Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set

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boiling vegetables and discarding the water. It is not

possible to state an absolute amount for the advised

intake; 0.6–1 mmol kg

1

IBW will help to keep

the plasma levels below 5.5 mmol l

1

. The use of

potassium-losing diuretics and calcium resonium – a

potassium binder – may be appropriate.

Sodium and Water

0015 Kidney diseases such as diabetic nephropathy and

some forms of glomerular nephritis are characterized

by retention of sodium and water with resulting

hypertension and edema. However, interstitial neph-

ritis, e.g., chronic pyelonephritis, may initially pre-

sent with a failure to concentrate urine, leading to

sodium and water loss and potential dehydration.

The nonpharmacological approaches that have been

used to treat hypertension in the nonrenal population

may be of some benefit in the renal population: diet-

ary sodium restriction, weight control, and control of

other risk factors for coronary heart disease. Sodium

restriction also potentiates the action of ACE inhibi-

tors, diuretics, and b blockers. As the kidney loses its

ability to respond rapidly to changes in sodium

intake, any restrictions should be implemented grad-

ually. The dietary changes would include not adding

salt to cooking or at the table and reduction of

processed, tinned, or convenience foods. Comprom-

ises have to be made for the elderly patient who relies

on these foods as dietary staples. To improve the

palatability of the diet, a wide range of herbs and

spices can be used. The recommended level of restric-

tion is usually 80–100 mmol (1.8–2.3 g) of sodium

per day.

0016 Table 5 gives a summary of dietary advice for

conservative management (prior to starting RRT).

Other Nutritional Concerns

0017 Malnutrition A spontaneous decline in nutritional

intake has been recorded in patients approaching

ESRF. Unfortunately, loss of body weight is often

masked by increasing levels of fluid, giving the im-

pression that the weight is stable. A poor nutritional

state when the patient enters the dialysis program will

have a negative affect on morbidity and mortality,

so it is important to monitor these patients as they

approach ESRF irrespective of whether any dietary

restrictions have been advised.

0018Anemia The anemia of CRF has many causes, in-

cluding (1) decreased production of EPO, (2) poor

iron, folate or B

intake due to a low protein diet

or a poor appetite, (3) poor iron absorption due to

drug interactions, and (4) chronic blood loss due

to disturbed clotting mechanisms. Anemia contrib-

utes to extreme fatigue, loss of appetite, and taste

changes. Plasma levels of ferritin, hemoglobin, vita-

min B

, and red blood cell folate help determine the

need for iron, folate and B

supplements, and EPO

injections.

0019Hyperlipidemia Hyperlipidemia (raised cholesterol

and triglycerides) is a common complication of renal

failure. There is evidence in animal models that it may

increase the rate of progression of the disease, but this

has not been shown in humans except in the progres-

sion of diabetic nephropathy. There is, however, a

greatly increased risk of cerebro- and cardiovascular

disease, which accounts for 60% of deaths in renal

patients. HMG CoA (3 hydroxy, 3 methyl giutaryl

coenzyme A) reductase inhibitors are being used to

reduce cholesterol levels, and trials of fish oil supple-

ments are promising. Although diet and drug inter-

ventions have been shown to reduce risk factors,

including improving the lipid profile, as yet, there

have been no studies to show that this actually results

in decreased mortality in renal patients. Extrapolating

from the nonrenal population, it seems wise to en-

courage the principles of healthy eating, weight loss if

the body mass index is higher than 30, and regular

exercise.

tbl0005 Table 5 CRF diet (conservative management prior to ESRF)

Nutrient (recommended daily intake) Rationale

Protein 0.6–1.0 g kg

1

IBW As described in the text. With the lower-protein diet, the patient is given a meal

plan comprising HBV (60%) and LBV (40%) protein foods: to insure all the

amino acid requirements are met

Energy 35 kcal kg

1

IBW or use Schofield

equations, for example

Normal adult requirements. Calorie sources should not exacerbate

hyperlipidemia, i.e., total fat 30% of energy, low saturated fat. Encourage

good glycemic control in diabetics. NB: Monitor for signs of malnutrition

Phosphate 0.3–0.5 mmol kg

1

IBW Plasma levels should be maintained between 0.8 and 1.5 mmol l

1

Sodium 80–100 mmol per day. Fluid – no restriction

usually required

Salt restriction will help potentiate action of antihypertensives

Potassium 0.6–1 mmol kg

1

Levels should be maintained between 3.5 and 5.5 mmol l

1

. Restriction may not

be necessary until patient has reached ESRF

Vitamins and minerals May be required with lower protein diets and if potassium restriction is advised

4946 RENAL FUNCTION AND DISORDERS/Nutritional Management of Renal Disorders

Nephrotic Syndrome (NS)

0020 NS is characterized by proteinuria > 3 g per day,

hypoalbuminemia, edema, and hyperlipidemia. It is

usually also associated with hypertension. NS appears

as an additional complication in a number of types of

kidney disease (Table 6). Treatment involves antihy-

pertensive agents, immunosuppressants, diuretics,

salt-poor albumin, and dietary modifications.

Protein

0021 Historically, a high protein diet was advised on the

grounds that protein losses in the urine needed to be

replaced. However, studies comparing low (0.8 g

1

) and high protein (1.5 g kg

1

) diets showed

that proteinuria was reduced with the lower protein

diets, although not all studies showed a correspond-

ing increase in plasma albumin levels. It has been

shown that a high protein intake causes increased

permeability and hyperfiltration in the basement

membrance of the kidney glomeruli, and this may be

the mechanism that explains the poor results of high

protein diets in NS. In addition, phosphate, lipid and

renin levels tended to improve on the lower protein

diets. An intake of 0.8–1 g of protein per kilogram per

day has been recommended.

Salt

0022 The kidneys tend to retain sodium and water in NS,

and patients benefit from a moderate dietary sodium

restriction: 80–100 mmol per day, and if edema is

present, a fluid restriction is also necessary. Sodium

restriction can potentiate the antihypertensive and

antiproteinuric effects of ACE inhibitors.

Fat

0023 Both triglycerides and cholesterol are raised in NS.

The incidence of myocardial infarction has been

reported as 5.5 times greater in NS compared with

normal. Lipid lowering agents are used in conjunc-

tion with standard lipid-lowering advice.

Micronutrients

0024 Iron, copper, zinc, and vitamin D are also lost as a

result of proteinuria. Vitamin D losses can result in

derangements of calcium metabolism, and supple-

mentation may be necessary.

Renal Replacement Therapy

Hemodialysis (HD) and continuous ambulatory

peritoneal dialysis (CAPD)

0025The nutritional problems of renal patients do not stop

once renal replacement therapy is started. Even with

dialysis, it is not possible to maintain body fluid,

potassium, and phosphate levels within the normal

ranges without some degree of dietary restriction. On

the positive side, some of the symptoms of uraemia

such as nausea, taste changes and gastrointestinal

disturbances improve. Usually, there is an increase in

appetite within 1 month of starting dialysis.

0026Dialysis itself has a number of negative effects on

the nutritional state (Tables 7 and 8). In addition,

some global factors affect the patient’s well-being:

0027The procedure itself is time-consuming, and travel-

ing to and from hospital for unit HD severely

disrupts the patient’s day, including meal times.

0028It is important that the risk of infections from the

procedures be minimized as the catabolic effects of

line infections and peritonitis can have long-term

consequences for the patient’s nutritional status.

0029Underdialysis – as measured by urea and creatinine

clearance – leads to impaired nutritional intake.

There are now set standards that describe the

amount of dialysis required in order to minimize

morbidity and mortality.

0030Depression can affect the patient for a number of

reasons: inability to keep full-time employment,

financial problems, body-image problems – as the

treatment can be disfiguring, restrictions on travel-

ing, dietary restrictions, and physical weakness due

to the long-term metabolic effects on bone and

muscle metabolism.

0031It is important to maintain normal hemoglobin

levels as anemia causes decreased appetite and

poor physical functioning. Injections of EPO and

iron are normally required to achieve this.

A team of professionals is necessary to treat the renal

patient and help them achieve the best quality of life.

In addition to medical and nursing staff, this should

include a dietitian, social worker, physiotherapist,

and counselor.

0032It is estimated that 30 – 70% of dialysis patients fall

into the moderate- to high-risk categories for malnu-

trition. Protocols for routinely assessing the nutri-

tional status of each patient must be in place in

order to identify problems early. Subjective global

assessment has been validated for use in dialysis

tbl0006 Table 6 Renal diseases which may develop nephrotic

syndrome

Glomerulonephritis

Diabetic nephropathy

Amyloidosis

Systemic lupus erythematosus

Vasculitis

Toxic glomerulopathy (gold, penicillamine)

RENAL FUNCTION AND DISORDERS/Nutritional Management of Renal Disorders 4947

patients; this combines medical history, including

dietary assessment, with a physical examination of

fat and muscle stores. There is a wide range of nutri-

tional supplements available for the first-line treat-

ment of malnutrition, and for the more severely

malnourished patient, gastrostomy feeding (HD and

CAPD) and intradialytic parenteral nutrition (IDPN)

in HD patients have been used successfully. An amino

acid containing CAPD solution is available and may

be of use in certain cases of hypoalbuminemia caused

by a persistent low protein intake.

0033 The dialysis diet should be tailored to the individ-

ual patient taking into consideration their medical

treatment and psychosocial factors. It is also guided

by regular monitoring of biochemical profiles that

usually occur monthly for HD and every 2 months

for CAPD patients. For the well-nourished patient,

healthy eating principles should continue to be

encouraged within the constraints of the potassium

restriction.

Transplantation

0034The positive effects of transplantation are to relieve

the patient from dietary and other lifestyle restric-

tions imposed by dialysis, and the patient experiences

a general improvement in well-being. This in itself

can lead to large gains in body weight as the patient

eats more in general. In addition, the immuno-

suppressive therapy can exacerbate the long-term

metabolic effects of CRF such as bone disease, muscle

tbl0007 Table 7 HD diet

Nutrient (recommended daily intake) Rationale

Protein 1.1–1.3 g kg

1

IBW From nitrogen balance studies (although numbers were small and may not

be applicable to all ethnic groups). 8–12 g of amino acids lost per dialysis.

Possible poor intake on dialysis days

Energy 35 kcal kg

1

IBW or use Schofield equations. Normal adult requirements. 25 g of glucose lost if glucose free dialysate is

used

Phosphate 0.5 mmol kg

1

IBW Plasma levels should be maintained between 1.2 and 1.7 mmol l

1

Phosphate is not well dialyzed, so restriction is necessary, aided by

phosphate binders

Sodium 80–100 mmol per day. Fluid 500 ml þ previous

day’s urine output

Urine output decreases once dialysis starts. Salt restriction will help

prevent thirst. Maximum of 2 kg interdialytic weight gain recommended.

Fluid overload leads to left ventricular heart disease and hypertension

Potassium 1 mmol kg

1

Plasma levels should be maintained between 3.5 and 6.5 mmol l

1

tbl0008 Table 8 CAPD diet

Nutrient (recommended daily intake) Rationale

Protein 1.2–1.5

gkg

1

IBW From nitrogen balance studies (although numbers were small, and

nitrogen balance was achieved at lower levels in some individuals).

9 g of protein/amino acids lost per day.

Energy 25–30 kcal kg

1

IBW þ energy from dialysate or

use, e.g., Schofield equations

Normal adult requirements. 70% of glucose is absorbed from the ‘bag’

of dialysate fluid. This can provide 300–1000 calories per day,

depending on the glucose concentration in the bag. This leads to

hypertriglyceridemia, obesity, and poor glycemic control in diabetics

Phosphate 0.5 mmol kg

1

IBW Plasma levels should be maintained between 1.1 and 1.6 mmol l

1

Phosphate is not well dialyzed, so restriction is necessary, aided by

phosphate binders

Sodium 80–100 mmol per day. Fluid 500 ml þ previous

day’s urine output. Additional fluid may be taken if

the patient ultrafiltrates (removes fluid during

dialysis) well

Urine output decreases once dialysis starts. Salt restriction will help

prevent thirst. Overdrinking leads to overuse of the higher sugar

containing bags of dialysis fluid and the problems described above

Potassium *1 mmol kg

1

IBW Levels should be maintained between 3.5 and 5.5 mmol l

1

. As dialysis

is continuous, hyperkalemia is less of a risk than on HD. The diet can

be more varied with respect to high-potassium foods

Vitamins (HD and CAPD) There is no consensus on the routine use of vitamins. Folate, pyridoxine,

and vitamin C levels are reported to be low without supplementation.

Folic acid supplements may also reduce homocysteine (risk factor for

CVD). Fat-soluble vitamins are not supplemented, except vitamin D,

as discussed earlier.

Larger protein requirements applicable during peritonitis.

4948 RENAL FUNCTION AND DISORDERS/Nutritional Management of Renal Disorders

wasting, and cardiovascular disease. The main aims

of dietary therapy are to reduce the risk factors for

cardiovascular disease, which is the cause of 60% of

deaths in transplant patients. All the aspects of

‘Healthy Eating’ should be encouraged. Patients may

be reluctant at first to increase their intake of fruits

and vegetables and even oily fish, as these would have

been restricted on the dialysis diet. Intensive dietary

counseling prior to discharge with regular follow up

in outpatient clinics has been shown to reduce the

average weight gain from 12 to 6 kg in the first year.

Lipid levels can also be improved with advice on

appropriate fat and sugar intake. An increasing

amount of literature is showing that encouraging

exercise at all stages of renal disease helps to improve

physical mobility, and extrapolating from the nonre-

nal population may further reduce risk factors for

CVD.

Acute Renal Failure (ARF)

0035 ARF can be defined as an abrupt decline in renal

function. Initially, there is oliguria (< 400 ml per day)

or anuria, retention of the end products of protein

metabolism, acidosis, and electrolyte imbalance. Bio-

chemical profiles show a rapid increase in urea and

creatinine, and also potassium and phosphate levels

can increase. ARF is usually reversible, and as renal

function returns, there may be polyuria to an extent

where potassium and phosphate levels can drop

below normal, and salt and water depletion can

occur. As the causes of ARF are so varied, the effect

on nutritional requirements may be negligible or, in

the case of severe trauma or sepsis, cause a hypercata-

bolic state. Protein and energy requirements are cal-

culated using standard formulae and stress factors

and are related to the underlying causes. ARF in itself

has specific effects on protein, fat, and carbohydrate

metabolism, but the literature is less clear about how

this impacts on the final nutrient prescription. ARF

can be divided into three categories:

0036 Noncatabolic: nontraumatic causes such as

obstruction and interstitial nephritis from drugs.

0037 Catabolic: postsurgery, rhabdomyolysis, and

hemolytic uremic syndrome.

0038 Hypercatabolic: major trauma (road traffic acci-

dent), burns, and sepsis.

Noncatabolic ARF

0039 As in CRF, the aims of treatment are to slow down the

build-up of uremic toxins and fluid overload in order

to prevent or alleviate symptoms, to maintain good

nutritional status, and to prevent weight loss. Dialysis

may or may not be necessary. Nausea and lack of

appetite are common features, and the main concern

is insuring the patient is meeting their nutritional

requirements sometimes with the help of dietary sup-

plements. Restriction of dietary protein < 0.8 g protein

per kilogram is not recommended. It is usually accept-

able to aim for a ‘normal’ protein intake of 1 g per

kilogram IBW per day. Advice on salt intake – aiming

for 80–100 mmol per day, fluid restriction – 500 ml

plus PDUO (previous days urine output) and potas-

sium restriction < 1 mmol kg

1

may be necessary.

In practice, all that is usually required is a simple

diet sheet advising the patient and their relatives on

suitable snacks and drinks. The usual ‘treats’ that

people receive in hospital, i.e., fruit juice, fruit, and

chocolate, may not be acceptable. High plasma

phosphate levels can be controlled by phosphate

binders.

Catabolic and Hypercatabolic ARF

0040The patient will almost certainly require dialysis

treatment as the rate of production of waste products

will otherwise cause severe and potentially fatal

uremia. The type of dialysis will also affect nutrient

requirements and the ability to provide them through

nutritional support. Intermittent HD may be suf-

ficient in noncatabolic or moderately catabolic

patients, but as the severity of catabolism increases,

continuous dialysis may be required, e.g., continuous

arteriovenous HD (CAVHD). Losses of 9–13 g of

protein per day can occur with this therapy. With

1.5% glucose in the dialysate solution, there is a net

gain of glucose of 6 g h

1

, which represents an energy

intake from dialysis of 550 kcal per day. The effects

of dialysis on nutrient losses and gains should be

taken into consideration when prescribing the feeding

regimen.

0041Protein requirements Catabolic patients require in

the region of 9–14 g of nitrogen (56–87 g of protein)

per day. Hypercatabolic patients may break down up

to 40 g of nitrogen (235 g of protein) per day, but the

liver cannot deaminate more than 20 g of nitrogen

(117 g of protein) per day, so this is the maximum

that can be replaced by nutritional support.

0042Carbohydrate Glucose utilization is limited by ARF,

and excessive amounts can cause lipogenesis, fatty

liver, and increased carbon dioxide production. Pro-

vision of carbohydrate should not exceed the max-

imum oxidation rate of 4 mg per kilogram IBW per

minute.

0043Fat As the metabolism of fat is impaired in ARF, an

upper limit of 1 g of fat per kilogram per day is

recommended.

RENAL FUNCTION AND DISORDERS/Nutritional Management of Renal Disorders 4949

0044 Fluid and electrolytes With intermittent HD, a feed-

ing regimen containing reduced fluid, sodium, and

potassium may be necessary and may limit the macro-

nutrient provision from an enteral or parenteral

feed. Continuous dialysis and ultrafiltration obviate

the need for a fluid (and usually also electrolyte)

restriction.

0045 Phosphate Hyperphosphatemia is a common fea-

ture of ARF, and initially, TPN (total parenteral nu-

trition) regimens can be phosphate-free. Anabolism

and dialysis will lower serum phosphate, and the

requirements would be reassessed at this stage.

0046 Vitamins and minerals Requirements for micro-

nutrients are not well documented. Water-soluble

vitamins tend to be given daily in the standard

amounts and trace elements given only once or

twice a week. Fat-soluble vitamins are not required

in the short term.

Renal Stone Disease (Nephrolithiasis)

0047 Renal stone formation occurs as a result of increased

urinary concentration of promotor substances and

decreased concentration of inhibitor substances

(Table 9). This is partly influenced by dietary factors

but can also be linked to congenital abnormalities, as

seen in polycystic kidneys, horseshoe kidneys, and

medullary sponge kidney or to short bowel syn-

dromes such as Crohn’s disease. The stones vary in

composition, but the main types include combin-

ations of calcium, oxalate, and phosphate. The size

of the stones can vary from microscopic to the large

‘staghorn’ calculi, and can lead to kidney failure if the

kidney or urinary tract becomes obstructed.

0048 A number of dietary factors can contribute to the

management of stone disease.

Fluid

0049 An adequate fluid intake of 2–3 l a day is encouraged

to ensure a minimum urine output of 2 l per day.

Specifically, patients are told to drink 250 ml every

four waking hours, with 250 ml at meals. Compliance

with this single measure has been shown to reduce

new stone formation by diluting the concentration of

stone-forming salts, and may prevent new stone for-

mation in up to 60% of patients with ideopathic

calcium urolithiasis.

Calcium

0050Forty to 50% of people who develop stones have a

higher level of calcium in the urine (daily excretion

> 4 mg kg

1

, although absolute amounts are also

relevant).

0051There are a number of dietary factors that can

cause hypercalcuria:

0052excessive intake of calcium or vitamin D particu-

larly as supplements;

0053high salt intake; and

0054high protein intake, particularly from animal

protein.

The ideal level of calcium intake has not been ascer-

tained – what is known is that a low dietary intake of

calcium will exacerbate intestinal absorption of oxal-

ate and promote stone formation. In a number of

patients, a low calcium diet will also escalate an

underlying tendency to osteoporosis. Intake of cal-

cium supplements, however, is associated with an

increased risk of stone formation, and therefore, on

balance it is advisable to aim for the normal reference

nutrient intake for calcium (700–800 mg per day)

from diet, not supplements. There is also evidence

showing that calcium excretion increases with

sodium intake and protein intake. A moderate intake

of no more than 100 mmol of sodium per day is

recommended, and 1 g of protein per kilogram of

body weight is thought to be appropriate.

Oxalate

0055Calcium oxalate stones account for up to 75% of

stones formed. Oxalate is mostly formed endogen-

ously; only 10% comes from the diet, although the

proportional change in excretion is quite significant

if calcium intake is decreased or oxalate intake

increases. Therefore, it still helps to avoid or reduce

intake of high oxalate foods such as tea, rhubarb,

beetroot, chocolate, cocoa, nuts, spinach, and straw-

berries. American sources also name gooseberries,

sweet potato, leek, parsley, okra, and wheat bran.

Unfortunately, there are no comprehensive lists of

oxalate-containing foods and their bioavailability.

High vitamin C intake increases oxalate production,

although the doses stated are in excess of 1 g per day.

0056Other dietary factors that may have a role are

dietary fiber and phytates, which reduce the amount

of calcium absorbed by the gut, but this may then

increase the amount of oxalate absorbed.

tbl0009 Table 9 Risk factors for renal stones

Low urine volume particularly < 1000 ml per day

High urinary concentrations of:

Calcium

Oxalate

Low urinary concentrations of:

Citrate

Urine acidity

4950 RENAL FUNCTION AND DISORDERS/Nutritional Management of Renal Disorders

Uric Acid

0057 Uric acid excretion is involved in calcium and also uric

acid stone formation. Uric acid is an end product of

purine metabolism, and dietary restriction of purines

and animal protein will reduce its urinary excretion.

Purine-rich foods include liver, kidney, brain, ancho-

vies, sardines, herring, mackerel, mussels, scallops,

goose, partridge, and yeast.

0058 In summary, stone formation is multifactorial, so in

order to give appropriate dietary advice, it is neces-

sary to have an analysis of the stone composition and

urinary concentrations of the risk factors (Table 9). It

is then necessary to take a detailed diet history in

order to identify excesses or deficiencies or general

trends in dietary intake.

See also: Calcium: Physiology; Energy: Intake and Energy

Requirements; Hyperlipidemia (Hyperlipidaemia);

Malnutrition: The Problem of Malnutrition; Phosphorus:

Physiology; Potassium: Physiology; Protein:

Requirements; Sodium: Properties and Determination;

Vitamins: Overview; Water: Physiology

Further Reading

Brown MA and Whitworth JA (1992) Hypertension in

human renal disease. Journal of Hypertension 10:

701–712.

Engel B et al. (1998) Setting Standards and Achieving

Optimal Nutritional Status. Birmingham, UK: British

Dietetic Association.

Giovannetti S (1989) Nutritional Treatment of Chronic

Renal Failure. Dordrecht: Kluwer Academic.

Greenberg A (1994) Primer on Kidney Diseases. London:

Academic Press.

K/DOQI (2000) Clinical practice guidelines for nutrition in

chronic kidney failure. American Journal of Kidney

Diseases 35(6) (supplement 2): s1–s137.

Lazarus JM (1993) Nutrition in haemodialysis patients.

American Journal of Kidney Diseases 21(1): 99–105.

Levey AS (1998) Controlling the Epidemic of CVD in CRD.

USA: National Kidney Foundation.

Levey AS, Adler S, Gaggiula AW et al. (1996) Effects of

dietary protein restriction on the progression of ad-

vanced renal disease in the modification of diet in renal

disease study. American Journal of Kidney Diseases

27(5): 652–663.

McCann L (1996) Subjective global assessment as it

pertains to the nutritional status of dialysis patients.

Dialysis and Transplantation 25(4): 190–225.

Massy ZA, Jennie Z et al. (1995) Lipid lowering therapy in

patients with renal disease. Kidney International 48:

188–198.

Mitch W and Klahr S (1998) Handbook of Nutrition and

the Kidney, 3rd edn. Philadelphia, Pennsylvania, USA:

Lippincott-Raven.

RCP and Renal Association (1997) Treatment of Adult

Patients with Renal Failure: Recommended Standards

and Audit Measures 2nd edn. UK: Royal College of

Physicians and Renal Association, Lavenham Press.

Smith CL, Davis M and Berkseth RO (1992) Dietary factors

in calcium nephrolithiasis. Journal of Renal Nutrition

2(4): 146–153.

Toigo G, Aparicio M, Altman PO et al. (2000) Expert

Working Group Report on nutrition in adult patients

with renal insufficiency. Clinical Nutrition 19(3):

197–207.

Rennin See Cheeses: Types of Cheese; Starter Cultures Employed in Cheese-making; Chemistry and

Microbiology of Maturation; Manufacture of Extra-hard Cheeses; Manufacture of Hard and Semi-hard Varieties of

Cheese; Cheeses with ‘Eyes’; Soft and Special Varieties; White Brined Varieties; Quarg and Fromage Frais;

Processed Cheese; Dietary Importance; Mold-ripened Cheeses: Stilton and Related Varieties; Surface Mold-

ripened Cheese Varieties

Residue Determination See Antibiotics and Drugs: Uses in Food Production; Residue Determination;

Contamination of Food; Fumigants; Pesticides and Herbicides: Types of Pesticide; Types, Uses, and

Determination of Herbicides; Residue Determination; Toxicology

Resistant Starch See Starch: Structure, Properties, and Determination; Sources and Processing;

Functional Properties; Modified Starches; Resistant Starch

RENAL FUNCTION AND DISORDERS/Nutritional Management of Renal Disorders 4951

RETINOL

Contents

Properties and Determination

Physiology

Properties and Determination

D C Woollard, AgriQuality NZ, Auckland, New Zealand

H E Indyk, Anchor Products, NZMP, Waitoa,

New Zealand

Physical Properties

0001 Retinol (9,13-dimethyl-7-[1,1,5-trimethyl-6-cyclo-

hexene-5-yl]-7,9,11,13-nonatetraene-15-ol) is a pale

yellow crystalline powder or oily mass, depending on

purity. It is insoluble in water but readily miscible

with most organic solvents. Its formula, formula

weight, and certain other characteristic physical

properties are summarized in Table 1, along with

those of the two commercially significant ester

derivatives.

Chemical Properties

0002 All-trans retinol, considered the parent compound of

the vitamin A group, is a complex unsaturated alco-

hol. Its trivial name originated with the historical

recognition of its role in vision. This generic structure,

illustrated in Figure 1, shares a common b-ionone

ring, with attached conjugated isoprenoid side chain.

0003 Chemical and structural modifications to the ring,

side chain, or polar functional group generate many

retinoids possessing a wide spectrum of properties. In

nature only relatively few of these compounds exhibit

significant vitamin A activity. These include the pre-

dominant all-trans forms of retinol (originally desig-

nated vitamin A

) and its esters, retinal, retinoic acid,

and their associated 9-, 11-, and 13-cis isomers. The

cis-isomers are selectively interconvertible with the

trans-forms in the body and thereby express frac-

tional biological activities of approximately 0.25,

0.50, and 0.75, respectively, relative to the all-trans

vitamer. Some marine and fresh-water fish contain

significant quantities of the cyclic diene 3-dehydro-

retinol (originally designated vitamin A

), which

possesses approximately 40% of the bioactivity of

all-trans retinol.

0004Vitamin A activity is commonly expressed in inter-

national units (1 IU is equivalent to 0.300 mg all-trans

retinol, 0.344 mg retinyl acetate, or 0.549 mg retinyl

palmitate), or, more recently, retinol equivalents

(1 RE is equivalent to 1.0 mg all-trans retinol). Such

units have been useful in nutritional studies where

contributions from numerous vitamin A active con-

geners may be combined to yield a single value. For

the food scientist, it is probably more appropriate to

express vitamin A content as the summation of each

retinoid, in absolute mass units (usually mg).

0005The dominant structural feature of retinol is the

extensive conjugated double-bond system, to which

many of the physicochemical and biological proper-

ties may be attributed. It is also the principal factor

in the lability of vitamin A. Thus, retinol and its

derivatives are particularly sensitive to oxidizing

conditions and are rapidly destroyed by heat, light,

tbl0001 Table 1 Physical properties of retinol (all-trans) and its esters

Property Retinol Retinyl

acetate

Retinyl

palmitate

Formula C

Formula weight 286.46 328.50 524.88

Melting point (



C) 63–64 57–59 28–29

max

(nm)

325 326 326

Extinction coefficient, E

1cm

1820 1530 960

Molar absorptivity, e 52 140 50 260 50 390

Fluorescence

Excitation max. (nm) 325 325 325

Emission max. (nm) 470 470 470

In 2-propanol. Spectral properties vary slightly between protic and

aprotic solvents.

17 16

19 20

11 13 R97

1081214

fig0001Figure 1 Structures of the basic retinoids. The cis-isomer

positional variants are indicated by the side-chain numbering

system.

R¼CH

OH all-trans retinol

OCOCH

all-trans retinyl acetate

OCO(CH

)

all-trans retinyl palmitate

CHO all-trans retinal

COOH all-trans retinoic acid

4952 RETINOL/Properties and Determination

and acids when in solution. Isomerization, oxidation

and, ultimately, molecular cleavage may all occur

concurrently, depending on the extent of environ-

mental stress. Cleavage may result in the formation

of volatile b-ionone fragmentation products which

have importance in the development of off-flavor in

some foods. Retinol is, however, relatively resistant

towards alkali, and most degradation processes are

minimized if it is maintained under inert gas at low

temperature and in the absence of short-wavelength

light.

0006 In solution, several fat-soluble antioxidants offer

protection, while in foods and food extracts, accom-

panying lipids and endogenous antioxidants such

as phospholipids, tocopherols, and carotenes act

to stabilize retinol until they are sacrificially depleted.

Both thermal processing and storage expose vitamin

A in foods to the risks of considerable loss (5–40%),

although published data are often highly variable.

(See Antioxidants: Natural Antioxidants.)

0007 Retinyl esters are considerably more stable than

the parent alcohol, a feature which is exploited in the

principal commercial formulations available to the

food industry. Although minor differences in absorp-

tion efficiency have been reported, dietary retinyl

esters are considered to exhibit identical biological

activities as a result of their conversion to retinol in

the intestinal wall.

Occurrence and Forms in Foods

0008 All forms of vitamin A found in foods ultimately

derive from the provitamin A carotenoids, which are

ubiquitous in the higher plants and lower animal

organisms. Humans obtain preformed vitamin exclu-

sively from animal sources, while carotenoids are

gained from foods of both plant and animal origin.

0009 Retinol and its derivatives are not widely distrib-

uted in foods. Fish liver oils are by far the most

concentrated natural source, while animal liver, milk

(and dairy products), and eggs contain significant

quantities. The average western diet is generally

assessed as satisfying the recommended daily intake

level of 1000 RE total vitamin A, with about 25%

supplied by b-carotene. (See Carotenoids: Occur-

rence, Properties, and Determination; Physiology.)

0010 Retinoids in foods occur mainly as mixtures of

retinyl esters, with lesser contributions from retinol

itself. The predominant forms are long-chain esters,

notably palmitate, with contributions from stearate

and oleate. However, eggs are an exception, where

unesterified retinol is the major form. Certain foods

also contain contributions from retinal (eggs and

fish roe) and cis-isomers (mainly 13-cis), the latter

particularly in foods subjected to processing.

0011Vitamin A deficiency is one of the prevalent diet-

related issues and has received global attention.

Consequently, nutritional tables are replete with

information regarding retinol distribution in foods.

Table 2 lists the vitamin A content of a few represen-

tative foods. Carotenoid-rich vegetable sources are

not included. Refer to individual foods.

Use in Food Fortification

0012Increasing the vitamin A intake amongst populations

at risk of retinol deficiency is a simple expediency and

has been employed for several decades, both prophyl-

actically and therapeutically. Many of the specific

symptoms of severe deficiency (e.g., xerophthalmia,

keratomalacia) are usually reversible, provided other

nutritional criteria are similarly satisfied. In the

developed nations, potential risks of subclinical defi-

ciency are also avoided through food enrichment,

thereby insuring satisfactory intake. (See Food

Fortification.)

0013Fat-based foods such as margarine, milk, and

infant formula provide an ideal carrier in which to

supply supplemental vitamin A. Dried milk, by

reason of cost and convenience, is globally the pre-

ferred foodstuff and additionally offers a high-quality

protein and mineral enrichment medium appropriate

to nutritional rehabilitation programs. An increasing

range of alternative food items are being used as

carriers, ranging from specialized dietary beverages

to breakfast cereals.

0014In most cases, supplementation is performed with

synthetic all-trans retinyl acetate or palmitate. The

esters in the case of margarine are usually added

directly in an oil carrier, often in the presence of

appropriate antioxidants. Where additional stability

is required, or when dried food products are involved,

it is common practice to use a powder preparation

in which vitamin A (and stabilizer) is deposited in

a suitable carrier, such as gelatin carbohydrate,

although alternatives (e.g., acacia gum) have re-

cently been developed. However, uneven vitamin

tbl0002Table 2 Preformed vitamin A content of selected foods,

expressed as retinol

Food Retinolcontent (range) of

edibleportion (mg100g

1

)

Milk 32–45

Butter 800–1000

Eggs 140–250

Beef 2–5

Liver (lamb) 7000–10 000

Mackerel 25–50

Cod liver oil 15 000–30 000

To convert to IU per 100 g, multiply by 3.33.

RETINOL/Properties and Determination 4953

distribution is a common problem when dry-blending

food products.

0015 Water-miscible vitamin A powders have been de-

veloped containing emulsifiers that facilitate reconsti-

tution into aqueous solution. These solutions can

then be processed directly into fluids such as milk

prior to drying. Using the wet-blending technique,

the protective environment of the additive is hope-

fully substituted by intimate interaction with the lipid

phase of the finished food. The principal advantage of

this supplementation route is an enhanced vitamin

homogeneity in the finished product. However, the

added ingredients are generally found to be less stable

than their endogenous counterparts. (See Emulsifiers:

Uses in Processed Foods.)

0016 During food storage there are significant advan-

tages in using packaging which provides effective

oxygen and light protection. The use of cans allows

nitrogen purging of the head space, thereby greatly

enhancing the oxidative stability of the food and

extending its shelf-life, particularly in developing

countries with extreme climates.

Extraction and Clean-up

0017 During analytical procedures, precautions are man-

datory to exclude exposure of vitamin A to ultraviolet

radiation, thermal, and oxidative stresses. Protective

antioxidants and exclusion of air are essential to the

success of the analysis. Purity of vulnerable retinoid

standards is important during quantitative investiga-

tions, and spectrophotometric procedures are gener-

ally necessary to ascertain accurately their purity

concentration.

0018 Alkaline digestion (saponification) is most com-

monly employed as the first stage during analysis of

retinol in foods. A representative sample is homogen-

ized and digested in ethanolic potassium hydroxide or

similar media. Saponification has the threefold effect

of eliminating the bulk of lipid materials, releasing

the vitamin from within the sample, and converting

the various esters into free retinol. The procedure can

be performed under reflux temperatures, or at ambi-

ent temperature (for longer periods), the details of

which are determined by the sample matrix. In some

food samples where the vitamin A concentration may

be low, a preliminary fat extraction step will assist in

achieving the required assay sensitivity.

0019 Retinol is partitioned from the digest into a binary

organic solvent, commonly consisting of hexane and

a polar modifier such as an ether. The solution is

washed with water, dried, and usually concentrated

by evaporation, to provide a crude extract. Direct

spectrophotometric or fluorometric assay of retinol

may be impractical in poorly characterized foods,

owing to interfering coextractives, and further clean-

up is often necessary. Traditionally this has been

achieved by open-column or thin-layer chromatog-

raphy, using silica or alumina stationary phases,

while gel-permeation chromatography has also been

advocated. The laborious nature of these clean-up

techniques has largely been overcome through the

online automated use of prepacked, solid-phase

extraction columns.

0020As the majority of native and supplementary

retinol in foods exists in esterified form, there are

analytical advantages to be gained through avoiding

preliminary saponification, providing the nature of

the food allows such simplified methodology. The

total lipid fraction of such foods may therefore be

directly extracted into organic solvent, which is then

ready for analysis of the intact esters. Advantages

include a reduction in the number of manipulative

steps and the decreased risk of analyte loss through

retinol degradation.

Chromatographic and Other Methods of

Determination

0021The detection of retinol is based on its extensive

conjugated double-bond functionality, which pro-

vides an intense and relatively specific chromophore

in the long-wavelength ultraviolet region. The sensi-

tivity and selectivity of spectral analysis are conse-

quently enhanced, irrespective of the separation

techniques used. In addition, retinol exhibits a strong

fluorescence which offers selectivity advantages and

often reduces the need for preliminary clean-up. In

situations involving well-characterized foods, and

where discrimination between retinol and related

compounds is unnecessary, spectrophotometric or

fluorometric measurement of the crude extracts can

often supply a reliable estimate, providing the limita-

tions of such strategies are recognized. (See Spectros-

copy: Fluorescence.)

0022The traditional Carr–Price method for determin-

ation of retinol in foods has exploited the reaction

with antimony trichloride to produce a blue complex

in direct proportion to vitamin A concentration. Al-

though the color is transient and difficult to control,

the reaction is still employed in laboratories with

limited access to modern chromatographic instru-

mentation. Other Lewis acids, notably trifluoroacetic

acid, will react in a similar way and offer some ma-

nipulative advantages over the Carr–Price approach.

0023It is now accepted that a reliable estimate of vitamin

A content in foods is best achieved through exploiting

chromatography to separate coextracted substances

and, in particular, to differentiate the active retinoid

species. Most variants of chromatography have been

4954 RETINOL/Properties and Determination

used during attempts to separate and quantify the

retinoids. Thin-layer chromatography (TLC) and

low-pressure liquid chromatography, while reason-

ably successful, have traditionally lacked the resolv-

ing power for reliable quantitative measurements,

although high-performance TLC shows potential.

Gas-liquid chromatography has not been widely util-

ized, as retinol (and its esters) degrades at elevated

temperatures. The use of high-performance liquid

chromatography (HPLC) has dominated vitamin

A measurement over the last 20 years and has been

largely responsible for the rapid proliferation

of knowledge regarding this vitamin. This non-

destructive technique facilitates a rapid analysis with

minimum sample preparation. Recently, variants of

micellar capillary electrophoresis (CE) have been

applied to fat-soluble vitamin separations. Although

representing an alternative to HPLC techniques,

the application of CE to the hydrophobic vitamins

iscurrently in its infancy. (SeeChromatography: High-

performance Liquid Chromatography; Thin-layer

Chromatography; Gas Chromatography.)

0024 Since isomerization can be a common phenomenon

during food production, cis and trans differentiation

may be required, with the application of appropriate

factors to account for their selective bioactivities.

In addition, inactive oxidation products such as

oxyretinoids, epoxyretinoids, and their fragmentation

products, as well as various retroretinoids, can exist in

many food samples. Published literature is available

for the determination of retinol isomers and esters,

3-dehydroretinol, retinal, and retinoic acid in a wide

variety of foods. These analyses are accomplished

using normal- or reversed-phase HPLC, often with

simple isocratic solvent systems. Normal-phase is

generally the more efficient mechanism for isomer

separations, while esters are best resolved under re-

versed-phase conditions. Figure 2 illustrates the iso-

meric distribution in a saponified sample of cod liver

oil utilizing normal-phase conditions.

0025 The estimation of retinal and retinoic acid in foods

is not frequently required. They exist in some foods as

metabolites of the live animal but their contribution

to the vitamin A pool is negligible compared to that of

retinol. Despite the occurrence of 3-dehydroretinol in

fish and particularly fish liver oils, retinol remains the

primary source of vitamin A owing to its higher bio-

potency. Thus retinol, and its esters, are generally the

retinoids of major interest during routine food

analysis.

0026 The specific details of HPLC procedures used

for retinol analysis are too numerous to cover

comprehensively. However, there are several features

common to most schemes, notably the almost

universal use of ultraviolet (either dual-wavelength

or photodiode array) or fluorescence detection. Both

electrochemical and mass spectrometric detection

techniques have been reported but are not currently

in widespread use. Normal-phase separations are

generally performed on 5–10-mm particulate silica

columns, replacing the earlier use of alternative ad-

sorbents (alumina, keiselguhr, etc.). Amino-, cyano-

and diol-bonded silica is sometimes advocated to

circumvent the problems associated with moisture

on underivatized silica. The primary mobile-phase

component is usually a hydrocarbon in binary com-

bination with a polar organic modifier, although

ternary systems are sometimes recommended. Re-

versed-phase separations are usually confined to C

bonded-phase columns, although other hydrophobic

derivatives are sometimes used (C

,and

phenyl). Mobile phases are often a simple binary

Time (min)

fig0002Figure 2 A 1-g sample of commercially refined cod liver oil was

saponified with alcoholic potassium hydroxide and extracted into

hydrocarbon. A portion was analyzed by normal-phase high-

performance liquid chromatography using a Waters Radial-PAK

silica column with a mobile phase of hexane:2-propanol (96:4 v/v)

at 1.5 ml min

1

. Measurement was by fluorescence detection at

325 nm (excitation) and 470 nm (emission). Peak identification: 1,

11,13-di-cis-retinol; 2, 11-cis-retinol; 3, 13-cis-retinol; 4, 9,13-di-cis-

retinol; 5, 9-cis-retinol; 6, all-trans-retinol.

RETINOL/Properties and Determination 4955