Renal function is often evaluated using two primary biochemical parameters: blood urea nitrogen (BUN) and serum creatinine. Despite their convenience, these markers prove to be less sensitive indicators of glomerular function.
Blood Urea Nitrogen (BUN)
Urea originates in the liver through the conversion of amino acids, whether derived from ingested sources or tissues. Amino acids play a crucial role in energy production, protein synthesis, and are subject to catabolism, leading to the formation of ammonia. The liver, in the Krebs urea cycle, transforms this ammonia into urea. Given the toxicity of ammonia, its conversion to urea ensures safe elimination through urine excretion (refer to Figure 1).
The concentration of blood urea is commonly expressed as blood urea nitrogen (BUN), a practice rooted in older methods that exclusively assessed the nitrogen content in urea. With urea's molecular weight being 60, a gram mole of urea contains 28 grams of nitrogen. This relationship, expressed as 60/28, allows the conversion of BUN to urea by multiplying BUN by 2.14, thereby establishing the real concentration of urea as BUN × (60/28).
Glomeruli completely filter urea, and depending on an individual's hydration status, approximately 30-40% of the filtered amount is reabsorbed in the renal tubules.
The blood level of urea is susceptible to various non-renal factors, such as a high-protein diet, upper gastrointestinal hemorrhage, and liver function. Consequently, the utility of BUN as a reliable indicator of renal function is limited. Significant destruction of renal parenchyma is necessary before an elevation in blood urea can be observed.
Azotemia refers to an increase in the blood level of urea, while uremia represents the clinical syndrome resulting from this elevation. In the absence of renal function, BUN experiences a daily rise of 10-20 mg/dl.
Causes of increased BUN
- Pre-renal Azotemia: Conditions such as shock, congestive heart failure, and salt and water depletion
- Renal Azotemia: Impairment of renal function
- Post-renal Azotemia: Obstruction of the urinary tract
- Increased Rate of Urea Production:
- Adoption of a high-protein diet
- Elevated protein catabolism due to factors such as trauma, burns, or fever
- Absorption of amino acids and peptides resulting from significant gastrointestinal hemorrhage or tissue hematoma
Methods for estimation of BUN
Two methods are commonly used.
- Diacetyl Monoxime Urea Method: A direct approach involving the reaction of urea with diacetyl monoxime at high temperatures, facilitated by a strong acid and an oxidizing agent. This reaction yields a yellow diazine derivative, and the color intensity is quantified using a colorimeter or spectrophotometer.
- Urease-Berthelot Reaction: An indirect method where the enzyme urease catalyzes the separation of ammonia from the urea molecule at 37°C. The resulting ammonia is then reacted with alkaline hypochlorite and phenol in the presence of a catalyst, producing a stable color known as indophenol. The intensity of the color produced is subsequently measured at 570 nm using a spectrophotometer.
The established reference range for Blood Urea Nitrogen (BUN) in adults spans from 7 to 18 mg/dl. However, for individuals aged over 60 years, the acceptable range extends slightly, ranging from 8 to 21 mg/dl.
Serum Creatinine
Creatinine, a nitrogenous waste product, originates in muscle through the conversion of creatine phosphate. Its endogenous production correlates with muscle mass and body weight, with exogenous creatinine from meat ingestion exerting minimal influence on daily creatinine excretion.
When compared to Blood Urea Nitrogen (BUN), serum creatinine emerges as a more specific and sensitive indicator of renal function for several reasons:
- Creatinine is consistently produced by muscles at a steady rate, remaining unaffected by dietary variations, protein catabolism, or other external factors.
- Unlike BUN, creatinine is not reabsorbed, and only a minimal amount is secreted by the renal tubules.
While an increased creatinine level reflects a reduction in glomerular filtration rate when muscle mass is constant, the manifestation of elevated serum creatinine levels (e.g., from 1.0 mg/dl to 2.0 mg/dl) in blood is delayed until about 50% of kidney function is lost, owing to significant kidney reserve. Consequently, serum creatinine proves less sensitive in detecting early renal impairment. It's important to note that a laboratory report indicating serum creatinine within the normal range does not necessarily denote normalcy; the level should be correlated with the individual's body weight, age, and sex. In the absence of renal function, serum creatinine rises by 1.0 to 1.5 mg/dl per day (refer to Figure 2).
Causes of Increased Serum Creatinine Level
- Pre-renal, renal, and post-renal azotemia
- High intake of dietary meat
- Presence of active acromegaly and gigantism
Causes of Decreased Serum Creatinine Level
- Pregnancy
- Increasing age (reduction in muscle mass)
Methods for Estimation of Serum Creatinine
The assay for serum creatinine stands out for its cost-effectiveness, widespread availability, and simplicity in execution. Two commonly employed methods are as follows:
- Jaffe’s Reaction (Alkaline Picrate Reaction): This method holds prominence as the most widely used. In an alkaline solution, creatinine reacts with picrate, yielding a spectrophotometric response at 485 nm. Notably, certain plasma components like glucose, protein, fructose, ascorbic acid, acetoacetate, acetone, and cephalosporins exhibit a similar reaction with picrate, collectively termed non-creatinine chromogens. Their interaction can lead to a false elevation of serum creatinine levels, resulting in a 'true' creatinine value that is understated by 0.2 to 0.4 mg/dl when assessed through Jaffe’s reaction.
- Enzymatic Methods: This alternative approach employs enzymes that catalyze the cleavage of creatinine. Subsequent to the production of hydrogen peroxide, its reaction with phenol and a dye generates a colored product, measurable through spectrophotometry.
Reference Range
- Adult males: 0.7-1.3 mg/dl
- Adult females: 0.6-1.1 mg/dl
Relying solely on serum creatinine for the evaluation of renal function is not recommended. The concentration of serum creatinine is influenced by factors such as age, sex, muscle mass, glomerular filtration, and the extent of tubular secretion. Consequently, the normal range for serum creatinine is broad. The elevation of serum creatinine becomes apparent when the glomerular filtration rate (GFR) falls below 50% of the normal level. Even a minor increase in serum creatinine is indicative of a significant reduction in GFR, as illustrated in Figure 2. Consequently, the early stages of chronic renal impairment cannot be effectively identified through the measurement of serum creatinine alone.
BUN/Serum Creatinine Ratio
Clinicians commonly calculate BUN/creatinine ratio as a diagnostic tool to differentiate pre-renal and post-renal azotemia from renal azotemia. The standard range for this ratio is 12:1 to 20:1.
Causes of Increased BUN/Creatinine Ratio (>20:1):
- Elevated BUN with normal serum creatinine:
- Pre-renal azotemia (resulting from reduced renal perfusion)
- High protein diet
- Increased protein catabolism
- Gastrointestinal hemorrhage
- Elevation of both BUN and serum creatinine with a disproportionately greater increase in BUN:
- Post-renal azotemia (caused by obstruction to urine outflow)
- Obstruction to urinary outflow induces the diffusion of urinary urea back into the bloodstream from tubules due to increased backpressure.
Causes of Decreased BUN/Creatinine Ratio (<10:1)
- Acute tubular necrosis
- Low protein diet and starvation
- Severe liver disease