Clinical Assessment of Renal Function: New Methods, Old Ideas
World Small Animal Veterinary Association World Congress Proceedings, 2003
Scott A. Brown, VMD, PhD, DACVIM (Internal Medicine)
College of Veterinary Medicine, University of Georgia
Athens, GA, USA

The clinical assessment of the urinary tract generally focuses separately upon (i) identifying the presence of a disease and (ii) evaluating the effects of a disease process upon function of the tract. Thus, renal structure and function must be evaluated separately as they are often not clearly related. Tests performed to detect the presence of structural change affecting the kidneys include urinalysis, imaging studies, and renal biopsy. The impact of a disease process on renal function, however, is generally assessed by tests that evaluate glomerular filtration rate (e.g., measurement of serum concentrations of creatinine and blood urea nitrogen or specialized tests to estimate glomerular filtration rate and renal blood flow), glomerular permselectivity (e.g., measures of proteinuria), and by consideration of renal solute handling and urinary concentrating ability.

Evaluating glomerular function: Glomerular filtration rate (GFR)

Massive amounts of glomerular filtrate are formed continuously, necessitating energy expenditure and complex carrier processes as most filtered solutes and water are reabsorbed in a futile cycle. The GFR amounts to approximately 115 liters/day in a 20 kg dog, nearly 20 times the dog's extracellular fluid volume. Still, the central measure of renal function is an evaluation of GFR, largely because formation of glomerular filtrate is the primary event that drives urine formation and nitrogenous waste excretion. Although measurement methods will alter exact values, normal ranges for GFR are generally 3.5-4.5 ml/min/kg body weight in dogs and 2.5-3.5 ml/min/kg body weight in cats.

Assessing GFR: Measurement of urinary clearance

The ideal measure of renal function is the determination of GFR via a urinary clearance procedure in which a timed, total collection of urine is used for the standard clearance formula:

C = (Uv X Uc)/Pc

Where C = clearance (ml/minute), Uv is urine flow rate (ml/minute), Uc is concentration of the solute in urine, and Pc is concentration of solute in plasma. As intraspecies GFR is positively related to body mass and surface area, the clearance is usually expressed per kg body weight as noted above.

Inulin, a fructose polymer that is freely filtered, not metabolized, and is neither reabsorbed nor secreted, is often used in the research laboratory for measurement of GFR (urinary inulin clearance). Urinary inulin clearance determined by the above formula from timed collection of urine following parenteral administration of inulin is the gold standard for measurement of GFR in dogs, cats, people, and other species. An alternative endogenous marker of GFR is urinary clearance of creatinine. However, all urinary clearance measurements require an indwelling urethral catheter and considerable technical time and expertise. While any clinic can utilize these procedures, these limitations generally restrict the clinical application of urinary clearance testing.

Assessing GFR: Measurement of plasma clearance

Clearance from plasma of a variety of substances, such as iohexol, determined from serial determinations of plasma concentration of the indicator substance is technically easier than urinary clearance determination and may be used to estimate GFR. For these procedures, a known amount of an indicator substance is injected intravenously and the blood concentration of the substance is then determined at various intervals thereafter. Pharmacokinetic models are then employed to estimate GFR from calculated plasma clearance of the test substance. Plasma clearance procedures do not require the collection of urine, substantially reducing the technical difficulties of measurement of GFR by urinary clearance procedures. Such techniques may provide a more reliable measure of GFR than determination of plasma concentration of creatinine and BUN, but they are clearly less reliable than urinary clearance procedures.

Assessing GFR: Serum creatinine and blood urea nitrogen

Despite the increased utility of urinary and plasma clearance determinations to estimate GFR, clinical assessment of adequacy of renal function generally focuses upon measurement of plasma concentrations of creatinine and BUN. These compounds provide an index of the level of GFR and thus are markers to detect deterioration of renal function.

Urea is the product of the hepatic urea cycle, being involved in amino acid metabolism and nitrogen excretion. Urea is passively filtered through the renal glomeruli. Because some segments of the tubular epithelium are permeable to urea, urea may exit or enter tubular fluid, passively recycling during the urine concentrating process. Thus, the BUN reflects not only GFR but also urea production by the liver and renal tubular fluid flow rate. Therefore, ingestion of a high protein meal, gastrointestinal hemorrhage, the presence of a catabolic state, and dehydration all will tend to raise BUN even with no change in GFR. In contrast, hepatic insufficiency, low protein diets, anabolic states, and polyuria will tend to lower BUN independent of changes in GFR. These important extrarenal factors complicate the interpretation of BUN values.

Muscle cells take up creatine produced by the liver, which then undergoes irreversible decomposition to creatinine. Creatinine is excreted by the kidneys through filtration in dogs and cats and also by a small amount of proximal tubular secretion in dogs. Creatinine production will be affected by lean muscle mass, and thus there are trends among gender, age, and breed that alter plasma concentration of creatinine. However, this is rarely taken into account in veterinary medicine. Nomograms for determining normal ranges for plasma creatinine concentration in people consider these and other factors. Furthermore, the presence of noncreatinine chromogens in the plasma of normal dogs and cats complicates interpretation of plasma concentrations of creatinine, particularly with mild increases.

The pattern of change in the reciprocal of serum creatinine (1/[creatinine]) over time has been used to identify a temporal pattern of renal function in animals with chronic renal failure.1 The limitations of measurement of serum creatinine remain, and although some affected animals have a linear decline in this value (i.e., 1/[creatinine]) over time, others do not. Utility of this ratio has been questioned because of increasing extrarenal creatinine catabolism in end-stage kidney disease and poor correlation between rate of change of GFR and this reciprocal.

Evaluating glomerular function: Permselectivity

The glomerular filtration barrier is composed of glomerular capillary endothelial cells, a negatively charged basement membrane, and podocyte slit membranes. This barrier serves to allow water and electrolytes to freely traverse into the urinary space, while preventing macromolecules from leaving the plasma. Loss of normal selectivity of the glomerular filtration barrier (loss of permselectivity) can be identified by the presence of proteinuria, using urine dipstick evaluation or by quantitative assessment of proteinuria. In veterinary medicine, determination of the urine protein-to-creatinine ratio is frequently a useful adjunctive measurement. The urine protein-to-creatinine ratio is calculated as the urine concentration of protein divided by the urine concentration of creatinine, with both expressed as mg/100 mL of urine, providing a useful method for semi-quantitative assessment of urine protein excretion. It should be remembered that any leakage of plasma protein into the urine (e.g., hematuria, traumatic cystocentesis, and urinary tract inflammation of any kind) often dramatically increase the ratio. Values for the urine protein-to-creatinine ratio, which vary somewhat depending upon analytical methods employed, are generally < 0.5 in normal dogs and cats. Disruption of the glomerular filtration barrier, such as that observed with glomerular amyloidosis or glomerulonephritis, may cause the ratio to rise several-fold, and the ratio will occasionally exceed 15.

Assessing renal tubular function: Electrolyte and mineral imbalances

Tubular functions may have a dramatic impact on surgical patients through consequent electrolyte disturbances. Kidney disease is associated with a variety of disorders of mineral and electrolyte balance. These are most readily assessed with routine plasma biochemical determinations. As an adjunct specifically for evaluating difficult cases of hypokalemia, the fractional excretion (fractional clearance) of potassium can be determined from a single urine sample as:

FE K+ = 100% X (UK X Pcr)/Ucr X PK

Where FE K+ is fractional excretion (or clearance) of potassium, UK and PK are the concentrations of potassium in the urine and plasma respectively, Ucr and Pcr are the concentrations of creatinine in the urine and plasma respectively. This determination can have utility when the excretion rate is high (>20-25%) for potassium in the face of hypokalemia (if evaluated prior to potassium supplementation). Fractional clearances can be calculated for any solute but interpretation is often problematic. Except in specific circumstances, the measurement of urinary electrolyte clearances (fractional excretion rates) or urine solute concentrations adds little to the information provided by serial biochemical determinations and other routine clinical observations.

Assessing renal tubular function: Urinary concentrating ability

A urinary concentrating defect is a frequent consequence of diseases of the kidneys, and it may be the only clinically identifiable consequence of renal disease in some patients. Urine specific gravity will vary considerably in animals with normal renal function, particularly when fluid therapy and/or water intake vary. Thus, any value for urine specific gravity between 1.001 and 1.070 may be "normal" and should be interpreted in the context of therapy, hydration status, and other clinical information. In this regard, a urinary concentrating defect in dogs and cats is generally assumed to be present whenever urine specific gravity is inappropriately below 1.035 (i.e., in the presence of clinical dehydration).


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Speaker Information
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Scott A. Brown, VMD, PhD, DACVIM (Internal Medicine)
College of Veterinary Medicine, University of Georgia
Athens, GA, USA

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