Published in Clinical Pathology
Sunday, 27 August 2017 01:43
Two biochemical parameters are commonly used to assess renal function: blood urea nitrogen (BUN) and serum creatinine. Although convenient, they are insensitive markers of glomerular function.
Blood Urea Nitrogen (BUN)
Urea is produced in the liver from amino acids (ingested or tissue-derived). Amino acids are utilized to produce energy, synthesize proteins, and are catabolized to ammonia. Urea is produced in the liver from ammonia in the Krebs urea cycle. Ammonia is toxic and hence is converted to urea, which is then excreted in urine (Figure 842.1).
Figure 842.1 Formation of urea from protein breakdown
Figure 842.1 Formation of urea from protein breakdown 
The concentration of blood urea is usually expressed as blood urea nitrogen. This is because older methods estimated only the nitrogen in urea. Molecular weight of urea is 60, and 28 grams of nitrogen are present in a gm mole of urea. As the relationship between urea and BUN is 60/28, BUN can be converted to urea by multiplying BUN by 2.14, i.e. the real concentration of urea is BUN × (60/28).
Urea is completely filtered by the glomeruli, and about 30-40% of the filtered amount is reabsorbed in the renal tubules depending on the person’s state of hydration.
Blood level of urea is affected by a number of non-renal factors (e.g. high protein diet, upper gastrointestinal hemorrhage, liver function, etc.) and therefore utility of BUN as an indicator of renal function is limited. Also considerable destruction of renal parenchyma is required before elevation of blood urea can occur.
The term azotemia refers to the increase in the blood level of urea; uremia is the clinical syndrome resulting from this increase. If renal function is absent, BUN rises by 10-20 mg/dl/day.
Causes of increased BUN:
  1. Pre-renal azotemia: shock, congestive heart failure, salt and water depletion
  2. Renal azotemia: impairment of renal function
  3. Post-renal azotemia: obstruction of urinary tract
  4. Increased rate of production of urea:
    • High protein diet
    • Increased protein catabolism (trauma, burns, fever)
    • Absorption of amino acids and peptides from a large gastrointestinal hemorrhage or tissue hematoma
Methods for estimation of BUN:
Two methods are commonly used.
  1. Diacetyl monoxime urea method: This is a direct method. Urea reacts with diacetyl monoxime at high temperature in the presence of a strong acid and an oxidizing agent. Reaction of urea and diacetyl monoxime produces a yellow diazine derivative. The intensity of color is measured in a colorimeter or spectrophotometer.
  2. Urease- Berthelot reaction: This is an indirect method. Enzyme urease splits off ammonia from the urea molecule at 37°C. Ammonia generated is then reacted with alkaline hypochlorite and phenol with a catalyst to produce a stable color (indophenol). Intensity of color produced is then measured in a spectrophotometer at 570 nm.
Reference range for BUN in adults is 7-18 mg/dl. In adults > 60 years, level is 8-21 mg/dl.
Serum Creatinine
Creatinine is a nitrogenous waste product formed in muscle from creatine phosphate. Endogenous production of creatinine is proportional to muscle mass and body weight. Exogenous creatinine (from ingestion of meat) has little effect on daily creatinine excretion.
Serum creatinine is a more specific and more sensitive indicator of renal function as compared to BUN because:
  • It is produced from muscles at a constant rate and its level in blood is not affected by diet, protein catabolism, or other exogenous factors;
  • It is not reabsorbed, and very little is secreted by tubules.
With muscle mass remaining constant, increased creatinine level reflects reduction of glomerular filtration rate. However, because of significant kidney reserve, increase of serum creatinine level (from 1.0 mg/dl to 2.0 mg/dl) in blood does not occur until about 50% of kidney function is lost. Therefore, serum creatinine is not a sensitive indicator of early renal impairment. Also, laboratory report showing serum creatinine “within normal range” does not necessarily mean that the level is normal; the level should be correlated with body weight, age, and sex of the individual. If renal function is absent, serum creatinine rises by 1.0 to 1.5 mg/dl/day (Figure 842.2).
Figure 842.2 Relationship between glomerular filtration rate and serum creatinine
Figure 842.2 Relationship between glomerular filtration rate and serum creatinine. Significant increase of serum creatinine does not occur till a considerable fall in GFR

Causes of Increased Serum Creatinine Level
  1. Pre-renal, renal, and post-renal azotemia
  2. Large amount of dietary meat
  3. Active acromegaly and gigantism
Causes of Decreased Serum Creatinine Level
  1. Pregnancy
  2. Increasing age (reduction in muscle mass)
Methods for Estimation of Serum Creatinine
The test for serum creatinine is cheap, readily available, and simple to perform. There are two methods that are commonly used:
  1. Jaffe’s reaction (Alkaline picrate reaction): This is the most widely used method. Creatinine reacts with picrate in an alkaline solution to produce spectrophotometer at 485 nm. Certain substances in plasma (such as glucose, protein, fructose, ascorbic acid, acetoacetate, acetone, and cephalosporins) react with picrate in a similar manner; these are called as non-creatinine chromogens (and can cause false elevation of serum creatinine level). Thus ‘true’ creatinine is less by 0.2 to 0.4 mg/dl when estimated by Jaffe’s reaction.
  2. Enzymatic methods: These methods use enzymes that cleave creatinine; hydrogen peroxide produced then reacts with phenol and a dye to produce a colored product, which is measured in a spectrophotometer.
Reference range:
Adult males: 0.7-1.3 mg/dl.
Adult females: 0.6-1.1 mg/dl.
Serum creatinine alone should not be used to assess renal function. This is because serum creatinine concentration depends on age, sex, muscle mass, glomerular filtration and amount of tubular secretion. Thus, normal serum creatinine range is wide. Serum creatinine begins to rise when GFR falls below 50% of normal. Minor rise of serum creatinine is associated with significant reduction of GFR (Figure 842.2). Therefore early stage of chronic renal impairment cannot be detected by measurement of serum creatinine alone.
BUN/Serum Creatinine Ratio
Clinicians commonly calculate BUN/creatinine ratio to discriminate pre-renal and post-renal azotemia from renal azotemia. Normal ratio is 12:1 to 20:1.
Causes of Increased BUN/Creatinine Ratio (>20:1):
  1. Increased BUN with normal serum creatinine:
    • Pre-renal azotemia (reduced renal perfusion)
    • High protein diet
    • Increased protein catabolism
    • Gastrointestinal hemorrhage
  2. Increase of both BUN and serum creatinine with disproportionately greater increase of BUN:
    • Post-renal azotemia (Obstruction to the outflow of urine)
    Obstruction to the urine outflow causes diffusion of urinary urea back into the blood from tubules because of backpressure.

Causes of Decreased BUN/Creatinine Ratio (<10:1)
  • Acute tubular necrosis
  • Low protein diet, starvation
  • Severe liver disease

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