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Azotemia is is a laboratory abnormality and is defined as an increase in urea nitrogen and creatinine. It can result from a variety of disorders including, but not limited to, renal failure. Uremia is the term for the clinical syndrome of renal failure with azotemia and multisystemic problems such as polyuria, polydipsia, vomiting, weight loss, depression, and other sequelae of inadequate renal function (alterations in electrolyte and acid-base balance and water homeostasis).

Azotemia can be due to prerenal, renal or post-renal causes. Differentiation of the causes of azotemia requires urinalysis (especially assessment of urine specific gravity), evaluation of clinical signs and results of other diagnostic tests (e.g. radiographic evidence of urinary tract obstruction). Remember that the kidney is essential to acid-base and electrolyte homeostasis. Any cause of azotemia will result in retention of organic acids normally excreted by the kidney (i.e. a high anion gap metabolic acidosis) and hyperphosphatemia.

Prerenal azotemia

Prerenal azotemia is due to a decrease in glomerular filtration rate (GFR) from circulatory disturbances causing decreased renal perfusion (hypovolemia, cardiac disease, renal vasoconstriction). Prerenal azotemia can usually be distinguished from renal azotemia by clinical signs (evidence of dehydration or hypovolemia), urinalysis (urine should be “adequately” concentrated i.e. > 1.030 in the dog, > 1.035 in the cat, > 1.025 in large animals; with no evidence of renal tubule dysfunction such as proteinuria, cylindriuria) and response to therapy. Urine specific gravity may be decreased (despite a prerenal azotemia) if there are other factors reducing concentrating ability (see urine specific gravity). Therefore, often a response to therapy (fluid administration) is required to differentiate between a primary renal and prerenal azotemia (the azotemia should correct with appropriate fluid therapy within 24-48 hours in a pre-renal azotemia).

Many causes of prerenal azotemia will result in renal hypoxia and ischemia. If this is severe or chronic enough, a primary renal azotemia may result, and may co-exist with a prerenal azotemia. As urea levels in blood are dependent on flow rate through the renal tubules (decreased flow rate in prerenal azotemia enhances renal absorption of urea, and increases urea levels in blood), urea may increase without any increase in creatinine in early pre-renal azotemia.

Renal azotemia

Renal azotemia results from decreased GFR when more than ¾ of the nephrons are non-functional. Renal azotemia may be due to primary intrinsic renal disease (glomerulonephritis, ethylene glycol toxicity) or may be secondary to renal ischemia from prerenal causes or from kidney damage from urinary tract obstruction (post-renal azotemia). Loss of kidney function (which manifests as azotemia, which requires loss of 3/4 of kidney mass) usually follows concentrating defects (requires loss of 2/3 of kidney mass), therefore isosthenuric urine (USG 1.008-1.012) is common in renal azotemia.

Azotemia with a urine specific gravity less than adequate is presumptive evidence of renal azotemia or renal failure unless there are other diseases or conditions affecting urine concentrating ability independently of renal failure. The greatest difficulty in differentiating renal from prerenal azotemia is encountered in those cases with a urine specific gravity greater than isosthenuric, but less than adequate (< 1.030 in the dog, < 1.035 in the cat and < 1.025 in large animals). In addition, there may be other evidence of renal tubular dysfunction in the urinalysis (such as proteinuria, granular or cellular casts, and glucosuria without hyperglycemia).

Note that in cats, primary glomerular disease may occur without loss of renal concentrating ability (so the cat may have renal azotemia with concentrated urine). In horses and cattle, increases in urea are modest in renal azotemia due to excretion of urea into the gastrointestinal system (the urea is broken down into amino acids in the cecum and rumen, respectively). Therefore, creatinine is a more reliable indicator of GFR in these species.

Other findings in renal azotemia

Other findings that are useful for assessment of renal azotemia include changes in: phosphate and calcium, electrolytes and acid base, albumin and the presence of a non-regenerative anemia.

  • Phosphate and calcium
    • Phosphate is primarily excreted through glomerular filtration in the kidneys in most mammals, so decreased GFR leads to increased serum phosphate. However, cattle and horses with decreased GFR may not always have hyperphosphatemia due to other sources of phosphate elimination such as saliva and GI tract.
    • Calcium concentration in renal failure patients is highly variable, and can be decreased, normal, or increased due to a variety of mechanisms. If there is decreased calcitriol synthesis by the kidney, it will contribute to decreases in total and ionized calcium. Hyperphosphatemia can lead to increased complexing of calcium with anions, causing an increase in total calcium without an increase in ionized calcium.
  • Electrolytes and acid-base
    • Potassium is often increased in oliguric renal failure and post-renal azotemia due to reduced urinary elimination of potassium. The following electrolyte abnormalities are observed in different species with renal failure:
      • Bovine: Decreased sodium chloride is seen, with decreases in chloride being most consistent. This is associated with a concurrent metabolic alkalosis. Hypokalemia may be seen in polyuric renal failure, and hyperkalemia is seen in oliguric renal failure. Hypocalcemia (total calcium) is common as is increased fibrinogen.
      • Equine: Often see a decrease in sodium chloride (especially chloride). In acute renal failure, total calcium is often low and phosphate is high (especially in young horses), whilst in chronic renal failure, hypercalcemia (total calcium) and hypophosphatemia occur (not in all cases). Hyperkalemia is a feature (with low sodium and chloride) of uroabdomen.
      • Small animals: Hyperkalemia is usually only seen in anuric or oliguric renal failure. Total calcium is often normal (may be increased or decreased, especially in the dog), hypokalemia is common in cats in polyuric renal failure and hyperfibrinogenemia is often seen in cats with acute or chronic renal failure.
    • Anion gap: A high anion gap metabolic acidosis is common in all species with renal failure. This may be due to decreased renal elimination of “uremic acids”, such as phosphates, sulfates, and citrates that are normally excreted by the kidneys. Significant decreases in GFR can cause build-up of these acids. Additionally, volume depletion can lead to decreased perfusion and increased lactic acid that can contribute to an increased anion gap. Bicarbonate may be decreased in kidney disease due to “titration” from uremic acids or lactic acid and/or impaired tubular reabsorption of bicarbonate/secretion of H+.
  • Albumin:
    • Albumin can be decreased with glomerular disease due to large losses of albumin into the urine through the damaged glomeruli. In this case, there is usually a marked proteinuria on the urinalysis.
  • Non-regenerative anemia:
    • Non-regenerative anemia can occur with chronic kidney disease due to decreased erythropoietin production. In acute renal injury, the clinical course is usually too rapid for decreased erythropoietin to contribute to the anemia.  If non-regenerative anemia is present in animals with acute renal injury, other mechanisms should be considered (e.g. anemia of inflammatory disease).

Post-renal azotemia

Post-renal azotemia results from obstruction (urolithiasis) or rupture (uroabdomen) of urinary outflow tracts. This is best diagnosed by clinical signs (e.g. frequent attempts to urinate without success or presence of peritoneal fluid due to uroabdomen) and ancillary diagnostic tests (e.g. inability to pass a urinary catheter) as urine specific gravity results are quite variable. Animals with post-renal azotemia are markedly hyperkalemic and hypermagnesemic. Uroperitoneum can be confirmed by comparing the concentration of creatinine in the fluid to that in serum or plasma; leakage of urine is indicated by a higher creatinine in fluid than in serum. Post-renal azotemia can result in primary renal azotemia (failure) due to tubule dysfunction from impaired renal flow.

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