Vitamin Status and Needs for People with Stages 3-5 Chronic Kidney Disease Alison L

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 nutritional 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 established 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. Thus, it is some- dialysis treatment. DRI values for the general pop- what difficult to compare these results by Frank ulation will be shown for adults aged 50 to 70 years. et al.6 with those by Weber and Kewitz19 in 91 This age range was selected because it is similar to generally healthy hospital employees that indicate the ages of a large proportion of adults with CKD. what are presumably normal or healthy thiamin values. These latter investigators found the normal Water-Soluble Vitamins plasma thiamin concentrations to have a skewed distribution and presented their data as a median Vitamin B1-Thiamin and range. The volunteers had a median plasma Action thiamin concentration of 11.6 nmol/L and a range Thiamin is a hydrophilic B vitamin involved of 6.6 to 43 nmol/L. Contrary to the ETK-AC with many metabolic functions. Thiamin serves findings, the patients with CKD appear to have in- as a cofactor for oxidative decarboxylation reac- creased concentrations of plasma thiamin when tions. These include the conversion of pyruvate compared with the normal volunteers. The to acetyl coenzyme A (CoA) in the pyruvate mean plasma thiamin values of these patients dehydrogenase complex, the conversion of a-ke- were higher than the upper range value of the toglutarate to succinyl CoA in the a-ketoglutarate healthy volunteers. It should be noted that plasma dehydrogenase complex, and the conversion of thiamin concentrations are not considered to be a reliable indicator of nutritional adequacy for thi- leucine, isoleucine, and valine to isovaleryl CoA, 18 a-methylbutyryl CoA, and isobutyryl CoA in amin. Although the data do not indicate that all the branched chain a-ketoacid dehydrogenase patients have a deficiency of thiamin, there are data complex. Additionally, thiamin is a cofactor in that indicate the risk for insufficient or deficient the transketolase reactions of the nonoxidative concentrations in patients with CKD. Whether phase of the pentose pathway which leads to the the DRI level of intake is sufficient for patients production of ribose-5-phosphate and nicotin- with CKD is also unknown. However, a daily sup- amide adenine dinucleotide phosphate. The plement at the DRI to augment dietary intake DRI for thiamin (age, 50 to 70 years) is 1.2 mg/ seems prudent to prevent possible deficiencies. day and 1.1 mg/day for normal men and women, respectively.17 Vitamin B2-Riboflavin Action Food Sources Riboflavin is a hydrophilic B vitamin with The following food items are rich in thiamin: 18 phosphorescent properties. It is necessary for pork, oat bran, whole grains, and enriched grains. oxidation–reduction reactions. When phosphory- lated by adenosine triphosphate, riboflavin is con- Evidence for Altered Requirements verted to flavin mononucleotide (FMN). This Dietary intake and nutritional status for thiamin molecule can then be complexed with various in patients with CKD (n 5 14) was assessed by apoenzymes to form several flavoproteins. Most Frank et al.6 Patients with stages 4 and 5 CKDs of the FMN is converted to flavin adenine 358 STEIBER AND KOPPLE dinucleotide (FAD) by FAD synthetase. Hence, cycle, electron transport chain, and b-oxidation FAD is the predominant flavoenzyme in the of lipids. Niacin also prevents and is the therapeutic body. The enzymes with which FMN and FAD agent for pellagra, which is a condition caused by are associated include oxygenases, monooxyge- niacin deficiency and often referred to by ‘‘the nases, dehydrogenases, oxidoreductases, and elec- D’s’’: dermatosis, diarrhea, dementia, and death. tron transferases. This wide range of enzyme Pellagra is associated with the chronic intake of activities is based on the fact that the molecules low riboflavin diets, alcoholism, food faddism, can transition well between oxidized, single elec- and when untreated maize is a primary staple of tron reduced semiquinoid, and double electron the diet.21 It has been shown that diets prescribed reduced hydroquinoid states. Normally, the DRI for patients with CKD are often not well accepted for riboflavin is 1.1 mg/day for women and 1.3 and may lead to poor intake.22 The DRI for mg/day for men.17 healthy individuals is 14 mg/day for women and 16 mg/day for men.17 Food Sources The following foods are rich sources of ribofla- Food Sources vin: liver, duck, milk, eggs, mushrooms, spinach, Niacin is unusual in that it has an amino acid 18 chicken, and enriched grains. precursor, tryptophan; some of the tryptophan in the body is routinely converted to niacin. Thus, Evidence for Altered Requirements when niacin stores are low, the conversion of tryp- Porrini et al.20 studied patients with advanced tophan can become a source of niacin. Primary CKD who were not undergoing dialysis using the food sources that are rich in niacin are meat, fish, 18 a-erythrocyte glutathione reductase (a-EGR) legumes, coffee, and tea, all of which tend to stimulation index to assess riboflavin status. In be reduced in low-protein, low phosphorus diets. this study, 8% of patients were found to have elevated a-EGR, thus indicating riboflavin defi- Evidence for Altered Requirements ciency. When the prescribed protein intake of It is possible that patients with CKD who are these patients was intentionally reduced to 1.0 g prescribed with low-protein diets (such as 0.6 g protein/kg/day or 0.6 g protein/kg/day, from the protein/kg/day) with phosphorus restriction patients’ usual intake, according to the research (such as 800 mg/day) may be at risk for niacin de- protocol, the prevalence of elevated a-EGR ficiency because of the low niacin content of plant increased from 8% to 25% and 41%, respectively. food; thus, their dietary niacin intake may be quite The increased prevalence of elevated a-EGR was low. However, the authors are unaware of any attributed to the fact that riboflavin is particularly clinical trials that have examined the niacin intake abundant in foods containing animal proteins (see of patients with CKD and whether that amount is earlier in the text). Indeed, several works have rec- sufficient to maintain adequate niacin status. ommended riboflavin supplements for patients Recently,a novel use for niacin has been discov- with CKD, especially when they ingest very low- ered. The niacin metabolite, nicotinamide, has , 5,13,14 protein diets (i.e., 0.6 g protein/kg/day). been successfully used to reduce serum phosphorus concentrations in patients on hemodialysis Niacin-Vitamin B3 who have been using megadoses of niacin, 500 to 1500 mg/day, given twice daily.23,24 The Action mechanisms of action involve the inhibition of Niacin is another hydrophilic B vitamin that is the sodium/phosphorus type IIb cotransporter ingested as either nicotinamide from animal sour- (Na Pi-2b) and type IIa cotransporter (NaPi-2a), ces or nicotinic acid from plant sources. Niacin which are the major transporters of inorganic becomes active in human beings when it is con- phosphorus in the intestinal brush border and in verted to either nicotinamide adenine dinucleotide the proximal renal-tubular epithelial cells of the or nicotinamide adenine dinucleotide phosphate. kidneys, respectively.25,26 Therefore, it is likely These molecules are necessary cofactors for many that in nondialyzed patients with stages 3-5 oxidation–reduction reactions. A few notable pro- CKD, the action of nicotinamide on the Na cesses involving niacin activity are the citric acid Pi-2a and Na Pi-2b cotransporters will inhibit VITAMINS IN CHRONIC KIDNEY DISEASE 359 both renal-tubular phosphorus reabsorption and mg/dL) to 1.2 6 0.5 mg/day in 7 nondialyzed phosphorus absorption in the intestinal brush bor- patients with stages 4 and 5 CKD.28 The mean der, thereby increasing renal phosphorus excretion intake of vitamin B6 for patients with severe in urine and feces. At present, the authors are CKD was significantly lower than the DRI for unaware of published studies on the effects of nia- their age cohort. These declining intakes were cin supplementation on urinary phosphorus reflected in the stimulation index of erythrocyte excretion in CKD patients who are not receiving glutamic pyruvic transaminase (EGPT) activity. dialysis. The use of nicotinamide is associated EGPT activity and the EGPT index are measure- with many side effects; most relevant are flushing, ments of adequacy of body pyridoxine levels. An thrombocytopenia, hepatoxicity (especially with EGPT index .1.25 is an indicator of vitamin B6 sustained release doses), gastrointestinal symptoms deficiency.20 The mean EGPT stimulation index such as diarrhea, vomiting, and constipation, and increased (indicating vitamin B6 deficiency) increased serum uric acid concentrations.26 The inversely with the stage of CKD, in which patients increased serum uric acid may be of concern as with higher GFR levels (stages 3 and 4 CKD) had hyperuricemia has been associated with both a mean EGPT index of 1.23 6 0.09 (SD); CKD hypertension and more rapid progression of renal patients with lower GFR levels (stages 4 and 5 failure.27 At this time, there does not seem to be CKD) had a mean index of 1.30 6 0.11. These data to warrant supplementation with niacin. were all significantly higher than the normal con- However, CKD patients with chronically subopti- trol values of 1.16 6 0.06. mal dietary intake may benefit from a supplement Podda et al.29 found significantly lower serum at the DRI level to prevent deficiency. PLP concentrations, 37.3 6 51.7 versus 79.3 6 65.6 pmol/mL, in patients with the nephrotic syndrome as compared with healthy controls. The Vitamin B-6—Pyridoxine serum B6 values correlated with the magnitude of Action their proteinuria (r 5 0.41, P ,.001). These studies Vitamin B6 exists in vivo as 6 compounds. provide evidence that there are suboptimal levels of These are pyridoxal, pyridoxine, pyridoxamine, serum vitamin B6 in many patients with CKD. and the 5’ phosphates of these 3 compounds. Many medicines and other compounds can Pyridoxal-5-phosphate (PLP) is a cofactor for interfere with the actions or metabolism of vitamin many enzymes, particularly those involving amino B6 and may increase the likelihood that they will de- acid metabolism and which include aminotransfer- velop B6 deficiency.This is especially likely to occur ases, decarboxylases, racemases, and dehydratases. in patients with CKD, because their vitamin B6 intake is often low, they may have increased dietary Notably, PLP is necessary for (d)-aminolevulinate 5 synthase to initiate heme synthesis. The DRI for needs for B6, anditislikelythattheymaybepre- pyridoxine (age, 50 to 70 years old) in men is 1.7 scribed some of these medicines. These interfering mg/day and in women is 1.5 mg/day.17 compounds include isoniazid, thyroxine, iproniazid, theophylline, hydralazine, caffeine, penicillamine, Food Sources ethanol, and oral contraceptives. The data presented in this study suggest that patients at stage 3 or worse The following food sources are rich in vitamin CKD are at an increased risk for deficient concen- B6: liver, fish, meat, poultry, plums, bananas, trations of vitamin B6 and therefore should be sup- plantains, barley, sweet potatoes, potatoes, and 18 plemented adequately. It has been recommended by enriched grains. both the European Society of Parenteral and Enteral Nutrition and Caring for Australians with Renal Evidence for Altered Requirements Insufficiency guidelines that vitamin B6 should be Kopple et al.28 conducted both dietary and bio- supplemented daily at a dose of 5 mg.30–32 chemical assessments of pyridoxine status on patients with different stages of CKD. In a cross- Folic Acid sectional analysis, the amount of vitamin B6 consumed in foods declined as GFR decreased, from Action 2.2 6 0.8 (SD) mg/day in 6 patients with stages Folic acid is a pteroylmonoglutamic acid. It 3 and 4 CKD (serum creatinine from 2.1 to 3.5 transfers single-carbon or methyl groups mainly 360 STEIBER AND KOPPLE as the tetrahydrofolate, thereby providing methyl impaired excretion rather than altered metabolism groups for pyrimidine and purine synthesis. Folate of folic acid. is also necessary for histidine catabolism, the The optimal or safe daily intake for folate for conversion between serine and glycine, and the patients with CKD before dialysis is unknown. conversion of homocysteine to methionine, in ad- Considering that there is currently no evidence dition to other processes. Deficiency of folic acid for impaired folate activity or metabolism for non- results in megaloblastic anemia. The DRI for dialyzed people with stages 3-5 CKD, the daily both healthy men and women is 400 mg/day.17 intake for these individuals may be similar to that of people who do not have CKD. Food Sources The following food sources are rich in folic Cyanocobalamin––B-12 acid: legumes, orange juice, spinach and other Action leafy greens, broccoli, beets, artichokes, papaya, and enriched grains.18 B12 is critical in 2 major reactions. It acts as a coenzyme in the reaction that converts homocysteine to methionine and for the reaction that Evidence for Altered Requirements 8 converts L-methylmalonyl-coA to succinyl-coA. The causes for folic acid deficiency have been B12 has the following two metabolically active discussed earlier in the text (see Overview). As forms: (1) coenzyme 12 and (2) methylcobalamin. indicated earlier, low folate intake can be an impor- B12 is unique in its process for absorption in tant contributor to folate deficiency in patientswith which it requires an intrinsic factor for absorption CKD. The primary source of dietary folic acid is by the brush border of the ileum.5 The DRI for fresh green vegetables which, because of their B12 is 2.4 mg/day for both men and women high potassium content, are frequently restricted aged $51 years.17 in the diet of these patients. Medicines that interfere with folic acid and might lead to deficiency, partic- Food Sources ularly in peoplewith low folate intakes, include bar- biturates, primidone, cycloserine, pyrimethamine, The following food sources are naturally rich in diphenylhydantoin, triamterene, methotrexate, tri- B12: liver, beef, chicken, eggs, trout, and salmon. Fortified foods, such as breakfast cereal, are also methoprim, mysoline, pentamidine, salicylazosul- 18 fapyridine, and ethanol. Said et al.33 reported that a good source of B12. radiolabeled 5-methyltetrahydrofolate absorption is reduced in the intestinal tract in azotemic rats. Evidence for Altered Requirements This does not seem to be confirmed in human In healthy adults, there is a 3- to 6-year body beings.34 A possibly dialyzable compound or com- supply of B12.8 Therefore, if a healthy person con- pounds in the azotemic rats may be responsible sumed insufficient quantities of B12 for a short for the impaired absorption.33 Anions found in period (,3 years), they would not have insuffi- uremic sera may impair folate transport across cient B12 levels. However, there are no data on membranes.35 the body storage amounts in patients with CKD. In patients with advanced CKD (such as stages 4 A paucity of data has suggested that patients with and 5 before dialysis), the metabolism of folic acid CKD receiving hemodialysis respond favorably appears to be altered, although the cause and tim- and quickly when supplemented with B12, even ing of the alteration is not well defined. Hannisdal when the plasma values indicate normal ranges.37 et al.36 compared the serum concentrations of This may be related to the fact that plasma B12 is folate and folic acid metabolites between healthy not a sensitive indicator of B12 status. Methylma- volunteers and nondialyzed patients with stages lonic acid and homocysteine are more sensitive 3-5 CKD. Folate metabolites were analyzed by liq- indicators of B12 status. Additionally, B12 is found uid chromatography–tandem mass spectrometry. in high protein foods. Thus, patients who con- The samples from patients with CKD had 22 to sume low amounts or remain on very low- 30 times higher concentrations of folate metabo- protein diets for extended period, for example lites than in sera from healthy volunteers. These .3 years, with no B12 supplementation, may elevated serum metabolite levels may reflect have insufficient B12 levels. Currently, the data VITAMINS IN CHRONIC KIDNEY DISEASE 361 on B12 are limited and what is available does not is associated with greater cardiovascular risk.43 At indicate that patients with CKD are routinely the conclusion of this trial, there was no difference deficient. However, it is prudent to have patients between the treatment group and the control on low (0.6 g/day) or very low (0.3 g/day) protein group with regard to serum asymmetric dimethy- diets receive a supplement with the DRI for B12. larginine levels. The serum homocysteine concentrations were not reported; however, when the asymmetric dimethylarginine results were strati- Homocysteine fied by baseline homocysteine, a significant Serum total homocysteine appears to be in- decrease in serum asymmetric dimethylarginine creased to approximately 1.5 to 2 times the upper was observed in the patients in the highest stratum limit of normal in most of the patients with stage of serum homocysteine as compared with the indi- 5 CKD.38 This is of particular concern because in viduals receiving placebo. Mann et al.44 also found the general population elevated serum homocys- that lowering serum homocysteine with folic acid, teine concentrations are associated with an in- B6, and B12 in patients with CKD did not reduce creased incidence of adverse cardiovascular events cardiovascular risk. and mortality.39This relationship is less clear in Another marker that has received attention in patients with CKD, because hyperhomocysteine- cardiovascular disease and homocysteine is mia has been associated with both increased and re- S-adenosylhomocysteine (SAH). This molecule is duced mortality in these individuals,40,41 probably the result of the conversion of S-adenosylmethio- because of the interaction of serum homocysteine nine, a universal donor for a large variety of accep- levels with protein–energy wasting. Several tor compounds, into SAH via transmethylation. In clinical trials have tested treatment of the patients a study with CKD patients and healthy controls by with stages 4 and 5 CKD with large doses of folic Valli et al.,45 SAH was significantly elevated in acid, pyridoxine HCl, and often vitamin B6 to patients with cardiovascular disease compared reduce elevated plasma homocysteine levels. A with those without (683 [201 to 3,057 nmol/L] vs. post hoc analysis of the Modification of Diet in 485 [259 to 2,620 nmol/L, median [range], P , Renal Disease Study indicates that serum .001). Furthermore, in a multinomial logistic homocysteine is increased in many patients with regression analysis, SAH was a significant predictor both stages 3 and 4 CKD and that the elevated of cardiovascular disease (r2 5 0.31). serum levels appear to be influenced by the intake Perhaps the largest clinical trial with the longest and blood levels of serum folate, vitamin B12, follow-up concerning vitamins to lower homocys- and possibly vitamin B6, and also by the GFR teine (Hcy) concentrations and improve clinical level. This analysis indicated that prescription of outcome was the Homocysteinemia in Kidney a daily multivitamin that provided 1 mg folic and End Stage Renal Disease (HOST) study. acid, 10 mg pyridoxine HCl, and 6 mg vitamin This was a randomized, double-blind, placebo- B12, which, essentially doubled the estimated controlled trial conducted in 2,056 Veterans Ad- daily folate and vitamin B12 intake, was ministration patients with stages 4 and 5 CKD associated with a 7% to 10% decrease in serum who were either nondialyzed (n 5 1,305) or homocysteine concentrations.39 were on maintenance hemodialysis (n 5 751).23 Conversely, Nanayakkarra et al.42 conducted All patients were hyperhomocysteinemic (Hcy, a secondary analysis of a randomized clinical trial .15 umol/L), and they were randomized to re- in patients with stages 2-4 CKD who were not ceive daily treatment with 40 mg folic acid, 100 taking a vitamin supplement. The researchers mg pyridoxine HCl, and 2 mg vitamin B12, or used a step-wise intervention with pravastatin with placebo. Patients were treated for a mean of 40 mg/day, at baseline; vitamin E 300 mg/day, ini- 4.5 years. Serum homocysteine levels decreased tiated after 6 months; and finally, the B vitamins by 25.8% in the vitamin group (P ,.001) as com- pyridoxine HCl 100 mg/day, folic acid 5 mg/day, pared with the placebo group38; however, there and B12 1 mg/day after another 6 months. were no significant differences between the treat- The primary outcome of this study was asymmet- ment group and the control group with regard to ric dimethylarginine, which inhibits the mortality, myocardial infarction, or amputations. endothelium-dependent nitric oxide-mediated In a recently published study, patients with 238 response. Increased asymmetric dimethylarginine diabetic nephropathy and nephrotic syndrome, 362 STEIBER AND KOPPLE stage 3 or earlier, were randomized to treatment studies plasma concentrations do not correlate well with either placebo or a combination of folic with whole blood pantothenic acid levels or acid 2.5 mg/day, pyridoxine HCl 25 mg/day, dietary intake8; therefore, these findings may not and vitamin B12 1 mg/day, for a mean of 31.9 accurately reflect body stores. Given the ubiqui- months.46 Patients randomized to vitamin treat- tous nature of pantothenic acid in the general ment had a significantly faster reduction in GFR food supply and the lack of evidence for insuffi- (216.5 6 1.7, mean change at 36 months) com- ciency or deficiency in patients with CKD, at pared with patients receiving placebo (210.7 6 this time intake beyond the AI is not warranted. 1.7, P 5 .045). The patients taking the vitamins were significantly more likely to have a myocardial infarction, stroke, revascularization, or all-cause Vitamin C mortality.46 Actions Thus, there currently does not seem to be any Vitamin C, or ascorbic acid, is a hydrophilic, clinical advantage to the routine use of megavita- 6-carbon lactone that is capable of inhibiting the min therapy to lower the moderately elevated oxidation of other compounds by donating a max- serum homocysteine levels in typical patients imum of 2 electrons and, in the process, undergoes with CKD. It should be noted that genetic causes oxidation. When 1 electron is donated, the of severe hyperhomocysteinemia occur uncom- ascorbic acid becomes a free radical known as monly and can be associated with ESRD. Patients semidehydroascorbic acid. After receiving a second with this condition are at increased risk for serious electron, semidehydroascorbic acid is converted to thromboembolic events, which can involve the dehydroascorbic acid. This process scavenges free major renal blood vessels. These individuals can radicals in the body, after oxidation of which, the respond to large doses of pyridoxine HCl or folic threat of cellular damage is reduced. The DRI acid, depending on the genetic defect, and they 47 for vitamin C is 75 mg/day for women and 90 should be treated accordingly. mg/day for men.48

Pantothenic Acid Food Sources Actions The following food sources are rich in vitamin C: citrus fruits, berries, papaya, peppers, mangos, Pantothenic acid is derived from pantothenate pineapple, broccoli, cauliflower, melons, greens, and is used in the synthesis of CoA. Coenzyme tomatoes, and tubers.18 is critical for many metabolic processes such as fatty acid oxidation, transport of proteins, and Evidence for Altered Requirements the formation of acetyl CoA, a key molecule in energy metabolism.8 There is inadequate informa- The causes of low vitamin intake and deficiency tion to determine an RDA for pantothenic acid; have been discussed earlier in the text. Vitamin C however, the AI is set at 5 mg/day for men and intake is particularly likely to be low in patients women aged .51 years.17 with CKD because of the potassium restriction. The authors are unaware of studies of vitamin C Food Sources levels or requirements in nondialyzed patients with CKD. Although pantothenic acid appears to be ubiq- Oxalate is a metabolite of ascorbic acid. Urine uitous in the food supply, the following foods are oxalate and, in renal failure patients, serum oxalate rich sources: beef, poultry, whole grains, potatoes, 18 may increase when individuals ingest supplemental tomatoes, and broccoli. ascorbic acid.5 Thus, high doses of vitamin C traditionally are not recommended for patients with Evidence for Altered Requirements advanced CKD because of the possible increased There are currently no reports in the published risk for hyperoxalosis. However, in a recent study data demonstrating pantothenic acid deficiency in of people without CKD who were at increased patients with CKD. There are a few reports of risk for oxalate formation, 500 mg/day of vitamin lower dietary intake by patients with CKD who C did not increase 24-hour urinary oxalate excre- are on low-protein diets.34 However, in validation tion.49 Because of these concerns, for nondialyzed VITAMINS IN CHRONIC KIDNEY DISEASE 363 patients with CKD, the CARI guidelines recom- increased in CKD, and this may partly explain mend no more than 60 mg/day of vitamin C and the elevated plasma concentrations in CKD the ESPEN guidelines recommend supplementa- patients. The National Health and Examination tion with 30 to 60 mg/day of vitamin C for the Survey III data demonstrated an association patients with CKD.31,50 between elevated serum creatinine and elevated serum vitamin A concentrations54; this correlation Fat-soluble Vitamins was consistent across ethnicities and persisted after adjustment for confounding factors. This finding Vitamin A reinforces earlier studies that described elevated Action vitamin A levels in nondialyzed patients with CKD, ESRD patients, and kidney transplant Vitamin A is a set of fat-soluble compounds 55–57 classified as retinoids. Human beings ingest pre- recipients. Because serum vitamin A concentrations begin formed vitamin A (retinyl esters) or carotenoids, 53 which are vitamin A precursors. Retinyl esters to increase with the increase in serum creatinine, can go through conversions to form retinol (the there would seem to be no need to provide supple- alcohol form of the retinoids), which can be sub- mental vitamin for patients with CKD, except in sequently converted to retinal (the aldehyde form) unusual conditions. This is consistent with the and then to retinoic acid (the acid form). Retinal current recommendations against the need for and retinoic acid (the acid form) are required for supplemental vitamin A in CKD unless the patient various reactions in the eye to support vision. is commonly ingesting less than the RDA for vitamin A.31 In this latter circumstance, supplemental Retinoic acid also promotes embryonic develop- 5 ment, and retinoids are necessary for normal vitamin A up to the RDA can be given. immune function. The carotenoids are b-carotene, a-carotene, Vitamin E and b-cryptoxanthin,51 with b-carotene being the most common form. It can be converted to Action retinol; however, it has only approximately 50% Vitamin E is a lipophilic molecule that typically of the activity of retinyl esters. resides in cell membranes. It acts as an anti-oxidant Vitamin A is transported in blood bound to because it remains highly stable even after it scav- retinol-binding protein (RBP). RBP associates enges free radicals. Vitamin E exists in 4 forms, with 2 other proteins to form a trimolecular com- a-tocopherol, b-tocopherol, g-tocopherol, and plex, called transthyretin. The current RDA for d-tocopherol; however, only a-tocopherol has healthy men and women aged .51 years is 900 an established RDA. These forms differ by the and 700 mg retinol activity equivalents/day, level of methylation. The DRI for vitamin respectively, and the upper intake level is 3,000 E(a-tocopherol) is 15 mg/day for both healthy mg retinol activity equivalents/day.52 men and women.48

Food Sources Food Sources The following food sources are rich in vitamin The following food sources are rich in vitamin A: liver, fish liver oils, dairy products, butter, and E: vegetable oils, unprocessed grains, nuts, fruits, eggs. b-carotene is found in red and yellow col- vegetables, and meat.18 ored fruits and vegetables such as cantaloupe, car- rots, sweet potatoes, winter squash, and dark green Evidence for Altered Requirements 18 leafy vegetables such as spinach. The role of oxidative stress as a pathologic agent in several disease states has become increasingly Evidence for Altered Requirements apparent, and vitamin E has concurrently been con- Serum vitamin A concentrations are often sidered as a potential treatment for this condition. increased in patients with advanced CKD. Poten- Plasma vitamin E levels in patients with CKD do tial mechanisms include decreased catabolism of not appear to be different from healthy controls,58,59 RBPs. Frey et al.53 showed that isoforms of RBP even when dietary intake of vitamin E is reduced.59 4 (the main transporter or retinol in blood) is The vitamin E metabolite, carboxyethyl- 364 STEIBER AND KOPPLE hydroxychromans (CEHC), significantly increases and ileum and is primarily stored in the liver. in serum with declining renal function; this increase Bacteria in the gut also produce vitamin K in the in serum CEHC has been observed with creatinine form of menaquinones which are absorbed from clearances of 45 mL/min (stage 3). Galli et al.59 sug- the distal bowel and stored in the liver. If vitamin gest that the accumulation of this metabolite K deficiency occurs, body proteins may be under- (CEHC) could interfere with the functions of vita- carboxylated. Carboxylation status of proteins, min E in patients with uremic CKD. such as osteocalcin, can be measured and used to The results of clinical trials evaluating the effec- diagnose vitamin K deficiency. The normal AI tiveness of vitamin E for the prevention of cardio- for vitamin K is 90 mg/day for women and 120 vascular disease in people with CKD have been mg/day for men.52 mixed. Mann et al.60 examined outcomes in patients with mild-moderate kidney failure (serum creatinine, 1.4 to 2.3 mg/dL; approximately stage Food Sources 3 CKD) and increased risk for cardiovascular The following food sources are rich in vitamin events who were given 400 IU/day of vitamin E K: green vegetables, cabbage, and plant oils.18 as part of the Heart Outcomes Prevention Evalu- ation (HOPE) trial. Consistent with studies in such patients who did not have CKD, there was Evidence for Deficiency no cardiovascular benefit to taking this dose of Till date, there is little evidence that the refer- vitamin E. Moreover, the long-term use of this ence intake for patients with CKD differs from dose (400 IU/day or 363 mg/day) of supplemental the DRI for normal individuals. However, vitamin E in individuals with or without CKD a decrease in dietary intake of vitamin K (phyllo- who were at high risk for adverse cardiovascular quinones), and/or a reduction in vitamin K pro- events in the HOPE trial resulted in an increased duction by gut bacteria can lower vitamin K incidence of heart failure, heart failure-related hos- levels. Antibiotics that suppress gut flora, and pitalizations, and all-cause mortality (hazard ratio, hence bacterial production of vitamin K, may 1.13; 95% confidence intervals, 1.01 to 1.26, increase the risk of vitamin K deficiency and P 5 .4).38,39 This increased risk was associated impaired blood clotting. This is especially likely with vitamin E intakes as low as 150 IU/day (136 to happen if the patient is also not eating or tak- mg/day).61,62 ing vitamin supplements and therefore has a low These studies, taken together, suggest that vitamin K intake. In one study of hospitalized among people at high risk for cardiovascular patients with extended prothrombin times, one- events, supplemental vitamin E may not be indi- third of the patients had CKD and were not cated in the general population or in nondialysis receiving dialysis.63 CKD patients. At present, we recommend that A recent study in 172 patients with stages 3-5 nondialyzed patients with stages 2-5 CKD CKD found that depending on the vitamin K receive the normal DRI for vitamin E of 15 indicator used, 6% to 97% of patients were IU/day. vitamin K deficient. When serum phylloquinone was used as a measure, 6% deficiency was found in this population. However, when the more Vitamin K accurate maker, percent under carboxylated osteocalcin, was measured 60% of the patients were Action found to be deficient in vitamin K. Finally, when Vitamin K participates in the posttranslational Proteins Induced by Vitamin k Absence-II carboxylation of specific glutamic acid (Gla) resi- (PIVKA-II), a less used but a potentially very accu- dues in proteins (such as blood clotting proteins rate marker was measured, 97% of the patients and osteocalcin), enabling the protein to bind to were found to be deficient.64 calcium and interact with other compounds. These considerations suggest that men and This is a necessary step for such processes involving women with CKD should ingest a minimum of calcium interactions as blood clotting and bone 90 mg/day and 120 mg/day of vitamin K, respec- mineralization. The dietary form of vitamin K is tively. When such individuals receive oral or phylloquinone, which is absorbed in the jejunum parenteral antibiotics that may suppress VITAMINS IN CHRONIC KIDNEY DISEASE 365 gastrointestinal bacteria for extended period, they ciferol levels ,15 ng/mL, were at increased risk of may be considered for vitamin K supplements; all-cause mortality (hazard ratio, 1.56 [95% confi- this is particularly the case if they have prolonged dence intervals, 1.12 to 2.18]). Furthermore, low prothrombin times. serum 25-hydroxycholecalciferol levels or deficient intake is associated with increased risk of car- Vitamin D diovascular disease, cancer, and mortality in the 73,74 Action general population. It has been suggested that serum 25-hydroxycholecalciferol levels of Vitamin D is found as 25-hydroxycholecalci- ,15 ng/mL indicate deficiency, serum levels of ferol or 1,25-dihydroxycholecalciferol (calcitriol) 15 to 30 ng/mL indicate insufficiency, and levels in the body. Vitamin D is important in bone for- .30 ng/mL are adequate. mation, immune function, vascular and nervous 65 The fact that extra-renal 1-alpha-hydroxylase is systems, and reproduction. widely distributed may help to explain the potential positive benefits of ergocalciferol and cholecal- Food Sources ciferol.75 Receptors for these latter compounds and for calcitriol are widely distributed in various Cholecalciferol or D3 is formed in the skin through sunlight exposure or is absorbed from in- cell types, which is consistent with the findings gested foods which are high in the vitamin; that the benefits of vitamin D extend far beyond bone health. Cell receptors for 25-hydroxychole- whereas ergocalciferol or D2 is synthetically man- ufactured from yeast. The amount of sun exposure calciferol are also widely distributed, which may needed for an individual to reach their daily provide further support that this latter compound has beneficial effects that are independent from requirement of D3 varies by the amount of mela- 69,72 nin in the skin, whether sun screen is used, the sea- calcitriol. son of the year, and their location in relationship to The accumulating evidence indicating benefits the equator. Foods containing high amounts of to the importance of nutritional vitamin D was re- vitamin D are often high in fat because vitamin flected in the recent Kidney Disease: Improving D is a fat-soluble vitamin. Thus, vitamin D in for- Global Outcomes (KDIGO) recommendations tified milk may be better absorbed in milk with fat, for bone and mineral metabolism, which suggest such as $1%, verses skim milk which contains lit- serially measuring serum 25-hydroxycholecalci- tle to no fat. Other foods high in vitamin D are ferol levels in stages 3-5 CKD; if serum levels are fatty fish, such as salmon or sardines, and eggs.18 low, supplements of this compound should be given.76 Clinically, it may be suggested that patients Evidence for Altered Requirements with stages 3-5 CKD should be routinely pre- The use of 1,25-dihydroxycholecalciferol scribed cholecalciferol or ergocalciferol without (calcitriol) and its analogues for people with ascertaining whether serum levels are de- CKD has been scientifically investigated and dis- creased.77 The rational for this is that (1) a high cussed extensively,66–68 however; space does not prevalence of deficient serum 25-hydroxychole- allow us to review this important subject. calciferol levels in patients with CKD, (2) the Emerging evidence, not yet definitive, also expensive costs of routinely measuring serum indicates that supplemental calcitriol precursors, 25-hydroxycholecalciferol, and (3) the safety of such as ergocalciferol or cholecalciferol, may taking this compound. This proposal may be par- benefit patients with CKD.69 Because of the new ticularly relevant because patients with CKD and nondefinitive nature of the evidence regarding might develop low serum 25-hydroxycholecalci- the nutritional needs for these latter compounds, ferol levels some months after a normal serum they will be discussed in more detail. value is obtained. Recent studies show that low serum 25-hydrox- Against this suggestion, a recent meta-analysis ycholecalciferol levels are associated with adverse by Palmer et al. reported that, ‘‘vitamin D is of outcomes in CKD and incident MD patients.70,71 unproven efficacy in CKD except for its effects Mehrotra et al.72 found that patients with CKD, on some biochemical indexes.’’78 This meta- regardless of CKD stage or underlying cardiovas- analysis has been criticized for combining the re- cular disease, who had serum 25-hydroxycholecal- sults of many discordant studies into single sets of 366 STEIBER AND KOPPLE analyses.79 However, there is a consensus that Acknowledgment more randomized controlled clinical trials are nec- The authors thank Drs. Laura Byham-Gray, Dr. Nilesh essary before definitive answers will be available Mhaskar, and Grissim Connery for their helpful thoughts. concerning vitamin D supplementation.69,76,78,79 Dr. Steiber and Dr. Kopple contributed to the content and Despite the accumulating evidence for the writing of the article. potential benefits of taking cholecalciferol or ergocalciferol, most renal vitamin preparations do not References contain vitamin D. If vitamin D is to be prescribed, there is no consensus as to the compound and the 1. Kovesdy CP, Kalantar-Zadeh K: Why is protein-energy wasting associated with mortality in chronic kidney disease? dose that should be used. Holick et al. have Semin Nephrol 29:3-14, 2009 recently reported that in otherwise normal vita- 2. Kalantar-Zadeh K, Abbott KC, Salahudeen AK, et al: min D deficient individuals, 1,000 IU/day of Survival advantages of obesity in dialysis patients. 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