The nuts and bolts of azotemia (Proceedings)

Azotemia is defined as increased concentrations of urea and creatinine (and other nonproteinaceous nitrogenous substances) in the blood. The interpretation of serum urea nitrogen and creatinine concentrations as a measure of renal function requires a knowledge of the production and excretion of these substances. Urea is synthesized in the liver from ammonia, which is in turn generated from the catabolism of ingested and endogenous proteins. Urea production is increased in the settings of a high dietary protein intake, upper gastrointestinal tract hemorrhage, and occasionally catabolic states that result in the breakdown of body proteins (e.g., corticosteroid administration). Conversely, urea production is decreased in the settings of a low dietary protein intake, decreased hepatic function, or decreased delivery of ammonia to the liver (e.g., portosystemic shunt). Urea has a small molecular weight (60 daltons) and is a permeate solute that readily diffuses throughout all body fluid compartments; its concentration is similar in intracellular and extracellular fluid and in plasma, serum, and blood. Urea that diffuses into the intestinal lumen is degraded by enteric organisms to ammonia, which is then reabsorbed into the portal circulation and again converted to urea by the liver. Urea is principally excreted by the kidneys; it is freely filtered through the glomeruli and passively resorbed by the renal tubules. The tubular resorption of urea is increased when tubular flow rates and volumes are decreased. Decreased tubular reabsorption of urea results in increased excretion and over time, decreased blood concentrations of urea. Conversely, the tubular resorption of urea is decreased and excretion increased in the presence of diuresis. Decreased renal blood flow (prerenal causes, e.g., dehydration or decreased cardiac output) and decreased excretion of urine (postrenal causes, e.g., urethral obstruction or ruptured bladder), as well as primary renal dysfunction, will result in decreased excretion of urea.

Creatinine is irreversibly formed by the nonenzymatic metabolism of creatine and phosphocreatine in muscle. Creatinine production is relatively constant and proportional to muscle mass; animals with a large muscle mass produce more creatinine each day than do animals with a small muscle mass. For example, serum creatinine concentrations would be expected to be relatively low in an older cat with loss of muscle mass and decreased body condition score. Muscle trauma and inflammation do not increase the production of creatinine. In comparison with the urea nitrogen concentration, the creatinine concentration is relatively unaffected by the dietary protein level; however, serum creatinine concentrations can increase after the ingestion of meat and the subsequent increased absorption of creatinine from the gastrointestinal tract. The molecular weight of creatinine is 113 daltons; therefore it diffuses throughout body fluid compartments more slowly than urea does. Some creatinine diffuses into the intestinal lumen, is degraded by enteric bacteria, and is excreted from the body in the feces; however, most creatinine is excreted by the kidneys. Creatinine is freely filtered by the glomeruli and is not significantly resorbed or secreted by the renal tubules. Because the production of creatinine is relatively constant, an increase in the serum creatinine concentration is indicative of decreased renal excretion. It is important to remember, however, that prerenal and postrenal factors influence renal function, and therefore, the excretion of creatinine. Disproportionate increases in BUN relative to creatinine can be caused by high protein diets, upper gastrointestinal hemorrhage, and increased tubular reabsorption of urea nitrogen associated with prerenal azotemia. Conversely, a disproportionately low BUN can be observed with decreased liver function, portosystemic shunts, low protein diets and prolonged diuresis.

Although an increased production of urea may result in an increased serum urea nitrogen concentration, the production of creatinine is relatively stable and unaffected by non-renal factors. Therefore, when an animal presents with azotemia, decreased renal excretion should be the main diagnostic consideration. The decreased renal excretion of urea nitrogen and creatinine may result from extra renal (prerenal and postrenal) or primary renal causes. Any condition that causes a decrease in renal blood flow may result in prerenal azotemia, including hypovolemia (e.g., dehydration, hypoadrenocorticism), hypotension (e.g., anesthesia, shock), and aortic or renal arterial thrombus formation. Initially the kidneys are structurally and functionally normal in dogs and cats with prerenal azotemia, and they respond to the decreased renal blood flow by conserving water and sodium. Hypersthenuric urine (i.e., specific gravity greater than 1.030 in dogs and greater than 1.035 in cats) with a low concentration of sodium and a high concentration of creatinine is produced. Elimination of the underlying disorder (e.g., fluid therapy to correct hypovolemia) results in rapid resolution of the azotemia, unless the underlying disorder has persisted for long enough or is severe enough to have caused renal parenchymal damage.

Postrenal azotemia is usually caused by an obstruction to urine outflow or a rupture of the urine outflow tract. Similar to prerenal azotemia, in postrenal azotemia the kidneys are initially normal; however, the urine specific gravity varies, depending on the animal's hydration status. Catheterization is difficult in cases of urethral obstruction, and dysuria and stranguria are common clinical signs. Rupture of the urinary tract usually involves the bladder or urethra, is more common in male than female animals, and frequently results in abdominal effusion or subcutaneous perineal fluid accumulation. Fluid obtained by abdominocentesis is usually sterile and contains a higher concentration of creatinine than the serum does. (Even though creatinine is a small molecule and equilibrates rapidly, the concentration of creatinine in the abdominal fluid will be higher than that of serum if the kidneys are producing urine that is draining into the abdomen.) Positive contrast–enhanced urethrography or cystography is the best way to confirm a rupture of the urethra or bladder.

Renal azotemia occurs as a result of nephron loss or damage. A diagnosis of renal azotemia is confirmed if the azotemia is persistently associated with isosthenuria or minimally concentrated urine. Inasmuch as urine is usually stored in the bladder for several hours, it is important not to evaluate the specific gravity of urine produced before the onset of the azotemia. For example, prerenal azotemia may occur in response to acute, severe dehydration; however, the animal may appear to have renal azotemia if the hypersthenuric urine being produced in response to the dehydration is diluted by a larger volume of previously formed, less concentrated urine. The differentiation of prerenal from renal azotemia can be a diagnostic challenge in some animals. Prerenal dehydration causing azotemia and accompanied by a decreased urine-concentrating ability can be confused with renal azotemia. Examples of conditions that can cause this syndrome include furosemide treatment, which causes dehydration, and hypercalcemia, which compromises the urine-concentrating ability and results in dehydration secondary to vomiting. Although fluid therapy is often implemented initially in animals with either prerenal or renal azotemia to manage the dehydration, the prognosis is quite different. Frequently the response to fluid therapy is the best way to differentiate prerenal from renal azotemia; renal azotemia does not resolve in response to fluid therapy alone.

Renal failure is a state of decreased renal function in which azotemia and the inability to produce hypersthenuric urine persist concurrently. The treatment and prognosis vary for animals with acute and chronic renal failure; therefore it is important to distinguish between these two entities. Acute kidney injury (AKI) leading to acute renal failure (ARF) develops within hours or days. Unique clinical signs and clinicopathologic findings often associated with AKI/ARF include enlarged or swollen kidneys, hemoconcentration, good body condition, an active urine sediment, relatively severe hyperkalemia and metabolic acidosis, and relatively severe clinical signs for the degree of azotemia. Chronic kidney disease (CKD) develops over a period of weeks, months, or years, and the clinical signs are often relatively mild for the magnitude of azotemia. Unique signs of CKD often include a history of weight loss and polydipsia-polyuria, poor body condition, nonregenerative anemia, small and irregular kidneys, and osseous fibrodystrophy caused by secondary renal hyperparathyroidism.