REVIEW

Vitamin Status and Needs for People

with Stages 3-5 Chronic Kidney Disease
Alison L. Steiber, PhD,* and Joel D. Kopple, MD†‡

Patients with chronic kidney disease (CKD) often experience a decline in their nutrient intake starting at early stages
of CKD. This reduction in intake can affect both energy-producing nutrients, such as carbohydrates, proteins, and
fats, as well as vitamins, minerals, and trace elements. Knowledge of the burden and bioactivity of vitamins and their
effect on the health of the patients with CKD is very incomplete. However, without sufficient data, the use of nutri-
tional supplements to prevent inadequate intake may result in either excessive or insufficient intake of micronutrients
for people with CKD. The purpose of this article is to briefly summarize the current knowledge regarding vitamin
requirements for people with stages 3, 4, or 5 CKD who are not receiving dialysis.
Ó 2011 by the National Kidney Foundation, Inc. All rights reserved.

Overview generally address nutritional contributions from

M EASURES OF PROTEIN–ENERGY
wasting are strongly correlated with mortal-
ity 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 inde-
pendent 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 Harbor-
UCLA 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, Depart-
ment of Nutrition, Case Western Reserve University School of Med-
icine, Cleveland, OH 44106. E-mail: Alison.steiber@case.edu
Ó 2011 by the National Kidney Foundation, Inc. All rights
reserved.
1051-2276/$36.00
doi:10.1053/j.jrn.2010.12.004
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 nutri-
tional 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 prescrip-
tion 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 Sea-
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
biochemical values of these compounds––usually
of vitamins.7
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
ommended amount of a specific nutrient which is
and those on dialysis,10,11 is unclear. Data from
considered to support health is referred to as the
the National Health and Examination Survey8,9
dietary reference intake (DRI).16
and the Modification of Diet in Renal Disease
Study10 show that the daily ingestion of nutrients Hence, the DRIs can be standards by which the
begins to decline in as early as stage 3 CKD.11–13 adequacy of nutrient intake could be assessed.
This reduction in intake may affect energy They allow clinicians to compare the quantity of
producing nutrients (carbohydrates, protein, and a given nutrient in a patient’s diet with an estab-
lished standard. The DRIs for nutrients are gener-
fat), macrominerals, vitamins, and trace elements.
ally determined by considering several other
The Dialysis Outcome Practice Patterns Study
reported that patients on maintenance established standards regarding nutrient intake.
hemodialysis taking water-soluble vitamin supple- These include the estimated average requirement
ments had a 16% lower mortality than similar (EAR) for the nutrient, the recommended daily
patients not taking such preparations.14 This latter allowance (RDA), and the adequate intake (AI)
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 RDA is 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-
mine these values for some nutrients. When there
vitamins.15 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
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 mor-
bid 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 pop-
ulation 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 reac-
tions. These include the conversion of pyruvate
to acetyl coenzyme A (CoA) in the pyruvate
dehydrogenase complex, the conversion of a-ke-
toglutarate 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 nicotin-
amide 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 coef-
ficients, 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 some-
what 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 in-
creased 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 thi-
amin.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 sup-
plement 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 phosphory-
lated by adenosine triphosphate, riboflavin is con-
verted 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
358 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, monooxyge-
nases, dehydrogenases, oxidoreductases, and elec-
tron transferases. This wide range of enzyme
activities is based on the fact that the molecules
can transition well between oxidized, single elec-
tron 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 ribofla-
vin: 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 ele-
vated a-EGR, thus indicating riboflavin defi-
ciency. 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 rec-
ommended riboflavin supplements for patients
with CKD, especially when they ingest very low-
protein 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 sour-
ces or nicotinic acid from plant sources. Niacin
becomes active in human beings when it is con-
verted to either nicotinamide adenine dinucleotide
or nicotinamide adenine dinucleotide phosphate.
These molecules are necessary cofactors for many
oxidation–reduction reactions. A few notable pro-
cesses 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 tryp-
tophan 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 de-
ficiency 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 discov-
ered. The niacin metabolite, nicotinamide, has
been successfully used to reduce serum phospho-
rus 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 bor-
der, thereby increasing renal phosphorus excretion
in urine and feces. At present, the authors are
unaware of published studies on the effects of nia-
cin 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 subopti-
mal 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 aminotransfer-
ases, 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 bio-
chemical assessments of pyridoxine status on
patients with different stages of CKD. In a cross-
sectional analysis, the amount of vitamin B6 con-
sumed 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 measure-
ments 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 con-
trol 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 syn-
drome 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 de-
velop B6 deficiency. This is especially likely to occur
in patients with CKD, because their vitamin B6 in-
take is often low, they may have increased dietary
needs for B6,5 and it is likely that they may be pre-
scribed 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 concen-
trations of vitamin B6 and therefore should be sup-
plemented 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
360 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 ad-
dition 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 impor-
tant 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, partic-
ularly in people with low folate intakes, include bar-
biturates, primidone, cycloserine, pyrimethamine,
diphenylhydantoin, triamterene, methotrexate, tri-
methoprim, mysoline, pentamidine, salicylazosul-
fapyridine, 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 com-
pounds 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 tim-
ing 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 liq-
uid chromatography–tandem mass spectrometry.
The samples from patients with CKD had 22 to
30 times higher concentrations of folate metabo-
lites 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 non-
dialyzed 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 homo-
cysteine 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 con-
sumed insufficient quantities of B12 for a short
period (,3 years), they would not have insuffi-
cient 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. Methylma-
lonic acid and homocysteine are more sensitive
indicators of B12 status. Additionally, B12 is found
in high protein foods. Thus, patients who con-
sume low amounts or remain on very low-
protein 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 in-
creased 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 homocys-
teine concentrations are associated with an in-
creased incidence of adverse cardiovascular events
and mortality.39This relationship is less clear in
patients with CKD, because hyperhomocysteine-
mia has been associated with both increased and re-
duced 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, ini-
tiated 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 asymmet-
ric 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 dimethy-
larginine levels. The serum homocysteine concen-
trations were not reported; however, when the
asymmetric dimethylarginine results were strati-
fied 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 indi-
viduals 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-adenosylmethio-
nine, a universal donor for a large variety of accep-
tor 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 homocys-
teine (Hcy) concentrations and improve clinical
outcome was the Homocysteinemia in Kidney
and End Stage Renal Disease (HOST) study.
This was a randomized, double-blind, placebo-
controlled trial conducted in 2,056 Veterans Ad-
ministration 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 re-
ceive 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 com-
pared with the placebo group38; however, there
were no significant differences between the treat-
ment 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 treat-
ment had a significantly faster reduction in GFR
(216.5 6 1.7, mean change at 36 months) com-
pared 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 megavita-
min 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 uncom-
monly 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 informa-
tion 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 ubiq-
uitous 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 ubiqui-
tous nature of pantothenic acid in the general
food supply and the lack of evidence for insuffi-
ciency 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 max-
imum 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 tra-
ditionally 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 excre-
tion.49 Because of these concerns, for nondialyzed
 VITAMINS IN CHRONIC KIDNEY DISEASE
patients with CKD, the CARI guidelines recom-
mend no more than 60 mg/day of vitamin C and
the ESPEN guidelines recommend supplementa-
tion 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 pre-
formed 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 sub-
sequently 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 develop-
ment, 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 com-
plex, 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 col-
ored fruits and vegetables such as cantaloupe, car-
rots, 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. Poten-
tial 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 supple-
mental 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 vita-
min 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 scav-
enges 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 con-
sidered 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 sug-
gest that the accumulation of this metabolite
(CEHC) could interfere with the functions of vita-
min E in patients with uremic CKD.
The results of clinical trials evaluating the effec-
tiveness of vitamin E for the prevention of cardio-
vascular 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 Evalu-
ation (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 hos-
pitalizations, 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 indi-
cated 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) resi-
dues 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 under-
carboxylated. 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 refer-
ence intake for patients with CKD differs from
the DRI for normal individuals. However,
a decrease in dietary intake of vitamin K (phyllo-
quinones), and/or a reduction in vitamin K pro-
duction 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 tak-
ing vitamin supplements and therefore has a low
vitamin K intake. In one study of hospitalized
patients with extended prothrombin times, one-
third 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 osteo-
calcin, 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 accu-
rate 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, respec-
tively. 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-hydroxycholecalci-
ferol or 1,25-dihydroxycholecalciferol (calcitriol)
in the body. Vitamin D is important in bone for-
mation, 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 in-
gested foods which are high in the vitamin;
whereas ergocalciferol or D2 is synthetically man-
ufactured from yeast. The amount of sun exposure
needed for an individual to reach their daily
requirement of D3 varies by the amount of mela-
nin in the skin, whether sun screen is used, the sea-
son 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 for-
tified milk may be better absorbed in milk with fat,
such as $1%, verses skim milk which contains lit-
tle 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 dis-
cussed 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-hydrox-
ycholecalciferol 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 cardiovas-
cular 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% confi-
dence intervals, 1.12 to 2.18]). Furthermore, low
serum 25-hydroxycholecalciferol levels or defi-
cient intake is associated with increased risk of car-
diovascular 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 poten-
tial positive benefits of ergocalciferol and cholecal-
ciferol.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-hydroxychole-
calciferol 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 re-
flected in the recent Kidney Disease: Improving
Global Outcomes (KDIGO) recommendations
for bone and mineral metabolism, which suggest
serially measuring serum 25-hydroxycholecalci-
ferol 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 pre-
scribed cholecalciferol or ergocalciferol without
ascertaining whether serum levels are de-
creased.77 The rational for this is that (1) a high
prevalence of deficient serum 25-hydroxychole-
calciferol 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 par-
ticularly relevant because patients with CKD
might develop low serum 25-hydroxycholecalci-
ferol 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 meta-
analysis has been criticized for combining the re-
sults 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 nec-
essary 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 ergo-
calciferol, 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 vita-
min 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 ergocalci-
ferol /d may be a more adequate dosage for many
patients with CKD, perhaps particularly for those
aged .60 years. Although 50,000 IU of ergocalci-
ferol, 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 out-
comes, 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 individ-
uals. 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 sug-
gest 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 neces-
sary 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.
References
1. Kovesdy CP, Kalantar-Zadeh K: Why is protein-energy
wasting associated with mortality in chronic kidney disease?
Semin Nephrol 29:3-14, 2009
2. Kalantar-Zadeh K, Abbott KC, Salahudeen AK, et al:
Survival advantages of obesity in dialysis patients. Am J Clin
Nutr 81:543-554, 2005
3. Kalantar-Zadeh K, Kopple JD, Kilpatrick RD, et al: Associ-
ation of morbid obesity and weight change over time with cardio-
vascular survival in hemodialysis population. Am J Kidney Dis 46:
489-500, 2005
4. Kovesdy CP, Anderson JE, Kalantar-Zadeh K: Paradoxical
association between body mass index and mortality in men with
CKD not yet on dialysis. Am J Kidney Dis 49:581-591, 2007
5. Kopple JD, Massry SG: Kopple and Massry’s Nutritional
Management of Renal Disease, 2nd ed. Philadelphia, PA: Lippin-
cott Williams & Wilkins, 2004
6. Frank T, Czeche K, Bitsch R, et al: Assessment of thiamin
status in chronic renal failure patients, transplant recipients and
hemodialysis patients receiving a multivitamin supplementation.
Int J Vitam Nutr Res 70:159-166, 2000
7. Piper CM: Very-low-protein diets in chronic renal failure:
nutrient content and guidelines for supplementation. J Am Diet
Assoc 85:1344-1346, 1985
8. Institute of Medicine: For Thiamin, Riboflavin, Niacin,
Vitamin B6, Folate, B12, Pantothenic Acid, Biotin/Choline.
Washington, DC: National Academy Press, 2000
9. Rucker D, Allan JA, Fick GH, et al: Vitamin D insufficiency
in a population of healthy western Canadians. CMAJ 166:
1517-1524, 2002
10. Kopple JD, Greene T, Chumlea WC, et al: Relationship
between nutritional status and the glomerular filtration rate:
results from the MDRD study. Kidney Int 57:1688-1703, 2000
11. Eustace JA, Astor B, Muntner PM, et al: Prevalence of
acidosis and inflammation and their association with low serum
albumin in chronic kidney disease. Kidney Int 65:1031-1040,
2004
12. Weiner DE, Tighiouart H, Elsayed EF, et al: The relation-
ship between nontraditional risk factors and outcomes in individ-
uals with stage 3 to 4 CKD. Am J Kidney Dis 51:212-223, 2008
13. Kovesdy CP, Anderson JE, Kalantar-Zadeh K: Association
of serum bicarbonate levels with mortality in patients with non-
dialysis-dependent CKD. Nephrol Dial Transplant 24:1232-1237,
2009
14. Andreucci VE, Fissell RB, Bragg-Gresham JL, et al: Dial-
ysis Outcomes and Practice Patterns Study (DOPPS) data on
medications in hemodialysis patients. Am J Kidney Dis 44(5 Suppl
2):61-67, 2004
15. Qato DM, Alexander GC, Conti RM, et al: Use of pre-
scription and over-the-counter medications and dietary supple-
ments among older adults in the United States. JAMA 300:
2867-2878, 2008
16. Institute of Medicine (U.S.), Panel on Dietary Reference
Intakes for Electrolytes and Water: DRI, Dietary Reference
 VITAMINS IN CHRONIC KIDNEY DISEASE
Intakes for Water, Potassium, Sodium, Chloride, and Sulfate.
Washington, DC: National Academies Press, 2005
17. Institute of Medicine (U.S.), Standing Committee on the
Scientific Evaluation of Dietary Reference Intakes and its Panel
on Folate, Other B Vitamins and Choline, and Subcommittee
on Upper Reference Levels of Nutrients: Dietary Reference
Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate,
Vitamin B12, Pantothenic Acid, Biotin, and Choline.
Washington, DC: National Academy Press, 1998
18. Combs G: The Vitamins: Fundamental Aspects in Nutri-
tion and Health. San Diego, CA: Academic Press, 1998
19. Weber W, Kewitz H: Determination of thiamine in human
plasma and its pharmacokinetics. Eur J Clin Pharmacol 28:
213-219, 1985
20. Porrini M, Simonetti P, Ciappellano S, et al: Thiamin,
riboflavin and pyridoxine status in chronic renal insufficiency.
Int J Vitam Nutr Res 59:304-308, 1989
21. Seal AJ, Creeke PI, Dibari F, et al: Low and deficient niacin
status and pellagra are endemic in postwar Angola. Am J Clin Nutr
85:218-224, 2007
22. Zimmerer JL, Leon JB, Covinsky KE, et al: Diet monotony
as a correlate of poor nutritional intake among hemodialysis
patients. J Ren Nutr 13:72-77, 2003
23. Takahashi Y, Tanaka A, Nakamura T, et al: Nicotinamide
suppresses hyperphosphatemia in hemodialysis patients. Kidney
Int 65:1099-1104, 2004
24. Cheng SC, Young DO, Huang Y, et al: A randomized,
double-blind, placebo-controlled trial of niacinamide for reduc-
tion of phosphorus in hemodialysis patients. Clin J Am Soc Neph-
rol 3:1131-1138, 2008
25. Laroche M, Boyer JF: Phosphate diabetes, tubular phos-
phate reabsorption and phosphatonins. Joint Bone Spine 72:
376-381, 2005
26. Berns JS: Niacin and related compounds for treating hyper-
phosphatemia in dialysis patients. Semin Dial 21:203-205, 2008
27. Feig DI: Uric acid and hypertension in adolescents. Semin
Nephrol 25:32-38, 2005
28. Kopple JD, Mercurio K, Blumenkrantz MJ, et al: Daily
requirement for pyridoxine supplements in chronic renal failure.
Kidney Int 19:694-704, 1981
29. Podda GM, Lussana F, Moroni G, et al: Abnormalities of
homocysteine and B vitamins in the nephrotic syndrome. Thromb
Res 120:647-652, 2007
30. Pollock C, McMahon L: The CARI guidelines. Biochem-
ical and haematological targets guidelines. Haemoglobin.
Nephrology (Carlton) 10(Suppl 4):S108-S115, 2005
31. Cano N, Fiaccadori E, Tesinsky P, et al: ESPEN guidelines
on enteral nutrition: adult renal failure. Clin Nutr (Edinburgh,
Scotland) 25:295-310, 2006
32. Pollock C, Voss D, Hodson E, et al: The CARI guidelines.
Nutrition and growth in kidney disease. Nephrology (Carlton)
10(Suppl 5):S177-S230
33. Said HM, Vaziri ND, Kariger RK, et al: Intestinal absorp-
tion of 5-methyltetrahydrofolate in experimental uremia. Acta
Vitaminol Enzymol 6:339-346, 1984
34. Mackenzie JC, Ford JE, Waters A, et al: Erythropoiesis in
patients undergoing regular dialysis treatment without transfusion.
Proc Eur Dial Transplant Assoc 5:172-178, 1968
35. Jennette JC, Goldman ID: Inhibition of the membrane
transport of folates by anions retained in uremia. J Lab Clin
Med 86:834-843, 1975
367
36. Hannisdal R, Ueland PM, Svardal A: Liquid
chromatography-tandem mass spectrometry analysis of folate and
folate catabolites in human serum. Clin Chem 55:1147-1154,
2009
37. Bastow MD, Woods HF, Walls J: Persistent anemia associ-
ated with reduced serum vitamin B12 levels in patients undergo-
ing regular hemodialysis therapy. Clin Nephrol 11:133-135, 1979
38. Jamison RL, Hartigan P, Kaufman JS, et al: Effect of homo-
cysteine lowering on mortality and vascular disease in advanced
chronic kidney disease and end-stage renal disease: a randomized
controlled trial. JAMA 298:1163-1170, 2007
39. Menon V, Wang X, Greene T, et al: Homocysteine in
chronic kidney disease: effect of low protein diet and repletion
with B vitamins. Kidney Int 67:1539-1546, 2005
40. Suliman M, Stenvinkel P, Qureshi AR, et al: The reverse
epidemiology of plasma total homocysteine as a mortality risk fac-
tor is related to the impact of wasting and inflammation. Nephrol
Dial Transplant 22:209-217, 2007
41. Mallamaci F, Zoccali C, Tripepi G, et al: Hyperhomocys-
teinemia predicts cardiovascular outcomes in hemodialysis
patients. Kidney Int 61:609-614, 2002
42. Nanayakkara PW, Kiefte-de Jong JC, ter Wee PM, et al:
Randomized placebo-controlled trial assessing a treatment strat-
egy consisting of pravastatin, vitamin E, and homocysteine lower-
ing on plasma asymmetric dimethylarginine concentration in mild
to moderate CKD. Am J Kidney Dis 53:41-50, 2009
43. Anderssohn M, Schwedhelm E, Luneburg N, et al: Asym-
metric dimethylarginine as a mediator of vascular dysfunction and
a marker of cardiovascular disease and mortality: an intriguing
interaction with diabetes mellitus. Diab Vasc Dis Res 7:
105-118, 2010
44. Mann JF, Sheridan P, McQueen MJ, et al: Homocysteine
lowering with folic acid and B vitamins in people with chronic
kidney disease—results of the renal Hope-2 study. Nephrol Dial
Transplant 23:645-653, 2008
45. Valli A, Carrero JJ, Qureshi AR, et al: Elevated serum levels
of S-adenosylhomocysteine, but not homocysteine, are associated
with cardiovascular disease in stage 5 chronic kidney disease
patients. Clin Chim Acta 395:106-110, 2008
46. House AA, Eliasziw M, Cattran DC, et al: Effect of
B-vitamin therapy on progression of diabetic nephropathy: a ran-
domized controlled trial. JAMA 303:1603-1609
47. Varga EA, Sturm AC, Misita CP, et al: Cardiology patient
pages. Homocysteine and MTHFR mutations: relation to throm-
bosis and coronary artery disease. Circulation 111:e289-e293,
2005
48. Institute of Medicine (U.S.), Panel on Dietary Antioxidants
and Related Compounds: dietary Reference Intakes for Vitamin
C, Vitamin E, Selenium, and Carotenoids: A Report of the Panel
on Dietary Antioxidants and Related Compounds, Subcommit-
tees on Upper Reference Levels of Nutrients and of Interpretation
and Use of Dietary Reference Intakes, and the Standing Commit-
tee on the Scientific Evaluation of Dietary Reference Intakes,
Food and Nutrition Board, Institute of Medicine. Washington,
DC: National Academy Press, 2000
49. Moyad MA, Combs MA, Crowley DC, et al: Vitamin C
with metabolites reduce oxalate levels compared to ascorbic
acid: a preliminary and novel clinical urologic finding. Urol
Nurs 29:95-102, 2009
50. Toigo G, Aparicio M, Attman PO, et al: Expert Working
Group report on nutrition in adult patients with renal
368 STEIBER AND KOPPLE
insufficiency (part 1 of 2). Clin Nutr (Edinburgh, Scotland) 19:
197-207, 2000
51. Intakes CoDR: Dietary Reference Intakes for Vitamin C,
Vitamin E, Selenium, and Carotenoids. Washington, DC:
National Academy Press, 2000
52. Institute of Medicine (U.S.), Panel on Micronutrients:
DRI: Dietary Reference Intakes for Vitamin A, Vitamin K,
Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese,
Molybdenum, Nickel, Silicon, Vanadium, and Zinc: A Report
of the Panel on Micronutrients and the Standing Committee on
the Scientific Evaluation of Dietary Reference Intakes, Food and
Nutrition Board, Institute of Medicine. Washington, DC:
National Academy Press, 2001
53. Frey SK, Nagl B, Henze A, et al: Isoforms of retinol bind-
ing protein 4 (RBP4) are increased in chronic diseases of the kid-
ney but not of the liver. Lipids Health Dis 7:29, 2008
54. Chen J, He J, Ogden LG, et al: Relationship of serum
antioxidant vitamins to serum creatinine in the US population.
Am J Kidney Dis 39:460-468, 2002
55. Smith FR, Goodman DS: The effects of diseases of the
liver, thyroid, and kidneys on the transport of vitamin A in human
plasma. J Clin Invest 50:2426-2436, 1971
56. Yatzidis H, Digenis P, Fountas P: Hypervitaminosis A
accompanying advanced chronic renal failure. BMJ 3:352-353,
1975
57. Kelleher J, Humphrey CS, Homer D, et al: Vitamin A and
its transport proteins in patients with chronic renal failure receiv-
ing maintenance haemodialysis and after renal transplantation.
Clin Sci (Lond) 65:619-626, 1983
58. Karamouzis I, Sarafidis PA, Karamouzis M, et al: Increase in
oxidative stress but not in antioxidant capacity with advancing
stages of chronic kidney disease. Am J Nephrol 28:397-404, 2008
59. Galli F, Buoncristiani U, Conte C, et al: Vitamin E in ure-
mia and dialysis patients. Ann N Y Acad Sci 1031:348-351, 2004
60. Mann JF, Lonn EM, Yi Q, et al: Effects of vitamin E on car-
diovascular outcomes in people with mild-to-moderate renal
insufficiency: results of the HOPE study. Kidney Int 65:
1375-1380, 2004
61. Lonn E, Bosch J, Yusuf S, et al: Effects of long-term vitamin
E supplementation on cardiovascular events and cancer: a random-
ized controlled trial. JAMA 293:1338-1347, 2005
62. Miller ER 3rd, Pastor-Barriuso R, Dalal D, et al: Meta-
analysis: high-dosage vitamin E supplementation may increase
all-cause mortality. Ann Intern Med 142:37-46, 2005
63. Alperin JB: Coagulopathy caused by vitamin K deficiency
in critically ill, hospitalized patients. JAMA 258:1916-1919, 1987
64. Holden RM, Morton AR, Garland JS, et al: Vitamins K
and D status in stages 3-5 chronic kidney disease. Clin J Am Soc
Nephrol 5:590-597, 2010
65. Bhan I, Thadhani R: Vitamin D therapy for chronic kidney
disease. Semin Nephrol 29:85-93, 2009
66. Al Aly Z, Gonzalez EA, Martin KJ, et al: Achieving
K/DOQI laboratory target values for bone and mineral metabo-
lism: an uphill battle. Am J Nephrol 24:422-426, 2004
67. Andress DL, Coyne DW, Kalantar-Zadeh K, et al: Manage-
ment of secondary hyperparathyroidism in stages 3 and 4 chronic
kidney disease. Endocr Pract 14:18-27, 2008
68. Coen G, Ballanti P, Balducci A, et al: Serum osteoprote-
gerin and renal osteodystrophy. Nephrol Dial Transplant 17:
233-238, 2002
69. Thadhani R: Is calcitriol life-protective for patients with
chronic kidney disease? J Am Soc Nephrol 20:2285-2290, 2009
70. Mailliez S, Shahapuni I, Lecaque C, et al: Vitamin D levels
and early mortality among incident hemodialysis patients. Kidney
Int 74:389. author reply, 2008.
71. Ravani P, Malberti F, Tripepi G, et al: Vitamin D levels and
patient outcome in chronic kidney disease. Kidney Int 75:88-95,
2009
72. Mehrotra R, Kermah DA, Salusky IB, et al: Chronic
kidney disease, hypo vitaminosis D, and mortality in the United
States. Kidney Int 76:977-983, 2009
73. Martins D, Wolf M, Pan D, et al: Prevalence of cardiovas-
cular risk factors and the serum levels of 25-hydroxyvitamin D
in the United States: data from the Third National Health and
Nutrition Examination Survey. Arch Intern Med 167:
1159-1165, 2007
74. Bao Y, Ng K, Wolpin BM, et al: Predicted vitamin D status
and pancreatic cancer risk in two prospective cohort studies. Br J
Cancer 102:1422-1427, 2010
75. Jean G, Terrat JC, Vanel T, et al: Evidence for persistent
vitamin D 1-alpha-hydroxylation in hemodialysis patients: evolu-
tion of serum 1,25-dihydroxycholecalciferol after 6 months of
25-hydroxycholecalciferol treatment. Nephron Clin Pract 110:
c58-c65, 2008
76. Kidney Disease, Improving Global Outcomes (KDIGO)
CKD-MBD Work Group: KDIGO clinical practice guideline
for the diagnosis, evaluation, prevention, and treatment of
Chronic Kidney Disease-Mineral and Bone Disorder (CKD-
MBD). Kidney Int Suppl 113:S1-S130, 2009
77. Holick MF: The D-lemma: to screen or not to screen for
25-hydroxyvitamin D concentrations. Clin Chem 56:729-731,
2010
78. Palmer SC, McGregor DO, Macaskill P, et al: Meta-
analysis: vitamin D compounds in chronic kidney disease. Ann
Intern Med 147:840-853, 2007
79. Thadhani R: Activated vitamin D sterols in kidney disease.
Lancet 371:542-544, 2008
80. Holick MF, Biancuzzo RM, Chen TC, et al: Vitamin D2 is
as effective as vitamin D3 in maintaining circulating concentra-
tions of 25-hydroxyvitamin D. J Clin Endocrinol Metab 93:
677-681, 2008
81. Qunibi WY, Abdellatif A, Sankar S, et al: Treatment of
vitamin D deficiency in CKD patients with ergocalciferol: are cur-
rent K/DOQI treatment guidelines adequate? Clin Nephrol 73:
276-285, 2010