment with 1,25(OH)2D or an analog reduces urine albumin excretion (14,15). Over the short term, treatment with 1,25(OH)2D or an analog also lowers estimated GFR. In the PRIMO (Paricalcitol Capsule Benefits in Renal Failure–Induced Cardiac Morbidity) trial, this effect, combined with an imbalance of baseline GFR, may have contributed to an excess progression to ESRD (six patients versus one patient over 48 weeks) (16). Whether continued treatment with 1,25(OH)2D or an analog leads to progressive 1844
Copyright © 2013 by the American Society of Nephrology
GFR loss or long-term renoprotection, as with reninangiotensin system inhibitors, remains to be determined. “Nutritional” forms of vitamin D, such as cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2), are an interesting and promising alternative treatment to 1,25(OH)2D. These agents require metabolism to 25(OH)D and then 1,25(OH)2D to tightly bind the VDR. Because the conversion of 25(OH)D to 1,25(OH)2D is tightly regulated, nutritional vitamin D supplementation leads less to toxicity, particularly hypercalcemia, than does 1,25(OH)2D treatment. Moreover, tissuespecific production of 1,25(OH) 2 D from 25(OH)D may most effectively enhance beneficial paracrine effects of 1,25(OH)2D. Observational studies of circulating 25(OH)D offer an important tool to gauge the degree to which nutritional vitamin D supplementation may affect health. Circulating 25(OH)D concentration largely reflects the total intake of cholecalciferol and ergocalciferol through cutaneous synthesis and dietary consumption. In this issue of CJASN, Fernández-Juárez et al. report a cohort study testing associations of circulating 25(OH)D concentration with CKD progression and death among 103 people with type 2 diabetes and a urine albumin/creatinine ratio $300 mg/g (17). The authors report that 25(OH)D ,15 ng/ml was associated with substantial increases in the risk of the primary composite outcome (.50% increase in serum creatinine, ESRD, or death; adjusted hazard ratio, 2.88; 95% confidence interval, 1.84 to 7.67) and the risk of a more limited renal outcome (.50% increase in serum creatinine or ESRD; adjusted hazard ratio, 3.79; 95% confidence interval, 1.20 to 12.02), compared with 25(OH)D $15 ng/ml. A remarkable feature of the report is the magnitude of association, which is substantially larger than that observed in prior studies of 25(OH)D and CKD progression, which have observed smaller (18,19) or null associations (20,21). Together, these studies suggest a large range of potential renal benefit from vitamin D supplementation. The study by Fernández-Juárez et al. has important strengths, including the measurement of 25(OH)D at three time points near study baseline to improve ascertainment of long-term 25(OH)D exposure, frequent regular follow-up for the primary study outcome, a reasonably long median follow-up of 32 months, and a large number of events observed. Of course, as with other studies in the field, this study also has limitations that must be considered when interpreting
*Division of Nephrology, and Kidney Research Institute, Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington; and † Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts Correspondence: Dr. Ian H. de Boer, Division of Nephrology and Kidney Research Institute, Departments of Medicine and Epidemiology, University of Washington, Box 359606, 325 Ninth Avenue, Seattle, WA 98104. Email: deboer@ u.washington.edu
www.cjasn.org Vol 8 November, 2013
Clin J Am Soc Nephrol 8: 1844–1846, November, 2013
and applying results. These include the focus on a single biomarker, limits to external validity, and potential confounding due to the observational design. Circulating 25(OH)D is a valuable biomarker because it largely reflects cholecalciferol and ergocalciferol intake, is modifiable with supplementation, and has favorable measurement characteristics, including relatively high circulating concentrations and a long circulating t1/2 of approximately 4 weeks. However, 25(OH)D is also affected by genetic factors (22), regulatory hormones including PTH and fibroblast growth factor-23 (FGF-23), and common CKD treatments. For example, in stage 3–4 CKD, treatment with VDR agonists substantially reduces 25(OH)D concentration by inducing its catabolism (23). Biomarkers of vitamin D metabolism are therefore interrelated. Fernández-Juárez et al. did not measure FGF-23 or 1,25(OH)2D, and it is possible that these biomarkers, PTH, or vitamin D treatments partially explain the observed association of low 25(OH)D with study outcomes. More importantly, it should be recognized that supplementation with cholecalciferol and ergocalciferol is likely to affect more than just 25(OH)D. The study from Fernández-Juárez et al. derives from a multicenter clinical trial in Spain. Similarities between participants due to geographic proximity may help reduce bias and increase internal validity, which can help identify important relationships. As a trade-off, homogeneity also limits external validity. In community-based populations, associations of 25(OH)D with nonrenal clinical outcomes have been reported to vary by race/ethnicity and by polymorphisms in the VDR gene (24,25). Results may therefore not necessarily extrapolate to more geographically or racially diverse populations. In addition, 25(OH)D assays vary in quality and calibration. Without careful calibration to an accepted standard, such as that provided by the National Institute of Standards and Technology, and without careful statistical analyses focused on identifying a suitable 25(OH)D threshold associated with disease risk, readers should not assume that the 25(OH)D threshold used in this study (15 ng/ml) is a proven therapeutic target. Like the observational studies that preceded it, the most important limitation of the study by Fernández-Juárez et al. is its observational design, which can lead to confounding. Physical inactivity, diets low in dairy and oily fish, adiposity, heavy proteinuria, and other unfavorable health habits and conditions lead to low 25(OH)D concentrations. It could be these characteristics, rather than insufficient 25(OH)D itself, that adversely affect the kidney. Observational studies of 25(OH)D are therefore insufficient on their own to change practice. Clinical trials are necessary to determine the effects of vitamin D supplementation on CKD and other health outcomes. As with 1,25(OH)2D trials, trials of vitamin D supplementation to date have been of short duration. In addition, these trials have mostly focused on vitamin D– and bonerelated outcomes, such as circulating 25(OH)D and PTH concentrations, and most have been small in size. Larger, longer trials are needed. Observational studies are critical to designing such trials. For example, observational studies, including that by Fernández-Juárez et al., suggest that the association of circulating 25(OH)D with CKD progression may be largest among people with diabetes, who tend to have greater urine albumin excretion and a
Editorial: Vitamin D and CKD, de Boer and Thadhani
1845
faster rate of GFR loss (17,19).On the basis of this observation and others, one ongoing clinical trial (NCT01684722) has enrolled 1320 participants with type 2 diabetes to test the effects of cholecalciferol on urine albumin excretion and estimated GFR over at least 2 years of follow-up. It is important to note that a single clinical trial rarely answers an important scientific question. Any given trial has a limited target population, a limited nature or dose of intervention(s), and a discrete primary outcome. Given the compelling evidence now supporting potential beneficial effects of vitamin D–related interventions on the kidney and other health outcomes, additional trials in this field are warranted (26). How should the expanding literature on circulating 25 (OH)D concentration, including the article by FernándezJuárez et al., affect clinical practice? It is quite reasonable to be excited about the prospects of vitamin D as a potential new tool to improve kidney health. However, it remains premature to measure 25(OH)D concentrations or prescribe vitamin D–related therapies for the purpose of improving kidney or other nonbone outcomes. Instead, vitamin D–related therapies should be guided by our knowledge of how CKD affects the vitamin D endocrine system and bone health. In the future, the table may turn, with focus directed instead on the effect of the vitamin D endocrine system on CKD. Acknowledgments I.H.d.B. is supported by National Institutes of Health (NIH) Grants DK088762, DK087726, and HL096875. R.T. is supported by NIH grants DK094872, DK094486, and HL112746. Disclosures I.H.d.B. and R.T. have each received a research grant from Abbott Laboratories to perform a randomized trial with a vitamin D analogue. References 1. Kodicek E, Lawson DE, Wilson PW: Biological activity of a polar metabolite of vitamin D. Nature 228: 763–764, 1970 2. Omdahl J, Holick M, Suda T, Tanaka Y, DeLuca HF: Biological activity of 1,25-dihydroxycholecalciferol. Biochemistry 10: 2935–2940, 1971 3. Lawson DE, Fraser DR, Kodicek E, Morris HR, Williams DH: Identification of 1,25-dihydroxycholecalciferol, a new kidney hormone controlling calcium metabolism. Nature 230: 228– 230, 1971 4. Brickman AS, Coburn JW, Norman AW: Action of 1,25dihydroxycholecalciferol, a potent, kidney-produced metabolite of vitamin D, in uremic man. N Engl J Med 287: 891–895, 1972 5. Slatopolsky E, Weerts C, Thielan J, Horst R, Harter H, Martin KJ: Marked suppression of secondary hyperparathyroidism by intravenous administration of 1,25-dihydroxy-cholecalciferol in uremic patients. J Clin Invest 74: 2136–2143, 1984 6. Andress DL, Norris KC, Coburn JW, Slatopolsky EA, Sherrard DJ: Intravenous calcitriol in the treatment of refractory osteitis fibrosa of chronic renal failure. N Engl J Med 321: 274–279, 1989 7. Schwarz U, Amann K, Orth SR, Simonaviciene A, Wessels S, Ritz E: Effect of 1,25 (OH)2 vitamin D3 on glomerulosclerosis in subtotally nephrectomized rats. Kidney Int 53: 1696–1705, 1998 8. Kuhlmann A, Haas CS, Gross ML, Reulbach U, Holzinger M, Schwarz U, Ritz E, Amann K: 1,25-Dihydroxyvitamin D3 decreases podocyte loss and podocyte hypertrophy in the subtotally nephrectomized rat. Am J Physiol Renal Physiol 286: F526–F533, 2004 9. Zhang Z, Zhang Y, Ning G, Deb DK, Kong J, Li YC: Combination therapy with AT1 blocker and vitamin D analog markedly
1846
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13.
14.
15.
16.
17.
18. 19.
20.
Clinical Journal of the American Society of Nephrology
ameliorates diabetic nephropathy: Blockade of compensatory renin increase. Proc Natl Acad Sci U S A 105: 15896–15901, 2008 Branisteanu DD, Leenaerts P, van Damme B, Bouillon R: Partial prevention of active Heymann nephritis by 1 alpha, 25 dihydroxyvitamin D3. Clin Exp Immunol 94: 412–417, 1993 Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP: 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 110: 229–238, 2002 Hirata M, Makibayashi K, Katsumata K, Kusano K, Watanabe T, Fukushima N, Doi T: 22-Oxacalcitriol prevents progressive glomerulosclerosis without adversely affecting calcium and phosphorus metabolism in subtotally nephrectomized rats. Nephrol Dial Transplant 17: 2132–2137, 2002 Wang Y, Deb DK, Zhang Z, Sun T, Liu W, Yoon D, Kong J, Chen Y, Chang A, Li YC: Vitamin D receptor signaling in podocytes protects against diabetic nephropathy. J Am Soc Nephrol 23: 1977–1986, 2012 de Zeeuw D, Agarwal R, Amdahl M, Audhya P, Coyne D, Garimella T, Parving HH, Pritchett Y, Remuzzi G, Ritz E, Andress D: Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): A randomised controlled trial. Lancet 376: 1543–1551, 2010 de Borst MH, Hajhosseiny R, Tamez H, Wenger J, Thadhani R, Goldsmith DJ: Active vitamin D treatment for reduction of residual proteinuria: A systematic review [published online ahead of print August 8, 2013]. J Am Soc Nephrol doi:10.1681/ASN.2013030203 Thadhani R, Appelbaum E, Pritchett Y, Chang Y, Wenger J, Tamez H, Bhan I, Agarwal R, Zoccali C, Wanner C, Lloyd-Jones D, Cannata J, Thompson BT, Andress D, Zhang W, Packham D, Singh B, Zehnder D, Shah A, Pachika A, Manning WJ, Solomon SD: Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: The PRIMO randomized controlled trial. JAMA 307: 674–684, 2012 Ferna´ndez-Jua´rez G, Lun˜o J, Vicente Barrio V, Garcı´a de Vinuesa S, Praga M, Goicoechea M, Lahera V, Casas L, Oliva J; on behalf of the PRONEDI Study Group: 25(OH) vitamin D levels and renal disease progression in patients with type 2 diabetic nephropathy and blockade of the renin-angiotensin system. Clin J Am Soc Nephrol 8: 1870–1876, 2013 Ravani P, Malberti F, Tripepi G, Pecchini P, Cutrupi S, Pizzini P, Mallamaci F, Zoccali C: Vitamin D levels and patient outcome in chronic kidney disease. Kidney Int 75: 88–95, 2009 de Boer IH, Katz R, Chonchol M, Ix JH, Sarnak MJ, Shlipak MG, Siscovick DS, Kestenbaum B: Serum 25-hydroxyvitamin D and change in estimated glomerular filtration rate. Clin J Am Soc Nephrol 6: 2141–2149, 2011 Kendrick J, Cheung AK, Kaufman JS, Greene T, Roberts WL, Smits G, Chonchol M; HOST (Homocysteinemia in Kidney and End Stage Renal Disease) Study Investigators: Associations of plasma
21.
22.
23.
24.
25.
26.
25-hydroxyvitamin D and 1,25-dihydroxyvitamin D concentrations with death and progression to maintenance dialysis in patients with advanced kidney disease. Am J Kidney Dis 60: 567– 575, 2012 de Boer IH, Sachs MC, Cleary PA, Hoofnagle AN, Lachin JM, Molitch ME, Steffes MW, Sun W, Zinman B, Brunzell JD; Diabetes Control and Complication Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group: Circulating vitamin D metabolites and kidney disease in type 1 diabetes. J Clin Endocrinol Metab 97: 4780–4788, 2012 Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D, Kiel DP, Streeten EA, Ohlsson C, Koller DL, Peltonen L, Cooper JD, O’Reilly PF, Houston DK, Glazer NL, Vandenput L, Peacock M, Shi J, Rivadeneira F, McCarthy MI, Anneli P, de Boer IH, Mangino M, Kato B, Smyth DJ, Booth SL, Jacques PF, Burke GL, Goodarzi M, Cheung CL, Wolf M, Rice K, Goltzman D, Hidiroglou N, Ladouceur M, Wareham NJ, Hocking LJ, Hart D, Arden NK, Cooper C, Malik S, Fraser WD, Hartikainen AL, Zhai G, Macdonald HM, Forouhi NG, Loos RJ, Reid DM, Hakim A, Dennison E, Liu Y, Power C, Stevens HE, Jaana L, Vasan RS, Soranzo N, Bojunga J, Psaty BM, Lorentzon M, Foroud T, Harris TB, Hofman A, Jansson JO, Cauley JA, Uitterlinden AG, Gibson Q, Ja¨rvelin MR, Karasik D, Siscovick DS, Econs MJ, Kritchevsky SB, Florez JC, Todd JA, Dupuis J, Hyppo¨nen E, Spector TD: Common genetic determinants of vitamin D insufficiency: A genome-wide association study. Lancet 376: 180–188, 2010 de Boer IH, Sachs M, Hoofnagle AN, Utzschneider KM, Kahn SE, Kestenbaum B, Himmelfarb J: Paricalcitol does not improve glucose metabolism in patients with stage 3-4 chronic kidney disease. Kidney Int 83: 323–330, 2013 Robinson-Cohen C, Hoofnagle AN, Ix JH, Sachs MC, Tracy RP, Siscovick DS, Kestenbaum BR, de Boer IH: Racial differences in the association of serum 25-hydroxyvitamin D concentration with coronary heart disease events. JAMA 310: 179–188, 2013 Levin GP, Robinson-Cohen C, de Boer IH, Houston DK, Lohman K, Liu Y, Kritchevsky SB, Cauley JA, Tanaka T, Ferrucci L, Bandinelli S, Patel KV, Hagstro¨m E, Michae¨lsson K, Melhus H, Wang T, Wolf M, Psaty BM, Siscovick D, Kestenbaum B: Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes. JAMA 308: 1898– 1905, 2012 de Boer IH, Kestenbaum B: Vitamin D in chronic kidney disease: Is the jury in? Kidney Int 74: 985–987, 2008
Published online ahead of print. Publication date available at www. cjasn.org. See related article, “25 (OH) Vitamin D Levels and Renal Disease Progression in Patients with Type 2 Diabetic Nephropathy and Blockade of the Renin-Angiotensin System,” on pages 1870–1876.
