Medical Care

Renal Function and Kidney Disease

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Chronic Kidney Disorder

The two leading causes of chronic renal failure and entry into a regular dialysis program are type 2 diabetes mellitus and arterial hypertension, highly present in elderly patients. Creatinine clearance (CCr or CrCl) reflects more accurately glomerular filtration rate (GFR) and may detect early renal function worsening. Creatinine is derived from skeletal muscle metabolism and daily meat intake, and it is eliminated from circulation at a constant rate. Its plasma levels remain constant as well. In steady state conditions, creatinine excretion is equal to creatinine production, so that plasma creatinine levels vary inversely to glomerular filtration rate. But a plasma creatinine increase >2 mg/dL makes the excretion process to become saturated and indicates an already important loss of glomerular filtration. Plasma creatinine alone should not be used to assess kidney function. Also monitor the concentration of cystatin C.

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Estimated GFR

Although glomerular filtration rate (GFR) is equal to the sum of the filtration rates in all functioning nephrons and can be regarded as a rough measure of the number of them, it is important to recognize that this estimated value can be insensitive in detecting the number of lost nephrons because of compensatory increases in the GFR of working nephrons, secondary to increased glomerular capillary pressure or glomerular hypertrophy. In 2002, a new definition and classification of chronic kidney disease was published. A glomerular filtration rate <60 ml/min/1.73m2 measured repeatedly for 3 months or more was adapted to define chronic kidney disease irrespective of other signs of kidney damage. This value represents a reduction of more than half of the normal value (125 ml/min/1.73m2) in young adults. A decrease in glomerular filtration rate enhances the risk for accumulation of medications that depend on renal excretion.

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Formula-based estimates of the GFR

It is obvious that glomerular filtration rate (GFR) measures how well the kidneys remove the waste from blood. Since GFR is an evaluation of kidney function, special formulae have been developed to estimate GFR. The two best known equations are the equation published by Cockcroft-Gault in 1976 and the most recent equation published by Levey et al. in 1999 using data from the Modification of Diet in Renal Disease (MDRD) study. The creatinine-based Cockcroft-Gault and MDRD equations are widely used to estimate GFR in general populations. The MDRD study-equation is considered the gold-standard in nephrology. The MDRD study estimates GFR in comparison to its measurement by the iothalamate method, whereas the Cockcroft-Gault equation estimates creatinine clearance — which is not identical to the eGFR (estimated GFR) in the narrow sense.

The MDRD4 equation
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Cockcroft-Gault and MDRD [equations]

The most commonly used formulas to calculate creatinine clearance (CCr) and glomerular filtration rate (GFR) are the Cockcroft-Gault (C&G) and MDRD (Modification of Diet in Renal Disease) formulas which tend to underestimate renal function by approximately 25% to 30% at its upper limit in normal individuals as well as patients with chronic kidney disease. The Cockcroft-Gault formula, derived with adjusted body weight [AjBW ref № 31] instead of total body weight (TBW), performs best. Creatinine clearance measured from 24-hour urine samples is associated with problems when determining the glomerular filtration rate. Improper urine collection is a major factor which could significantly affect the final result. Nonetheless, 24-hour urine collection is unfortunately still the method that is frequently used in many clinics and hospitals to evaluate renal function.

A modified Cockcroft-Gault equation
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Reference Intervals for Creatinine Clearance

The accuracy of creatinine clearance is influenced by the completeness of timed urine collections, the amount of red meat in the diet, high protein supplements, the within-subject and analytical variability, strenuous exercise, some medications, and stress. Trauma, severe infection, and menstrual cycle, have been shown to affect urinary creatinine excretion and therefore potentially creatinine clearance. Longitudinal studies in men however suggest that, the loss of renal function with age (-1.07±0.42ml/min/1.73m2 per year) is not an inevitable process. Creatinine clearance is proportional to body size, resulting in gender differences. Consequently, age- and gender-adjusted reference ranges are warranted for creatinine clearance. In general, reference values for women are not determined directly, but are calculated by adjusting male values.

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Calculated Creatinine Clearance

Creatinine clearance can be calculated from serum creatinine by using previously established nomograms or formulas without collecting a timed urine specimen. The use of formula-based estimates eliminate the need for a often-inaccurate urine collection, the cost of an additional laboratory test, and the wait for completion (usually 24 h) of the urine collection. Creatinine clearance which is calculated from serum creatinine, age and adjusted body weight, is preferred and frequently used for elderly patients, who may often suffer from urinary incontinence, mental confusion, or forgetfulness. It is useful to be able to determine creatinine clearance without the need for urine collections, which are inconvenient to obtain, often inaccurate, and prevent timely determination of drug dosage. It is suggested that cooked meat be substantially avoided during the clearance evaluation period.

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Creatinine Based Equations

A number of formulas and nomograms that are all "minimally" based on serum creatinine have been developed. The principle governing the use of formula-based estimates is that, the excretion of creatinine is constant and equal to creatinine production, which is proportional to the muscle mass, and can be predicted from the age and weight. Significant differences in the body composition of men and women influence these estimates. The Cockcroft-Gault (C&G) formula, which was generated from data in men, is commonly used because of its simplicity and the inclusion of age and weight, which vary with creatinine clearance. The developers of this formula suggested a correction factor of 15%, i.e., 0.85 for women due to their lower muscle mass. Formula-based estimates are unacceptable in situations of muscle wasting.

GFR prediction equations
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MDRD4 or MDRD6 for estimating GFR

The MDRD formula is the best tool to predict GFR when estimating kidney function. The most precise MDRD formula is based on six variables. Since the six-variable equation performs best, the estimated value for the glomerular filtration rate (GFR), should be derived by applying the six-variable formula (MDRD6) which is most accurate. The inclusion of variables like serum albumin and serum urea nitrogen improves the predictive ability of the MDRD6 formula. A simplified equation based on four parameters [ref № 19] was later developed showing similar performance as the MDRD6 equation. Since the exclusion of some variables would promote affordable prices and reduce the bias that may occur due to alterations of the applied parameters by non-renal diseases, the MDRD4 formula may seem appropriate for routine practice.

The MDRD6 equation