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Urea and indicanuria

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Urea Overview (BUN)

Urea is the primary nitrogenous waste product resulting from the breakdown (metabolism) of proteins and amino acids in the body. In clinical practice, blood urea levels are often measured and reported as Blood Urea Nitrogen (BUN), which represents the nitrogen content of urea.

Urea Synthesis

Urea synthesis occurs almost exclusively in the liver through a series of biochemical reactions known as the urea cycle (or Ornithine cycle). This cycle converts ammonia (NH₃), a highly toxic byproduct of amino acid deamination, into the much less toxic urea ((NH₂)₂CO). The nitrogen atoms in urea come from ammonia and the amino acid aspartate.

The rate of urea synthesis is generally stable under normal conditions but can increase with high protein intake or increased protein catabolism (breakdown of body tissues) and decrease with very low protein intake or severe liver disease.

Significant impairment of urea synthesis only occurs in cases of very severe liver disease (e.g., end-stage liver failure) or rare hereditary defects in the urea cycle enzymes.

Urea Excretion

Urea is transported via the blood to the kidneys, where it is the main nitrogenous solute excreted in urine.

  • Glomerular Filtration: Urea is freely filtered from the blood into the primary urine by the glomeruli.
  • Tubular Reabsorption & Secretion: Unlike creatinine, urea undergoes significant tubular handling. A portion (around 35-50%, varying with hydration status) is passively reabsorbed back into the blood, primarily in the proximal tubules along with water. Some urea is also secreted into the thin limbs of the loop of Henle.

Ultimately, about 50-75% of the filtered urea is excreted in the final urine, playing a role in the kidney's ability to concentrate urine.

Urea Levels and Clinical Significance

The concentration of urea (or BUN) in the blood reflects the balance between urea production (related to protein metabolism and liver function) and urea excretion (primarily determined by kidney function).

  • Normal Range: Blood urea levels typically range from about 2.5-8.3 mmol/L (or BUN 7-20 mg/dL), influenced by diet and hydration.
  • Increased Urea/BUN (Azotemia): Elevated levels can result from:
    • Decreased Kidney Function (Renal Azotemia): Impaired glomerular filtration (acute or chronic kidney disease) leads to reduced urea excretion and accumulation in the blood. Very high levels (e.g., > 50 mmol/L or BUN > 140 mg/dL) are often seen in acute renal failure or end-stage renal disease, associated with significantly decreased urine urea excretion.
    • Increased Urea Production (Pre-renal Azotemia): High protein diet, gastrointestinal bleeding (digestion of blood protein), increased tissue breakdown (trauma, burns, fever, corticosteroids).
    • Dehydration/Decreased Renal Perfusion (Pre-renal Azotemia): Reduced blood flow to the kidneys enhances urea reabsorption, raising blood levels disproportionately to creatinine.
    • Urinary Tract Obstruction (Post-renal Azotemia): Blockage below the kidneys can impede urine flow and cause urea to back up.
  • Decreased Urea/BUN: Lower levels can be seen with:
    • Severe liver disease (impaired synthesis).
    • Malnutrition or very low protein diet.
    • Overhydration (dilution effect).
    • Rare genetic disorders of the urea cycle.
    • Pregnancy (due to increased GFR and hemodilution).

The BUN/Creatinine ratio can help differentiate causes of azotemia (e.g., a high ratio often suggests pre-renal causes or GI bleed).

Indicanuria Overview

Indican (chemically, indoxyl sulfate potassium salt) is a compound derived from the breakdown of the amino acid tryptophan by bacteria in the intestine. Indicanuria refers to the presence of detectable or increased levels of indican in the urine.

Indican Formation

  1. Dietary tryptophan that is not absorbed in the small intestine reaches the colon.
  2. Intestinal bacteria metabolize tryptophan into indole.
  3. Indole is absorbed into the bloodstream and transported to the liver.
  4. In the liver, indole is hydroxylated to form indoxyl.
  5. Indoxyl is then conjugated with sulfate to form indoxyl sulfate (indican).
  6. Indican is water-soluble and excreted by the kidneys into the urine.

Clinical Significance of Indicanuria

Indican is normally present in urine in very small amounts. Increased urinary excretion (indicanuria) generally indicates an increase in the bacterial breakdown of tryptophan in the intestine, often associated with:

  • Intestinal Stasis or Obstruction: Slow movement of intestinal contents allows more time for bacterial putrefaction of proteins.
  • Malabsorption Syndromes: Conditions where protein digestion or absorption is impaired (e.g., celiac disease, pancreatic insufficiency) lead to more undigested protein reaching the colon.
  • Increased Protein Putrefaction: Conditions involving significant bacterial overgrowth in the small or large intestine (SIBO/LIBO), or excessive breakdown of tissue proteins within the body (e.g., gangrene, empyema, large abscesses where indole might be produced locally and absorbed).
  • High Protein Diet (less common): Extremely high protein intake might slightly increase indican production.
  • Hartnup Disease: A rare genetic disorder impairing tryptophan absorption.

Historically, indicanuria testing (often qualitative colorimetric tests like Obermayer's test) was used as a non-specific indicator of "intestinal toxemia" or putrefaction. While less common in mainstream clinical labs today, it is sometimes used in functional or alternative medicine settings as a marker suggestive of gut dysbiosis or impaired protein digestion.

Laboratory Testing

  • Urea: Commonly measured in blood serum or plasma as BUN (Blood Urea Nitrogen). Part of standard chemistry panels (e.g., Basic Metabolic Panel, Comprehensive Metabolic Panel). Can also be measured in urine (random or 24-hour) for clearance calculations.
  • Indican: Measured in urine. Qualitative tests provide a color reaction. Quantitative tests measure the concentration, often reported per gram of creatinine to adjust for urine concentration.

References

  1. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). (n.d.). Blood Urea Nitrogen (BUN). NIH. Retrieved from https://www.niddk.nih.gov/health-information/diagnostic-tests/blood-urea-nitrogen
  2. Lab Tests Online. (n.d.). BUN (Blood Urea Nitrogen). Retrieved from https://labtestsonline.org/tests/bun-blood-urea-nitrogen
  3. Mayo Clinic Staff. (n.d.). Blood urea nitrogen (BUN) test. Mayo Clinic Patient Care & Health Information. Retrieved from https://www.mayoclinic.org/tests-procedures/bun-test/about/pac-20384821
  4. Wrong, O. M. (1978). Nitrogen metabolism in the gut. *The American Journal of Clinical Nutrition*, 31(9), 1587–1593. https://doi.org/10.1093/ajcn/31.9.1587 (Discusses indole production)
  5. Ghoshal, U. C. (2011). How to interpret hydrogen breath tests. *Journal of Neurogastroenterology and Motility*, 17(3), 312–317. https://doi.org/10.5056/jnm.2011.17.3.312 (Context of bacterial overgrowth, though not directly about indican)