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C H A P T E R

24
Vitamin Metabolism and Requirements
in Renal Disease and Renal Failure
Charles Chazot1, Joel D. Kopple2
1
NephroCare Tassin-Charcot, 69110 Sainte Foy Les Lyon, France
2
Division of Nephrology and Hypertension, Torrance, CA, USA

INTRODUCTION vitamin A content have changed from International


Units (IU) to Retinol Equivalents (RE), where 1.0 IU
Kidney diseases and kidney failure commonly alter 0.3 mg RE [2]. Carotenoids (40 carbon compounds) may
the biochemistry, metabolism and nutritional require- be biologically active and are considered to be vitamin
ments for many vitamins and enhance the risk of A precursors. Variable quantities of carotenoids are con-
abnormal vitamin function. Both deficiencies and abnor- verted to retinol; this conversion is regulated according
mally high levels of vitamins occur in patients with renal to the body vitamin A levels [3]. The allo-trans-b caro-
failure. These abnormalities are reviewed in this chapter. tene is the main bioactive carotenoid. Retinoids and
Since the last edition of this book, important data have carotenoids are fat soluble and are predominantly found
emerged such as the beneficial effect of multi-vitamins in foods derived from animals for retinyl esters and from
on the outcome of maintenance dialysis (MD) patients, vegetables for carotenoids [4]. During digestion, retinyl-
the role of vitamin K in vascular calcification, the associ- esters are hydrolyzed in the intestinal lumen by pancre-
ation of oxidant stress with cardiovascular morbidity in atic lipase. Retinol and carotenoids are incorporated into
chronic kidney disease (CKD), and the disappointing micelles and absorbed by enterocytes where b-carotene
trials on homocysteine lowering therapy. Moreover, is converted to retinol. Retinol is esterified, combined
several guidelines have been released that concern in chylomicrons and broken down into chylomicron
vitamin supplementation for MD patients. Vitamin D remnants in the lymphatic system by lipoprotein-lipase.
nutrition is reviewed elsewhere (Chapters 19, 21, 32, The hepatic cells incorporate the chylomicron remnants
33, 34, 35 and 36) and will not be addressed in this through apo-E or B receptors. A significant part (10 to
chapter. 40%) of the absorbed retinoids are oxidized or conju-
gated and excreted into bile and urine. At least 50% of
the retinoid compounds are transferred into the perisi-
nusoidal stellate cells of the liver where they are stored
STRUCTURE AND PHYSIOLOGICAL
as retinyl palmitate and other retinyl-esters. In plasma,
ROLE OF VITAMINS
retinol is largely bound to apo-retinol binding protein
(RBP 4), a 21.3 kD protein primarily synthesized in the
Vitamin A liver and adipose tissue. This equimolar complex is
The structure and biochemistry of vitamin A in bound as part of the molecule, prealbumin (also called
normal individuals have been reviewed [1]. Vitamin A transthyretin), and delivered to the target where it binds
is composed of several compounds including retinol to RBP cell-surface receptors. Retinol is incorporated
(Table 24.1) and the biologically active retinoids which into the cell, whereas apo-RBP is released and catabo-
have a common structure consisting of four isoprenoid lized by the kidney.
units (20 carbons) with five double bonds. Retinol, reti- Vitamin A is necessary for normal nocturnal vision; it
noic acid and retinal are the main bioactive retinoic plays a role in the immune response, differentiation of
compounds. Since the 1990s, the accepted units for epithelial cells and morphogenesis of solid organs

Nutritional Management of Renal Disease 351 Copyright 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/B978-0-12-391934-2.00024-2
352
TABLE 24.1 Physicochemical and Some Clinical Characteristics of Vitamins

Protein Binding Peritoneal


Vitamin Main Compound Solubility MW in Plasma HD Losses Losses Body Stores Toxicitya

A Retinol Lipid 286 Rbp None Controversialb Large Yes


Pre-albumin
E a-tocopherol Lipid 431 Lipoproteins None Small Small Possible
c c
K Phylloquinone Lipid 451 Lipoproteins Na Na Small No
(K1)

NUTRITIONAL MANAGEMENT OF RENAL DISEASE


B1 Thiamin Water 337 Albumin 13e40 Low 4e10 days No
mL/mind
B2 Riboflavin Water 376 Weak 27e52 High 2e3 months No
Albumin, IgG mL/mind
B6 Pyridoxine Water 169 Albumin 54 mL/mine or < Urinary excretion 3e4 months Yes
f
B12 Cyanocobalamin Water 1355 Transcobalamin Controversial None Years Nac
Ii
C Ascorbic Water 176 No 80e280 40e56 mg/day 3e4 months Yes
acid mg/sessiond
Folates Pteroylglutamic Water 441 No 135 mL/mine 1/3 of RDA > one year Yes
acid
Niacin Nicotinic acid nicotinamide Water 123 Weak Very low Nac 2 months Nac
Biotin Biotin Water 244 Weak 52 mL/mind Nac 5 weeks None
c d c
Pantothenic acid Pantothenic Water 219 Na 30 mL/min Na Several weeks None
acid
a
For normal individuals.
b
See Vitamin A section.
c
Not available.
d
Values obtained with low flux/low efficiency dialysis.
e
Values obtained with high flux/high efficiency dialysis.
f
Possible effect of convective forces.
VITAMIN METABOLISM AND REQUIREMENTS IN RENAL DISEASE 353
including the kidney, and it has anti-oxidant properties scale clinical trials failed to demonstrate a benefit of
[1,5]. Due to the promoting effect of 13-cis retinoic acid vitamin E for the prevention of cancer or cardiovascular
on cellular differentiation, it has been used to treat acute disease [7].
promyelocytic leukemia [6]. Large scale clinical trials
failed to demonstrate a benefit of large doses of retinol
and carotenoids for the prevention of cancer or cardio-
Vitamin K
vascular disease [7]. An increased death rate was even Vitamin K metabolism has been well reviewed
reported in patients given vitamin A supplements, [14,15]. Two classes of compounds, phylloquinone (K1)
which may be attributed to the pro-oxidant effects of and menaquinones (K2), are primarily responsible for
carotenoids [3]. The physiological effects of vitamin A vitamin K activity. Phylloquinone (Table 24.1) is found
are mediated through the retinoic acid nuclear receptor essentially in green and leafy vegetables (e.g., spinach,
(RAR) and retinoid X receptor (RXR), which belong to kale, cabbage, and broccoli) and cows milk. Menaqui-
the same nuclear receptor superfamily as the vitamin nones are of bacterial origin and are found in yogurt
D receptor. Plasma vitamin A is usually measured by but are also produced by colonic bacteria. The intestinal
high pressure liquid chromatography (HPLC) which absorption of these compounds requires biliary and
has replaced older colorimetric methods. pancreatic juices and occurs in the small bowel where
vitamin K is incorporated into chylomicrons. The impor-
tance of intestinal bacterial synthesis of vitamin K
Vitamin E
(menaquinone) as a vitamin source is still controversial.
Vitamin E is a fat soluble vitamin for which the main Its importance had been emphasized because of the
active compound is a-tocopherol (Table 24.1); there are frequent vitamin K deficiency states associated with
other naturally occurring isomers of vitamin E as well. the use of large spectrum antibiotics. However, antibi-
The main sources of vitamin E are vegetable oils, such otic therapy is not necessary for the development of
as corn, soybean, wheat germ and sunflower oil [8]. vitamin K deficiency. Moreover, certain antibiotics may
Animal products are not rich sources of vitamin E. After promote vitamin K deficiency by an independent mech-
intestinal absorption of vitamin E congeners, these anism. Antibiotics that have a N-methyl-5-thiotetrazole
compounds are transported with fat, mainly through side chain like cefamandole and cefaperazone have
the lymphatic flow, into the venous circulation [9]. In a warfarin-like effect and interfere directly with the
plasma, there is no specific carrier for a-tocopherol. It gamma-carboxylation of proteins, independently of
is carried in plasma by lipoproteins, and its plasma any suppression of intestinal flora [16]. Furthermore,
concentration is affected by the lipid content of blood. a vitamin K1 deficient state is easily induced experimen-
Assessment of the nutritional vitamin E status is diffi- tally by restricting food for a few days or weeks. This
cult. HPLC is widely used to measure serum vitamin E leads to decreased levels of plasma descarboxy-
levels [10]. The cell membrane concentration of prothrombin and reduced urinary excretion of gamma-
a-tocopherol and/or its antioxidant activity might give carboxyglutamic acid [17]. The uptake of vitamin K by
more helpful information concerning the activity and the liver depends on b-lipoproteins and the clearance
adequacy of tissue a-tocopherol levels than plasma of the chylomicron remnants including its apo-E compo-
a-tocopherol concentrations. nent. There is no specific carrier for vitamin K in plasma.
Vitamin E is the main antioxidant in biological The plasma level of phylloquinone is found to be lower
membranes, protecting phospholipid membranes from in elderly individuals, as compared to young subjects
oxidative stress. Vitamin E deficiency caused by intes- [18]. Vitamin K turnover is rapid, and the body pool is
tinal malabsorption has been reported to increase small (Table 24.1). The kidney has no major role in
hemolysis by causing membrane fragility [10]. Vitamin vitamin K metabolism. The reference method for
E is also an antiatherogenic agent. Epidemiological measuring plasma vitamin K levels is liquid chromatog-
studies have found a reduced risk of coronary heart raphy. There is a seasonal variation in fasting plasma
disease in men and women with higher intakes of vitamin K concentrations, with higher levels found at
vitamin E from foods [11,12]. The mechanism of this the end of summer.
protective effect is attributed to the decreased oxidation Vitamin K is a coenzyme for the post-translational
of LDL-cholesterol, a key step in the pathogenesis of the carboxylation of glutamate residues in several proteins
fatty streak, the first step in the development of the resulting in gamma-carboxyglutamate (Gla) residues
atheromatous plaque. On the other hand, vitamin E on these latter proteins. These latter proteins are called
may promote synthesis and secretion of selectin, an Gla-proteins, and they may be highly functional
adhesion molecule involved in the endothelial attach- (see below). The Gla-residue in protein binds to calcium.
ment of monocytes to endothelial cells, another step in In the process of forming the Gla-residue, vitamin K is
atherogenesis [13]. However, as with vitamin A, large transformed from the hydroquinone form (KH2) to the
354 NUTRITIONAL MANAGEMENT OF RENAL DISEASE

FIGURE 24.1 The vitamin K cycle from [235] with


permission. This figure is reproduced in color in the
color plate section.

epoxide form (KO), releasing the amount of energy that patients receiving warfarin therapy have greater
required to generate the carboxylation reaction (see bone density loss, but this remains controversial [23].
Figure 24.1). The epoxide form of vitamin K is then
recycled back to the hydroquinone form; thus, a rather
small quantity of vitamin K can generate a much larger
Vitamin B1 (Thiamin)
amount of the Gla proteins. Indeed, the urinary excre-
tion of Gla residues is 200e500 times greater than the It has been stated that the syndrome of beriberi has
dietary intake of vitamin K. The currently known Gla- been recognized for over 4000 years [24]. In 1911, an anti-
proteins are found in the coagulation cascade, in bone beriberi principle was discovered in rice bran extracts,
and dentin, in microsomes of tubular cells [19] and in and in 1934 the structure of thiamin was identified.
atherogenic plaques. The importance of vitamin K for Vitamin B1 or thiamin (Table 24.1) is a compound
the normal coagulation cascade is well known. In fact, formed by the condensation of pyrimidine and thiazole
the name vitamin K reflects this association (K for rings. Thiamin forms esters with phosphate, function-
Koagulation). The procoagulant factors which contain ally the most important of which are thiamin pyrophos-
Gla residues, and hence require vitamin K for their phate (TPP), monophosphate (TMP), and triphosphate
post-translational carboxylation, are prothrombin (TTP). Thiamin is rather labile and may be destroyed
(Factor II), proconvertin (Factor VII), Christmas factor by heat, high pH (above 8), oxidants and ultraviolet irra-
(Factor IX) and Stuart factor (Factor X). The anticoagula- diation. Thiamin is abundant in only a few food foods of
tion effect of coumarin derivatives is related to the animal and vegetable origin. These foods include lean
blockade of the dithiol-dependent reductases that are pork, yeast, and legumes. Because thiamin is water
necessary for the recycling of vitamin K. However, the soluble, foods cooked with water can be leached of
production of several inhibitors of coagulation is also significant amounts of thiamin. Thiamin is absorbed
vitamin K dependent, including proteins C, S and Z. from the small intestine by active and passive processes.
This is the explanation for the uncommon and paradox- In plasma, thiamin is mainly bound to albumin. Most
ical thrombotic complications of coumarin therapy, such thiamin in the body is present as thiamin pyrophos-
as skin necrosis [20]. Two Gla-proteins are present in phate. The availability or activity of thiamin is inhibited
bone: osteocalcin and matrix Gla protein (MGP). Osteo- by alcohol, thiaminases, folate deficiency and protein-
calcin is the most abundant noncollagenous protein of energy malnutrition. Catabolism of thiamin produces
bone and is a specific marker for osteoblast activity. In many metabolites that are excreted in the urine. In
vitro, osteocalcin binds to hydroxyapatite and inhibits its vivo, thiamin stores can be indirectly assessed by
formation. This action requires the vitamin K-dependent measuring the erythrocyte transketolase activity
carboxylation of the protein. Matrix Gla-protein (MGP) (ETKA), before (ETKAo) and after (ETKAs) stimulation
regulates calcium deposition in the tissues. MGP knock- by thiamin pyrophosphate [25]. The ETKA stimulation
out mice present with extensive lethal vascular index (aETKA) (i.e., the ETKA after addition of TPP X
calcifications [21]. These carboxylated-proteins in 100, divided by ETKAo) is considered to be a more sensi-
bone play a key role in bone homeostasis. Women tive indicator of thiamin deficiency. HPLC has become
with hip fractures have been found to have lower the preferred method for measuring thiamin status in
plasma vitamin K levels [22]. It has been suggested many laboratories [26]. HPLC can measure whole blood
VITAMIN METABOLISM AND REQUIREMENTS IN RENAL DISEASE 355
thiamin and RBC TPP, the active functional form of a fluorometric method and by HPLC, which has been
thiamin. used to study CKD patients [30].
Thiamin pyrophosphate (TPP), in association with
CoA, flavine adenine nucleotide (FAD) and nicotin-
amide adenine nucleotide (NAD), is a coenzyme for
Vitamin B6
the oxidative decaboxylation of a-ketoacids. TPP is Normal vitamin B6 metabolism has been reviewed
a coenzyme for many other enzymes, particularly those by Leklem [31]. Vitamin B6 is composed of three deriv-
involved with carbohydrate metabolism, including atives of the pyridine ring: pyridoxine, pyridoxal and
pyruvate dehydrogenase. This enzyme catalyzes the pyridoxamine. Some characteristics of vitamin B6 are
conversion of pyruvate to acetyl CoA. Hence, thiamin listed in Table 24.1. Phosphorylation in the 5 position
deficiency may impair lactate utilization and lead to is necessary for the biological activity of vitamin B6.
thiamin-responsive lactic acidosis [27]. As indicated Pyridoxal-5-phosphate (PLP) and pyridoxamine-5-
above, thiamin is also a coenzyme for the transketolase phosphate are the active coenzyme forms. Pyridoxine
reaction which is an integral part of the pentose phos- is mainly found in plant foods (especially wheat bran,
phate pathway. Transketolase is found abundantly in avocado, banana, lentils, walnuts, cooked soybean
myelinated structures of nervous tissues [28]. This may and potatoes), and pyridoxal and pyridoxamine are
account for the peripheral neuropathy that occurs in primarily obtained from animal products (e.g., tuna,
beriberi. Independently of its activity as a coenzyme raw chicken breast, ground beef). These compounds
for transketolase, it has been suggested that thiamin are absorbed by a nonsaturable, passive process in the
may play a role in nerve impulse transmission, by inter- jejunum. These three vitamers are phosphorylated in
acting with sodium channels [24]. the liver by pyridoxine kinase, which requires zinc
and adenosine triphosphate. PLP is derived from the
other vitamers by the action of a flavin mononucleotide
Vitamin B2 or Riboflavin
oxidase and is transported in plasma bound to albumin
Riboflavin (vitamin B2) is an alloxazine derivative and in red cells bound to hemoglobin. The major pool
with a MW of 376.4 (Table 24.1). The main active ribo- of PLP is in the skeletal muscle, where it is bound to
flavin compounds are the flavin mononucleotide glycogen phosphorylase. In liver, PLP and the other
(FMN, an alloxazine ring combined with ribitol, a sugar phosphorylated forms of vitamin B6 are dephosphory-
moiety and phosphate) and flavin adenine dinucleotide lated by alkaline phosphatase, leading first to pyridoxal
(FAD) (FMN molecule modified by the addition of an and then 4-pyridoxic acid (4-PA) by the irreversible
activated adenosine monophosphate (AMP)). Riboflavin action of a flavin adenine dinucleotide-dependent alde-
is modestly soluble in aqueous solutions, heat-stable hyde oxidase.
and photosensitive. It is present in many plant and Functional tests have been utilized to assess vitamin
animal products, such as milk, eggs, bread, cereals, B6 deficiency. Erythrocyte glutamate oxaloacetate trans-
lean meats and broccoli [29]. An active sodium and aminase (EGOT) or glutamic pyruvate transaminase
glucose-dependent absorption pathway for riboflavin (EGPT) activity is measured in the basal state (EGOTo,
occurs in the proximal jejunum and is important for EGPTo) and after stimulation by adding an excess of
the transport of small quantities of this vitamin. Large PLP. The ratio of the stimulated to basal activity is the
amounts are absorbed from the intestine by passive activation coefficient or index (a-EGOT and a-EGPT).
diffusion. Bile salts appear to facilitate intestinal absorp- If stores of the coenzyme (PLP) are adequate, the addi-
tion of riboflavin. tion of an excess of the coenzyme will have only a small
After cellular uptake, riboflavin is transformed by the effect on the apoenzyme activity, and the ratio will be
action of flavokinase and FAD synthetase to FMN and close to 1.0. If there is deficiency of PLP, the apoenzyme
FAD to form functional flavoproteins. Riboflavin metab- will be stimulated by the addition of the coenzyme, and
olites are excreted in urine. Flavoenzymes are involved the index value will be higher [31]. The nutritional status
in numerous oxidation-reduction reactions that are of vitamin B6 may also be assessed by direct measure-
necessary for many metabolic pathways including ment of total pyridoxine by microbiological tests or by
energy production. The erythrocyte glutathione reduc- measurement of the urinary metabolites of tryptophan
tase (EGR) activity without (EGRo) and with the satura- or methionine, particularly after a load of the respective
tion of this enzyme with FAD has been used to assess amino acid is given. Currently, plasma levels of PLP and
ribloflavin status [25]. The ratio of EGR with FAD  other B6 compounds are usually measured using HPLC
100 divided by EGRo indicates the EGR stimulation [31]. Several factors are associated with higher or lower
index (a-EGR). The a-EGR is a rather reproducible and plasma PLP levels. People over 65 years have lower
sensitive test, a high a-EGR indicating riboflavin plasma PLP levels than younger individuals. Females
deficiency. Riboflavin may be measured directly by have lower levels than males. One explanation for these
356 NUTRITIONAL MANAGEMENT OF RENAL DISEASE

TABLE 24.2 Medicines and Other Substances hormones through the binding of PLP to steroid
Interfering with Vitamin B6 and receptors.
Folic Acid Metabolism which May
Contribute to Vitamin Deficiency
Vitamin C
Vitamin B6 Folic Acid
Vitamin C (ascorbic acid, Table 24.1), whose defi-
Isoniazide Salicylazosulfapyridine
ciency leads to scurvy, is oxidized to dehydroascorbic
Hydralazine Ethanol acid (DHAA) which also possesses antiscorbutic
Iproniazide Diphenylhydantoin activity. Ascorbic acid is mainly found in fresh fruits
(e.g., blackcurrant, strawberry, lemon, orange, lime)
Penicillamine Metothrexate
and vegetables (e.g., broccoli, Brussels sprouts, cauli-
Oral contraceptives Pyrimethamine flower, cabbage). Ascorbic acid in food can be degraded
Cycloserine Pentamidine by heat or extracted in cooking water. Intestinal absorp-
tion of ascorbic acid is an active, energy-requiring and
Thyroxine Trimethoprim
saturable process. About 70 to 90% of the usual dietary
Theophylline Triamterene vitamin C intake is absorbed, but this fraction decreases
Caffeine Cycloserine substantially when large loads of ascorbic acid are
ingested. In plasma, vitamin C is nonprotein-bound
Ethanol Mysoline
and is present in a reduced form. Ascorbic acid enters
Primidone the cell by active transport. The average half-life of
Barbiturates ascorbic acid in normal adult humans is about 16 to 20
days. The body ascorbic acid pools are regulated by
Yeasts, beans
intestinal absorption, renal tubule reabsorption, and
the catabolism of ascorbic acid [33]. Excess ascorbic
acid is filtered at the glomerulus and excreted intact in
the urine. The catabolic rate for ascorbic acid is directly
findings could be differences in muscle mass. Plasma related to the body pool size. Ascorbic acid can be
PLP levels are inversely correlated with dietary protein oxidized to DHAA and then to a variety of compounds
intake. Tobacco smoking decreases plasma B6 levels. A including L-xylose, threonic acid and oxalic acid which
large epidemiological study in normal individuals are excreted in urine. Oxalic acid represents 5 to 10%
confirmed higher plasma vitamin B6 levels in young of the metabolites of ascorbic acid.
people as compared to the elderly, and the association The methods for assessment of ascorbic acid have
of increased serum acute phase proteins, alkaline phos- evolved from colorimetric methods, based on the reduc-
phatase activity and impaired renal function with lower tive properties of ascorbic acid, to HPLC technology
plasma B6 levels [32]. Also, many medicines interfere which is sensitive and specific [33]. The oxidized form
with the actions or metabolism of vitamin B6. Many of of ascorbic acid, the ascorbyl free radical (AFR), can be
these medicines are taken by patients with CKD (Table detected by electron paramagnetic resonance spectros-
24.2). The intake of these medicines must be considered copy. Ascorbic acid is measured in plasma, which
when evaluating studies of the dietary requirements for reflects recent dietary intake, and in leukocytes, which
vitamin B6 or when prescribing vitamin B6 intake. gives a more accurate estimate of the body pool of ascor-
PLP is a coenzyme for almost 100 enzymatic reac- bic acid. Women usually have higher plasma ascorbic
tions, and particularly for those enzymes involved acid levels than men; smokers and elderly individuals
with the metabolism of amino acids and some lipids. have lower values of plasma ascorbic acid. The function
PLP forms a Schiff base with the -amino group of of ascorbic acid is largely due to its reversible reducing
lysine in the enzyme. The Schiff base alters the charge power. For instance, ascorbic acid plays an important
of the rest of the PLP molecule and strongly increases role in metal catalysed hydroxylations by reducing the
its reactivity, particularly to other amino acids. Vitamin metal catalyst and by allowing the metaleenzyme
B6 is essential for gluconeogenesis, by facilitating complex to reconstitute after it is oxidized. Perhaps the
transamination and glycogen phosphorylation; for most well recognized activities of ascorbic acid are
niacin formation, via the PLP dependent kinureninase collagen synthesis via lysyl and prolyl hydroxylations,
which transforms tryptophan to niacin; and for normal hydroxylation of peptidyl proline, enhanced secretion
erythrocyte metabolism, by acting as coenzyme for of procollagen that contains hydroxyproline, carnitine
transaminase and influencing the O2 affinity of hemo- synthesis, hydroxylation of dopamine to form norepi-
globin. Vitamin B6 facilitates the synthesis of several nephrine and of tryptophan to form serotonin, amida-
neurotransmitters and modulates the action of certain tion of peptide hormones, intestinal iron absorption
VITAMIN METABOLISM AND REQUIREMENTS IN RENAL DISEASE 357
and antioxidant protection of folate and vitamin E. for DNA synthesis. The 5,10-methylene THF (requiring
Potential immune activities, actions on cholesterol the vitamin B12-dependent transmethylation of homo-
metabolism, and anti-cancer effects of ascorbic acid are cysteine-methionine) delivers its methyl group to deox-
still the subjects of investigation. yuridilate, which is transformed to thymidilate and is
necessary for DNA synthesis. A defect in this step in
DNA synthesis leads to megaloblastosis, which occurs
Folic Acid or Vitamin B9 in all replicating cells in the body but is most striking
Folic acid (pteroylglutamic acid) is composed of in bone marrow cells. Folic acid plays a role in amino
three subunits: a pteridine moiety, para-aminobenzoic acid metabolism, particularly for those amino acids
acid and glutamic acid (Table 24.1). Reduced forms of that are methyl donors, including the interconversion
folic acid are present both in foods and in the human of glycine and serine, the transformation of homocys-
body, usually as tetrahydrofolate (THF). Folic acid is teine to methionine (Figure 24.2), and the conversion
found in many foods and is present in large amounts of histidine to glutamic acid. Moreover, folic acid is
in polyglutamate forms, usually of tetrahydrofolates or required for purine synthesis in the methylation of
dihydrofolates, in yeast, liver, meats, green vegetables transfer RNA. Unlike vitamin B12, folate is not involved
and fruits. Very sensitive to oxidation, folate is readily in myelin synthesis, and therefore folate deficiency does
destroyed by extensive cooking and also by food pro- not cause neurological disease.
cessing such as canning or refining [34]. Intestinal
absorption occurs mainly in the proximal one-third of
Vitamin B12
the small bowel. Polyglutamates require the action of
conjugases, present in the brush border of enterocytes, Vitamin B12 or cobalamin (Table 24.1) has been iden-
to be transformed to folate monoglutamates, such as tified as the extrinsic factor (i.e., present in food),
5-methyl-THF, formyl-THF or dihydrofolates. Another which, when combined to the intrinsic factor (present
enzyme, the glutamate carboxypeptidase II anchored in gastric juice), results in the absorption of the antiper-
in the intestinal brush border, participates in polygluta- nicious anemia factor. The molecule of vitamin B12 is
mate catabolism. Devlin et al. [35] identified a H475Y constituted by a corrin nucleus, a nucleotide and a cobalt
DNA variant coding for this enzyme; low folate levels atom. Cobalamins are unstable in light and destroyed by
and hyperhomocysteinemia are associated with a 53% strong oxidation and reduction agents. Cyanocobal-
reduction of the enzyme activity. Cellular transport amin, the pharmaceutical form of vitamin B12, has
relies on specific folate membrane receptors, carriers, been isolated from liver extracts. Coenzyme B12 and
and cellular exit pumps. Folates are stored in the methylcobalamin are the metabolically active forms.
body as polyglutamates and require the action of conju- All forms of B12 in large doses are equally potent [36].
gases, which are present in many tissues, to yield the The only source of vitamin B12 is bacterial synthesis.
biologically active monoglutamate form. However, Cobalamins are present in animal tissues, mostly liver,
polyglutamates may have physiological actions them- meat and seafood, but also in lesser amounts in egg
selves. Actions of conjugases can be inhibited by yolk and milk. Very small amounts are present in fruits
various substances including medicines. Indeed, many and vegetables. Physiological intestinal absorption
medicines may inhibit the actions of folate, including follows several steps: free cobalamin is combined with
ones that are commonly prescribed for CKD patients a salivary peptide binder, then is released in small intes-
(Table 24.2). Folic acid in plasma is mainly free or tine by trypsin and is combined again with the intrinsic
loosely bound to nonspecific carriers. Delivery of folic factor, a glycoprotein molecule of gastric origin. Absorp-
acid to tissues requires a specific cell membrane tion of the vitamin B12-intrinsic factor complex occurs
receptor protein. Also, vitamin B12, which like folate is after binding to a receptor on the brush border of
involved in transmethylation reactions, is necessary mucosal cells in the ileum. However, large pharmaco-
for cellular transport and storage of folate. Excretion logical doses of cobalamins may be absorbed by the
of free folate and metabolites of folic acid occurs in small intestine via passive diffusion. Three binding
urine and bile. There is an enterohepatic cycle that proteins (transcobalamins I, II and III) participate in
helps to preserve the body pool of folates and that is cobalamin transport in plasma and also in the storage
impaired by alcohol consumption. Folate nutriture is of vitamin B12. Cobalamin stores can be comprised of
assessed mainly by measuring serum, plasma or red several milligrams of vitamin B12 and may prevent
cell folate levels with radioimmunological measure- vitamin B12 deficiency from occurring for several years
ments which are able to detect nanogram quantities of after intestinal absorption ceases [37] (Table 24.1).
5-methyl THF. Vitamin B12 is not catabolized and is excreted in bile,
The fundamental action of folate can be summarized with an efficient enterohepatic cycle. Vitamin B12 assess-
as one carbon unit transfers [34]. Folic acid is required ment is performed using microbiologic assays and
358 NUTRITIONAL MANAGEMENT OF RENAL DISEASE

FIGURE 24.2 Role of folic acid, vitamin B12 and B6 in methionine-homocysteine-cysteine metabolism.

currently by radioassays. Radioassays are not affected then nicotinic acid. However, niacin bioavailability
by antibiotic treatment. may be reduced because of its binding to carbohydrate
Vitamin B12 has a key role in folic acid metabolism. Its and peptide macromolecules. Intestinal absorption by
essential function is the demethylation of methyltetrahy- diffusion is efficient, even for large doses of niacin. Tryp-
drofolate and methylation of Hcy (Figure 24.2). This step tophan is a precursor for niacin, and tryptophan intake
is essential for regeneration of THF, which is involved in alone may be sufficient to provide the RDA for nicotinic
DNA synthesis by thymidilate synthesis, and for folate acid. Niacin is quickly removed from plasma by tissues
delivery to tissues. In the absence of demethylation, (mainly by liver and RBC) where it is converted to coen-
signs of folate deficiency may occur [36]. Furthermore, zyme forms. Storage, mostly in the liver, is limited, and
vitamin B12 is required for myelin synthesis, as demon- signs of pellagra may occur within 50e60 days in
strated by the severe neurological disturbances that may humans fed a corn diet deficient in niacin. Excess niacin
occur with pernicious anemia. The exact mechanism of is methylated in the liver, and the methylated metabo-
cobalamin action on myelin is unknown. lites are excreted in the urine. Niacin status is assessed
by measuring nicotinic acid and nicotinamide in blood
and red cells, using microbiological or, currently, chem-
ical assays or HPLC. The NAD/NADP ratio in red cells,
Niacin or Vitamin B3
which is decreased in niacin deficiency, may be used as
Niacin has been identified as the therapeutic agent for an indicator of niacin depletion in renal failure patients.
pellagra, a condition described initially in maize-eating Pyridine nucleotides are involved in many enzymatic
populations [38]. Niacin is a generic term including reactions (at least 200). These may include NAD which is
nicotinic acid and nicotinamide (Table 24.1). Active mainly involved in catabolic reactions, such as oxidation
coenzymes are pyridine nucleotides, nicotinamide of fuel molecules, and NADP, which is primarily con-
adenine dinucleotide (NAD) and NAD phosphate cerned with synthesis, such as for steroids. These coen-
(NADP). High amounts of NAD and NADP (the main zymes are key elements for carbohydrate, fatty acid
forms of niacin intake from foods) are present in meat, and amino acid metabolism. There is a close relationship
fish, legumes, coffee and tea. These compounds are between the metabolism of niacin and of other vitamins.
hydrolyzed in the intestine to yield nicotinamide and Vitamin B6 and riboflavin are necessary for niacin
VITAMIN METABOLISM AND REQUIREMENTS IN RENAL DISEASE 359
synthesis from tryptophan. Niacin is necessary for the Pantothenic Acid or Vitamin B5
synthesis of active forms of vitamin B6, riboflavin and
folic acid. Pharmacological doses of nicotinic acid Pantothenic acid or chick antidermatitis factor is
reduce total cholesterol, increase the HDL-cholesterol formed from the combination of pantoic acid and
fraction, and decrease LDL and VLDL fractions and b-alanine. Some of its characteristics are given in Table
triglycerides [39]. Another important property of 24.1. Pantothenic acid, after passing through several
nicotinamide is inhibition of the Na/Pi type IIb cotrans- biochemical steps, is incorporated into the coenzyme
porter (Na Pi-2b) and the type IIa cotransporter A (CoA) macromolecule which is comprised of panto-
(NaPi-2a) in the intestinal brush border and in the prox- thenic acid, adenosine monophosphate and b-mercap-
imal renal tubular epithelial cells of the kidneys, respec- toethylamine. Pantothenic acid is ubiquitous and
tively [40]. Large doses of nicotinamide, 500 to 1500 mg/ present in large amounts in many foods, especially
day given twice-daily, can reduce serum phosphorus liver, kidney, egg yolk, fresh vegetables, royal bee jelly
concentrations in hemodialysis patients. and ovaries of tuna and cod [43]. After CoA hydrolysis,
pantothenic acid is liberated and excreted in the urine.
Pantothenic acid is assessed by microbiological assays
Biotin or Vitamin B8 or, more currently, by radioimmunoassay.
Biotin or vitamin B8 is a bi-cyclic compound contain- Pantothenic acid, in its function as a cofactor for CoA,
ing an ureido ring and a tetrahydrothiophene ring (Table is necessary for the synthesis of many compounds
24.1). Although biotin is synthetized by intestinal flora, including fatty acids, cholesterol, steroid hormones,
it is controversial as to whether this synthesis can satisfy molecules containing isoprenoid units (e.g., vitamins A
the daily need for biotin in humans [41]. Main food sour- and D), d-aminolevulinic acid, and some neurotransmit-
ces of biotin are liver, egg yolk, soybean and yeast. ters and amino acids. It is also necessary for energy
Cereals, legumes and nuts contain moderate amounts extraction during the b-oxidation of fatty acids and oxida-
of biotin, and fruits and vegetables are poor sources of tion of amino acids. Also, pantothenic acid and CoA play
biotin, except for cauliflower and mushrooms. Biotin a central role in the acetylation of proteins, microtubules
absorption occurs mainly in the jejunum and requires and histones and in the acylation of proteins with fatty
the release of biocytin (biotinyl lysine) from ingested acids, mainly myristic and palmitic acids. The acetylation
proteins and the action of biotinidase to free lysine and and acylation of proteins affect both their structure and
biotin, which are each absorbed by a diffusive saturable activity. In animals, pantothenic acid deficiency results
process. Long-term anticonvulsivant therapy may inter- in retarded growth, neuromuscular disorders, abnormal-
fere with the binding of biotin to biotinidase. The pres- ities of skin and hair and gastrointestinal symptoms. In
ence of avidin, a glycoprotein which strongly binds to young men fed a pantothenic-free diet for nine weeks,
biotin, may impair biotin absorption. Free biotin and their main complaint was fatigue [44].
its metabolites are excreted in the urine. Biotin stores
appear to cover biotin needs about one month. A biotin
deficient diet in human volunteers leads to symptoms of VITAMIN INTAKE IN CHRONIC
deficiency in 5 weeks [42]. Biotin is assessed in plasma RENAL DISEASE
with microbiological assays.
Biotin mainly acts as a CO2 carrier being the coen- Data regarding vitamin intake in patients with
zyme for carboxylases (Acetyl CoA carboxylase, pyru- advanced CKD, except for vitamin C, are often conflict-
vate carboxylase, propionyl CoA carboxylase, B ing. No data are currently available about vitamin intake
methylcrotonyl CoA carboxylase). Biotin is covalently for nephrotic patients. The vitamin intake with the
bound to the -amino group of a lysine residue of protein-restricted diets usually prescribed to CKD
carboxylases. Thus, it plays an important role in the patients who do not have ESRD is reported in Table
metabolism of carbohydrates, fatty acids and some 24.3 from Stein et al. [45]. Protein-restricted diets are
amino acids. Experimental biotin deficiency was most likely to engender low intakes of vitamin K, biotin,
induced in seven healthy human volunteers who were folic acid, B12, niacin and pantothenic acid. More studies
given a biotin-free diet and an excessive intake of raw have been published regarding vitamin intakes of chronic
egg white (rich in avidin). In five weeks, the subjects dialysis patients. Vitamin B6 intake is often low, according
developed mild depression, somnolence, muscle pains, to dietary surveys of maintenance dialysis patients
hyperesthesia, anorexia and later a maculosquamous [46,47]. In 242 CAPD patients, Wang et al. [48] reported
dermatitis with greyish palor and fine desquamation. inadequate intakes for vitamin B1 and B6 and folic acid
All symptoms disappeared within five days of starting in patients with loss of residual renal function and/or
biotin injections [41]. Alopecia is also a common feature low urea clearance. Martin-Del-Campo et al. [49]
of biotin deficiency [42]. reported that 50% of 73 CPD patients had low intakes
360
TABLE 24.3 Calculated Vitamin Content of Different Diets Prescribed to Chronic Renal Failure Patients (from Stein [45])

NUTRITIONAL MANAGEMENT OF RENAL DISEASE


Dietary Vitamin Folic Ascorbic
Protein A Vitamin Vitamin Thiamin Riboflavin Biotin Pyridoxine acid Vitamin Niacin Acid Pantothenic
Intake (mg REb) E (mg) K (mg) (mg) (mg) (mg) (mg) (mg) B12(mg) (mg) (mg) Acid (mg)

40 ga 556 16.0 80 1.2 0.8 13.4 1.4 50 0.6 9.0 107 3.0
a
60 g 570 12.0 80 1.5 1.4 17.8 1.5 80 1.2 10.5 88 4.0
a
80 g 568 14.0 80 1.3 1.2 15.8 1.8 70 2.5 15.0 60 3.2
c d e f
RDA 700e900 15 80e120 1.1e1.2 1.1e1.3 30 1.3e1.7 400 2.4 14e16 75e90 5d
a
Data refer to 24 hour intake of the nutrient from the diet.
b
RE: Retinol Equivalents.
c
Recommended Dietary Allowance for healthy, nonpregnant, nonlactating adults.
d
This value is not a RDA; there is inadequate scientific evidence to allow calculation of RDA. Recommended intake, termed Adequate Intake is used instead. It is derived from experimental data or by an approximation of observed mean
intakes, as suggested by the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes [234].
e
In female and male adults below the age of 50, the RDA is 1.3 mg/d. Over the age of 50, the RDA is respectively 1.5 and 1.7 mg/d for women and men.
f
Values of the RDA are for nonsmoking female and male adults. Add 35 mg/d for smokers [53].
VITAMIN METABOLISM AND REQUIREMENTS IN RENAL DISEASE 361
of vitamin A, B2, B6, C, folate and niacin. Patients in the retinol and retinyl esters levels are reported to be
higher quartile of serum C reactive protein (CRP) levels increased [58] even in the absence of renal failure. Data
had significantly lower intakes of riboflavin and vitamin are conflicting for vitamin E in this condition. In 33
A. Dietary habits may influence the amount of vitamins adults with the nephrotic syndrome, erythrocyte
ingested by CKD or maintenance dialysis patients. For thiamin pyrophosphate and riboflavin were found to
example, lower intakes of vitamin B6 and folic acid be normal by Midlyk et al. [59], whereas plasma PLP
were found when MHD patients ingested meals of pro- was significantly decreased. More recently, Podda et al.
cessed foods rather than traditionally prepared complete [60] reported a significant decrease of blood vitamin B6
dinners [50]. These data underscore the nutritional supe- concentrations in 84 nephrotic patients as compared to
riority of traditional foods and cooking above most pro- controls, and there was a correlation between the blood
cessed foods. Takagi et al. [51] reported that sevelamer vitamin B6 levels and the magnitude of proteinuria.
HCl binds a significant amount of vitamin B6. Rajbala et al. [61] found decreased serum vitamin C in
More extensive data have been reported for vitamin C 45 children presenting with the nephrotic syndrome.
intake. In the early days of chronic dialysis treatment, This was confirmed by Fydryk et al. [62] who found
the average ascorbic acid intake of maintenance hemodi- decreased blood vitamin C during relapse of steroid-
alysis (MHD) patients was reported by Sullivan et al. dependent nephrotic syndrome in 18 children. Twenty-
[52] to be 34 mg/day, whereas the recommended dietary nine nephrotic patients were studied with regarding to
allowance (RDA) for ascorbic acid is respectively 75 mg their vitamin C and E status and compared with 25
and 90 mg/day in nonsmoking female and male adults patients with hematuria [63]. Plasma vitamin C and
[53]. Allman et al. [46] showed a low spontaneous intake the ascorbate/vitamin E ratio were significantly lower
of vitamin C in their MHD patients (69% consumed less in the nephrotic patients. These data suggest that for
than two-thirds of the RDA). In children undergoing nephrotic patients, vitamin C and vitamin B6 levels
MHD and CAPD, the vitamin C intake was found should be assessed or, alternatively, multivitamin
respectively at 51% and 77% of the RDA [54]. Prescrip- supplements should be routinely administered.
tion of a low potassium diet is likely to reduce intake
of vitamin C containing foods. Both ascorbic acid and
potassium are abundant in fresh fruits and leafy vegeta- Chronic Kidney Disease 2e5 Stages Including
bles. Hence, restriction of foods high in potassium will Dialysis Therapy
reduce the intake of ascorbic acid and may predispose
to vitamin C deficiency [55]. Among the prescribed Vitamin A
restrictions in dietary intake for maintenance dialysis In comparison to normal individuals, high plasma
patients, the reduction in potassium is the one most vitamin A levels and an increased rise in plasma vitamin
likely to be adhered to [56], and it increases the risk of A in response to a vitamin A load test was reported in
low vitamin C intake. Moreover, prolonged soaking CKD patients as long ago as 1945 [64]. Many authors
and boiling of vegetables, which may be employed to have constantly confirmed elevated plasma concentra-
reduce the potassium content of food, may leech out or tions of total vitamin A, RBP bound vitamin A and free
degrade ascorbic acid. Bohm et al. [57] reported that vitamin A in nondialyzed CKD patients and maintenance
renal transplant recipients have a vitamin C intake equal dialysis patients, including children [45,65e70]. The
to the RDA. Hence, ingesting the RDA for vitamins increase of vitamin A in CKD is attributed to RBP metab-
will depend on many factors including the dietary olism. After the delivery of retinol to target tissues, the
prescription and the patients adherence to the prescrip- free RBP can be filtered by the glomerulus and catabo-
tion, appetite, medicinal intake and superimposed lized by the tubular cells. Thus, in renal failure there is
illnesses (see below). The renal dietitian is the key an increase in plasma RBP, and the plasma RBP/prealbu-
person in the outpatient setting and in the dialysis unit min and RBP/retinol ratios [71]. The small proportion
to evaluate this situation and to alert the patient and (5%) of the RBP-retinol complex that is not bound to
the nephrologist regarding his vitamin intake and needs. transthyretin normally is filtered by the glomerulus. In
renal failure, this reduction in glomerular filtration may
contribute to the elevated plasma levels. The complex is
captured by the proximal tubular cell by a specific apical
VITAMINS STATUS IN CHRONIC
receptor, megalin, allowing for retinol recycling into the
RENAL DISEASE
blood stream at the basolateral level of the cell. Knockout
mice for megalin display a urinary loss of the RBP-retinol
Nephrotic Syndrome
complex [72].
Few data have been published regarding the vitamin As shown many years ago, hemodialysis (HD) treat-
status in patients with nephrotic syndrome. Plasma RBP, ment does not change vitamin A levels [66]; indeed
362 NUTRITIONAL MANAGEMENT OF RENAL DISEASE

losses of vitamin A into dialysate would not be expected


because of the relatively large size of the vitamin A-RBP-
prealbumin complex. However, b-carotene, ubiquinol
and lycopene have been found to be lower in MHD
patients than in controls [68,73], and b-carotene and
ubiquinol fall further after a single HD session. There
are no published data on the dialysis kinetics of vitamin
A and RBP handling in MHD patients treated with high
flux membranes, convective techniques and daily dial-
ysis. The data are conflicting as to whether vitamin A
and RBP are present in the effluent peritoneal dialysate
FIGURE 24.3 Influence of vitamin A plasma levels on sudden
[67,74]. cardiac death in hemodialysis patients ([81] with permission). Quartile
Whether there is an increased risk of vitamin A 1 includes patients with the lowest plasma retinol levels as assessed
toxicity in individuals with CKD and in chronic dialysis with HPLC.
patients is controversial. Intriguingly, in patients who
did not have other evidence for vitamin A toxicity,
a correlation between plasma vitamin A concentrations death, infection-related and overall mortality. The lower
and serum calcium levels has been reported in CRF retinol quartile remained above the normal range of
patients [75]. MHD patients who were taking modest plasma retinol. It confirms previous data reported in
doses of vitamin A supplements, 2500 to 15,000 IU per a smaller cohort of prevalent MHD patients [82]. The
day, had higher serum vitamin A and calcium concen- possible interpretation is that the lower retinol level is
trations than those who were not. However, such corre- an indirect marker of inflammation. This is consistent
lations between plasma vitamin A and increased serum with data in CPD patients by Martin-Del-Campo et al.
calcium or serum alkaline phosphatase have not been [49] who found a significant lower vitamin A intake in
found consistently. The mechanism of hypercalcemia the patients belonging to the higher serum CRP quartile.
with vitamin A toxicity is related to the osteolytic action
of the retinoids on bone [76]. Many chronic renal failure Vitamin E
patients who have increased plasma vitamin A (up to In nondialyzed patients with advanced CKD,
3e4 times normal levels) do not show evidence for plasma vitamin E levels are usually within the normal
toxicity [77,78]. Elevated plasma vitamin A in renal range [83]. Protein restricted diets generally provide
failure is considered by many authors to be relative, a normal and nutritionally sufficient vitamin E intake
due to increased plasma RBP and to have no clinical (Table 24.3). Malnutrition may also influence vitamin
significance as long as the vitamin A/RBP ratio is E status, and lower serum a-tocopherol levels are found
normal or low. in malnourished CKD patients than in well-nourished
Vitamin A toxicity is believed to occur when plasma individuals [84]. Peuchant et al. [85] found decreased
retinyl esters in the lipoprotein fractions increase a-tocopherol in red blood cells (RBC) from nondialyzed
[1,71]. Whether vitamin A accumulates in solid tissues CKD patients who had increased erythrocyte peroxida-
in ordinary renal failure patients is controversial tion, as determined by elevated intraerythrocyte malo-
[65,78e80]. Therefore, it is not known whether the nyldialdehyde (MDA) concentrations. In MHD
increased vitamin A levels that are commonly found in patients, serum a-tocopherol levels have been found
CKD and chronic dialysis patients are hazardous. In reported low [73], normal [83] or increased [45]. There
nonuremic people with vitamin A overload and toxicity, is no difference in plasma vitamin E concentrations
large amounts of vitamin A may accumulate in the liver. between pre- and postdialysis samples [73]. In CPD
The clinical signs of vitamin A intoxication, cutaneous patients, data regarding vitamin E status are also
lesions (fissures, dryness, desquamation, yellowish conflictory.
appearance), headaches and CNS manifestations, joint
pains, bone tenderness to palpation, anemia, hepato- Vitamin K
megaly and muscle stiffness are not specific indicators Few studies have systematically examined the vitamin
for vitamin A toxicity. K status of CKD and dialysis patients, and they are con-
The prognostic value of plasma vitamin A levels in flicting. Plasma vitamin K levels were found to be normal
MHD and renal transplant patients has been recently by Malyszko et al. [86] in CKD, MHD and CPD patients.
analyzed. In a post-hoc analysis of the 4-D study Robert et al. [87] reported a high plasma level of phyllo-
including prevalent diabetic MHD patients, Espe et al. quinone in MHD patients. In contrast, a plasma low phyl-
[81] found that the lower quartiles of retinol (Figure 24.3) loquinone level was identified in some CKD (6%), MHD
and RBP4 were associated with increased risk of sudden (29%) and PD (24%) patients [88e90]. But the plasma
VITAMIN METABOLISM AND REQUIREMENTS IN RENAL DISEASE 363
phylloquinone level itself is not a sensitive indicator of Hence, highly permeable membranes may increase the
subclinical vitamin K deficiency. In a cohort of nondia- risk of thiamin deficiency in MHD patients, presumably
lyzed CKD 3e5 patients, the phylloquinone plasma level by increasing the thiamin losses from hemodialysis.
was found to be normal in 94% of the patients, whereas Blumberg et al. [47] and Boeschotten and coworkers
60% and 97% had subclinical deficiency as assessed, [74] reported thiamin deficiency in 50% and 26% of
respectively, from the proportion of uncarboxylated CPD patients who were not receiving thiamin supple-
osteocalcin in serum and the serum level of PIVKA-2. ments. Losses of this vitamin into the peritoneal dialy-
PIVKA-2 is a protein induced by vitamin K. The absence sate were substantially lower than the normal daily
or inhibition of PIVKA-2 leads to an increase in serum urine excretion of thiamin [74]. These findings suggest
des-gamma-carboxy prothrombin; an increase in these that even if blood thiamin levels are normal, this does
levels is a very early manifestation of vitamin K defi- not rule out a functional deficiency. Moreover, in exper-
ciency before the prolongation of coagulation) [89]. imental CKD rats, it has been shown that thiamine
transporters are down regulated in the heart, the brain,
Vitamin B1 the liver and the intestine. These observations raise
The EKTA stimulation index was found to be normal questions concerning the appropriate methods for
by Kopple et al. [91] in 15 nondialyzed advanced CKD assessing thiamin status in advanced CKD and dialysis
patients who were receiving 1-mg/day thiamine HCl patients.
supplements. No relationship was observed between Clinical manifestations of thiamin deficiency have
EKTA or the EKTA stimulation index and the level of rarely been described in ESKD patients. Beriberi has
renal function. Uremic toxins may impair thiamine func- been reported in two MHD patients [98,99]. Case reports
tion. In the early days of dialysis, Lonergan reported of Wernickes encephalopathy are increasing and have
a dialysable compound in uremic serum that inhibited been described in MHD and CPD patients but may be
ETKA and suggested that it might be guanidosuccinic frequently overlooked because the classical triad of
acid [92]. This inhibitory effect of uremic sera was this syndrome (confusional state, ataxia, opthalmople-
ameliorated by dialysis treatment. Sterzel et al. [93] gia) is present in only 20% of the cases [100e102]. In
reported that transketolase activity of nervous tissue the report by Ueda et al. [102], typical pathologic lesions
was inhibited by uremic plasma and by cerebrospinal of Wernickes encephalopathy were found in five
fluid from uremic patients and by a low MW fraction patients who had been given such other diagnoses by
(<500 kD) of dialysate. However, in the early years of clinicians as uremic encephalopathy, dysequilibrium
dialysis therapy, Kopple et al. [91] did not find acute syndrome, dialysis dementia, or brainstem hemorrhage.
changes in ETKA observed during a single hemodialysis Also, chorea has been reported in two cases of thiamin
treatment. Kuriyama confirmed a low basal ETKA deficiency in MHD patients [103]. The same authors
(EKTAo) or stimulated ETKA (ETKAs) in a group of 72 found thiamin deficiency in 10 MHD patients presenting
MHD, CPD and nondialysed patients with chronic renal with mental disturbances. Nine out of 10 recovered with
failure, even though they had high blood thiamin levels intravenous thiamin supplementation [104]. Infection,
following ingestion of supplements [94]. Other investi- surgery and large glucose loads may increase the nutri-
gators reported that the blood thiamin level is usually tional needs for thiamin, and precipitate clinical mani-
in the normal range in MHD patients [95]. In 43 unsup- festations of thiamin deficiency.
plemented MHD patients, Descombes et al. found low
or marginal ETKAo in 56% of patients, and the ETKA Riboflavin (Vitamin B2)
stimulation index was increased in 21% of the patients Porrini et al. [105] have reported increased aEGR
[37]. In ETKAo deficient patients, whole blood thiamin activity (indicating riboflavin deficiency) in CKD
was normal. The functional deficiency was reversed patients prescribed a low protein diet. However, its clin-
with large amounts of thiamin hydrochloride (100 mg ical significance remains unknown. In dialysis patients,
after each hemodialysis). In the same study, patients most studies show normal or excess riboflavin in plasma
undergoing MHD with a polyacrilonitrile membrane of MHD and CPD patients even when they are not
dialyzer had lower ETKAo than those treated with prescribed vitamin supplements [37,74,106] and despite
cellulose acetate. Heinz et al. [96] reported that the the losses of riboflavin into peritoneal dialysate [74].
hemodialysis procedure induces a greater decrease in However, Skoupy et al. found that 18.5% of CAPD
plasma thiamin levels with high-flux versus low-flux patients had increased a-EGR [107]. More recently, ribo-
membranes. Coveney et al. [97] have reported lower flavin deficiency was not found in 12 pediatric CPD and
plasma thiamin in patients treated with extended dial- MHD patients who were not receiving supplements
ysis sessions when compared to patients treated by [108]. Also in MHD patients receiving multivitamin
conventional dialysis. However, no patient was found supplements, and treated with standard or daily long
to have blood thiamin levels below the normal range. HD sessions, no riboflavin deficiency was found even
364 NUTRITIONAL MANAGEMENT OF RENAL DISEASE

with the more extensive dialysis treatment [109]. No [116] were able to reverse decreased reactivity in mixed
clinical syndromes associated with ribloflavin excess lymphocyte culture by giving MHD patients 300 mg/
or deficiency have been reported in CKD or ESRD day of pyridoxine HCl for two weeks. Casciato et al.
patients. [117] improved immunologic function of polymorpho-
nuclear neutrophils and lymphocytes in eight MHD
Vitamin B6 patients, most of whom had vitamin B6 deficiency, by
Blunted weight gain was observed during a four giving 50 mg/day of pyridoxine hydrochloride for three
week period in chronically azotemic compared to sham- to five weeks.
operated rats and was significantly more pronounced in
the rats that were fed a vitamin B6-deficient-diet when Vitamin C
compared to vitamin B6-surfeit diet [110]. Most but Few studies of vitamin C status are available for non-
not all surveys detect a high incidence of vitamin B6 dialyzed, advanced CKD patients. Marumo [118]
deficiency in both adult and pediatric advanced surprisingly found low plasma ascorbic acid levels in
CKD, MHD and CPD patients. Methodologic differ- patients with mild to moderate CKD but not in nondia-
ences in the measurements of vitamin B6 could explain lyzed individuals with advanced CKD or in MHD
these observed differences in vitamin B6 deficiency. patients. In contrast, Clermont et al. [83] found
The use of red cell transaminase activity (EGOT0 or decreased vitamin C levels, with an increased ascorbyl
EGPT0) as the criterion for deficiency [111] has been free radical/ascorbic acid ratio in CKD patients. Intrave-
criticized because of the shortened life span of red nous furosemide increases urinary vitamin C excretion
cells in CKD and the higher activities of some enzymes in CKD patients [119]. In the early days of MHD treat-
in younger erythrocytes. Studies that assessed plasma ment, Sullivan and Eisenstein described ascorbic acid
pyridoxal-5-phosphate (PLP) concentrations also found deficiency in MHD patients [52]. Latter reports
decreased levels in most dialyzed and nondialyzed confirmed a high incidence of vitamin C deficiency in
CKD patients. In a recent systematic review of vitamin MHD and PD patients not given vitamin C supplements
B6 status in MHD patients, Corken & Porter [112] [46,47,74,83,120,121] and even in some patients receiving
reported a 33e56% prevalence of vitamin B6 deficiency supplements [37]. However, Tarng et al. [122] found
when low plasma PLP was used as the criterion for normal vitamin C levels in 65 nonsupplemented
deficiency. Removal of vitamin B6 by dialysis has not patients treated with MHD for a mean of 48.7 months.
been confirmed. Lacour et al. [113] did not find PLP Ramirez et al. [95] monitored plasma ascorbic acid levels
in the hemodialysis ultrafiltrate from low-flux hemodi- for one year after discontinuing vitamin C supplements.
alysis. This is not surprising since PLP is bound to A dramatic decrease in plasma ascorbic acid was
albumin. The effect of PLP clearance with high flux observed, but no patient reached a deficient level.
membrane is contradictory. Kasama et al. [114] Mydlik et al. [123] found normal plasma vitamin C
observed a significant reduction of serum PLP in six levels in 32 CAPD patients not receiving ascorbic acid
MHD patients after they switched from cuprophane supplements. Recently, Zhang et al. [124] reported in
to cellulose triacetate, whereas Heinz et al. [96] did that in plasma of 284 MHD and CAPD patients, 64%
not find any difference in serum PLP with the same of the patients presented with deficiency or insufficiency
study design. No data are currently available on PLP for vitamin C.
clearance with convective techniques. Boeschotten Ascorbic acid is a small molecular weight (MW) and
and coworkers reported that the quantity of PLP lost nonprotein bound molecule, which is readily dialyzable.
into peritoneal dialysate, assessed by HPLC, is similar Bohm et al. [57] measured the amount of vitamin C in
to the normal urinary vitamin B6 excretion [74]. In dialysate and found it to range from 92 to 334 mg per
another study of peritoneal dialysis, much lower losses treatment, with a 50% decrease in plasma ascorbic acid
of PLP were reported [115]. Moreover, additional during an individual HD treatment and a return to pre-
PLP bound to proteins may be lost into peritoneal dialysis levels by 44 hours. Hultqvist et al. [120] found
dialysate. a 40% decrease in plasma ascorbic acid during
Vitamin B6 deficiency in experimental animals and a 3-hour HD treatment. In peritoneal dialysate, 56 mg
humans is associated with many alterations in immune of ascorbic acid were recovered in the 24-hour cycle
function including reduced numbers of blood granulo- [74]. According to Mydlik et al. [123], the peritoneal
cytes and lymphocytes, decreased lymphocyte matura- transfer of ascorbic acid was 136.4 mmoles/6 hours
tion, reduced blastogenic response of lymphocytes to with 1.5% glucose in dialysate, and increased to 175.8
mitogenic stimuli, delayed cutaneous hypersensitivity mmoles/6 hours with 2.5% dialysate glucose. Whereas
and decreased antibody production. B6 deficiency may low plasma ascorbic acid levels are not infrequently
play a role in the alterations of immune function in reported in MHD and CPD patients who do not receive
advanced CKD. Many years ago, Dobbelstein et al. vitamin C supplements, scurvy has been described only
VITAMIN METABOLISM AND REQUIREMENTS IN RENAL DISEASE 365
rarely in CKD patients. Ihle reported a MHD patient folate levels. The incidence of folate deficiency might
with cutaneous symptoms (pruritus, bruising and have been greater if 20 of the patients had not been
ecchymoses), impaired platelet function, a low vitamin prescribed folate supplements. Leblanc et al. [131]
C intake and decreased plasma and leukocyte ascorbic reported the folic acid clearance to be 134.7  22.2
acid levels [125]. The defect in platelet function was mL/min with high flux/high efficiency MHD, with
similar to that reported with scurvy. Treatment with a 26.3% decrease in plasma folic acid during an indi-
one gram of vitamin C per day for a few days rapidly vidual MHD treatment. But the risk of folic acid deple-
corrected the ecchymoses, prolonged bleeding time tion with high flux membranes is not confirmed [132].
and platelet dysfunction. However, fatigue and peri- The incidence of folate deficiency in CPD patients is
odontal lesions are frequent in dialysis patients, and also controversial [47,74,133,134]. Folate losses into peri-
their relationship to the frequent vitamin C deficiency toneal dialysate averaged 107 mg/day in one study [74].
has never been addressed [126]. The influence of EPO therapy on folate status is reported
below.
Folic Acid
Folate metabolism is altered in renal failure. CKD Vitamin B12
impairs the intestinal absorption of THF. Using in vivo Plasma vitamin B12 is usually within the normal
perfusion of the jejunum, Said et al. [127] showed that range in CKD and chronic dialysis patients even without
azotemic rats had significantly lower absorption of 5- supplementation and even with extended hemodialysis
methyl THF than sham-operated controls. Using an in vintage [97]. Because cobalamin is a larger molecule in
vitro everted jejunal sac technique, these authors found its own right (MW: 1355) and is also protein-bound, los-
that predialysis sera obtained from MHD patients ses of vitamin B12 in dialysate are low. Fehrman-Ekholm
showed suppression of intestinal absorption of 5-methyl et al. [135] did not find decreased serum vitamin B12
THF, whereas postdialysis sera caused significantly less levels in hemodialfiltration patients. In CPD patients,
suppression. In rats with chronic kidney failure, Bukhari no cobalamin was recovered in peritoneal fluid by
et al. [128] demonstrated a downregulation of folic acid Boeschoten et al. [74].
transporters in tissues and especially in the intestine.
This could lead to decreased folate absorption. Livant Niacin
et al. [129] reported that plasma conjugase activity was There are few data regarding niacin status in nondia-
reduced in predialysis sera and rose to normal levels lyzed and dialyzed CKD patients. Because of its rapid
posthemodialysis. The authors suggest that there are metabolic clearance, losses of niacin in dialysate are
one or more circulating heat stable compounds in expected to be low. Ramirez et al. [95] did not find differ-
uremic plasma which may inhibit plasma folate conju- ences between pre- and postdialysis red cell niacin
gase activity. concentrations in MHD patients. No data are available
Marumo et al. [118] reported that in CKD patients on niacin losses in peritoneal dialysate. DeBari reported
who were not receiving folate supplements, serum folic low concentrations of niacin in leukocytes, but normal
acid was normal in those with mild to moderate CKD niacin content in red cells of MHD patients [136]. Ram-
and was increased above normal in patients with irez et al. [95,111] did not find evidence of low niacin
advanced CKD who were not undergoing MHD. In levels in whole blood or erythrocytes of MHD patients
the 1960s to 1980s, reports regarding folic acid status who were not receiving supplements or in whom
in MHD patients were contradictory, describing both supplements had been stopped for at least one year.
normal and deficient status. Marked increases in plasma Pellagra (characterized by diarrhea, dementia, derma-
and red cell folate levels have been found in patients titis) has never been reported in CKD patients, but
receiving folate supplements [130]. Folate pools are niacin deficiency has been suggested as the cause of ony-
believed to contain sufficient quantities to satisfy folic cholysis in MHD patients [137].
acid requirements for at least one year [37]. Thus, at least
several months, if not more than one year of follow-up, Biotin
after interruption of supplementation may be necessary Uremic toxins have been shown to impair tubulin
to assess the risk of folate depletion. Moreover, most of polymerization which leads to microtubule formation,
these studies were conducted before the advent of and biotin counteracts the effects of uremic toxins on
high flux/high efficiency HD which appears to have tubulin [138]. Biotin intake in CKD patients prescribed
dramatically increased the risk of folic acid deficiency low protein diets has been estimated to be much lower
in MHD patients. Livant et al. [129] found that in 32 than the RDA (Table 24.3). With the exception of an occa-
MHD patients treated with high flux polysulfone dia- sional deficient patient, several studies did not find
lyzers, five individuals had reduced predialysis plasma biotin deficiency in chronic renal failure patients. Biotin
folate concentrations and four had decreased red cell concentrations in plasma, leukocytes and RBC were
366 NUTRITIONAL MANAGEMENT OF RENAL DISEASE

found to be high in MHD patients [139], and even higher plasma PLP decreased, and the calculated PLP loss was
in anuric patients and in MHD patients treated for 80 nmol/day [148]; the PLP clearance was about 49% of
longer periods of time [37]. the urea clearance and the amount of folic acid removed
has been estimated to be 650 nmoles/day, with a clear-
Pantothenic Acid ance as high as 76% of urea clearance. Plasma vitamin
There are few data concerning the pantothenic acid E levels are decreased in patients with AKI, regardless
status of renal failure patients. Conflicting data have of whether they are or not treated with continuous hemo-
been reported regarding the pantothenic acid status in filtration [149].
MHD patients. Debari et al. [136] found in 12 nonsupple-
mented MHD patients that pantothenic acid concentra-
tions in plasma, leukocytes and red cells were VITAMINS AS THERAPY FOR PEOPLE
significantly higher than in normal controls. Lasker WITH KIDNEY DISEASE
et al. [140] reported normal or high concentrations of pan-
tothenic acid in blood of six MHD and three CPD patients Effect of Water-Soluble Vitamin
who were not receiving vitamin supplements. On the Supplementation on Patient Outcomes
other hand, Mackenzie et al. [141] reported low concen-
trations of plasma pantothenic acid in six MHD patients According to the DOPPS report, MHD patients
who were not receiving supplemental pantothenic acid. receiving a supplementation of vitamins B6, B12 and C,
and folates had better nutritional status (indicated by
serum albumin levels and nPNA) and a 16% decrease
Kidney Transplant Patients in mortality [150]. The reduced mortality persisted after
There are few published data regarding the vitamin adjustment for nutritional markers. It was not possible
status of renal transplant recipients. Plasma vitamin A to distinguish the specific effects of each vitamin.
levels decrease slowly toward normal after renal trans- Vitamin prescription varied substantially across conti-
plantation, Yatzidis and coworkers reported that more nents, but the impact on mortality did not vary when
than 20 months may elapse in patients with a well func- stratified by geographic regions. The interpretation to
tioning kidney transplant before plasma vitamin A levels explain this effect includes the possible plasma homo-
are normal [142]. In renal transplant recipients as in cysteine (Hcy) lowering effect of these vitamins,
MHD patients, a decreased survival has been observed increased appetite and protein intake with vitamin
in patients in the lower tertile for plasma retinol. In supplementation, better patient-care in chronic dialysis
contrast, vitamin E and a variety of carotenoids, programs where supplements are prescribed and better
including b-carotene, are not associated with patient socio-economical status associated with this prescrip-
survival [143]. McGrath et al. [144] found vitamin E to tion. However, the prospective trials of Hcy-lowering
be normal in 40 transplant patients, 20 of whom were with vitamin supplements do not support the first
receiving cyclosporine and 20 of whom were receiving hypothesis (see below).
azathioprine and glucocorticoids. Malyszko et al. [86]
did not found vitamin K deficiency in renal transplant
patients. Bohm et al. [57] reported normal plasma Homocysteine Lowering Therapy
vitamin C levels in renal transplant recipients. The folic Increased plasma homocysteine (Hcy) is a recognized
acid status in renal transplant patient is normal or cardiovascular risk factor, and elevation of plasma Hcy
decreased. The MTHFR genotypes, labeled 677 and in advanced CKD and chronic dialysis patients has
1298, have been shown to significantly influence plasma been recognized for at least two decades. The possibility
folic acid levels in a group of 733 renal transplant that reducing plasma homocysteine might improve
patients; the 677TT/1298AA group had lower plasma outcomes in CKD, maintenance dialysis and renal trans-
folic acid levels [145]. plant patients has been tantalizing. Homocysteine is an
intermediate in the formation of cystathionine from
methionine (Figure 24.2). Three vitamins, B6, B12 and
Acute Kidney Injury Patients
folates are directly involved in its synthesis and metabo-
In patients with acute kidney injury (AKI), serum lism. The formation of cysteine from methionine requires
vitamin A levels were found to be normal in one study vitamin B6. PLP is a coenzyme for cystathionine syn-
[71], decreased in another study (with normal serum thase, which transforms methionine to cystathionine,
RBP levels) [146] and increased in a third study of AKI and for cystathionase, which cleaves cystathionine to
patients receiving total parenteral nutrition (TPN) contain- form cysteine. As suggested in Figure 24.2, PLP or folate
ing standard retinol supplementation [147]. With contin- deficiency, which occurs not infrequently in CKD and
uous veno-venous hemofiltration or hemodiafiltration, dialysis patients, could participate in the pathogenesis
VITAMIN METABOLISM AND REQUIREMENTS IN RENAL DISEASE 367
of increased plasma Hcy in CKD and dialysis patients. regard to patency of the blood access has not been
However, renal patients who have normal levels of confirmed. In a prospective study of 733 renal transplant
folate, cobalamin and PLP still manifest increased recipients, Winkelmeier et al. [163] found that the risks of
plasma Hcy [151]. In advanced CKD patients and main- death and graft loss were associated with plasma Hcy
tenance dialysis patients, plasma homocysteine levels levels >12 mmoles/L with hazard ratios, respectively,
tend to be about one and one-half to two times higher at 2.44 and 1.63 after adjustment. The mechanisms of
than in healthy controls and correlate inversely with homocysteine toxicity have been thoroughly reviewed
the GFR [152,153]. Plasma Hcy is routinely increased [164]. Homocysteine is one of the factors in the transsul-
(>15 mmoles/L) in dialysis patients. However, plasma furation-transmethylation pathways and the complex
Hcy levels are influenced by the nutritional status and folate cycle. Its accumulation may lead to altered DNA
may be low in patients with protein-energy wasting methylation with epigenetic consequences and homo-
[154]. Plasma Hcy is also increased in nondialyzed chil- cysteine binding to proteins with resulting functional
dren with CKD and in children undergoing MHD treat- deficiencies.
ment. Arnadottir et al. [155] found that 6 months after Many studies have examined the effects of lowering
renal transplantation, plasma Hcy had decreased by an plasma Hcy levels in patients with advanced CKD, in
average of 14%, but that plasma Hcy was still signifi- those undergoing dialysis or in renal transplant recipi-
cantly higher in the renal transplant recipients as ents. The findings can be summarized as follows. The
compared to a control group matched for renal function. usual effect is a 30e50% decrease in Hcy with folic acid
Plasma homocysteine levels are affected by the dial- therapy, but with few patients attaining normal plasma
ysis technique. Despite a greater intradialytic decrease Hcy levels. The magnitude of the lowering effect of folic
in plasma Hcy with high vs. low flux membranes (42 acid is positively related to the pretreatment plasma
vs. 32%), no difference was found in predialysis plasma Hcy values and negatively associated with the RBC folic
Hcy levels with high- as compared to low-flux acid concentration. Most clinical trials using low doses
membranes during a 3-month period [156]. Recently (2.5e5 mg/d) of folic acid treatment to lower plasma
Pedrini et al. [157] found in a randomized cross-over Hcy levels in advanced CKD and maintenance dialysis
trial that on-line hemodiafiltration sustainly decreases patients show about the same magnitude of reduction
predialysis Hcy level when compared to low-flux as in the trials that used larger folic acid doses. Bostom
conventional HD. Vychtyl et al. [158] studied peritoneal et al. [165] reported a more effective lowering effect of
losses of Hcy in 39 CPD patients. Daily peritoneal Hcy plasma Hcy with a combination of folic acid, vitamin B6
removal (38.9  20.8 mmoles) was correlated with and vitamin B12 in renal transplant recipients than in
plasma Hcy, effluent volume, and the D/P creatinine MHD patients. Recent prospective, large scale trials
ratio [158]. Free Hcy represented 47.5% and 75.2% of addressed the efficacy of Hcy-lowering therapy on clin-
total Hcy in plasma and dialysate, respectively. It was ical outcomes in CKD patients. The HOST trial included
concluded that CPD, like, MHD, is not sufficiently effec- 2056 nondialyzed advanced CKD patients and chronic
tive to normalize plasma Hcy levels. dialysis patients who were randomized in a blinded
More than 10 years ago, two prospective studies fashion to receive daily either a combination of the vita-
described the association between plasma Hcy and mins, folic acid, 40 mg; pyridoxine hydrochloride
cardiovascular risk in chronic renal failure patients. (vitamin B6), 100 mg; and cyanocobalamin (vitamin B12)
Moustapha et al. [159] followed 167 ESRD patients for 2 mg or placebo [153]. The average follow-up was 3.2
a 17.4-month period and reported an increased cardiovas- years. No decrease of overall mortality or CV events
cular morbidity and mortality risk of 1% for each mmole was observed in the treated group even though plasma
rise in plasma Hcy. In CPD and MHD patients, Bostom Hcy fell significantly in the treated group. In a substudy
et al. [160] found a relative risk for nonfatal and fatal of this trial, cognition was analyzed as an outcome and
cardiovascular events of 3.0 and 4.4, respectively, when was not improved by the Hcy lowering therapy [166].
comparing the highest quartile versus the lower three Heinz et al. [167] enrolled 650 MHD patients in a random-
quartiles of plasma Hcy levels also during a follow-up ized control trial comparing a combination of folic acid,
period of 17.0 months. Elevated plasma Hcy is a risk vitamins B6 and B12 with placebo. Again no difference
factor for endothelial dysfunction and for cardiovascular in clinical outcomes (overall and CV mortality and CV
disease in CKD patients [161]. However, Kalantar-Zadeh events) was found. A large prospective trial in renal trans-
et al. [162] found an increased mortality in the lowest Hcy plant patients is in process (the FAVORIT trial [168]).
quartile of 367 MHD patients, even after adjustment for
the nutritional and inflammatory state. These authors
concluded that Hcy is an independent nutritional marker
Vitamins and Oxalate Burden in Renal Failure
explaining the reverse association of plasma values with As shown in Figure 24.4, oxalate is a metabolic end
patient outcome. Furthermore, the role of Hcy with product of ascorbic acid. In normal humans, urinary
368 NUTRITIONAL MANAGEMENT OF RENAL DISEASE

FIGURE 24.4 Pathways for oxalate metabolism.

excretion of oxalate increases when these individuals are oral supplementation of 0.5 to 1 g/day of ascorbic acid,
fed an ascorbic acid load. However, the relationship and cessation of ascorbic acid supplements results in
between ascorbic acid intake and urinary oxalate excre- a decrease in plasma oxalate [177]. The calcium oxalate
tion is not linear, and only a fraction of the ascorbic acid saturation threshold was exceeded in 7 of 18 patients
ingested is normally recovered in the urine as oxalate (40%) during the course of 6 months of ascorbic acid
[169]. Plasma oxalate concentrations are virtually always therapy, 500 mg/wk [178]. Ott et al. [179] observed bone
increased in nondialyzed advanced CKD and chronic oxalate deposits in a bone biopsy from a patient who
dialysis patients [170,171]. Plasma oxalate is correlated had undergone MHD for 23 years and who had ingested
with serum creatinine [172] and may be increased 2.6 g/day of ascorbic acid for seven years. A bone biopsy
several times above normal values in renal failure in the same patient obtained before commencing ascorbic
patients, close to the levels found in primary hyperoxa- acid supplements showed no evidence for bone oxalate
luria. Calcium oxalate deposits are described in several deposits. A case of calcium oxalate deposits in kidneys
tissues in advanced CKD and appear to be most and pancreas was reported in a pediatric patient with
pronounced in kidneys, heart, blood vessels, thyroid, the hemolytic uremic syndrome who received 500 mg/
and skin and to increase with the duration of MHD day of ascorbic acid by parenteral nutrition [180]. Hyper-
therapy [173]. Mydlik et al. [123] reported increased oxalemia is also associated with ascorbic acid supplemen-
plasma oxalic acid in 32 CAPD patients (23.6  7.4 tation in CPD patients [181].
mmoles/L; normal range: 2e5.5 mmoles/L) despite Vitamin B6 is the coenzyme for the transamination of
a large peritoneal oxalate clearance. In 15 MHD patients, glyoxylate to glycine (Figure 24.4). Since vitamin B6 defi-
plasma oxalate was increased (40.3  9.8 mmoles/L) and ciency is not uncommon in CKD, this might contribute to
oxalate clearance was greater with postdilutional hemo- increased oxalate plasma levels. Hence both decreased
filtration (74.2% of urea clearance) then with conven- clearance of oxalate because of impaired renal function
tional hemodialysis (58.1% of urea clearance) or and impaired vitamin B6 status may play a role. Recently
postdilutional hemodiafiltration (69%) [174]. In children, Mydlik et al. [182] have reported a close relationship
there appears to be a large discrepancy between oxalate between the vitamin B6 status and serum oxalate levels
clearances in those undergoing CAPD (7.14 mL/min, in MHD patients (Figure 24.5). Several attempts have
n 15) and MHD (115.6 mL/min, n 10). Nonetheless, been made to decrease plasma oxalate levels with phar-
the weekly elimination of oxalate was similar, and blood macological doses of pyridoxine HCl. Conflicting results
oxalic acid levels remained high and not different were obtained. Tomson et al. [183] did not observe
between the two groups [175]. An oxalemia level a significant decrease in oxalemia in 21 chronic dialysis
>30mmoles/L has been proposed to indicate calcium- patients treated for four months with pyridoxine HCl,
oxalate supersaturation in plasma [176]. 100 mg/day. In contrast, a 46% decrease of plasma
There is strong evidence that a high vitamin C intake oxalate was observed by Balcke et al. [184] after one
may contribute to hyperoxalemia and to oxalate deposi- month of treatment with pyridoxine HCl, 600 mg/day
tion in soft tissues of CKD patients. The mechanism of orally or 600 mg three times per week intravenously after
oxalate accumulation with low doses of ascorbic acid is hemodialysis treatment. However, the plasma oxalate
related to the decrease or absence of renal function. In level remained elevated and in the supersaturation range
such circumstances, excess ascorbic acid and the oxalate [171]. In a controlled study, Costello was unable to reduce
subsequently produced cannot be eliminated in the urine, plasma oxalate levels after six months of treatment
unlike in normal subjects who can tolerate much higher with 100 mg/day of pyridoxine HCl or after four weeks
intakes of ascorbic acid without oxalate accumulation. of therapy with 750 mg/day of pyridoxine HCl [185].
In MHD patients, plasma oxalate levels increased with The reason for these discrepant results is not clear.
VITAMIN METABOLISM AND REQUIREMENTS IN RENAL DISEASE 369
FIGURE 24.5 Indirect relationship between the
plasma vitamin B6 and plasma oxalate concentrations in
maintenance hemodialysis (HD) patients ([182] with
permission).

Descombes et al. [186] reported a high plasma oxalic acid number of studies to improve the iron utilization. There
level in 33 patients receiving high flux dialysis and 50 mg has been much interest concerning the potential value of
of pyridoxine HCl after each dialysis treatment, indi- ascorbic acid as an adjuvant therapy to EPO to increase
cating that current dialysis techniques and vitamin B6 hemoglobin and reduce the cost of anemia therapy,
supplementation are not sufficient to normalize oxalic particularly in MHD and CPD patients with erythropoi-
acid levels. Patients with type I or type II primary hyper- etin resistant anemia. Tarng et al. [122] have reported
oxaluria have been treated with different doses of pyri- that in MHD patients hyporesponsive to EPO and with
doxine (25e1000 mg/day), also with variable results normal vitamin C levels who were treated with
[187]. Oxalate clearance differs among different filters 300 mg of vitamin C given at the end of dialysis for 8
and dialysis modalities; the most efficient ones are weeks, there was increased hematocrit and transferrin
high-flux membranes such as polysulphone and hemo- saturation and decreased EPO needs. However, only
diafiltration [188]. Renal transplantation remains the half of these patients had a positive response to vitamin
most efficient therapy for hyperoxalemia [172]. C administration. Plasma oxalate levels increased
slightly, but not to a statistical significant degree during
the vitamin C therapy. In the last decades, numerous
Vitamins in Anemia Management studies have indicated that vitamin C administration
Reference is made to Chapter 25 for a comprehensive reduces anemia in renal failure. A recent meta-analysis
discussion of this subject. The following is a brief identified 157 reports, with only six of these reports ful-
summary of vitamins in anemia management. Since filling the selection criteria [191]. The meta-analysis
the advent of the erythropoietin (EPO) era, concerns concludes that vitamin C (between 200 and 500 mg three
have been raised regarding the status of vitamins times per week) increases the transferin saturation coef-
directly involved in erythropoiesis, such as vitamin B12 ficient and decreases EPO needs. However, the long-
and folates because of their increased consumption term safety of such treatments is not addressed in this
and the possibility that they might reduce the needed report, and oxalate supersaturation might have been
dose of EPO or iron. Mydlik et al. [189] reported a signif- reached in a significant number of patients with these
icant decrease of erythrocyte folic acid after one year of dosages [178]. In the forthcoming KDIGO guidelines
EPO therapy in 15 MHD patients. This was not on anemia management, no adjuvants such as folates
confirmed by Pollock et al. [190] who did not find any or vitamin C are recommended with EPO therapy [192].
difference in folates and vitamin B12 concentrations
before and after 18 months of EPO treatment in 81
MHD and 31 CPD patients. No information was given Vitamins (Except Vitamin D) and Bone Mineral
concerning folic acid or vitamin B12 supplements in
these patients.
Metabolism
Both the not uncommon prevalence of EPO resis- Besides vitamin D and its pivotal role in bone mineral
tance, especially of inflammatory origin, and the quest metabolism (BMD), other vitamins may be involved in
for cost reduction of EPO therapy have triggered a large these complex interactions, mainly vitamins K and A
370 NUTRITIONAL MANAGEMENT OF RENAL DISEASE

and niacin. Administration of vitamin K1 reduces the differential diagnosis of hypercalcemia in renal
urinary calcium excretion in postmenopausal women failure patients. Elevated serum vitamin A levels and
who have increased calciuria (i.e., urine Ca/creatinine vitamin A toxicity in CKD are discussed above.
ratio >0.5) [193]. Coumarin-derivatives increase urinary Large doses of niacin, and its amide form, niacin-
calcium excretion in young adults [194]. The anti-calciu- amide, have been proposed to treat hyperphosphatemia
ric effects of vitamin K may be mediated through the in CKD because of their capacity to inhibit the Na-Pi
carboxylation of bone proteins (i.e., osteocalcin and cotransporter in the GI tract [202]. The usual side-effects
other Gla proteins which bind calcium). The reduced of the molecule, hepatotoxicity and flush, have been
bone mineral content found in patients receiving oral reduced by the change in the formulation from imme-
anticoagulants supports the possibility that vitamin K diate to extended-release and are less pronounced with
antagonists increase urinary calcium by mobilizing niacinamide than with niacin itself. A decrease in plate-
bone calcium. However, a direct effect of vitamin K or lets may occur but is observed inconstantly. The poten-
its antagonists on the kidney cannot be ruled out. tial advantages of niacin as a phosphate absorption
The use of coumarin-derivatives in dialysis patients is inhibitor are the low cost, the absence of calcium in the
associated with an increased risk of calciphyllaxis [195] medication, the potential benefits on the lipid profile,
and aortic valve calcification [196]. Vascular and and the medicine can be taken at a time that is indepen-
valvular calcifications are associated with the high prev- dent of the meal [40]. However, at present, these phos-
alence of cardiovascular morbidity and mortality in phate-lowering effects have been reported in only
CKD and chronic dialysis patients. Matrix Gla-protein small cohorts of patients with no studies on long-term
(MGP), a vitamin K-dependent factor, interferes with clinical outcomes.
the genesis of vascular calcifications, and MGP knock-
out mice present with extensive lethal vascular calcifica-
tions [21]. With quantitative or functional vitamin-K Vitamins and Anti-Oxidant Therapy in Renal
deficiency, MGP is predominantly present in the uncar- Disease
boxylated form (ucMGP) and can be found in the media
of calcified vessels. Thus, vitamin K deficiency may play Oral Anti-Oxidant Therapy
a role in the complex pathophysiology of accelerated It is mainly vitamin E and vitamin C that have been
tissue calcification in this setting. It is not known studied for their anti-oxidant properties in renal disease
whether vitamin K therapy may prevent such patients. There is much evidence that nondialyzed
calcification. patients with CKD and individuals undergoing MHD
Another vitamin K-dependent protein, osteocalcin or CPD suffer from oxidant stress and that this condition
plays a role on bone mineralization. In the general pop- is associated with adverse cardiovascular complications
ulation, vitamin K supplementation seems to reduce the [203]. This important issue is discussed in more detail
incidence of fractures, as summarized by Fusaro et al. in Chapters 6 and 9. Numerous studies have examined
[197]. In MHD patients, an inverse relationship has the effects of oral vitamin E supplementation on oxidant
been reported between a history of bone fractures and stress, and this has been extensively analyzed by
the plasma phylloquinone levels or the proportion of Coombes and Fassett [204]. Most studies using a-tocoph-
carboxylated vs. noncarboxylated osteocalcin in plasma erol have shown that it reduces measures of oxidant
[198]. In this latter study, serum PTH levels were found stress. The most important trial is the SPACE study,
to be high (>300 ng/L) only in patients with low plasma a randomized controlled trial including 196 MHD
phylloquinone concentrations. These patients also had patients that demonstrated the efficiency of oral vitamin
an abnormally high incidence of the apolipoprotein E, 800 IU/day, in the secondary prevention of cardiovas-
E3/4 and E4/4 genotype that may indicate impaired cular events [205]. Because many studies using statins or
tissue uptake of phylloquinone from chylomicrons cardiovascular drugs in this setting have failed to demon-
[199]. MHD patients with adynamic bone disease who strate a clinical benefit, this trial remains almost unique in
received vitamin K supplementation for one year dis- lowering the high burden of cardiovascular disease in
played a significant increase in serum PTH, alkaline CKD patients. Another study using N-acetyl-cysteine
phosphatase and the cross-linked N-terminal telopep- also showed reduced adverse cardiovascular events in
tide of type I collagen in association with a trend toward ESRD patients [206]. Oxidant stress in CKD and dialysis
a decrease in serum osteoprotegerin, a well-recognized patients should be a target for future studies. Other trials
factor associated with vascular calcification [200]. in small numbers of MHD and/or CAPD patients have
The bone reabsorptive effects of excess vitamin A shown that a-tocopherol therapy has a number of poten-
have been known for many years with a report of hyper- tially beneficial effects including vitamin E enrichment
calcemia with serum high vitamin A levels in CRF content of LDL [207], increased erythrocyte life span or
patients [201]. This condition should be considered in decreased EPO dose [208,209] and reduced LDL
VITAMIN METABOLISM AND REQUIREMENTS IN RENAL DISEASE 371
susceptibility to oxidation [210]. Studies with supple- neuropathy, there was dramatic improvement of symp-
mental vitamin C have shown conflicting results with toms in 14 patients who received pyridoxine HCl,
regard to the patients oxidant status, and none of them 60 mg/day, for four weeks, but not in 12 patients who
have addressed the patients clinical outcome. received vitamin B12, 500 mg/day orally, even though
the initial serum PLP was only slightly and not signifi-
Vitamin E-Coated Hemodialysis Membranes cantly lower than in controls [218]. However, no objec-
These membranes have been investigated as a way to tive measurement of motor nerve conduction velocity
reduce oxidative stress during HD treatment. Most clin- was reported. Also vitamin E alone or combined with
ical trials with these membranes have been carried out vitamin C is reported to reduce the incidence of cramps
for at least three months and have reported an increase in MHD patients [219].
in plasma or RBC vitamin E levels [211] and a decrease As indicated above, nicotinamide in large doses may
in plasma malondialdehyde (MDA) [212]. Other inhibit the Na/Pi type IIb cotransporter (Na Pi-2b) and
observed potentially beneficial effects of vitamin E the type IIa cotransporter (NaPi-2a) in the intestinal
coated membranes include decreased neutrophil activa- brush border and in the proximal renal tubular epithelial
tion, reduced decreased pro-oxidant activity of leuko- cells of the kidneys, respectively [40]. Twice-daily doses
cytes, reduced intradialytic IL-6 production, lower of 500 to 1500 mg of nicotinamide can reduce serum
serum oxidized-LDL and ADMA (asymmetrical di- phosphorus concentrations in maintenance hemodial-
methyl arginine) and reduced oxidative damage to ysis patients by blocking intestinal absorption of phos-
DNA. A recent study has provided evidence that in phorus. Large, randomized, prospective clinical trials
a 6-month controlled trial the use of vitamin E-coated are needed to demonstrate the long-term efficacy and
dialyzer membranes decreased serum CRP and safety of this treatment for preventing and treating
oxidized-LDL levels [213]. There is currently no trial excess body burden of phosphorus in CKD and chronic
that has examined morbidity and mortality with the dialysis patients.
use of these membranes.

Oxidant Stress in Renal Transplantation RECOMMENDATIONS FOR VITAMIN


Oxidative damage is particularly likely to occur at SUPPLEMENTATION AND VITAMIN
several steps during the course of kidney transplanta- THERAPY IN RENAL DISEASES
tion. Reperfusion after cold ischemia may lead to
marked oxidative bursts in the kidney. An antioxidant Vitamin supplementation to avoid deficiency and
mixture, including 10 mg of a-tocopherol, given 30 vitamin therapy to improve complications of renal
minutes before reperfusion, was able to reduce the failure are important issues for renal patients, as
degree of lipid peroxidation as assessed by the plasma morbidity and mortality remain high in this population.
MDA levels [214]. Cristol et al. [215] found evidence The DOPPS report [150] has stimulated new interest
for increased oxidative stress in 77 longstanding kidney in water-soluble vitamin supplementation in CKD
transplant recipients, including individuals with and patients. Also new data or the absence of confirmation
without chronic rejection. Evidence indicated that oxida- of previous ones (such as the SPACE study) has raised
tive stress was greater in the patients with chronic rejec- questions concerning the usual recommendations for
tion. However, McGrath et al. [144] did not observe fat soluble vitamins. Last but not least, vitamin supple-
differences in plasma TBARS (thiobarbituric acid reac- mentation, besides protein and energy intake, must not
tive substances) and plasma vitamin E concentrations be ignored in the ongoing debate regarding the delete-
in patients receiving cyclosporine or azathioprine rious effects and prevention and treatment of malnutri-
when compared to controls. Patients treated with tacro- tion on clinical outcome in CKD and ESRD patients.
limus were found to have increased susceptibility to
oxidation when compared to cyclosporine-treated
patients [216]. However, there is not enough evidence Vitamin Supplementation Across the World
yet to recommend the routine administration of antiox-
idant vitamins in renal transplant recipients [217]. The DOPPS report [150] has highlighted the wide
disparity of vitamin supplementation in hemodialysis
patients across the continents from 3.7% in the UK to
71.9% of MHD and CPD patients in the United States.
Potential Miscellaneous Clinical Benefits
Both the availability of specifically designed supplements
of Vitamin Therapy in CRF Patients for renal patients and the absence of strong clinical
In a randomized, blinded, prospective clinical trial evidence for a positive effect of vitamin supplementation
in 26 MHD patients with symptoms of peripheral on patient outcome may explain such differences.
372 NUTRITIONAL MANAGEMENT OF RENAL DISEASE

Existing Recommendations for Vitamin take a daily supplement of a multivitamin that provides
Supplementation or Therapy in Renal Patients the RDA or AI of the water soluble vitamins.

During the last decade, several guidelines on nutri- Vitamin A


tion in renal patients have been published (see Table Plasma vitamin A levels in CKD and maintenance
24.4). A few of them have issued statements on vitamin dialysis patients are elevated, and vitamin A deficiency
supplementation. The DOQI guidelines on nutrition has rarely been observed, and even small supplements
decided not to address vitamins because of lack of of vitamin A (i.e., 2500e15,000 IU, i.e. 750e4500 mg of
evidence regarding the effect of vitamin supplements retinol equivalents (RE)) may cause vitamin A toxicity.
on quality of life, morbidity or mortality [220]. The There is a consensus that supplemental doses of vitamin
CARI guidelines for nondialysis CKD patients [221] A larger then the Recommended Daily Allowance for
propose only suggestions for vitamin supplementation vitamin A in normal healthy adults (i.e., 700e900 mg of
because of the absence of Level I or II evidence. These RE, [53]) should not be given. However, the new find-
guidelines suggest that CKD patients following ings demonstrating that low plasma retinol levels are
a protein-restricted diet should receive supplementa- associated with increased mortality of chronic dialysis
tion with thiamine (>1 mg/day), B2 (1e2 mg/day) patients [81,82] raises questions concerning this
and B6 (1.5e2.0 mg/day of pyridoxine hydrochloride). consensus. Prudence dictates that vitamin A supple-
Recently Steiber & Kopple have reviewed the vitamin ments larger than the RDA should not be taken by
status in CKD 3e5 nondialysis patients and underlined advanced CKD or maintenance dialysis patients until
the risk of deficiency in these patients [222]. The Euro- more long term prospective trials demonstrate clinical
pean Best Practice Guidelines [219] recommend for benefits to greater supplements.
MHD patients 400e800 IU/day of vitamin E based on Since patients with the nephrotic syndrome may
the SPACE study for prevention of cardiovascular excrete vitamins that bind to protein, a daily intake of
events and the following daily amounts for vitamin B1 the RDA for vitamin A in these individuals is recom-
(1.1e1.2 mg), vitamin B2 (1.1e1.3 mg), vitamin B6 (10 mended. For renal transplant recipients, vitamin A
mg of pyridoxine HCl), vitamin C (75e90 mg), folic supplements do not appear to be necessary unless
acid (1 mg), vitamin B12 (2.4 mg), niacin (14e16 mg), patients received their renal transplant more than one
biotin (30 mg) and pantothenic acid (5 mg). They do or two years previously, their vitamin A intake is low
not recommend vitamin A supplementation, but tran- and their renal function is not markedly reduced.
sient vitamin K supplementation (10 mg/day) is sug- Vitamin A supplements are probably not necessary for
gested for patients undergoing prolonged antibiotic AKI patients unless they are given total parenteral nutri-
therapy or presenting with increased blood coagulation. tion without vitamin supplements for at least two or
Druml has summarized the needs for micronutrients three weeks. Given the risks of vitamin A toxicity in
in AKI receiving total parenteral nutrition [223] advanced CKD patients, and reports of vitamin A
(see Chapter 36). The ESPEN guidelines for parenteral toxicity in TPN patients with AKI receiving as little as
nutrition in adults with renal failure have emphasized 1500 mg of RE per day [147], it is recommended that no
the daily needs of vitamin C (up to 100 mg/day) and more then the RDA for vitamin A (800e1000 mg RE for
folates (up to 600 nmoles/day) because of losses with nonpregnant, nonlactating adults) should be given for
continuous dialysis techniques [224]. AKI patients receiving TPN as the sole nutritional
source.

Vitamin E
Vitamin Supplementation Reappraisal
The SPACE study [205] and the well-recognized
To analyze and comment on the foregoing published pro-oxidant state of uremia would support the recom-
recommendations, it is necessary to summarize our mendation of a-tocopherol supplementation in MHD
knowledge regarding the nutritional status of each patients to prevent cardiovascular events at the dose
vitamin in CKD3-5 and ESRD patients and the evidence of the SPACE study, i.e. 800 IU. However the HOPE
supporting supplementation. The following recommen- study did not show clinical benefit of vitamin E
dations for nondialyzed CKD3-5 patients also apply to supplements in individuals with or without chronic
nondialyzed CKD1-5 patients with the nephrotic renal insufficiency [225,226]. Moreover, subsequent
syndrome unless stated otherwise. Not withstanding analysis of the HOPE trial and its extension (HOPE-
the foregoing recommendations, in locations where TOO) have shown an increased risk of heart failure
multivitamin preparations specifically designed for in patients under vitamin E supplementation [227].
CKD and chronic dialysis patients are not available, it In individuals without renal disease, platelet dysfunc-
may be prudent to recommend that such individuals tion and interference with the vitamin K-dependent
TABLE 24.4 Recommendations/Suggestions for Daily Vitamin Supplementation in Renal Patients

Nephrotic
Syndrome Acute Renal
RDA in Healthy CKD3-5 Non-Dialysis Non-Dialysis Failure Patients
Subjects Patients CKD3-5 Patients CKD3-5 Patients MHD Patients MHD Patients CPD Patients with TPNa,b

Origin Dietary reference Authors CARI [221], Steiber & Koppleb EBPG [219] Authors Authors Chapter 36
intake [53,234,236] suggestions [222] suggestions suggestions [223]
700e900 REc Up to RDAd Up to the RDAd Nonee

VITAMIN METABOLISM AND REQUIREMENTS IN RENAL DISEASE


Vitamin A None None RDA
d d d,f d,f
Vitamin E 22.5 IU Up to RDA Up to the RDA 400e800 IU up to the RDA up to the RDA RDA
g g g
Vitamin K 80e120 mg None Supplements if None None None RDA
antibiotherapy
Vitamin B1 1.1e1.2 mg Unknownh >1 mg 1.1e1.2 mg 1.1e1.2 mg 1.1e1.2 mg 1.1e1.2 mg RDA2
h i
Riboflavin 1.1e1.3 mg Unknown 1e2 mg ?? 1.1e1.3 mg 1.1e1.3 mg 1.1e1.3 mg RDA2
j
Vitamin B6 1.3e1.7 mg 5 mg 1.5e2 mg 5 mg 10 mg 10 mg 10 mg RDA2

Vitamin C 75e90 mg 75e90 mg 30e60 mg 75e90 mg 75e90 mg 75e90 mg RDA2


h d
Folic acid 400 mg Unknown Up to the RDA 1 mg 1 mg 1 mg RDA2
Vitamin B12 2.4 mg RDA RDA 2.4 mg 2.4mg 2.4 mg RDA2
h d
Niacin 14e16 mg Unknown up to the RDA 14e16 mg 14e16 mg 14e16 mg RDA2
h k,l
Biotin 30 mg Unknown Up to AI 30 mg 30 mg 30 mg RDA2
h k
Pantothenic acid 5 mg Unknown Up to AI 5 mg 5 mg 5 mg RDA2
a
TPN: Total Parenteral Nutrition.
b
Endorsed by the authors.
c
Retinol equivalent.
d
For patients ingesting less than the DRI.
e
Recent data on vitamin A and survival question this usual recommendation.
f
Caution is required after subsequent analysis and extension of the HOPE study.
g
10 mg/d if prolonged antibiotic therapy or low food intake.
h
Insufficient data.
i
To supplement if restricted protein diet. Amount nonspecified.
j
Refers to pyridoxine HCl.
k
Refers to Adequate Intake reflecting the average intake in the normal population. There not enough data to establish RDA. Risk of deficiency in low protein diet.
l
Absent from Steiber & Kopple review [222]. Reported by the authors of the current review.

373
374 NUTRITIONAL MANAGEMENT OF RENAL DISEASE

coagulation factors have been reported with pharma-


cological doses of vitamin E [16]. As the SPACE trial Vitamin B6
has not been confirmed and the findings of the Most workers in the field agree that there is a need
HOPE study follow-up and extension, it appears for routine pyridoxine supplementation in CKD,
necessary to wait for more data before recommending MHD, CPD patients and nephrotic patients. Recommen-
a supplemental daily vitamin E intake in CKD and ded supplemental pyridoxine HCl doses vary from
dialysis patients. 1.2 mg/day [46] to 50 mg 3 times/week [186]. These
recommended doses were not based on dose response
Vitamin K studies, and therefore the daily vitamin need might
Because of the high risk of thrombosis associated actually be lower than was recommended. Kopple
with the nephrotic condition and the frequent need et al. [228], in a dose response study, described normal-
of coumarin-derivatives for its prevention, vitamin K ization of the EGPT index in all nondialyzed CKD
supplementation is not recommended for nephrotic patients given a supplement of 5 mg/day of pyridoxine
patients. Since CKD and dialysis patients generally HCl (4.1 mg/day of the pyridoxine base); in patients
do not have evidence for vitamin K deficiency, as given a lower amount of pyridoxine HCl, the EGPT
determined by clotting factors or clotting function, index became normal more slowly or did not normalize
vitamin K supplements generally have not been rec- at all. In MHD patients, various doses of pyridoxine HCl
ommended. However, it could be argued that vitamin have normalized one or more parameters of vitamin B6
K status should also be assessed using ucMGP and status. However, the lowest pyridoxine HCl supplement
ucBGP in order to determine whether a CKD or that has consistently normalized a parameter of vitamin
ESRD patient should receive supplemental vitamin B6 deficiency (i.e., the EGPT index) is 10 mg per day
K. Traditionally, vitamin K supplements have been [229]. In CAPD patients, the lowest pyridoxine HCl
proposed for patients who are eating poorly and dose that normalized vitamin B6 nutriture (i.e., serum
receiving antibiotics that may suppress intestinal PLP levels) was also 10 mg per day [115]. In eight chil-
bacterial flora, particularly for extended periods of dren undergoing CPD, 10 mg daily of pyridoxine HCl
time, because they are probably at increased risk for increased serum PLP to twice the normal control levels
developing vitamin K deficiency. Patients receiving [230]; lower doses of pyridoxine HCl would probably
TPN for more than one to two weeks should receive be adequate for this pediatric population. It is important
vitamin K. to remember that the pyridoxine HCl dose that engen-
ders a normal serum PLP level may not necessarily indi-
Vitamin B1 cate the desirable daily dose. There may be inhibitors,
The recommended amounts of thiamin for supple- altered binding or cellular transport, or discrepant intra-
mentation of MHD and CPD patients have ranged cellular concentrations, etc. for vitamin B6 in renal
from 1 to 45 mg daily [37,46]. The thiamin intake from failure. In the absence of evidence to the contrary, it
food is generally about 0.6 to 1.5 mg/day in patients seems sensible to accept normal plasma levels as an
with CKD, MHD or CPD. ETKA stimulation index and appropriate or criterion for determining the desirable
serum thiamin levels are usually normal in patients daily vitamin B6 dose. In MHD patients, Mydlik et al.
with CKD, MHD or CPD. When thiamin deficiency is [189] recommended 20 mg/day of pyridoxine HCl to
present, correction is readily obtained by feeding low correct or prevent a decrease in RBC vitamin B6 levels
quantities of thiamin. Thus, we recommend a thiamin that may occur after several months of EPO treatment.
supplement of 1.1e1.2 mg/day in nondialyzed CKD3- Again, this was not a dose response study. In renal trans-
5, MHD and CPD patients (Table 24.4). Although these plant recipients, no dosage studies have been con-
patients may receive adequate thiamin from their ducted. Based on these foregoing data, we
ingested foods, their food intake is not uncommonly recommended a daily of 5 mg of pyridoxine HCl for
low, and, as indicated above, thiamin deficiency has CKD3-5 patients and 10 mg for MHD and CPD patients
been reported in these patients. (Table 24.4).
Pyridoxine has been given as pyridoxilate, which is
Riboflavin a vasodilator that has been used to treat coronary artery
Recommendations regarding riboflavin supplemen- and peripheral circulatory insufficiency. This medicine
tation vary from no supplement to an amount equiva- can cause oxalate nephropathy and end stage renal
lent to the RDA. Low doses of riboflavin (1 mg/day) disease [231]. Also very high doses of pyridoxine HCl
were enough to normalize a-EGR in CAPD patients (i.e., 200 to 600 mg/day), occasionally have been associ-
[67]. We recommend a daily riboflavin supplement ated with peripheral neuropathy in patients without
equal to the RDA for CKD 3-5 and chronic dialysis renal disease [232]. CKD patients may have impaired
patients. ability to excrete metabolites of vitamin B6. Thus, it is
VITAMIN METABOLISM AND REQUIREMENTS IN RENAL DISEASE 375
possible that these metabolites might accumulate and and red cell folate levels are usually normal in CKD
interfere with the normal, active metabolites of B6. and maintenance dialysis patients, some patients still
Indeed, 4-pyridoxic acid, the main metabolite of vitamin have low folate concentrations. A low protein diet
B6, is excreted primarily in the urine and might be usually provides a folic acid daily intake below the
expected to accumulate in patients with renal failure, RDA. High efficiency/high flux dialysis increases the
particularly in those taking vitamin B6 supplements. risk of folate deficiency. Also, as indicated above, there
Therefore, until more information is available, caution may be endogenous as well as exogenous (i.e., from
should be exercised when prescribing very large doses medicines) inhibitors of folic acid in renal failure, and
of pyridoxine HCl to nondialyzed CKD and mainte- this inhibition may not be reflected in the plasma or
nance dialysis patients (i.e., 100 mg/day or greater) for red cell folate levels. Hence a daily supplement of 1
extended periods of time. mg of folic acid is recommended for CKD3-5, MHD
and CPD patients (Table 24.4).
Vitamin C
Many studies suggest that a substantial subset of Vitamin B12
MHD and CPD patients are at risk for vitamin C defi- Vitamin B12 deficiency is unusual in CKD and main-
ciency if they do not receive supplements, and several tenance dialysis patients, and most authors do not think
authors have recommended various amounts of daily that vitamin B12 supplementation is necessary. On the
ascorbic acid. The combination of insufficient dietary other hand a daily supplement of about 3 mg of vitamin
intake of vitamin C and dialysate losses appears to be B12, as part of a multivitamin preparation, is very safe
primarily responsible for the risk of deficiency. and inexpensive and might occasionally help to prevent
However, there is no clear evidence that the dietary vitamin B12 deficiency.
vitamin requirement is increased in maintenance dial-
ysis patients, at least with regard to the amount neces- Niacin
sary to maintain normal plasma ascorbic acid levels. A low protein diet may provide only small amounts of
Indeed the lack of urinary vitamin C excretion will at niacin, and some studies have demonstrated niacin defi-
least to some extent offset the dialysate losses. On the ciency in dialysis patients. We therefore recommend the
other hand, larger doses of vitamin C have been associ- RDA of niacin as a supplement for CKD3-5 and chronic
ated with increased oxalate concentrations in plasma dialysis patients. The use of niacin as phosphate lowering
and possibly soft tissues. It is possible that the ascorbic therapy or as a cholesterol-lowering therapy in CKD and
acid clearance with high efficiency and/or high flux chronic dialysis patients requires further study.
hemodialyzers may increase the dietary requirement
for vitamin C. However, considering the small size of Biotin
ascorbic acid (molecular weight, 176), it is not likely There is no RDA for biotin intake in healthy subjects,
that highly permeable dialyzers will markedly increase but there is an estimation of the biotin need referred to
the dialysis losses of vitamin C. Thus, at the present as the Adequate Intake [234]. In the absence of data
time, it is recommended that nondialyzed CKD3-5, to estimate the RDA, the Adequate Intake (AI) is
MHD and CPD patients be prescribed the nonpregnant, provided. It reflects the average intake in the normal pop-
nonlactating adult RDA for ascorbic acid, 75e90 mg/ ulation. The need for supplemental biotin in renal failure
day (Table 24.4). patients is controversial. Biotin deficiency is not reported
in CKD and chronic dialysis patients. However, a low
Folic Acid protein diet provides a biotin daily intake below the AI.
There is no consensus regarding the need for folate Again, because CKD3-5, MHD and CPD patients not
supplementation in patients with CKD patients not uncommonly have low food intakes, it is recommended
receiving dialysis as well as those undergoing MHD that they receive a daily biotin supplement equal to the
or CPD. Folic acid supplements appear to be safe for AI for healthy adults (Table 24.4).
such patients, even at the range of doses prescribed to
reduce plasma Hcy levels. Exceptions are the possi- Pantothenic Acid
bility that folate treatment could mask the hematolog- There are few data on which to base recommenda-
ical disturbances associated with vitamin B12 tions concerning the needs, if any, for supplemental pan-
deficiency or that metabolites of folate might be toxic, tothenic acid. Low protein diets have reduced
possibly by inhibiting cellular transport of folate. pantothenic acid content. The reported hemodialyzer
Possible mild side effects of folate, such as nausea, clearances of pantothenic acid in older reports are not
headache, or vivid dreams, have been reported, usually negligible, and the clearances with high flux and/or
with a dose of 5 mg/day or greater [233]. Although high efficient dialysis are unknown. Low concentrations
many of the more recent studies indicate that plasma of pantothenic acid have been found in one study in
376 NUTRITIONAL MANAGEMENT OF RENAL DISEASE

unsupplemented dialysis patients [136]. As with biotin, ESRD patients and what effective methods can eradicate
there is no RDA for pantothenic acid in normal individ- these increased levels. It therefore can be concluded that
uals, but only an estimation of needs; the Adequate the field of vitamin metabolism and nutriture in renal
Intake estimation. It is recommended that CKD3-5, diseases and renal failure is wide open for more basic
MHD and CPD patients receive daily the AI for panto- and clinical research.
thenic acid.

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