- Email: [email protected]
The ABCs of Micronutrients in Dialysis Patients
The ABCs of Micronutrients in Dialysis Patients Related Article, p. 513
M
uch attention has rightly been focused on providing adequate protein and calories (macronutrients) to dialysis patients in an effort to prevent development of malnutrition. A state of protein-energy wasting (PEW) can be diagnosed by low circulating levels of albumin and/or cholesterol, in conjunction with reduced total body and muscle mass.1 In most cases, the diagnosis of PEW represents a complex readout on several concomitant biological processes that include hypercatabolism, poor protein and calorie intake, and active inflammation. Study of the PEW syndrome has been emphasized in dialysis patients due to association with higher rates of morbidity and mortality, along with diminished quality of life. Comparatively less attention has been paid in recent years to the possibility that micronutrient deficiencies can also contribute to poor outcomes in dialysis patients. Yet micronutrients, such as coenzyme Q10, L-carnitine, taurine, and a variety of water- and fat-soluble vitamins, are essential cofactors that provide the necessary cellular machinery for energy transfer and the maintenance of physiological energy homeostasis. Micronutrient deficiency may be particularly important in the human heart.2 Described as a metabolic omnivore,3 the heart must constantly convert a huge amount of chemical energy into mechanical energy, and thus needs a steady stream of nutrients to function well. Moreover, provision of adequate micronutrients may be especially important in the setting of the failing heart, in order to prevent myocyte death and restore compromised function. Micronutrient deficiency is also emerging as a potential contributor to cognitive dysfunction, also a commonly observed complication in patients with advanced kidney disease.4 The general teaching regarding vitamin supplementation in hemodialysis patients is that watersoluble vitamins (such as the B vitamins and vitamin C [ascorbate]) are dialyzed and blood concentrations tend to be low without supplementation, while fat-soluble vitamins such as vitamin A are not dialyzed and blood levels are usually either normal or elevated without supplementation.5 As a consequence, several studies have focused attention on supplementation with either B vitamins or vitamin C in dialysis patients. The primary rationale for investigating aggressive B vitamin supple-
mentation has been to exploit their homocysteinelowering properties, in an effort to reduce cardiovascular risk. Unfortunately, the HOST (Homocysteinemia in Kidney and End-stage Renal Disease) trial, which compared the use of folic acid, vitamin B6, and vitamin B12 to placebo, supported the null hypothesis.6 Studies of vitamin C, an important antioxidant, have focused on alleviating the increased oxidative stress that accompanies kidney disease, and on increasing iron availability to promote erythropoeisis and treat refractory anemia.7 While pilot studies have been promising, the use of aggressive vitamin C supplementation is limited by accumulation of the metabolite oxalate, which may lead to calcium oxalate supersaturation in blood vessels of uremic patients.8 The potential for toxicity of vitamin A has generally precluded its use in kidney failure. However, the antioxidant potential of retinol, the active form of vitamin A, requires a review of this topic and may warrant closer examination in hemodialysis patients. Plasma concentration of retinol has been reported to be elevated in both adults and children treated by hemodialysis and peritoneal dialysis.9-13 The dialysis procedure is not associated with any decrease in plasma retinol concentration and there has been concern about risk for vitamin A toxicity in dialysis patients. Retinol is synthesized and released from the liver and circulates in blood bound to retinol binding protein (RBP) and transthyretin (TTR).14 The binding with carrier proteins ensures the appropriate delivery and availability of retinol at the tissue level. When complexed with retinol, RBP and TTR are not filtered by the glomeruli; however, after the tissue delivery of retinol, the smaller size of noncomplexed RBP allows for glomerular filtration followed by absorption in the proximal tubules through the megalin-cubulin complex. Eventually, retinol is catabolized by the tubular epithelia.15 Thus, kidney function plays a vital role in vitamin A metabolism, and in kidney failure the plasma concentration of both retinol and RBP increases, paralleling the rise in creatinine concenAddress correspondence to Jonathan Himmelfarb, MD, Kidney Research Institute, 325 9th Ave, Box 359606, Seattle, WA 98104-2499. E-mail:[email protected]. © 2010 by the National Kidney Foundation, Inc. 0272-6386/10/5603-0003$36.00/0 doi:10.1053/j.ajkd.2010.07.004
American Journal of Kidney Diseases, Vol 56, No 3 (September), 2010: pp 431-433
431
432
Ahmad and Himmelfarb
Figure 1. Cellular oxidation pathways and antioxidants. In the equations listing the antioxidant activities of the carotenoids (CAR), ROO represents either an alkyl chain linked to a peroxyl radical (ie, -C-O-O.) or an alkoxyl radical (-C-O.), but could equally be a radical formed from a hydroxyl (OH⫺), hypochlorite (OCl⫺), or toxic nitrogen derivative (NOO⫺).
tration.11 In addition to reduced glomerular filtration, impaired activity of enzymatic conversion of retinol to retinoic acid in kidney failure has been reported, which may also contribute to the observed elevation of plasma retinol levels.16,17 The article in this issue of the American Journal of Kidney Diseases by Kalousová et al18 evaluated the role of retinol, RBP, ␣-tocopherol, zinc, and selenium on mortality in 261 prevalent hemodialysis patients. Similar to previous reports, the study found elevated plasma concentrations of retinol and RBP. However Kalousová et al made the novel and surprising observation that lower plasma concentrations of retinol (and a lower retinol to RBP ratio) were strong predictors of overall and cardiovascular mortality. That a lower retinol to RBP ratio is a predictor of poor outcome has not been reported before. These data can be interpreted as suggesting that there is a lower bioavailability of retinol at the cellular and tissue level, despite elevated plasma concentration. This is analogous to the carnitine “insufficiency” described in dialysis patients with lower free to acyl-carnitine ratio (or elevated acyl to free carnitine ratio). It is interesting
that Abahusain and Al-Nahedh19 reported an increased retinol to RBP ratio in patients on dialysis. However, these authors also observed that the ratio increased with time, suggesting that ongoing dialysis is not associated with progressive reduction in availability of retinol. Retinol is derived from dietary carotenoids, which are important constituents of cell membrane, influence DNAstructure, and have antioxidant properties. Increased oxidative stress has been well documented in dialysis patients20,21 and it may play an important role in increased cardiovascular risk, the leading cause of death in this population. In vitro tests under appropriate conditions have shown that carotenoids have important antioxidant properties, and can neutralize superoxides or, through redox activity, act on other free radical compounds (Fig 1). However the efficacy of these compounds in vivo is far from clear, particularly since their concentration in human tissue is much lower and conditions may differ substantially from in vitro experiments. Retinol is a known antioxidant, although its role in humans does not appear to be as strong as that of vitamin E and vitamin C.22 In 1 trial, supplemen-
Editorial
433
tary vitamin A and other nutrients in malnourished dialysis patients had a positive effect on serum albumin levels.23 Trials using supplements in individuals without kidney failure have either shown no effect of vitamin A or even some potential harmful effects, including activation of protooncogenes, with an associated increase in risk of neoplasia. Similarly, the data on the markers of lipid peroxidation, malondialdehyde (MDA), aminolevulinate dehydratase (ALA-D), and retinol concentrations in 29 hemodialysis patients revealed a positive correlation between retinol and MDA,24 findings which suggest that retinol may paradoxically have prooxidant properties in some circumstances. Like other such studies, the article from Kalousová et al has raised more questions than it has answered. What is clear is that there is a general lack of available data regarding whether vitamin A and many other micronutrients are friend or foe in kidney failure. When it comes to understanding the role of micronutrient deficiencies in patients with kidney disease, we need to go back to the ABCs. Suhail Ahmad, MD Jonathan Himmelfarb, MD University of Washington Seattle, Washington
ACKNOWLEDGEMENTS Financial Disclosure: The authors declare that they have no relevant financial interests.
REFERENCES 1. Fouque D, Kalantar-Zadeh K, Kopple J, et al. A proposed nomenclature and diagnostic criteria for proteinenergy wasting in acute and chronic kidney disease. Kidney Int. 2008;73(4):391-398. 2. Soukoulis V, Dihu JB, Sole M, et al. Micronutrient deficiencies: an unmet need in heart failure. J Am Coll Cardiol. 2009;54(18):1660-1673. 3. Taegetmeyer H. Energy metabolism of the heart: from basic concepts to clinical applications. Curr Probl Cardiol. 1994;19(2):59-113. 4. Gómez-Pinilla F. Brain foods: the effects of nutrients on brain function. Nat Rev Neurosci. 2008;9(7):568-578. 5. Kopple JD. Trace elements and vitamins. In: Mitch WE, Ikizler TA, eds, Handbook of Nutrition and the Kidney, 6th edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2010:163-176. 6. Jamison RL, Hartigan P, Kaufman JS, et al. Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial. JAMA. 2007;298(1):1163-1170.
7. Deved V, Poyah P, James MT, et al. Ascorbic acid for anemia management in hemodialysis patients: a systematic review and meta-analysis. Am J Kidney Dis. 2009;54(6):1089-1097. 8. Canavese C, Petrarulo M, Massarenti P, et al. Longterm, low-dose, intravenous vitamin C leads to plasma calcium oxalate supersaturation in hemodialysis patients. Am J Kidney Dis. 2005;45(3):540-549. 9. Zima T, Janebová M, Nemecek K, Bártová V. Retinol and alpha-tocopherol in hemodialysis patients. Ren Fail. 1998;20(3):505-512. 10. Smith FR, Goodman DS. The effects of diseases of the liver, thyroid, and kidneys on the transport of vitamin A in human plasma. J Clin Invest. 1971;50(11):2426-2436. 11. Rock CL, Jahnke MG, Gorenflo DW, Swartz RD, Messana JM. Racial group differences in plasma concentrations of antioxidant vitamins and carotenoids in hemodialysis patients. Am J Clin Nutr. 1997;65(3):844-850. 12. Ono K. Hypervitaminosis A toxicity in regular hemodialysis patients. Trans Am Soc Artif Intern Organs. 1984;30:40-43. 13. Vannucchi MT, Vannuchi H, Humphreys M. Serum levels of vitamin A and retinol binding protein in chronic renal patients treated by continuous ambulatorial peritoneal dialysis. Int J Vitam Nutr Res. 1992;62(2):107-112. 14. Britton G. Structure and properties of carotenoids in relation to function. FASEB J. 1995;9(15):1551-1558. 15. Jaconi S, Rose K, Hughes GJ, Saurat JH, Siegenthalerl G. Characterization of two post-translationally processed forms of human serum retinol-binding protein: altered ratios in chronic renal failure. J Lipid Res. 1995;36(6):1247-1252. 16. Ono K, Waki Y, Takeda K. Hypervitaminosis A: a contributing factor to anemia in regular dialysis patients. Nephron. 1984;38(1):44-47. 17. Fishbane S, Frei GL, Finger M, Dressler R, Silbiger S. Hypervitaminosis A in two hemodialysis patients. Am J Kidney Dis. 1995;25(2):346-349. 18. Kalousová M, Kubeˇna AA, Koštírˇová M, et al. Lower retinol levels as an independent predictor of mortality in long-term hemodialysis patients: a prospective observational cohort study. Am J Kidney Dis. 2010;56(3):513-521. 19. Abahusain MA, Al-Nahedh NN. The biochemical status of vitamin A and alpha-tocopherol during different stages of renal disease and its relationship to diabetes. Saudi J Kidney Dis Transpl. 2002;13(1):18-23. 20. Descamps-Latscha B, Drüeke T, Witko-Sarsat V. Dialysisinduced oxidative stress: biological aspects, clinical consequences, and therapy. Semin Dial. 2001;14(3):193-199. 21. Sawant JM, Nair A, Redkar NN. Oxidative stress and serum paraoxonase activity in patients on maintenance hemodialysis. Internet J Nephrol. April 1 2010;6/1(0-13):15402665. 22. Komindr S, Puchaiwatananon O, Thirawitayakom J, Domrongkitchaiporn S, Songchitsomboon S. Effects of dietary counseling on vitamin A, B-1, B-2 and zinc status of chronic hemodialysis patients. J Med Assoc Thai. 1997;80(11):724-730. 23. Kalantar-Zadeh K, Braglia A, Chow J, et al. An anti-inflammatory and antioxidant nutritional supplement for hypoalbuminemic hemodialysis patients: a pilot/feasibility study. J Ren Nutr. 2005;15(3):318-331. 24. Roehrs M, Valentini J, Bulcão R, et al. The plasma retinol levels as pro-oxidant/oxidant agents in hemodialysis patients. Nephrol Dial Transplant. 2009;24(7):2212-2218.
M
uch attention has rightly been focused on providing adequate protein and calories (macronutrients) to dialysis patients in an effort to prevent development of malnutrition. A state of protein-energy wasting (PEW) can be diagnosed by low circulating levels of albumin and/or cholesterol, in conjunction with reduced total body and muscle mass.1 In most cases, the diagnosis of PEW represents a complex readout on several concomitant biological processes that include hypercatabolism, poor protein and calorie intake, and active inflammation. Study of the PEW syndrome has been emphasized in dialysis patients due to association with higher rates of morbidity and mortality, along with diminished quality of life. Comparatively less attention has been paid in recent years to the possibility that micronutrient deficiencies can also contribute to poor outcomes in dialysis patients. Yet micronutrients, such as coenzyme Q10, L-carnitine, taurine, and a variety of water- and fat-soluble vitamins, are essential cofactors that provide the necessary cellular machinery for energy transfer and the maintenance of physiological energy homeostasis. Micronutrient deficiency may be particularly important in the human heart.2 Described as a metabolic omnivore,3 the heart must constantly convert a huge amount of chemical energy into mechanical energy, and thus needs a steady stream of nutrients to function well. Moreover, provision of adequate micronutrients may be especially important in the setting of the failing heart, in order to prevent myocyte death and restore compromised function. Micronutrient deficiency is also emerging as a potential contributor to cognitive dysfunction, also a commonly observed complication in patients with advanced kidney disease.4 The general teaching regarding vitamin supplementation in hemodialysis patients is that watersoluble vitamins (such as the B vitamins and vitamin C [ascorbate]) are dialyzed and blood concentrations tend to be low without supplementation, while fat-soluble vitamins such as vitamin A are not dialyzed and blood levels are usually either normal or elevated without supplementation.5 As a consequence, several studies have focused attention on supplementation with either B vitamins or vitamin C in dialysis patients. The primary rationale for investigating aggressive B vitamin supple-
mentation has been to exploit their homocysteinelowering properties, in an effort to reduce cardiovascular risk. Unfortunately, the HOST (Homocysteinemia in Kidney and End-stage Renal Disease) trial, which compared the use of folic acid, vitamin B6, and vitamin B12 to placebo, supported the null hypothesis.6 Studies of vitamin C, an important antioxidant, have focused on alleviating the increased oxidative stress that accompanies kidney disease, and on increasing iron availability to promote erythropoeisis and treat refractory anemia.7 While pilot studies have been promising, the use of aggressive vitamin C supplementation is limited by accumulation of the metabolite oxalate, which may lead to calcium oxalate supersaturation in blood vessels of uremic patients.8 The potential for toxicity of vitamin A has generally precluded its use in kidney failure. However, the antioxidant potential of retinol, the active form of vitamin A, requires a review of this topic and may warrant closer examination in hemodialysis patients. Plasma concentration of retinol has been reported to be elevated in both adults and children treated by hemodialysis and peritoneal dialysis.9-13 The dialysis procedure is not associated with any decrease in plasma retinol concentration and there has been concern about risk for vitamin A toxicity in dialysis patients. Retinol is synthesized and released from the liver and circulates in blood bound to retinol binding protein (RBP) and transthyretin (TTR).14 The binding with carrier proteins ensures the appropriate delivery and availability of retinol at the tissue level. When complexed with retinol, RBP and TTR are not filtered by the glomeruli; however, after the tissue delivery of retinol, the smaller size of noncomplexed RBP allows for glomerular filtration followed by absorption in the proximal tubules through the megalin-cubulin complex. Eventually, retinol is catabolized by the tubular epithelia.15 Thus, kidney function plays a vital role in vitamin A metabolism, and in kidney failure the plasma concentration of both retinol and RBP increases, paralleling the rise in creatinine concenAddress correspondence to Jonathan Himmelfarb, MD, Kidney Research Institute, 325 9th Ave, Box 359606, Seattle, WA 98104-2499. E-mail:[email protected]. © 2010 by the National Kidney Foundation, Inc. 0272-6386/10/5603-0003$36.00/0 doi:10.1053/j.ajkd.2010.07.004
American Journal of Kidney Diseases, Vol 56, No 3 (September), 2010: pp 431-433
431
432
Ahmad and Himmelfarb
Figure 1. Cellular oxidation pathways and antioxidants. In the equations listing the antioxidant activities of the carotenoids (CAR), ROO represents either an alkyl chain linked to a peroxyl radical (ie, -C-O-O.) or an alkoxyl radical (-C-O.), but could equally be a radical formed from a hydroxyl (OH⫺), hypochlorite (OCl⫺), or toxic nitrogen derivative (NOO⫺).
tration.11 In addition to reduced glomerular filtration, impaired activity of enzymatic conversion of retinol to retinoic acid in kidney failure has been reported, which may also contribute to the observed elevation of plasma retinol levels.16,17 The article in this issue of the American Journal of Kidney Diseases by Kalousová et al18 evaluated the role of retinol, RBP, ␣-tocopherol, zinc, and selenium on mortality in 261 prevalent hemodialysis patients. Similar to previous reports, the study found elevated plasma concentrations of retinol and RBP. However Kalousová et al made the novel and surprising observation that lower plasma concentrations of retinol (and a lower retinol to RBP ratio) were strong predictors of overall and cardiovascular mortality. That a lower retinol to RBP ratio is a predictor of poor outcome has not been reported before. These data can be interpreted as suggesting that there is a lower bioavailability of retinol at the cellular and tissue level, despite elevated plasma concentration. This is analogous to the carnitine “insufficiency” described in dialysis patients with lower free to acyl-carnitine ratio (or elevated acyl to free carnitine ratio). It is interesting
that Abahusain and Al-Nahedh19 reported an increased retinol to RBP ratio in patients on dialysis. However, these authors also observed that the ratio increased with time, suggesting that ongoing dialysis is not associated with progressive reduction in availability of retinol. Retinol is derived from dietary carotenoids, which are important constituents of cell membrane, influence DNAstructure, and have antioxidant properties. Increased oxidative stress has been well documented in dialysis patients20,21 and it may play an important role in increased cardiovascular risk, the leading cause of death in this population. In vitro tests under appropriate conditions have shown that carotenoids have important antioxidant properties, and can neutralize superoxides or, through redox activity, act on other free radical compounds (Fig 1). However the efficacy of these compounds in vivo is far from clear, particularly since their concentration in human tissue is much lower and conditions may differ substantially from in vitro experiments. Retinol is a known antioxidant, although its role in humans does not appear to be as strong as that of vitamin E and vitamin C.22 In 1 trial, supplemen-
Editorial
433
tary vitamin A and other nutrients in malnourished dialysis patients had a positive effect on serum albumin levels.23 Trials using supplements in individuals without kidney failure have either shown no effect of vitamin A or even some potential harmful effects, including activation of protooncogenes, with an associated increase in risk of neoplasia. Similarly, the data on the markers of lipid peroxidation, malondialdehyde (MDA), aminolevulinate dehydratase (ALA-D), and retinol concentrations in 29 hemodialysis patients revealed a positive correlation between retinol and MDA,24 findings which suggest that retinol may paradoxically have prooxidant properties in some circumstances. Like other such studies, the article from Kalousová et al has raised more questions than it has answered. What is clear is that there is a general lack of available data regarding whether vitamin A and many other micronutrients are friend or foe in kidney failure. When it comes to understanding the role of micronutrient deficiencies in patients with kidney disease, we need to go back to the ABCs. Suhail Ahmad, MD Jonathan Himmelfarb, MD University of Washington Seattle, Washington
ACKNOWLEDGEMENTS Financial Disclosure: The authors declare that they have no relevant financial interests.
REFERENCES 1. Fouque D, Kalantar-Zadeh K, Kopple J, et al. A proposed nomenclature and diagnostic criteria for proteinenergy wasting in acute and chronic kidney disease. Kidney Int. 2008;73(4):391-398. 2. Soukoulis V, Dihu JB, Sole M, et al. Micronutrient deficiencies: an unmet need in heart failure. J Am Coll Cardiol. 2009;54(18):1660-1673. 3. Taegetmeyer H. Energy metabolism of the heart: from basic concepts to clinical applications. Curr Probl Cardiol. 1994;19(2):59-113. 4. Gómez-Pinilla F. Brain foods: the effects of nutrients on brain function. Nat Rev Neurosci. 2008;9(7):568-578. 5. Kopple JD. Trace elements and vitamins. In: Mitch WE, Ikizler TA, eds, Handbook of Nutrition and the Kidney, 6th edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2010:163-176. 6. Jamison RL, Hartigan P, Kaufman JS, et al. Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial. JAMA. 2007;298(1):1163-1170.
7. Deved V, Poyah P, James MT, et al. Ascorbic acid for anemia management in hemodialysis patients: a systematic review and meta-analysis. Am J Kidney Dis. 2009;54(6):1089-1097. 8. Canavese C, Petrarulo M, Massarenti P, et al. Longterm, low-dose, intravenous vitamin C leads to plasma calcium oxalate supersaturation in hemodialysis patients. Am J Kidney Dis. 2005;45(3):540-549. 9. Zima T, Janebová M, Nemecek K, Bártová V. Retinol and alpha-tocopherol in hemodialysis patients. Ren Fail. 1998;20(3):505-512. 10. Smith FR, Goodman DS. The effects of diseases of the liver, thyroid, and kidneys on the transport of vitamin A in human plasma. J Clin Invest. 1971;50(11):2426-2436. 11. Rock CL, Jahnke MG, Gorenflo DW, Swartz RD, Messana JM. Racial group differences in plasma concentrations of antioxidant vitamins and carotenoids in hemodialysis patients. Am J Clin Nutr. 1997;65(3):844-850. 12. Ono K. Hypervitaminosis A toxicity in regular hemodialysis patients. Trans Am Soc Artif Intern Organs. 1984;30:40-43. 13. Vannucchi MT, Vannuchi H, Humphreys M. Serum levels of vitamin A and retinol binding protein in chronic renal patients treated by continuous ambulatorial peritoneal dialysis. Int J Vitam Nutr Res. 1992;62(2):107-112. 14. Britton G. Structure and properties of carotenoids in relation to function. FASEB J. 1995;9(15):1551-1558. 15. Jaconi S, Rose K, Hughes GJ, Saurat JH, Siegenthalerl G. Characterization of two post-translationally processed forms of human serum retinol-binding protein: altered ratios in chronic renal failure. J Lipid Res. 1995;36(6):1247-1252. 16. Ono K, Waki Y, Takeda K. Hypervitaminosis A: a contributing factor to anemia in regular dialysis patients. Nephron. 1984;38(1):44-47. 17. Fishbane S, Frei GL, Finger M, Dressler R, Silbiger S. Hypervitaminosis A in two hemodialysis patients. Am J Kidney Dis. 1995;25(2):346-349. 18. Kalousová M, Kubeˇna AA, Koštírˇová M, et al. Lower retinol levels as an independent predictor of mortality in long-term hemodialysis patients: a prospective observational cohort study. Am J Kidney Dis. 2010;56(3):513-521. 19. Abahusain MA, Al-Nahedh NN. The biochemical status of vitamin A and alpha-tocopherol during different stages of renal disease and its relationship to diabetes. Saudi J Kidney Dis Transpl. 2002;13(1):18-23. 20. Descamps-Latscha B, Drüeke T, Witko-Sarsat V. Dialysisinduced oxidative stress: biological aspects, clinical consequences, and therapy. Semin Dial. 2001;14(3):193-199. 21. Sawant JM, Nair A, Redkar NN. Oxidative stress and serum paraoxonase activity in patients on maintenance hemodialysis. Internet J Nephrol. April 1 2010;6/1(0-13):15402665. 22. Komindr S, Puchaiwatananon O, Thirawitayakom J, Domrongkitchaiporn S, Songchitsomboon S. Effects of dietary counseling on vitamin A, B-1, B-2 and zinc status of chronic hemodialysis patients. J Med Assoc Thai. 1997;80(11):724-730. 23. Kalantar-Zadeh K, Braglia A, Chow J, et al. An anti-inflammatory and antioxidant nutritional supplement for hypoalbuminemic hemodialysis patients: a pilot/feasibility study. J Ren Nutr. 2005;15(3):318-331. 24. Roehrs M, Valentini J, Bulcão R, et al. The plasma retinol levels as pro-oxidant/oxidant agents in hemodialysis patients. Nephrol Dial Transplant. 2009;24(7):2212-2218.