Urea/Urea Nitrogen Measurement and Clinical Significance

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Urea Blood-Urea-Nitrogen-BUN

Urea (urea nitrogen) is the main component of NPN material in blood; it is distributed throughout the body water and has equal concentrations in intracellular and extracellular fluid. Gross changes in NPN are usually caused by a change in urea concentration. The liver is the only place where urea is produced. Ammonia is formed in greater quantities as protein degrades (for example, as amino acids deaminate). This potentially toxic substance is eliminated in the liver, where ammonia combines with other amino acids and is converted to urea by liver enzymes. Urea is a byproduct of protein metabolism that is normally excreted from the blood by the kidneys. The amount of urea in the blood is determined by the amount of protein consumed and the ability of the kidney to excrete urea. When the kidneys are damaged, urea is not removed from the blood and accumulates. An increase in serum or plasma urea concentrations may indicate a problem with the kidney’s filtering system.

In the past, it was common laboratory practice to determine urea as urea nitrogen using whole blood; this procedure was known as blood urea nitrogen (BUN). Methodologies used by automated instruments can directly measure urea in serum or plasma. Blood urea nitrogen, urea nitrogen, and urea are still terms that are used interchangeably. Urea’s chemical formula is NH2 CONH2. Because urea nitrogen is a measure of nitrogen rather than urea, one can convert milligrams of urea nitrogen to milligrams of urea by multiplying the urea nitrogen value by 2.14, or 60/28. Urea has a molecular weight of 60 and two nitrogen atoms with a total weight of 28.

The assay for urea is only a rough estimate of renal function and will not show any significant level of increased concentration until the glomerular filtration rate (GFR) is decreased

Clinical Significance

  • The urea assay is only a rough estimate of renal function, and it will not show any significant increase in concentration until the glomerular filtration rate (GFR) is reduced by at least 50%.
  • The serum creatinine test is a more reliable single indicator of renal function (SCR). Creatinine concentration, unlike urea concentration, is relatively independent of protein intake (from diet), degree of hydration, and protein metabolism.
  • Dietary protein and the kidney’s ability to excrete urea determine the amount of urea in the blood. If the kidneys are damaged, urea is not removed from the blood and accumulates, raising the urea level.
  • Diet also has an effect on urea concentration; people who are malnourished or on low-protein diets may have urea levels that are not accurate indicators of kidney function. Because urea concentration is directly related to protein metabolism, the amount of urea in the blood will be affected by the protein content of the diet. The ability of the kidneys to remove urea from the blood will also have an impact on the urea content. Protein consumption has the greatest influence on urea concentration.
  • Urea is removed from the blood and excreted in the urine by the normal kidney. If kidney function is impaired, urea is not removed from the blood, resulting in a high urea concentration. Considerable deterioration must usually be present before the urea level rises above the reference range.

Uremia is a condition in which there is an excessively high level of urea nitrogen in the blood. A high increase in urea and creatinine plasma concentrations with renal insufficiency is referred to as azotemia. Unless liver injury is suspected, decreased levels are usually not clinically significant. Lower-than-normal urea levels are common during pregnancy. Azotemia can be caused by prerenal, renal, or postrenal factors:

  • Prerenal azotemia is caused by inadequate kidney perfusion, which results in decreased glomerular filtration. Otherwise, the kidneys operate normally. Poor perfusion can be caused by dehydration, shock, decreased blood volume, or congestive heart failure. Increased protein breakdown, as seen in fever, stress, or severe burns, is another cause of prerenal azotemia.
  • Renal azotemia is primarily caused by decreased glomerular filtration as a result of acute or chronic renal illness. Acute glomerulonephritis, chronic glomerulonephritis, polycystic kidney disease, and nephrosclerosis are examples of such disorders.
  • Postrenal azotemia is typically caused by any form of restriction that allows urea to be reabsorbed into the circulation. Stones, an enlarged prostate gland, or tumors can all cause obstruction.


  • Urea concentrations can be measured directly from serum, heparinized (sodium or lithium heparin) plasma, urine, or other biological material. Fluoride-containing anticoagulants (gray-top evacuated tubes) will also interfere with urease-based techniques because fluoride suppresses the urease process.
  • Because urea can be lost due to bacterial action, the specimen should be examined within a few hours of collection or refrigerated. Refrigeration at 4 °C to 8 °C maintains the urea for up to 72 hours without significant alteration.
  • Because urine urea is particularly vulnerable to bacterial action, in addition to refrigerating the urine specimen at 4 °C to 8 °C, the pH can be kept below 4 to help decrease urea loss.

Methods for Quantitative Determination

The addition of the enzyme urease to whole blood, serum, or plasma is the most ancient method of urea assay. Urease converts urea to ammonium carbonate ([NH4 ]2 CO3 ) during incubation. The ammonia in (NH4 )2 CO3 is evaluated in one of several ways. Gentzkow’s traditional manual method quantifies the amount of (NH4 )2 CO3 produced by reacting it with Nessler’s solution.

The most prevalent automated methods in use today are indirect methods based on a preparatory hydrolysis step in which the enzyme urease converts the urea present to ammonia. The measurement of ammonia varies depending on the instrument used. An indicator reaction using glutamate dehydrogenase (GLDH) to oxidize nicotinamide adenine dinucleotide (NADH) to NAD+ is employed in one regularly used analyzer to do an enzymatic measurement of the ammonia produced. At 340nm, the depletion of NADPH is detected. It is a highly specific and quick urea test. The reaction is as follows:

Urea reaction
Urea reaction

The kidneys and lungs have the largest influence over electrolyte content.

There are potentiometric approaches that use an ammonia ISE. Urea can be quantified by forming a yellow diazine derivative from condensation with diacetyl monoxime in the presence of strong acid and an oxidizing agent. To stabilize the color, iron (III) and thiosemicarbizide are added to the reaction mixture.

Reference Values

Adult7-18mg/dL (2.5-6.4mmol urea/L)
>60yr8-21mg/dL (2.9-7.5mmol urea/L)
Infant/child5-18mg/dL (1.8-6.4mmol urea/L)
Urea Nitrogen, Serum
Adult5-39mg/dL (2.5-6.4mmol/L)
Urea, Serum
12-20g/24h(428-714mmol urea/24h)
Urea Nitrogen, Urine

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