Azotemia is is a laboratory abnormality and is defined as an increase in urea nitrogen and/or 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 indicates that there is a problem with the kidneys filtering nitrogenous waste (urea nitrogen) or products of muscle metabolism (creatinine), i.e. a decreased glomerular filtration rate (GFR). This filtration is the responsibility of the glomeruli and NOT the tubules of the nephron. Of course, azotemia can be due to renal disease that results in reduced function or number of glomeruli (renal azotemia) or factors outside the kidney that the kidney cannot control, such as dehydration or hypovolemia that decreased blood flow to the kidney (prerenal azotemia) or post-renal obstruction (post-renal azotemia), where tubular pressure feeds back on glomerular arterioles and venules decreasing blood flow into the glomeruli. Thus azotemia can be due to prerenal, renal or post-renal causes or a combination thereof in any given patient. Differentiation of the causes of azotemia requires urinalysis to assess tubular function (especially the urine specific gravity and looking for other evidence of insufficient tubular function, e.g. glucosuria without hyperglycemia, or tubular injury, e.g. granular, cellular or waxy casts), evaluation of clinical signs and results of other diagnostic tests (e.g. radiographic evidence of urinary tract obstruction). 

Prerenal azotemia

Prerenal azotemia is due to a decrease in 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, > 1.040 in the cat, > 1.025 in large animals; usually with no evidence of renal tubule dysfunction such as excessive 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 secondarily ensue, and thus may co-exist with a prerenal azotemia. As urea nitrogen 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 nitrogen may increase without any increase in creatinine in early pre-renal azotemia. Because the kidney is essential to acid-base and electrolyte homeostasis, a severe prerenal azotemia may lead to retention of organic acids normally excreted by the kidney (i.e. a high anion gap metabolic acidosis) and hyperphosphatemia but this should not happen in a mild or even more moderate prerenal azotemia.

Renal azotemia

Renal azotemia (based on increased serum creatinine concentrations) results from decreased GFR when there is loss of more than ¾ of renal mass. This equates to a roughly 35-35% decrease in renal function, because of compensatory glomerular hypertrophy. Renal azotemia may be due to primary intrinsic renal disease (glomerulonephritis, ethylene glycol toxicity) or may be due to renal injury that occurs secondary to renal ischemia, such as from prerenal causes, or urinary tract obstruction (post-renal azotemia). Loss of kidney function (which manifests as azotemia) usually comes after concentrating defects (requires loss of 2/3 of kidney mass and reflects tubular versus glomerular function), 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, < 1.040 in the cat and < 1.025 in large animals) or when results are borderline (e.g. close around the cutoffs). In addition, there may be other evidence of renal tubular dysfunction in the urinalysis (such as excessive proteinuria not explained by other reasons, 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 nitrogen can be modest in renal azotemia due to excretion of urea into the gastrointestinal system. Once in the gastrointestinal system, the urea is then broken down into amino acids in the cecum and rumen, respectively, and is reabsorbed as amino acids (reused for protein synthesis or gluconeogenesis) and not as urea nitrogen. Therefore, creatinine is a more reliable indicator of GFR in these species. Gastrointestinal secretion of urea nitrogen also occurs in small animals, but the urea is reabsorbed intact (causing a futile cycle of secretion and reabsorption) so the gastrointestinal system does not represent an efficient or alternative (to the kidney) means of excretion of nitrogenous waste in small animals. 

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. These changes differ depending on if the renal disease is acute kidney injury or chronic kidney disease and the severity of the disease. You can have renal disease without any azotemia at all.

  • Phosphate and calcium
    • Phosphate is primarily excreted through glomerular filtration in the kidneys in most mammals, so decreased GFR leads to increased serum phosphate, particularly with acute kidney injury. However, ruminants and horses with decreased GFR may not always have hyperphosphatemia due to other sources of phosphate elimination such as saliva and the GI tract. In fact, horses with azotemia due to chronic kidney disease often (but do not always) have high calcium and low phosphate concentrations.
    • 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 free ionized calcium as occurs in small animals. In dogs and cats with chronic kidney disease, total calcium concentrations are often normal or low, with a low percentage of animals having high total calcium concentrations. This is thought to be due to hyperphosphatemia which complexes with the calcium. In this situation, free ionized calcium may be normal or even low, i.e. you cannot predict (using any formula) free ionized calcium concentrations from total concentrations in animals with chronic kidney disease. In horses with acute kidney injury, calcium concentrations are often low whereas the opposite is true with chronic kidney disease. The hypercalcemia seen in horses and guinea pigs with chronic kidney disease is attributed to decreased renal excretion, because renal excretion is the main route of elimination of calcium in these species (and horses do not have the alpha1-hydroxylase enzyme in the kidney to convert vitamin D from 25-hydroxycholicalciferol to the most active form, 1,25-dihyroxycholicalciferol). Not all equine patients with chronic renal disease will have hypercalcemia (or hypophosphatemia) and not all equine patients with acute kidney injury will have hypocalcemia. Phosphate and calcium concentrations can be normal in this species with renal disease.
  • Electrolytes and acid-base
    • Potassium is often increased in oliguric or auric renal failure and post-renal azotemia due to reduced urinary elimination of potassium. Polyuric renal failure is more likely to result in low potassium (particularly in cats) or normal potassium. The following electrolyte abnormalities are observed in different species with renal failure:
      • Ruminants: Decreased sodium chloride is seen, with decreases in chloride being most consistent. This is associated with a concurrent metabolic alkalosis (the latter may be due to a secondary abomasal atony versus excretion of excess chloride by the failing kidney). Hypokalemia may be seen in polyuric renal failure, and hyperkalemia is seen in oliguric renal failure or an obstructed urethra or ruptured bladder. Hypocalcemia (total calcium) is common as is increased fibrinogen concentration.
      • Equine: Can see a decrease in sodium chloride (especially chloride) due to loss of these electrolytes in the urine. In acute kidney injury, 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 as indicated above). Hyperkalemia is a feature (with low sodium and chloride) of uroabdomen (most common in foals).
      • Small animals: Hyperkalemia is usually only seen in anuric or oliguric renal failure or urinary tract obstruction or rupture. Total calcium concentration 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.
    • Acid base: A high anion gap metabolic acidosis is common in all species with renal failure, particularly due to acute kidney injury with abrupt changes in renal function, but also occurs with chronic kidney disease, particularly in later stages with 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 concentrations 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+ by proximal convoluted tubules or lack of excretion of H+ by the distal tubules. Animals with specific types of renal disease can have impaired acid base status with or without azotemia. For example, in proximal renal tubular acidosis (e.g. Fanconi syndrome secondary to copper toxicity), the proximal tubules cannot reabsorb bicarbonate leading to a mild acidosis, because the distal tubules can still excrete hydrogen. In contrast in a distal renal tubular acidosis, excretion of hydrogen is impaired (even though bicarbonate absorption in the proximal tubules is intact) leading to a more severe metabolic acidosis (usually hyperchloremic with a normal anion gap) with an alkaline urinary pH.
  • 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 that is excessive for the urine specific gravity and usually a urine protein to creatinine ratio of >2.
  • Non-regenerative anemia:
    • A non-regenerative anemia can occur with chronic kidney disease due to decreased erythropoietin production by interstitial fibroblasts in the kidney. In acute kidney 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 kidney injury, other mechanisms should be considered (e.g. anemia of inflammatory disease). Other factors may contribute to the anemia in animals with chronic renal disease, including cytokine-mediated suppression of erythropoiesis (anemia of inflammatory disease), uremic “toxins” suppressing erythropoiesis, and blood loss secondary to gastric ulcers.

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 usually markedly hyperkalemic and hypermagnesemic and may have concurrently low sodium and chloride concentrations. 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 the peritoneal fluid than in serum (usually 2 or more times higher in the fluid than serum or plasma). Post-renal azotemia can result in secondary renal azotemia due to tubule dysfunction from impaired renal blood flow (glomerulotubular feedback).