Biomarkers of Kidney Function: Blood Urea Nitrogen (BUN)

Optimal Takeaways

Blood urea nitrogen is a byproduct of protein breakdown, usually from dietary protein but also from gastrointestinal bleeding or tissue breakdown. It is formed in the liver and sent to the kidney for excretion. 

Blood levels depend on protein intake as well as liver and kidney function and it is assessed alongside creatinine and estimated glomerular filtration rate (eGFR). It may be measured as total urea or blood urea nitrogen (BUN). Low levels are associated with inadequate protein intake, malnutrition, overhydration, liver failure, and nephrotic syndrome. High levels are associated with kidney failure, gastrointestinal bleeding, excess protein intake, pancreatitis, and myocardial infarction.

Standard Range: 7.00 – 25.00 mg/dL (2.50 – 8.92 mmol/L urea)

The ODX Range: 10.00 – 16.00 mg/dL (3.57 -5.71 mmol/L urea)

Low levels of BUN are associated with liver failure, overhydration, malabsorption, malnutrition, negative nitrogen balance, pregnancy, and nephrotic syndrome, as well as with the use of chloramphenicol and streptomycin (Pagana 2021).

High levels of BUN are associated with renal dysfunction, dehydration, excess protein intake, GI bleeding, shock, burns, heart failure, and myocardial infarction, as well as with certain medications, including allopurinol, diuretics, antibiotics, and aspirin (Pagana 2021). Elevated BUN is observed in acute pancreatitis and may predict severity as well as mortality from the condition (Dai 2022, Lin 2017, Wu 2011). Other catabolic processes, such as fever and infection, can increase BUN as well (Hosten 1990).

Overview

Blood urea nitrogen (BUN) reflects the amount of nitrogen found in circulating urea, a byproduct of protein metabolism. When protein is broken down, some of the nitrogen is released as ammonia and converted to urea in the liver. The urea is then transferred to the kidney for excretion. Therefore, blood levels of urea nitrogen are dependent on the amount of protein metabolized, liver function, and renal excretion. BUN is assessed alongside creatinine and estimated glomerular filtration rate (eGFR) (Pagana 2021).

BUN also reflects tissue protein turnover, which can affect levels, as well as fever and infection, which are catabolic processes that can increase urea production. The blood urea nitrogen test only measures the nitrogen portion of urea and is approximately one-half the of value of total urea. Some urea is lost through the GI tract, lungs, and skin, and substantial amounts may be lost in sweat during rigorous exercise. These losses aren’t reflected in the BUN (Hosten 1990).

One study of 40 subjects revealed that those with renal failure had a BUN of 18.1-31.7 mg/dL (6.46-11.32 mmol/L) with a mean of 25.1 mg/dL (8.96 mmol/L) versus 6.4-15 mg/dL (2.28-5.35 mmol/L) with a mean of 9.8 mg/dL (3.50 mmol/L) in healthy controls (Kamal 2014). Each 10 mg/dL (3.57 mmol/L) increase in BUN was associated with poorer outcomes and progression to end-stage renal disease in patients with stage 3-5 chronic kidney disease (Seki 2019).

An increased BUN can  also be seen with acute pancreatitis, a condition in which damage to the pancreas causes internal release of active digestive enzymes leading to significant “digestion” of the pancreas itself. A BUN of 20 mg/dL (7.14 mmol/L) or above was predictive of mortality in a secondary analysis of three prospective cohort studies comprising 1,043 cases of acute pancreatitis (Wu 2011).

A cut-off for BUN of 23.25 mg/dL (8.3 mmol/L) within 24 hours of hospital admission was predictive of severe acute pancreatitis in a group of 671 subjects, while a cut-off of 37.2 mg/dL (13.3 mmol/L) upon admission predicted mortality from the condition. Those with acute pancreatitis that was not severe presented with a median BUN of 4.7 mg/dL (13.17 mmol/L) on admission and 4.6 mg/dL (12.89 mmol/L) within 24 hours of admission (Lin 2017). Another study recommended a cut-off of 30.1 mg/dL (10.745 mmol/L) for predicting 30-day mortality in patients with severe acute pancreatitis (Dai 2022).

Increasing levels of BUN were found to predict in-hospital mortality as well. A retrospective analysis of 2,995 myocardial infarction patients found the lowest risk of mortality in the first tertile of 1.5-14.4 mg/dL (0.54-5.14 mmol/L) (Horiuchi 2018).

Elevated BUN is predictive of worse outcomes in critically ill ICU patients as well, especially above 28 mg/dL (10 mmol/L), independent of the presence of renal failure (Arihan 2018). BUN, along with elevated D-dimer, predicted increased mortality in hospitalized COVID-19 patients. A BUN of 12.89 mg/dL (4.6 mmol/L) or above, combined with a D-dimer of 0.845 ug/mL (4.63 nmol/L) or above, predicted mortality in COVID patients (Cheng 2020).

BUN is also considered a biomarker for heart failure, possibly due to a neurohormonal renal response to hemodynamic changes. One study observed a 21% increase in mortality for each 10 mg/dL (3.57 mmol/L) rise in BUN above 17 mg/dL (6.07 mmol/L) in chronic heart failure (Kazory 2010).

References

Arihan, Okan et al. “Blood Urea Nitrogen (BUN) is independently associated with mortality in critically ill patients admitted to ICU.” PloS one vol. 13,1 e0191697. 25 Jan. 2018, doi:10.1371/journal.pone.0191697

Cheng, Anying et al. “Diagnostic performance of initial blood urea nitrogen combined with D-dimer levels for predicting in-hospital mortality in COVID-19 patients.” International journal of antimicrobial agents vol. 56,3 (2020): 106110. doi:10.1016/j.ijantimicag.2020.106110

Dai, Minhui et al. “Blood Urea Nitrogen as a Prognostic Marker in Severe Acute Pancreatitis.” Disease markers vol. 2022 7785497. 29 Mar. 2022, doi:10.1155/2022/7785497

Hall, John E., and Michael E. Hall. Guyton and Hall textbook of medical physiology, 14th ed. Elsevier Health Sciences, 2020.

Horiuchi, Yu et al. “A High Level of Blood Urea Nitrogen Is a Significant Predictor for In-hospital Mortality in Patients with Acute Myocardial Infarction.” International heart journal vol. 59,2 (2018): 263-271. doi:10.1536/ihj.17-009

Hosten, Adrian O. “BUN and Creatinine.” Clinical Methods: The History, Physical, and Laboratory Examinations, edited by H Kenneth Walker et. al., 3rd ed., Butterworths, 1990.

Kamal, Azra. "Estimation of blood urea (BUN) and serum creatinine level in patients of renal disorder." Indian J Fundam Appl Life Sci 4.4 (2014): 199-202.

Kazory, Amir. “Emergence of blood urea nitrogen as a biomarker of neurohormonal activation in heart failure.” The American journal of cardiology vol. 106,5 (2010): 694-700. doi:10.1016/j.amjcard.2010.04.024

Lin, Suhan et al. “Blood Urea Nitrogen as a Predictor of Severe Acute Pancreatitis Based on the Revised Atlanta Criteria: Timing of Measurement and Cutoff Points.” Canadian journal of gastroenterology & hepatology vol. 2017 (2017): 9592831. doi:10.1155/2017/9592831

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Seki, Makiko et al. “Blood urea nitrogen is independently associated with renal outcomes in Japanese patients with stage 3-5 chronic kidney disease: a prospective observational study.” BMC nephrology vol. 20,1 115. 2 Apr. 2019, doi:10.1186/s12882-019-1306-1

Wu, Bechien U et al. “Blood urea nitrogen in the early assessment of acute pancreatitis: an international validation study.” Archives of internal medicine vol. 171,7 (2011): 669-76. doi:10.1001/archinternmed.2011.126