Download Vitamin Status and Needs for People with Stages 3-5

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
M
EASURES OF PROTEIN–ENERGY
wasting are strongly correlated with mortality in end-stage renal disease (ESRD).1 The findings
that body fat, skeletal muscle mass, and body mass
index (BMI), including very large BMIs, have independent and direct associations with survival in
chronic kidney disease (CKD) patients2–4 suggest
that reduced nutritional status, besides
inflammation, may be both a predictor and
a cause of death in these individuals. Although
there are many observational studies describing
the nutritional status of patients on maintenance
dialysis and those with CKD who are not
receiving maintenance dialysis, these investigations
*Department of Nutrition, School of Medicine, Case Western
Reserve University, Cleveland, Ohio.
†Division of Nephrology and Hypertension and Department of
Medicine, Los Angeles Biomedical Research Institute at HarborUCLA Medical Center, the David Geffen School of Medicine at
UCLA, Los Angeles, California.
‡David Geffen School of Medicine, UCLA School of Public
Health, Los Angeles, California.
Conflict of interest: The authors are members of the Clinical
Advisory Board for Nephroceuticals, Inc.
Address reprint requests to Alison L. Steiber, RD, PhD, Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH 44106. E-mail: [email protected]
Ó 2011 by the National Kidney Foundation, Inc. All rights
reserved.
1051-2276/$36.00
doi:10.1053/j.jrn.2010.12.004
generally address nutritional contributions from
proteins, energy, fats, macrominerals such as
sodium, chloride, and potassium, vitamin D, and
iron.2–6 Several reviews of the nutritional status
and requirements for vitamins in patients on
maintenance dialysis have been published in the
past several years.5,6 To the authors’ knowledge,
no such review currently exists for patients who
have stages 3-5 CKD and who are not at ESRD
or awaiting renal transplantation. This review
discusses the literature concerning nutritional
status and requirements for vitamins in patients
with CKD stages 3 (glomerular filtration rate
[GFR], ,60 mL/min/1.73 m2), 4 (GFR, ,29
months/min/1.73 m2), and 5 (GFR, ,15
months/min/1.73 m2), who are not receiving
renal replacement therapy.
Vitamin deficiencies are common in people
with advanced renal failure who do not take nutritional supplements.7 The causes for such vitamin
deficiencies have been reviewed and include low
dietary intake that may be because of anorexia, or
the impaired ability to buy, prepare, or ingest foods
that are high in nutrient content. Dietary prescription may limit foods which are high in vitamins,
particularly water-soluble vitamins, because of
their high potassium or phosphorus content.7
Also, some medicines may interfere with the
metabolism or actions of certain vitamins including
vitamin B6, folate, and possibly riboflavin.8 Seasonal 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
fruits and vegetables, to dietary protein restrictions,
and to sunlight.9 Superimposed illnesses may contribute to low intake, impaired digestion, absorption or actions of some vitamins, or may require
the use of medicines that interfere with the actions
of vitamins.7
Our knowledge of the body concentration,
function, metabolic effects, and clinical response
to reduced intake and low serum concentrations
on these nutrients in nondialyzed patients with
stages 3-5 CKD is incomplete. Whether there is
altered nutrient metabolism in stages 3-5 CKD,
as there can be in patients suffering from ESRD
and those on dialysis,10,11 is unclear. Data from
the National Health and Examination Survey8,9
and the Modification of Diet in Renal Disease
Study10 show that the daily ingestion of nutrients
begins to decline in as early as stage 3 CKD.11–13
This reduction in intake may affect energy
producing nutrients (carbohydrates, protein, and
fat), macrominerals, vitamins, and trace elements.
The Dialysis Outcome Practice Patterns Study
reported that patients on maintenance
hemodialysis taking water-soluble vitamin supplements had a 16% lower mortality than similar
patients not taking such preparations.14 This latter
analysis was adjusted for age, gender, race, comorbidity, hemoglobin, serum albumin, BMI, and
other potential confounders. Whether such supplements may increase survival in people with
stages 3-5 CKD is unknown.
Although the optimal intake of macrominerals,
iron, and vitamin D nutrition has received substantial attention, less is written or known concerning
recommended allowances or body burden of vitamins and trace elements in stage 3-5 CKD. Possible
adverse consequences of excessive vitamin intake
by patients with CKD are an important concern,
because vitamin supplements are commonly taken
in the United States. Approximately one-half of
elderly prescription medication users are reported
to take dietary supplements, predominantly multivitamins.15 It is likely that some CKD patients take
excessive and hazardous amounts of certain supplemental vitamins as well as inadequate quantities
of other vitamins. This review summarizes the previously published data concerning the function,
food sources, and evidence for inadequate or
excessive intake of vitamins in people with stage
3-5 CKD who are not receiving dialysis therapy
and do not have a functioning kidney transplant.
Definition of Terms Concerning
Nutritional Adequacy
Traditionally, the adequacy of the body content
and functional activity of vitamins are determined
by measuring dietary intake, the corresponding
biochemical values of these compounds––usually
measured in serum or plasma or red blood cells,
occasionally in urine, and in enzyme activities,
and other biological processes or clinical manifestations of deficiency or excess. For example, the
effects of certain vitamin intakes on hemoglobin
production or plasma and urinary oxalate levels
may be indicators of deficiency or excess. The recommended amount of a specific nutrient which is
considered to support health is referred to as the
dietary reference intake (DRI).16
Hence, the DRIs can be standards by which the
adequacy of nutrient intake could be assessed.
They allow clinicians to compare the quantity of
a given nutrient in a patient’s diet with an established standard. The DRIs for nutrients are generally determined by considering several other
established standards regarding nutrient intake.
These include the estimated average requirement
(EAR) for the nutrient, the recommended daily
allowance (RDA), and the adequate intake (AI)
of the nutrient in question. Initially, wherever sufficient data are available, an EAR is established for
a specific nutrient. The EAR is the amount of
nutrient needed by one-half of the healthy population to support normal biological and physiological processes. In the Dietary Reference Guidelines,
it should be noted that the terms, ‘‘healthy population’’ and ‘‘general population’’ are often conflated.
The RDA is statistically derived from the EAR; it is
calculated to be 2 standard deviations (SD) more
than the EAR. Thus, RDA values are the average
daily requirement for practically the entire general
population (97% to 98%) to support biochemical
and physiological processes. Data to establish the
EARs are obtained, where possible, from clinical
trials; however, there are insufficient data to determine these values for some nutrients. When there
are insufficient data, an AI is established instead. AI
is defined as the average amount of a nutrient that
a group of healthy people consume. It is assumed
that because these latter individuals are healthy,
their intake of the nutrient in question should be
adequate. Finally, the tolerable upper intake level
is the maximum daily amount of a nutrient that
seems to be safe for most healthy people and above
VITAMINS IN CHRONIC KIDNEY DISEASE
which there is an increased risk of adverse health
effects.
These terms and values are in reference to
healthy people and represent oral intakes; they do
not necessarily reflect the values for the intakes of
people with CKD, especially if their nutrients are
not taken orally. Thus, the DRIs can be used as
general benchmarks, but extrapolating these
benchmarks to patients with CKD or other morbid conditions should be done with caution. The
focus of this article is to describe what is currently
reported in the published data regarding vitamin
status and requirements for nontransplanted adult
patients with CKD stages 3-5 who do not require
dialysis treatment. DRI values for the general population will be shown for adults aged 50 to 70 years.
This age range was selected because it is similar to
the ages of a large proportion of adults with CKD.
Water-Soluble Vitamins
Vitamin B1-Thiamin
Action
Thiamin is a hydrophilic B vitamin involved
with many metabolic functions. Thiamin serves
as a cofactor for oxidative decarboxylation reactions. These include the conversion of pyruvate
to acetyl coenzyme A (CoA) in the pyruvate
dehydrogenase complex, the conversion of a-ketoglutarate to succinyl CoA in the a-ketoglutarate
dehydrogenase complex, and the conversion of
leucine, isoleucine, and valine to isovaleryl CoA,
a-methylbutyryl CoA, and isobutyryl CoA in
the branched chain a-ketoacid dehydrogenase
complex. Additionally, thiamin is a cofactor in
the transketolase reactions of the nonoxidative
phase of the pentose pathway which leads to the
production of ribose-5-phosphate and nicotinamide adenine dinucleotide phosphate. The
DRI for thiamin (age, 50 to 70 years) is 1.2 mg/
day and 1.1 mg/day for normal men and women,
respectively.17
Food Sources
The following food items are rich in thiamin:
pork, oat bran, whole grains, and enriched grains.18
Evidence for Altered Requirements
Dietary intake and nutritional status for thiamin
in patients with CKD (n 5 14) was assessed by
Frank et al.6 Patients with stages 4 and 5 CKDs
357
consumed an average of 1.26 mg of thiamin/day
from the foods in their diet. Their mean plasma
thiamin concentration was 64.2 nmol/L, and their
ETK-AC (erythrocyte transketolase activity coefficients, an indicator of thiamin adequacy) was
1.18 6 0.19 (SD) (an ETK-AC indicating no
deficiency is ,1.20). ETK-AC has been regarded
as a good functional indicator of thiamin status.8
Thus, according to the data generated by Frank
et al.,6 a substantial proportion of patients with
stages 4 and 5 CKD had ETK-AC values .1.20,
indicating a thiamin-deficient status. These data
are presented as mean 6 SD, and the medians
were not provided in this study. Thus, it is somewhat difficult to compare these results by Frank
et al.6 with those by Weber and Kewitz19 in 91
generally healthy hospital employees that indicate
what are presumably normal or healthy thiamin
values. These latter investigators found the normal
plasma thiamin concentrations to have a skewed
distribution and presented their data as a median
and range. The volunteers had a median plasma
thiamin concentration of 11.6 nmol/L and a range
of 6.6 to 43 nmol/L. Contrary to the ETK-AC
findings, the patients with CKD appear to have increased concentrations of plasma thiamin when
compared with the normal volunteers. The
mean plasma thiamin values of these patients
were higher than the upper range value of the
healthy volunteers. It should be noted that plasma
thiamin concentrations are not considered to be
a reliable indicator of nutritional adequacy for thiamin.18 Although the data do not indicate that all
patients have a deficiency of thiamin, there are data
that indicate the risk for insufficient or deficient
concentrations in patients with CKD. Whether
the DRI level of intake is sufficient for patients
with CKD is also unknown. However, a daily supplement at the DRI to augment dietary intake
seems prudent to prevent possible deficiencies.
Vitamin B2-Riboflavin
Action
Riboflavin is a hydrophilic B vitamin with
phosphorescent properties. It is necessary for
oxidation–reduction reactions. When phosphorylated by adenosine triphosphate, riboflavin is converted to flavin mononucleotide (FMN). This
molecule can then be complexed with various
apoenzymes to form several flavoproteins. Most
of the FMN is converted to flavin adenine
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STEIBER AND KOPPLE
dinucleotide (FAD) by FAD synthetase. Hence,
FAD is the predominant flavoenzyme in the
body. The enzymes with which FMN and FAD
are associated include oxygenases, monooxygenases, dehydrogenases, oxidoreductases, and electron transferases. This wide range of enzyme
activities is based on the fact that the molecules
can transition well between oxidized, single electron reduced semiquinoid, and double electron
reduced hydroquinoid states. Normally, the DRI
for riboflavin is 1.1 mg/day for women and 1.3
mg/day for men.17
Food Sources
The following foods are rich sources of riboflavin: liver, duck, milk, eggs, mushrooms, spinach,
chicken, and enriched grains.18
Evidence for Altered Requirements
Porrini et al.20 studied patients with advanced
CKD who were not undergoing dialysis using the
a-erythrocyte glutathione reductase (a-EGR)
stimulation index to assess riboflavin status. In
this study, 8% of patients were found to have elevated a-EGR, thus indicating riboflavin deficiency. When the prescribed protein intake of
these patients was intentionally reduced to 1.0 g
protein/kg/day or 0.6 g protein/kg/day, from the
patients’ usual intake, according to the research
protocol, the prevalence of elevated a-EGR
increased from 8% to 25% and 41%, respectively.
The increased prevalence of elevated a-EGR was
attributed to the fact that riboflavin is particularly
abundant in foods containing animal proteins (see
earlier in the text). Indeed, several works have recommended riboflavin supplements for patients
with CKD, especially when they ingest very lowprotein diets (i.e., ,0.6 g protein/kg/day).5,13,14
Niacin-Vitamin B3
Action
Niacin is another hydrophilic B vitamin that is
ingested as either nicotinamide from animal sources or nicotinic acid from plant sources. Niacin
becomes active in human beings when it is converted to either nicotinamide adenine dinucleotide
or nicotinamide adenine dinucleotide phosphate.
These molecules are necessary cofactors for many
oxidation–reduction reactions. A few notable processes involving niacin activity are the citric acid
cycle, electron transport chain, and b-oxidation
of lipids. Niacin also prevents and is the therapeutic
agent for pellagra, which is a condition caused by
niacin deficiency and often referred to by ‘‘the
D’s’’: dermatosis, diarrhea, dementia, and death.
Pellagra is associated with the chronic intake of
low riboflavin diets, alcoholism, food faddism,
and when untreated maize is a primary staple of
the diet.21 It has been shown that diets prescribed
for patients with CKD are often not well accepted
and may lead to poor intake.22 The DRI for
healthy individuals is 14 mg/day for women and
16 mg/day for men.17
Food Sources
Niacin is unusual in that it has an amino acid
precursor, tryptophan; some of the tryptophan in
the body is routinely converted to niacin. Thus,
when niacin stores are low, the conversion of tryptophan can become a source of niacin. Primary
food sources that are rich in niacin are meat, fish,
legumes, coffee, and tea,18 all of which tend to
be reduced in low-protein, low phosphorus diets.
Evidence for Altered Requirements
It is possible that patients with CKD who are
prescribed with low-protein diets (such as 0.6 g
protein/kg/day) with phosphorus restriction
(such as 800 mg/day) may be at risk for niacin deficiency because of the low niacin content of plant
food; thus, their dietary niacin intake may be quite
low. However, the authors are unaware of any
clinical trials that have examined the niacin intake
of patients with CKD and whether that amount is
sufficient to maintain adequate niacin status.
Recently, a novel use for niacin has been discovered. The niacin metabolite, nicotinamide, has
been successfully used to reduce serum phosphorus concentrations in patients on hemodialysis
who have been using megadoses of niacin, 500
to 1500 mg/day, given twice daily.23,24 The
mechanisms of action involve the inhibition of
the sodium/phosphorus type IIb cotransporter
(Na Pi-2b) and type IIa cotransporter (NaPi-2a),
which are the major transporters of inorganic
phosphorus in the intestinal brush border and in
the proximal renal-tubular epithelial cells of the
kidneys, respectively.25,26 Therefore, it is likely
that in nondialyzed patients with stages 3-5
CKD, the action of nicotinamide on the Na
Pi-2a and Na Pi-2b cotransporters will inhibit
VITAMINS IN CHRONIC KIDNEY DISEASE
both renal-tubular phosphorus reabsorption and
phosphorus absorption in the intestinal brush border, thereby increasing renal phosphorus excretion
in urine and feces. At present, the authors are
unaware of published studies on the effects of niacin supplementation on urinary phosphorus
excretion in CKD patients who are not receiving
dialysis. The use of nicotinamide is associated
with many side effects; most relevant are flushing,
thrombocytopenia, hepatoxicity (especially with
sustained release doses), gastrointestinal symptoms
such as diarrhea, vomiting, and constipation, and
increased serum uric acid concentrations.26 The
increased serum uric acid may be of concern as
hyperuricemia has been associated with both
hypertension and more rapid progression of renal
failure.27 At this time, there does not seem to be
data to warrant supplementation with niacin.
However, CKD patients with chronically suboptimal dietary intake may benefit from a supplement
at the DRI level to prevent deficiency.
Vitamin B-6—Pyridoxine
Action
Vitamin B6 exists in vivo as 6 compounds.
These are pyridoxal, pyridoxine, pyridoxamine,
and the 5’ phosphates of these 3 compounds.
Pyridoxal-5-phosphate (PLP) is a cofactor for
many enzymes, particularly those involving amino
acid metabolism and which include aminotransferases, decarboxylases, racemases, and dehydratases.
Notably, PLP is necessary for (d)-aminolevulinate
synthase to initiate heme synthesis. The DRI for
pyridoxine (age, 50 to 70 years old) in men is 1.7
mg/day and in women is 1.5 mg/day.17
Food Sources
The following food sources are rich in vitamin
B6: liver, fish, meat, poultry, plums, bananas,
plantains, barley, sweet potatoes, potatoes, and
enriched grains.18
Evidence for Altered Requirements
Kopple et al.28 conducted both dietary and biochemical assessments of pyridoxine status on
patients with different stages of CKD. In a crosssectional analysis, the amount of vitamin B6 consumed in foods declined as GFR decreased, from
2.2 6 0.8 (SD) mg/day in 6 patients with stages
3 and 4 CKD (serum creatinine from 2.1 to 3.5
359
mg/dL) to 1.2 6 0.5 mg/day in 7 nondialyzed
patients with stages 4 and 5 CKD.28 The mean
intake of vitamin B6 for patients with severe
CKD was significantly lower than the DRI for
their age cohort. These declining intakes were
reflected in the stimulation index of erythrocyte
glutamic pyruvic transaminase (EGPT) activity.
EGPT activity and the EGPT index are measurements of adequacy of body pyridoxine levels. An
EGPT index .1.25 is an indicator of vitamin B6
deficiency.20 The mean EGPT stimulation index
increased (indicating vitamin B6 deficiency)
inversely with the stage of CKD, in which patients
with higher GFR levels (stages 3 and 4 CKD) had
a mean EGPT index of 1.23 6 0.09 (SD); CKD
patients with lower GFR levels (stages 4 and 5
CKD) had a mean index of 1.30 6 0.11. These
were all significantly higher than the normal control values of 1.16 6 0.06.
Podda et al.29 found significantly lower serum
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
serum B6 values correlated with the magnitude of
their proteinuria (r 5 0.41, P ,.001). These studies
provide evidence that there are suboptimal levels of
serum vitamin B6 in many patients with CKD.
Many medicines and other compounds can
interfere with the actions or metabolism of vitamin
B6 and may increase the likelihood that they will develop B6 deficiency. This is especially likely to occur
in patients with CKD, because their vitamin B6 intake is often low, they may have increased dietary
needs for B6,5 and it is likely that they may be prescribed some of these medicines. These interfering
compounds include isoniazid, thyroxine, iproniazid,
theophylline, hydralazine, caffeine, penicillamine,
ethanol, and oral contraceptives. The data presented
in this study suggest that patients at stage 3 or worse
CKD are at an increased risk for deficient concentrations of vitamin B6 and therefore should be supplemented adequately. It has been recommended by
both the European Society of Parenteral and Enteral
Nutrition and Caring for Australians with Renal
Insufficiency guidelines that vitamin B6 should be
supplemented daily at a dose of 5 mg.30–32
Folic Acid
Action
Folic acid is a pteroylmonoglutamic acid. It
transfers single-carbon or methyl groups mainly
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STEIBER AND KOPPLE
as the tetrahydrofolate, thereby providing methyl
groups for pyrimidine and purine synthesis. Folate
is also necessary for histidine catabolism, the
conversion between serine and glycine, and the
conversion of homocysteine to methionine, in addition to other processes. Deficiency of folic acid
results in megaloblastic anemia. The DRI for
both healthy men and women is 400 mg/day.17
Food Sources
The following food sources are rich in folic
acid: legumes, orange juice, spinach and other
leafy greens, broccoli, beets, artichokes, papaya,
and enriched grains.18
Evidence for Altered Requirements
The causes for folic acid deficiency have been
discussed earlier in the text (see Overview). As
indicated earlier, low folate intake can be an important contributor to folate deficiency in patients with
CKD. The primary source of dietary folic acid is
fresh green vegetables which, because of their
high potassium content, are frequently restricted
in the diet of these patients. Medicines that interfere
with folic acid and might lead to deficiency, particularly in people with low folate intakes, include barbiturates, primidone, cycloserine, pyrimethamine,
diphenylhydantoin, triamterene, methotrexate, trimethoprim, mysoline, pentamidine, salicylazosulfapyridine, and ethanol. Said et al.33 reported that
radiolabeled 5-methyltetrahydrofolate absorption
is reduced in the intestinal tract in azotemic rats.
This does not seem to be confirmed in human
beings.34 A possibly dialyzable compound or compounds in the azotemic rats may be responsible
for the impaired absorption.33 Anions found in
uremic sera may impair folate transport across
membranes.35
In patients with advanced CKD (such as stages 4
and 5 before dialysis), the metabolism of folic acid
appears to be altered, although the cause and timing of the alteration is not well defined. Hannisdal
et al.36 compared the serum concentrations of
folate and folic acid metabolites between healthy
volunteers and nondialyzed patients with stages
3-5 CKD. Folate metabolites were analyzed by liquid chromatography–tandem mass spectrometry.
The samples from patients with CKD had 22 to
30 times higher concentrations of folate metabolites than in sera from healthy volunteers. These
elevated serum metabolite levels may reflect
impaired excretion rather than altered metabolism
of folic acid.
The optimal or safe daily intake for folate for
patients with CKD before dialysis is unknown.
Considering that there is currently no evidence
for impaired folate activity or metabolism for nondialyzed people with stages 3-5 CKD, the daily
intake for these individuals may be similar to that
of people who do not have CKD.
Cyanocobalamin––B-12
Action
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
converts L-methylmalonyl-coA to succinyl-coA.8
B12 has the following two metabolically active
forms: (1) coenzyme 12 and (2) methylcobalamin.
B12 is unique in its process for absorption in
which it requires an intrinsic factor for absorption
by the brush border of the ileum.5 The DRI for
B12 is 2.4 mg/day for both men and women
aged $51 years.17
Food Sources
The following food sources are naturally rich in
B12: liver, beef, chicken, eggs, trout, and salmon.
Fortified foods, such as breakfast cereal, are also
a good source of B12.18
Evidence for Altered Requirements
In healthy adults, there is a 3- to 6-year body
supply of B12.8 Therefore, if a healthy person consumed insufficient quantities of B12 for a short
period (,3 years), they would not have insufficient B12 levels. However, there are no data on
the body storage amounts in patients with CKD.
A paucity of data has suggested that patients with
CKD receiving hemodialysis respond favorably
and quickly when supplemented with B12, even
when the plasma values indicate normal ranges.37
This may be related to the fact that plasma B12 is
not a sensitive indicator of B12 status. Methylmalonic acid and homocysteine are more sensitive
indicators of B12 status. Additionally, B12 is found
in high protein foods. Thus, patients who consume low amounts or remain on very lowprotein diets for extended period, for example
.3 years, with no B12 supplementation, may
have insufficient B12 levels. Currently, the data
VITAMINS IN CHRONIC KIDNEY DISEASE
on B12 are limited and what is available does not
indicate that patients with CKD are routinely
deficient. However, it is prudent to have patients
on low (0.6 g/day) or very low (0.3 g/day) protein
diets receive a supplement with the DRI for B12.
Homocysteine
Serum total homocysteine appears to be increased to approximately 1.5 to 2 times the upper
limit of normal in most of the patients with stage
5 CKD.38 This is of particular concern because in
the general population elevated serum homocysteine concentrations are associated with an increased incidence of adverse cardiovascular events
and mortality.39This relationship is less clear in
patients with CKD, because hyperhomocysteinemia has been associated with both increased and reduced mortality in these individuals,40,41 probably
because of the interaction of serum homocysteine
levels with protein–energy wasting. Several
clinical trials have tested treatment of the patients
with stages 4 and 5 CKD with large doses of folic
acid, pyridoxine HCl, and often vitamin B6 to
reduce elevated plasma homocysteine levels. A
post hoc analysis of the Modification of Diet in
Renal Disease Study indicates that serum
homocysteine is increased in many patients with
both stages 3 and 4 CKD and that the elevated
serum levels appear to be influenced by the intake
and blood levels of serum folate, vitamin B12,
and possibly vitamin B6, and also by the GFR
level. This analysis indicated that prescription of
a daily multivitamin that provided 1 mg folic
acid, 10 mg pyridoxine HCl, and 6 mg vitamin
B12, which, essentially doubled the estimated
daily folate and vitamin B12 intake, was
associated with a 7% to 10% decrease in serum
homocysteine concentrations.39
Conversely, Nanayakkarra et al.42 conducted
a secondary analysis of a randomized clinical trial
in patients with stages 2-4 CKD who were not
taking a vitamin supplement. The researchers
used a step-wise intervention with pravastatin
40 mg/day, at baseline; vitamin E 300 mg/day, initiated after 6 months; and finally, the B vitamins
pyridoxine HCl 100 mg/day, folic acid 5 mg/day,
and B12 1 mg/day after another 6 months.
The primary outcome of this study was asymmetric dimethylarginine, which inhibits the
endothelium-dependent nitric oxide-mediated
response. Increased asymmetric dimethylarginine
361
is associated with greater cardiovascular risk.43 At
the conclusion of this trial, there was no difference
between the treatment group and the control
group with regard to serum asymmetric dimethylarginine levels. The serum homocysteine concentrations were not reported; however, when the
asymmetric dimethylarginine results were stratified by baseline homocysteine, a significant
decrease in serum asymmetric dimethylarginine
was observed in the patients in the highest stratum
of serum homocysteine as compared with the individuals receiving placebo. Mann et al.44 also found
that lowering serum homocysteine with folic acid,
B6, and B12 in patients with CKD did not reduce
cardiovascular risk.
Another marker that has received attention in
cardiovascular disease and homocysteine is
S-adenosylhomocysteine (SAH). This molecule is
the result of the conversion of S-adenosylmethionine, a universal donor for a large variety of acceptor compounds, into SAH via transmethylation. In
a study with CKD patients and healthy controls by
Valli et al.,45 SAH was significantly elevated in
patients with cardiovascular disease compared
with those without (683 [201 to 3,057 nmol/L] vs.
485 [259 to 2,620 nmol/L, median [range], P ,
.001). Furthermore, in a multinomial logistic
regression analysis, SAH was a significant predictor
of cardiovascular disease (r2 5 0.31).
Perhaps the largest clinical trial with the longest
follow-up concerning vitamins to lower homocysteine (Hcy) concentrations and improve clinical
outcome was the Homocysteinemia in Kidney
and End Stage Renal Disease (HOST) study.
This was a randomized, double-blind, placebocontrolled trial conducted in 2,056 Veterans Administration patients with stages 4 and 5 CKD
who were either nondialyzed (n 5 1,305) or
were on maintenance hemodialysis (n 5 751).23
All patients were hyperhomocysteinemic (Hcy,
.15 umol/L), and they were randomized to receive daily treatment with 40 mg folic acid, 100
mg pyridoxine HCl, and 2 mg vitamin B12, or
with placebo. Patients were treated for a mean of
4.5 years. Serum homocysteine levels decreased
by 25.8% in the vitamin group (P ,.001) as compared with the placebo group38; however, there
were no significant differences between the treatment group and the control group with regard to
mortality, myocardial infarction, or amputations.
In a recently published study, patients with 238
diabetic nephropathy and nephrotic syndrome,
362
STEIBER AND KOPPLE
stage 3 or earlier, were randomized to treatment
with either placebo or a combination of folic
acid 2.5 mg/day, pyridoxine HCl 25 mg/day,
and vitamin B12 1 mg/day, for a mean of 31.9
months.46 Patients randomized to vitamin treatment had a significantly faster reduction in GFR
(216.5 6 1.7, mean change at 36 months) compared with patients receiving placebo (210.7 6
1.7, P 5 .045). The patients taking the vitamins
were significantly more likely to have a myocardial
infarction, stroke, revascularization, or all-cause
mortality.46
Thus, there currently does not seem to be any
clinical advantage to the routine use of megavitamin therapy to lower the moderately elevated
serum homocysteine levels in typical patients
with CKD. It should be noted that genetic causes
of severe hyperhomocysteinemia occur uncommonly and can be associated with ESRD. Patients
with this condition are at increased risk for serious
thromboembolic events, which can involve the
major renal blood vessels. These individuals can
respond to large doses of pyridoxine HCl or folic
acid, depending on the genetic defect, and they
should be treated accordingly.47
Pantothenic Acid
Actions
Pantothenic acid is derived from pantothenate
and is used in the synthesis of CoA. Coenzyme
is critical for many metabolic processes such as
fatty acid oxidation, transport of proteins, and
the formation of acetyl CoA, a key molecule in
energy metabolism.8 There is inadequate information to determine an RDA for pantothenic acid;
however, the AI is set at 5 mg/day for men and
women aged .51 years.17
Food Sources
Although pantothenic acid appears to be ubiquitous in the food supply, the following foods are
rich sources: beef, poultry, whole grains, potatoes,
tomatoes, and broccoli.18
Evidence for Altered Requirements
There are currently no reports in the published
data demonstrating pantothenic acid deficiency in
patients with CKD. There are a few reports of
lower dietary intake by patients with CKD who
are on low-protein diets.34 However, in validation
studies plasma concentrations do not correlate well
with whole blood pantothenic acid levels or
dietary intake8; therefore, these findings may not
accurately reflect body stores. Given the ubiquitous nature of pantothenic acid in the general
food supply and the lack of evidence for insufficiency or deficiency in patients with CKD, at
this time intake beyond the AI is not warranted.
Vitamin C
Actions
Vitamin C, or ascorbic acid, is a hydrophilic,
6-carbon lactone that is capable of inhibiting the
oxidation of other compounds by donating a maximum of 2 electrons and, in the process, undergoes
oxidation. When 1 electron is donated, the
ascorbic acid becomes a free radical known as
semidehydroascorbic acid. After receiving a second
electron, semidehydroascorbic acid is converted to
dehydroascorbic acid. This process scavenges free
radicals in the body, after oxidation of which, the
threat of cellular damage is reduced. The DRI
for vitamin C is 75 mg/day for women and 90
mg/day for men.48
Food Sources
The following food sources are rich in vitamin
C: citrus fruits, berries, papaya, peppers, mangos,
pineapple, broccoli, cauliflower, melons, greens,
tomatoes, and tubers.18
Evidence for Altered Requirements
The causes of low vitamin intake and deficiency
have been discussed earlier in the text. Vitamin C
intake is particularly likely to be low in patients
with CKD because of the potassium restriction.
The authors are unaware of studies of vitamin C
levels or requirements in nondialyzed patients
with CKD.
Oxalate is a metabolite of ascorbic acid. Urine
oxalate and, in renal failure patients, serum oxalate
may increase when individuals ingest supplemental
ascorbic acid.5 Thus, high doses of vitamin C traditionally are not recommended for patients with
advanced CKD because of the possible increased
risk for hyperoxalosis. However, in a recent study
of people without CKD who were at increased
risk for oxalate formation, 500 mg/day of vitamin
C did not increase 24-hour urinary oxalate excretion.49 Because of these concerns, for nondialyzed
VITAMINS IN CHRONIC KIDNEY DISEASE
patients with CKD, the CARI guidelines recommend no more than 60 mg/day of vitamin C and
the ESPEN guidelines recommend supplementation with 30 to 60 mg/day of vitamin C for the
patients with CKD.31,50
Fat-soluble Vitamins
Vitamin A
Action
Vitamin A is a set of fat-soluble compounds
classified as retinoids. Human beings ingest preformed vitamin A (retinyl esters) or carotenoids,
which are vitamin A precursors. Retinyl esters
can go through conversions to form retinol (the
alcohol form of the retinoids), which can be subsequently converted to retinal (the aldehyde form)
and then to retinoic acid (the acid form). Retinal
and retinoic acid (the acid form) are required for
various reactions in the eye to support vision.
Retinoic acid also promotes embryonic development, and retinoids are necessary for normal
immune function.
The carotenoids are b-carotene, a-carotene,
and b-cryptoxanthin,51 with b-carotene being
the most common form. It can be converted to
retinol; however, it has only approximately 50%
of the activity of retinyl esters.
Vitamin A is transported in blood bound to
retinol-binding protein (RBP). RBP associates
with 2 other proteins to form a trimolecular complex, called transthyretin. The current RDA for
healthy men and women aged .51 years is 900
and 700 mg retinol activity equivalents/day,
respectively, and the upper intake level is 3,000
mg retinol activity equivalents/day.52
Food Sources
The following food sources are rich in vitamin
A: liver, fish liver oils, dairy products, butter, and
eggs. b-carotene is found in red and yellow colored fruits and vegetables such as cantaloupe, carrots, sweet potatoes, winter squash, and dark green
leafy vegetables such as spinach.18
Evidence for Altered Requirements
Serum vitamin A concentrations are often
increased in patients with advanced CKD. Potential mechanisms include decreased catabolism of
RBPs. Frey et al.53 showed that isoforms of RBP
4 (the main transporter or retinol in blood) is
363
increased in CKD, and this may partly explain
the elevated plasma concentrations in CKD
patients. The National Health and Examination
Survey III data demonstrated an association
between elevated serum creatinine and elevated
serum vitamin A concentrations54; this correlation
was consistent across ethnicities and persisted after
adjustment for confounding factors. This finding
reinforces earlier studies that described elevated
vitamin A levels in nondialyzed patients with
CKD, ESRD patients, and kidney transplant
recipients.55–57
Because serum vitamin A concentrations begin
to increase with the increase in serum creatinine,53
there would seem to be no need to provide supplemental vitamin for patients with CKD, except in
unusual conditions. This is consistent with the
current recommendations against the need for
supplemental vitamin A in CKD unless the patient
is commonly ingesting less than the RDA for vitamin A.31 In this latter circumstance, supplemental
vitamin A up to the RDA can be given.5
Vitamin E
Action
Vitamin E is a lipophilic molecule that typically
resides in cell membranes. It acts as an anti-oxidant
because it remains highly stable even after it scavenges free radicals. Vitamin E exists in 4 forms,
a-tocopherol, b-tocopherol, g-tocopherol, and
d-tocopherol; however, only a-tocopherol has
an established RDA. These forms differ by the
level of methylation. The DRI for vitamin
E (a-tocopherol) is 15 mg/day for both healthy
men and women.48
Food Sources
The following food sources are rich in vitamin
E: vegetable oils, unprocessed grains, nuts, fruits,
vegetables, and meat.18
Evidence for Altered Requirements
The role of oxidative stress as a pathologic agent
in several disease states has become increasingly
apparent, and vitamin E has concurrently been considered as a potential treatment for this condition.
Plasma vitamin E levels in patients with CKD do
not appear to be different from healthy controls,58,59
even when dietary intake of vitamin E is reduced.59
The vitamin E metabolite, carboxyethyl-
364
STEIBER AND KOPPLE
hydroxychromans (CEHC), significantly increases
in serum with declining renal function; this increase
in serum CEHC has been observed with creatinine
clearances of 45 mL/min (stage 3). Galli et al.59 suggest that the accumulation of this metabolite
(CEHC) could interfere with the functions of vitamin E in patients with uremic CKD.
The results of clinical trials evaluating the effectiveness of vitamin E for the prevention of cardiovascular disease in people with CKD have been
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
3 CKD) and increased risk for cardiovascular
events who were given 400 IU/day of vitamin E
as part of the Heart Outcomes Prevention Evaluation (HOPE) trial. Consistent with studies in
such patients who did not have CKD, there was
no cardiovascular benefit to taking this dose of
vitamin E. Moreover, the long-term use of this
dose (400 IU/day or 363 mg/day) of supplemental
vitamin E in individuals with or without CKD
who were at high risk for adverse cardiovascular
events in the HOPE trial resulted in an increased
incidence of heart failure, heart failure-related hospitalizations, and all-cause mortality (hazard ratio,
1.13; 95% confidence intervals, 1.01 to 1.26,
P 5 .4).38,39 This increased risk was associated
with vitamin E intakes as low as 150 IU/day (136
mg/day).61,62
These studies, taken together, suggest that
among people at high risk for cardiovascular
events, supplemental vitamin E may not be indicated in the general population or in nondialysis
CKD patients. At present, we recommend that
nondialyzed patients with stages 2-5 CKD
receive the normal DRI for vitamin E of 15
IU/day.
Vitamin K
Action
Vitamin K participates in the posttranslational
carboxylation of specific glutamic acid (Gla) residues in proteins (such as blood clotting proteins
and osteocalcin), enabling the protein to bind to
calcium and interact with other compounds.
This is a necessary step for such processes involving
calcium interactions as blood clotting and bone
mineralization. The dietary form of vitamin K is
phylloquinone, which is absorbed in the jejunum
and ileum and is primarily stored in the liver.
Bacteria in the gut also produce vitamin K in the
form of menaquinones which are absorbed from
the distal bowel and stored in the liver. If vitamin
K deficiency occurs, body proteins may be undercarboxylated. Carboxylation status of proteins,
such as osteocalcin, can be measured and used to
diagnose vitamin K deficiency. The normal AI
for vitamin K is 90 mg/day for women and 120
mg/day for men.52
Food Sources
The following food sources are rich in vitamin
K: green vegetables, cabbage, and plant oils.18
Evidence for Deficiency
Till date, there is little evidence that the reference intake for patients with CKD differs from
the DRI for normal individuals. However,
a decrease in dietary intake of vitamin K (phylloquinones), and/or a reduction in vitamin K production by gut bacteria can lower vitamin K
levels. Antibiotics that suppress gut flora, and
hence bacterial production of vitamin K, may
increase the risk of vitamin K deficiency and
impaired blood clotting. This is especially likely
to happen if the patient is also not eating or taking vitamin supplements and therefore has a low
vitamin K intake. In one study of hospitalized
patients with extended prothrombin times, onethird of the patients had CKD and were not
receiving dialysis.63
A recent study in 172 patients with stages 3-5
CKD found that depending on the vitamin K
indicator used, 6% to 97% of patients were
vitamin K deficient. When serum phylloquinone
was used as a measure, 6% deficiency was found
in this population. However, when the more
accurate maker, percent under carboxylated osteocalcin, was measured 60% of the patients were
found to be deficient in vitamin K. Finally, when
Proteins Induced by Vitamin k Absence-II
(PIVKA-II), a less used but a potentially very accurate marker was measured, 97% of the patients
were found to be deficient.64
These considerations suggest that men and
women with CKD should ingest a minimum of
90 mg/day and 120 mg/day of vitamin K, respectively. When such individuals receive oral or
parenteral antibiotics that may suppress
VITAMINS IN CHRONIC KIDNEY DISEASE
gastrointestinal bacteria for extended period, they
may be considered for vitamin K supplements;
this is particularly the case if they have prolonged
prothrombin times.
Vitamin D
Action
Vitamin D is found as 25-hydroxycholecalciferol or 1,25-dihydroxycholecalciferol (calcitriol)
in the body. Vitamin D is important in bone formation, immune function, vascular and nervous
systems, and reproduction.65
Food Sources
Cholecalciferol or D3 is formed in the skin
through sunlight exposure or is absorbed from ingested foods which are high in the vitamin;
whereas ergocalciferol or D2 is synthetically manufactured from yeast. The amount of sun exposure
needed for an individual to reach their daily
requirement of D3 varies by the amount of melanin in the skin, whether sun screen is used, the season of the year, and their location in relationship to
the equator. Foods containing high amounts of
vitamin D are often high in fat because vitamin
D is a fat-soluble vitamin. Thus, vitamin D in fortified milk may be better absorbed in milk with fat,
such as $1%, verses skim milk which contains little to no fat. Other foods high in vitamin D are
fatty fish, such as salmon or sardines, and eggs.18
Evidence for Altered Requirements
The use of 1,25-dihydroxycholecalciferol
(calcitriol) and its analogues for people with
CKD has been scientifically investigated and discussed extensively,66–68 however; space does not
allow us to review this important subject.
Emerging evidence, not yet definitive, also
indicates that supplemental calcitriol precursors,
such as ergocalciferol or cholecalciferol, may
benefit patients with CKD.69 Because of the new
and nondefinitive nature of the evidence regarding
the nutritional needs for these latter compounds,
they will be discussed in more detail.
Recent studies show that low serum 25-hydroxycholecalciferol levels are associated with adverse
outcomes in CKD and incident MD patients.70,71
Mehrotra et al.72 found that patients with CKD,
regardless of CKD stage or underlying cardiovascular disease, who had serum 25-hydroxycholecal-
365
ciferol levels ,15 ng/mL, were at increased risk of
all-cause mortality (hazard ratio, 1.56 [95% confidence intervals, 1.12 to 2.18]). Furthermore, low
serum 25-hydroxycholecalciferol levels or deficient intake is associated with increased risk of cardiovascular disease, cancer, and mortality in the
general population.73,74 It has been suggested
that serum 25-hydroxycholecalciferol levels of
,15 ng/mL indicate deficiency, serum levels of
15 to 30 ng/mL indicate insufficiency, and levels
.30 ng/mL are adequate.
The fact that extra-renal 1-alpha-hydroxylase is
widely distributed may help to explain the potential positive benefits of ergocalciferol and cholecalciferol.75 Receptors for these latter compounds
and for calcitriol are widely distributed in various
cell types, which is consistent with the findings
that the benefits of vitamin D extend far beyond
bone health. Cell receptors for 25-hydroxycholecalciferol are also widely distributed, which may
provide further support that this latter compound
has beneficial effects that are independent from
calcitriol.69,72
The accumulating evidence indicating benefits
to the importance of nutritional vitamin D was reflected in the recent Kidney Disease: Improving
Global Outcomes (KDIGO) recommendations
for bone and mineral metabolism, which suggest
serially measuring serum 25-hydroxycholecalciferol levels in stages 3-5 CKD; if serum levels are
low, supplements of this compound should be
given.76
Clinically, it may be suggested that patients
with stages 3-5 CKD should be routinely prescribed cholecalciferol or ergocalciferol without
ascertaining whether serum levels are decreased.77 The rational for this is that (1) a high
prevalence of deficient serum 25-hydroxycholecalciferol levels in patients with CKD, (2) the
expensive costs of routinely measuring serum
25-hydroxycholecalciferol, and (3) the safety of
taking this compound. This proposal may be particularly relevant because patients with CKD
might develop low serum 25-hydroxycholecalciferol levels some months after a normal serum
value is obtained.
Against this suggestion, a recent meta-analysis
by Palmer et al. reported that, ‘‘vitamin D is of
unproven efficacy in CKD except for its effects
on some biochemical indexes.’’78 This metaanalysis has been criticized for combining the results of many discordant studies into single sets of
366
STEIBER AND KOPPLE
analyses.79 However, there is a consensus that
more randomized controlled clinical trials are necessary before definitive answers will be available
concerning vitamin D supplementation.69,76,78,79
Despite the accumulating evidence for the
potential benefits of taking cholecalciferol or ergocalciferol, most renal vitamin preparations do not
contain vitamin D. If vitamin D is to be prescribed,
there is no consensus as to the compound and the
dose that should be used. Holick et al. have
recently reported that in otherwise normal vitamin D deficient individuals, 1,000 IU/day of
ergocalciferol resulted in the same serum
25-hydroxycholecalciferol levels as did 1,000
IU/day of cholecalciferol.80
Some multivitamins provide approximately 400
IU of vitamin D for a daily dose; however, that dose
is not evidence-based, it is possible that closer to
800 IU to 1,000 IU of cholecalciferol or ergocalciferol /d may be a more adequate dosage for many
patients with CKD, perhaps particularly for those
aged .60 years. Although 50,000 IU of ergocalciferol, given once a month, has been recommended
for these patients, some data suggest that this dose
of vitamin D may not be converted to adequate
amounts of 25-hydroxyvitamin D in all CKD
patients.81 This concern should be added to the
consideration that this once-monthly dosage of
vitamin D is decidedly unphysiological.
Until more evidence is available, given the high
prevalence of low serum 25-hydroxycholecaliferol
levels in patients with CKD, the epidemiological
association of low serum levels with adverse outcomes, and the apparent safety of a cholecalciferol
supplement of 800 to 1,000 IU per day, it could be
argued that a routine supplement of this dose of
the vitamin is clinically indicated for these individuals. At present, there is no clear evidence that
equivalent doses of ergocalciferol are not equally
safe and effective.
Conclusion
In conclusion, knowledge of vitamin and trace
element needs for patients with CKD remains
incomplete. The data reviewed in this article suggest that it is not unlikely that patients with stages
3-5 CKD may be at risk for deficiency of vitamins.
The risk of excess and toxicity and toxicity of some
vitamins also exists. Much research will be necessary before the nutritional needs for these essential
nutrients in CKD are well defined.
Acknowledgment
The authors thank Drs. Laura Byham-Gray, Dr. Nilesh
Mhaskar, and Grissim Connery for their helpful thoughts.
Dr. Steiber and Dr. Kopple contributed to the content and
writing of the article.
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