6.1.1.1 Creatinine and Serum Urea

The ability of the kidneys to filter blood can be evaluated by determining the GFR. While there are more complicated methods to precisely determine GFR, serum urea and creatinine provide a readily available estimation of GFR. If there is an elevation of these nitrogenous waste products in serum, termed azotemia, it indicates that GFR is decreased. Creatinine has been considered an insensitive method of detecting a decrease in renal functional capacity, as three‐fourths of nephron mass is typically lost before azotemia is seen. However, the loss of 75% renal mass translates to a lower functional loss due to compensatory renal hypertrophy, so the actual sensitivity of serum creatinine for detecting decreased renal function is higher than historically assumed [2]. For example, in dogs, creatinine was shown to increase after GFR decreases of 48% on average [3].

Decreases in GFR can be due to prerenal, renal, or postrenal factors or a combination of these processes. If the rate of glomerular filtration decreases, serum urea and creatinine concentrations will increase. Urea concentrations can rise faster than creatinine because of the tubules’ ability to reabsorb urea, particularly with a prerenal cause of decreased GFR. Other values that increase with a decrease in GFR are serum phosphorus and total magnesium concentrations.

If the cause of a decrease in GFR is purely prerenal and there are no extenuating circumstances, a horse should have a urine specific gravity >1.025 in the face of azotemia. If a horse is not able to concentrate its urine in the face of azotemia (and the animal has not been treated with fluids), the kidney is not functioning properly and one of the most common causes is renal disease. There are, however, other reasons for the kidneys not being able to concentrate urine, as discussed below. These factors need to be considered before a definitive diagnosis of renal failure is made. With postrenal azotemia, urine specific gravity can be variable and is often isosthenuric in the postobstructive phase. The diagnosis of most postrenal urinary tract disorders is usually predominantly based on history and clinical signs.

Both urea and creatinine concentrations can be elevated for reasons other than decreased GFR. Urea is a by‐product of protein metabolism so urea concentration can increase with a high protein diet or urea supplementation. Mild increases in urea may be seen with protein catabolism associated with fasting or prolonged exercise [1]. Interestingly, while urea concentration may increase with fasting in horses, it tends to decrease in ponies [1]. Decreases in urea can also occur with protein‐poor diets or liver failure.

Creatinine is a by‐product of muscle metabolism and therefore is correlated with total muscle mass. Heavily muscled animals may have creatinine concentrations that are normally slightly above reported reference intervals. Release of creatinine from muscle during exercise, fasting, muscle wasting, or rhabdomyolysis can influence creatinine concentration. In addition, if the Jaffe colorimetric method is used to measure creatinine, the concentration of creatinine may be artefactually increased in the presence of noncreatinine chromagens; this may actually be the main reason for the increase in creatinine associated with fasting. Spurious increases in creatinine have also been associated with various metabolic disorders and administration of cephalosporin antibiotics [4]. Hyperbilirubinemia can interfere with the measurement of creatinine, resulting in falsely low values. During the first few days of a foal’s life, creatinine concentration can be quite high relative to adult reference values, but should decrease to adult reference values by 3–5 days if the kidneys are healthy [1, 5].

The blood urea nitrogen (BUN):creatinine ratio is not very useful in determining whether azotemia is prerenal, renal, or postrenal, but it has been used to help differentiate between acute and chronic renal disease. In many (but not all) cases, the ratio will be <10:1 in acute renal failure (ARF) and >10:1 in chronic renal failure (CRF) [4]. If the ratio becomes >15:1 with CRF, this may be an indication of excess protein in the diet [6].

6.1.2 Reabsorption and Electrolyte Regulation

For many of the solutes that are filtered through glomeruli, reabsorption predominantly occurs in the proximal tubules, whereas additional regulation may occur further along the nephron. Because all glucose is normally absorbed in the proximal tubules unless the serum concentration exceeds the renal threshold, the presence of glycosuria without hyperglycemia is an indication of proximal tubule dysfunction. Glycosuria is more commonly seen with ARF than CRF.

Serum electrolyte abnormalities can also be seen with tubular dysfunction, including hyponatremia, hypochloremia, hyper‐ or hypocalcemia, hypophosphatemia, hyper‐ or hypokalemia, and increased or decreased bicarbonate levels. Horses normally excrete a large amount of calcium and serum calcium concentrations are often abnormal with equine renal failure. Hypercalcemia is commonly seen with CRF whereas hypocalcemia is more commonly associated with ARF.

A relatively easy way to assess whether there is decreased reabsorption of electrolytes by the kidney is to determine their fractional excretion (FE). The FE of sodium is most commonly determined; the second most common electrolyte used is phosphorus. FE is calculated using the concentrations of the electrolyte and creatinine in both serum and urine and plugging those numbers into the following equation:

(6.1)

The FE of sodium and phosphorus is normally <1%. Values greater than 1% (0.8%) imply tubular dysfunction, unless the animal is receiving a diet very high in sodium or phosphorus, has been administered polyionic intravenous fluids or certain medications (furosemide), recently performed low‐intensity exercise, or there is aldosterone or parathormone deficiency [9].