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During the evolution of chronic renal failure, malnutrition can appear when glomerular filtration, assessed by creatinine clearance (Box 1), becomes lower than 40 ml/min/1,73m².
Different mechanisms can explain this state of malnutrition: reduction in protein and caloric intakes, increasingly marked as renal function is altered; disorders in metabolism of the main nutrients; increased protein catabolism due to acidosis and related infections or inflammations (more frequent with age). Forty percent of patients show malnutrition symptoms when they begin dialysis, which in itself is a hypercatabolism factor. Malnutrition represents the main cause of morbidity and mortality in dialysed patients.
Previously asymptomatic, malnutrition has often been underestimated or simply ignored. Assessment of the nutritional state in a chronic renal failure patient must be systematic, even if clinical, biochemical and biophysical markers can be affected by the disease itself and by the age of the patient.

BOX 1

		CREATININE : INDEX OF RENAL FUNCTION
		Advantages Since creatinine concentration depends on constant muscular production and on renal elimination by glomerular filtration, it is a good index of renal function. Limitations Interpretation is difficult in aged patients whose muscular mass is reduced. A correction in the calculation of creatinine clearance overcomes this problem. The most frequently used formulae is the Cockroft and Gault formulae: Creatinine clearance (ml/min) = (140-age) x weight x 1,23 male Creatinine (µmol /l) 1,04 female
		Note: marked obesity makes results uninterpretable.

Food survey
A food survey is necessary to assess both the risk of malnutrition and the success of an oral refeeding regimen. Ideally the investigation should be 3-4 days; if not, a semi-quantitative food questionnaire (Box 2) can provide valuable information (although patients often overestimate their intakes).
Protein intake will be assessed in pre-dialysis stage patients by measurement of urinary urea and non-urea nitrogen appearance. The latest being relatively constant is in the order of 31 mg/kg/24 hours.
Nitrogen balance will then be positive in anabolic states, and negative in case of reduced protein intake or in hypercatabolic states. A positive nitrogen balance will confirm the efficiency of nutritional therapy.

Clinical examination
A clinical examination will assess the overall morphology of patients, the state of skin, teeth, hair and nails, and any change in weight and body mass index (BMI).
A BMI lower than 19 kg/m2 likely indicates malnutrition, whereas a BMI lower than 16 confirms it.

BOX 2

		EXAMPLE OF A FOOD QUESTIONNAIRE
		1. Did you lose weight? 2. Do you have the sensation to force feed yourself? 3. Are you having at least two main meals per day plus a breakfast or a snack? 4. Do you consume at least one dairy product at each of these three meals? 5. Do you consume one meat serving or the equivalent during the two main meals?

Anthropometric measurements
Anthropometric measurements are useful to determine body composition of patients. It is essential to assess the considerable body fluids variations in chronic renal failure patients and the possible shift from muscle to fat mass. The simplest anthropometric measurements are triceps skinfold for fat stores assessment and mid-upper arm and arm muscle circumferences for lean body mass assessment.

Serum albumin level
Serum albumin level is the most widely used indicator of malnutrition. However since its half-life is about 20 days, serious protein and calorie depletion is already present by the time it is shown. It is therefore useless to measure it every 15 days. Some states are accompanied by hypoalbuminemia during which albumin leaks in the interstitial fluid: nephrotic syndrome, old age and inflammation.
During inflammation, hepatic synthesis of inflammatory proteins such as CRP, SAA, α -1 antitrypsine and α-1 globulin is increased is stimulated by pro-inflammatory cytokines such as tumour necrosis factor-α, interleukin-1 and inteleukin-6, while the synthesis of nutritional proteins is reduced. In spite of its limitations serum albumin remains a good prognostic indicator in dialysed chronic renal failure patients, regardless of the cause of hypoalbumineria.

Tyroxine-binding pre-albumin and retinol-binding protein
These two proteins are metabolised in the proximal tubule, and their serum concentrations rise with renal failure. The short half-live of these transport proteins (respectively 2 days and 12 hours) allows a quick assessment of refeeding therapy in patients whose renal function is stabilised.

Serum transferrin level
Iron deficiency (common in renal failure patients), erythropoietin treatment and iron supplementation alters serum transferrin levels. Transferrin concentrations may also be lower during inflammatory syndromes and acute stress.

Serum albumin level, tyroxine-binding pre-albumin, retinol-binding protein and serum transferrin level are the commonly used biomarkers of malnutrition in clinical settings (Table 1).

Immunoglobulin F - 1:
This nutritional biomarker is only used in research and is not yet part of current medical practice. An IgF-1 concentration lower than 200 mg/ml suggests a state of malnutrition.

Serum cholesterol level
Serum cholesterol level is decreased in wasted patient with normal renal function. In chronic non-nephrotic renal failure patients, a reduction in serum cholesterol level is accompanied by an increase in mortality rate.

Lymphocytes
The number of the circulating lymphocytes and T-lymphocyte fractions as well as the delayed hypersensitivity skin test are difficult to interpret in chronic renal failure patients.

TABLE 1

SERUM VALUES INDICATING MALNUTRITION IN CHRONIC RENAL FAILURE
			Half life		Serum concentrations
					Normal subject		Malnourished subject
	- ALBUMIN   - PRE-ALBUMIN   - RETINOL BINDING   PROTEIN   - TRANSFERRIN		21 days 2 days 12 hours 8 days		40 - 50 g/l 0,3 - 0,4 g/l 0,05 - 0,07 g/l 2 to 3 g/l		< 30 g/l < 0,30 g/l < 0,05 g/l < 2 g/l

Creatine height index and 3-Methylhistidine output
These indices of muscular protein status are very difficult to interpret in chronic renal failure patients. Their measurement in a same patient only allows monitoring the evolution of muscular mass.

The decrease of one of these biomarkers is not in itself a reliable indicator of malnutrition. On the other hand the parallel change of many will indicate the quality and the efficiency of a refeeding therapy.

Biophysical methods to assess body composition are used only in research. Examinations must be conducted at fixed intervals with regard to dialysis.

Tomodensitometry measures the density of organs. It assesses lean, bone and fat masses.

Nuclear magnetic resonance performs the same measurements with good repeatability, in the order of 93 to 97%.

Electrical bio-impedance, is moderately costly, simple to run at bedside for a fast and reliable measurement of different body components. However in presence of dehydration, which is common with chronic renal failure, results are difficult to interpret.

Biphotonic absorptiometry provides measurements of bone, lean and fat masses, as well as distribution of lean and fat masses. Excellent repeatability of results ensures reliable longitudinal nutritional follow-up of patients.

In general, these biophysical methods help identify anomalies in body composition in 90% of chronic renal failure patients. Most often a reduction of lean body mass is masked by an increase in fat mass and extra-cellular fluids.

MAIN FEATURES OF MALNUTRITION DURING THE COURSE OF CHRONIC RENAL FAILURE
Onset		Appears when glomerular filtration becomes less than 40 ml/min.
Frequency and severity		Grow with the progression of the renal failure.
Effect of the dialysis		Sporadically alleviates nutritional problems
Consequence		Hypoalbuminemia is bound to an exponential growth of death risk.

CONCLUSION

In the later stages of chronic renal failure, 40% of patients suffer from malnutrition. Only a systematic investigation, including objective clinical and biological observations will help adjusting its evolution and avoiding complications.
Although malnutrition is closely bound to a prognostic of death, it is rarely a direct cause but will rather favour and/or accompany certain morbidity factors.

Pr. Michel Aparicio
Nephrology and Hemodialysis Units
Bordeaux University Hospital Centre

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