American Journal of Kidney Diseases
Volume 56, Issue 3 , Pages 431-433, September 2010

The ABCs of Micronutrients in Dialysis Patients

  • Suhail Ahmad, MD
    • ,
  • Jonathan Himmelfarb, MD

      Affiliations

    • Corresponding Author InformationAddress correspondence to Jonathan Himmelfarb, MD, Kidney Research Institute, 325 9th Ave, Box 359606, Seattle, WA 98104-2499

Article Outline

 

Related Article, p. 513

Much 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 water-soluble 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 supplementation has been to exploit their homocysteine-lowering 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, 10, 11, 12, 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 concentration.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, α-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 DNA structure, 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.

  • View full-size image.
  • 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−).

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, supplementary 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 proto-oncogenes, 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 pro-oxidant 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.

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Acknowledgements 

Financial Disclosure: The authors declare that they have no relevant financial interests.

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References 

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PII: S0272-6386(10)01080-2

doi:10.1053/j.ajkd.2010.07.004

Refers to article:

  • Lower Retinol Levels as an Independent Predictor of Mortality in Long-term Hemodialysis Patients: A Prospective Observational Cohort Study , 14 June 2010

    Marta Kalousová, Aleš A. Kuběna, Milada Koštířová, Marie Vinglerová, Oto Mestek Ing, Sylvie Dusilová-Sulková, Vladimír Tesař, Tomáš Zima
    American Journal of Kidney Diseases September 2010 (Vol. 56, Issue 3, Pages 513-521)

American Journal of Kidney Diseases
Volume 56, Issue 3 , Pages 431-433, September 2010

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