REVIEW Vitamin Status and Needs for People with Stages 3-5 Chronic Kidney Disease Alison L. Steiber, PhD,* and Joel D. Kopple, MD†‡ Patients with chronic kidney disease (CKD) often experience a decline in their nutrient intake starting at early stages of CKD. This reduction in intake can affect both energy-producing nutrients, such as carbohydrates, proteins, and fats, as well as vitamins, minerals, and trace elements. Knowledge of the burden and bioactivity of vitamins and their effect on the health of the patients with CKD is very incomplete. However, without sufficient data, the use of nutri- tional supplements to prevent inadequate intake may result in either excessive or insufficient intake of micronutrients for people with CKD. The purpose of this article is to briefly summarize the current knowledge regarding vitamin requirements for people with stages 3, 4, or 5 CKD who are not receiving dialysis. Ó 2011 by the National Kidney Foundation, Inc. All rights reserved. Overview generally address nutritional contributions from EASURES OF PROTEIN–ENERGY proteins, energy, fats, macrominerals such as sodium, chloride, and potassium, vitamin D, and M wasting are strongly correlated with mortal- 2–6 ity in end-stage renal disease (ESRD).1 The findings iron. Several reviews of the nutritional status that body fat, skeletal muscle mass, and body mass and requirements for vitamins in patients on maintenance dialysis have been published in the index (BMI), including very large BMIs, have inde- 5,6 pendent and direct associations with survival in past several years. To the authors’ knowledge, chronic kidney disease (CKD) patients2–4 suggest no such review currently exists for patients who that reduced nutritional status, besides have stages 3-5 CKD and who are not at ESRD inflammation, may be both a predictor and or awaiting renal transplantation. This review a cause of death in these individuals. Although discusses the literature concerning nutritional there are many observational studies describing status and requirements for vitamins in patients the nutritional status of patients on maintenance with CKD stages 3 (glomerular filtration rate [GFR], ,60 mL/min/1.73 m2), 4 (GFR, ,29 dialysis and those with CKD who are not 2 , receiving maintenance dialysis, these investigations months/min/1.73 m ), and 5 (GFR, 15 months/min/1.73 m2), who are not receiving renal replacement therapy. *Department of Nutrition, School of Medicine, Case Western Vitamin deficiencies are common in people Reserve University, Cleveland, Ohio. with advanced renal failure who do not take nutri- †Division of Nephrology and Hypertension and Department of 7 Medicine, Los Angeles Biomedical Research Institute at Harbor- tional supplements. The causes for such vitamin UCLA Medical Center, the David Geffen School of Medicine at deficiencies have been reviewed and include low UCLA, Los Angeles, California. dietary intake that may be because of anorexia, or ‡David Geffen School of Medicine, UCLA School of Public the impaired ability to buy,prepare, or ingest foods Health, Los Angeles, California. Conflict of interest: The authors are members of the Clinical that are high in nutrient content. Dietary prescrip- Advisory Board for Nephroceuticals, Inc. tion may limit foods which are high in vitamins, Address reprint requests to Alison L. Steiber, RD, PhD, Depart- particularly water-soluble vitamins, because of ment of Nutrition, Case Western Reserve University School of Med- their high potassium or phosphorus content.7 icine, Cleveland, OH 44106. E-mail: [email protected] Also, some medicines may interfere with the Ó 2011 by the National Kidney Foundation, Inc. All rights metabolism or actions of certainvitamins including reserved. 8 1051-2276/$36.00 vitamin B6, folate, and possibly riboflavin. Sea- doi:10.1053/j.jrn.2010.12.004 sonal variations may predispose to deficiency of Journal of Renal Nutrition, Vol 21, No 5 (September), 2011: pp 355–368 355 356 STEIBER AND KOPPLE some vitamins because of reduced access to fresh Definition of Terms Concerning fruits and vegetables, to dietary protein restrictions, Nutritional Adequacy and to sunlight.9 Superimposed illnesses may con- tribute to low intake, impaired digestion, absorp- Traditionally, the adequacy of the body content tion or actions of some vitamins, or may require and functional activity of vitamins are determined by measuring dietary intake, the corresponding the use of medicines that interfere with the actions 7 biochemical values of these compounds––usually of vitamins. measured in serum or plasma or red blood cells, Our knowledge of the body concentration, occasionally in urine, and in enzyme activities, function, metabolic effects, and clinical response and other biological processes or clinical manifes- to reduced intake and low serum concentrations tations of deficiency or excess. For example, the on these nutrients in nondialyzed patients with effects of certain vitamin intakes on hemoglobin stages 3-5 CKD is incomplete. Whether there is production or plasma and urinary oxalate levels altered nutrient metabolism in stages 3-5 CKD, may be indicators of deficiency or excess. The rec- as there can be in patients suffering from ESRD 10,11 ommended amount of a specific nutrient which is and those on dialysis, is unclear. Data from 8,9 considered to support health is referred to as the the National Health and Examination Survey dietary reference intake (DRI).16 and the Modification of Diet in Renal Disease Study10 show that the daily ingestion of nutrients Hence, the DRIs can be standards by which the begins to decline in as early as stage 3 CKD.11–13 adequacy of nutrient intake could be assessed. This reduction in intake may affect energy They allow clinicians to compare the quantity of producing nutrients (carbohydrates, protein, and a given nutrient in a patient’s diet with an estab- lished standard. The DRIs for nutrients are gener- fat), macrominerals, vitamins, and trace elements. ally determined by considering several other The Dialysis Outcome Practice Patterns Study reported that patients on maintenance established standards regarding nutrient intake. hemodialysis taking water-soluble vitamin supple- These include the estimated average requirement ments had a 16% lower mortality than similar (EAR) for the nutrient, the recommended daily 14 allowance (RDA), and the adequate intake (AI) patients not taking such preparations. This latter of the nutrient in question. Initially, wherever suf- analysis was adjusted for age, gender, race, comor- ficient data are available, an EAR is established for bidity, hemoglobin, serum albumin, BMI, and a specific nutrient. The EAR is the amount of other potential confounders. Whether such sup- nutrient needed by one-half of the healthy popula- plements may increase survival in people with tion to support normal biological and physiologi- stages 3-5 CKD is unknown. cal processes. In the Dietary Reference Guidelines, Although the optimal intake of macrominerals, it should be noted that the terms, ‘‘healthy popula- iron, and vitamin D nutrition has received substan- tion’’ and ‘‘general population’’ are often conflated. tial attention, less is written or known concerning The RDAis statistically derived from the EAR; it is recommended allowances or body burden of vita- calculated to be 2 standard deviations (SD) more mins and trace elements in stage 3-5 CKD.Possible than the EAR. Thus, RDA values are the average adverse consequences of excessive vitamin intake daily requirement for practically the entire general by patients with CKD are an important concern, population (97% to 98%) to support biochemical because vitamin supplements are commonly taken and physiological processes. Data to establish the in the United States. Approximately one-half of EARs are obtained, where possible, from clinical elderly prescription medication users are reported trials; however, there are insufficient data to deter- to take dietary supplements, predominantly multi- 15 mine these values for some nutrients. When there vitamins. It is likely that some CKD patients take are insufficient data, an AI is established instead. AI excessive and hazardous amounts of certain sup- is defined as the average amount of a nutrient that plemental vitamins as well as inadequate quantities a group of healthy people consume. It is assumed of other vitamins. This review summarizes the pre- that because these latter individuals are healthy, viously published data concerning the function, their intake of the nutrient in question should be food sources, and evidence for inadequate or adequate. Finally, the tolerable upper intake level excessive intake of vitamins in people with stage is the maximum daily amount of a nutrient that 3-5 CKD who are not receiving dialysis therapy seems to be safe for most healthy people and above and do not have a functioning kidney transplant. VITAMINS IN CHRONIC KIDNEY DISEASE 357 which there is an increased risk of adverse health consumed an average of 1.26 mg of thiamin/day effects. from the foods in their diet. Their mean plasma These terms and values are in reference to thiamin concentration was 64.2 nmol/L, and their healthy people and represent oral intakes; they do ETK-AC (erythrocyte transketolase activity coef- not necessarily reflect the values for the intakes of ficients, an indicator of thiamin adequacy) was people with CKD, especially if their nutrients are 1.18 6 0.19 (SD) (an ETK-AC indicating no not taken orally. Thus, the DRIs can be used as deficiency is ,1.20). ETK-AC has been regarded general benchmarks, but extrapolating these as a good functional indicator of thiamin status.8 benchmarks to patients with CKD or other mor- Thus, according to the data generated by Frank bid conditions should be done with caution. The et al.,6 a substantial proportion of patients with focus of this article is to describe what is currently stages 4 and 5 CKD had ETK-AC values .1.20, reported in the published data regarding vitamin indicating a thiamin-deficient status. These data status and requirements for nontransplanted adult are presented as mean 6 SD, and the medians patients with CKD stages 3-5 who do not require were not provided in this study.