Urea is synthesized by hepatocytes from ammonia generated by catabolism of amino acids derived either from digestion of proteins in the intestines or from endogenous tissue proteins. Urea is excreted by the kidneys, colon (high in horses), saliva and sweat. The rate of urea production in the liver is dependent on hepatic function and digestion and catabolism of protein, i.e. urea formation is decreased in certain liver diseases (e.g. portosystemic shunts, synthetic liver failure, not just hepatic injury) and increased with protein catabolism or protein digestion in the intestine (upper GI bleeding). Urea is excreted by the kidneys, colon (high in horses), saliva and sweat. In ruminants, urea is excreted into the gastrointestinal system (mostly saliva) where it is converted to amino acids and ammonia which are then used for protein production (remember urea is added as a supplement to many bovine diets). Urea is freely filtered through the glomerulus and passively diffuses out of the tubules at a rate dependent on flow rate through the tubules; the remainder of the filtered urea is excreted in urine. At high flow rates, approximately 40% of filtered urea is reabsorbed. At low flow rates, as happens in hypovolemic individuals, approximately 60% of filtered urea is reabsorbed and added back to the blood urea concentration. This explains the high UN levels seen with decreased GFR of any cause.
Measurement of urea concentration in serum is included in chemistry profiles mainly to screen for decreased glomerular filtration rate (GFR). The test for measurement of urea concentration is called urea nitrogen (UN) or serum urea nitrogen (SUN) (blood urea nitrogen [BUN] is not technically correct as UN is not measured in blood); this is where only the concentration of the nitrogen component of urea is measured. In some methods, the urea molecule is assayed. Thus, in the context of this website, “urea” refers to the molecule and “urea nitrogen” the test for measurement of urea (which is converted to traditional measurements of urea based on the nitrogen content).
In the first reaction of this two-step process, the enzyme urease catalyzes the hydrolysis of urea generating ammonium and carbonate ions. In the presence of glutamate dehydrogenase (GLDH) the ammonium ion then reacts with α-ketoglutarate and NADH to form L-glutamate. The oxidation of NADH to NAD+ causes a decrease in absorbance that is measured kinetically, and is proportional to the concentration of urea.
Reaction is shown below:
Urea + H2O urease > 2NH4+ + CO2
NH4+ + α-ketoglutarate + NADH GLDH > L-glutamate + NAD+ + H2O
Units of measurement
Urea and UN concentrations are measured in mg/dL (conventional units) and mmol/L (SI units). Because the method actually measures urea, the manufacturer of most urea reagents convert the provided results into urea nitrogen (mg/dL in conventional units), which is the traditional way of measuring and reporting urea concentrations. Since the nitrogen content of urea (MW 28) is lower than the whole molecule (MW 60), the difference in MW between urea and urea nitrogen is 2.14 (60/28). So for our urea nitrogen results, the urea value is UN x 2.14 in unit equivalent, e.g. mg/dL). The conversion formulas to convert mg/dL SI units of UN to urea in mmol/L units are shown below:
UN [mg/dL] x 0.357= urea [mmol/L]
urea [mg/dL] x 0.1665 = urea [mmol/L]
The conversion is confusing as you first have to convert UN in mg/dL to mg/L (x 10) and then divide the UN value in mg/L by 28 to get the urea value in mmol/L (i.e. 10/28 = 0.357 conversion factor).
Serum, plasma, and urine
Heparin or EDTA may be used for measuring urea nitrogen in plasma samples. Ammonium heparin should be avoided as it may lead to spuriously high values of urea.
The stability of urea in serum or plasma samples are as follows: 7 days at 15 – 25 °C or 2 – 8 °C, and 1 year at (-15)-(-25) °C.
The stability of urea in urine is as follows: 2 days at 15 – 25 °C, 7 days at 2 – 8 °C, and 4 weeks at (-15)-(-25) °C. Urine samples should be collected without preservatives.
- Lipemia: Severe lipemia (>1000 lipemia index) may decrease concentrations.
- Hemolysis: Will increase with severe hemolysis (>1000 hemolysis index).
- Icterus: Severe icterus may increase concentrations (>60 icteric index).
Increased urea nitrogen concentration
- Artifact: severe icterus (increased total bilirubin), ammonia contamination (uncommon)
- Increased protein catabolism: Fever, burns, corticosteroid administration, starvation, exercise.
- Increased protein digestion: Hemorrhage into the gastrointestinal system, high protein diets.
- Decreased GFR (azotemia): Due to prerenal, renal or postrenal causes.
Note that urea will be increased with a normal creatinine in the following situations:
- Increased production of urea, e.g. protein catabolism.
- Early prerenal azotemia (urea resorption in proximal convoluted tubules is affected by flow rate through the tubules – slowing down of proximal tubular flow rate will increase urea absorption whereas creatinine concentrations are not affected since creatinine is not resorbed in the tubules in most species).
Decreased urea nitrogen concentration
- Decreased protein intake or protein anabolism: Dietary restriction of protein, young animals (high anabolic rate).
- Increased excretion: Any cause of polyuria, e.g. hyperadrenocorticism, diabetes mellitus.
- Decreased production: Liver disease, enzyme deficiencies in urea cycle.
Discordant urea nitrogen and creatinine
Urea and creatinine should always be interpreted together and in relation to the glomerular filtration rate. Below is a summary table of interpretations of different urea and creatinine combinations.
|↑||N / ↓||Early prerenal azotemiaNormal glomerular filtration rate (GFR) with ↑ urea nitrogen
High protein diet, upper gastrointestinal (GI) bleed
↓ GFR with ↓ creatinine
Decreased muscle mass (cachexia)
|N / ↓||↑||↓ GFR with ↓ urea nitrogen
Hepatic failure, polyuria-polydipsia (in absence of chronic kidney disease), low protein diet, metabolism of urea nitrogen by GI flora (horses and cattle)
Normal GFR with ↑ creatinine
A normal finding in Greyhounds (increased muscle mass)