Relationship Between GFR, Creatinine, and Urea in Blood Samples
GFR, creatinine, and urea are inversely related: as GFR declines, both serum creatinine and blood urea nitrogen (BUN) rise, though creatinine is the preferred marker for estimating kidney function while the combined measurement of both provides the most accurate assessment when GFR is severely reduced. 1
Core Physiological Relationships
Creatinine and GFR
Serum creatinine has an inverse, non-linear relationship with GFR - when GFR declines to approximately half of normal, serum creatinine rises above the upper limit of normal 1
GFR must decline substantially before creatinine elevation becomes apparent - minor elevations in serum creatinine may indicate substantial reductions in GFR, particularly in elderly patients where age-related muscle mass decline masks the GFR decrease 1
The relationship is mathematically proven to be universally opposing - in creatinine kinetics, any decrease in GFR obligates creatinine to increase, and vice versa, throughout all clinical values 2
Creatinine alone should never be used as the sole measure of kidney function because it is affected by factors beyond GFR including creatinine generation (muscle mass), secretion, and extrarenal excretion 1
Urea and GFR
Blood urea nitrogen also rises as GFR falls, but urea is less reliable than creatinine because it is reabsorbed by renal tubules and affected by protein intake, hydration status, and catabolic states 1, 3
The BUN/creatinine ratio can be misleading - ratios significantly above 20:1 may indicate excessive creatinine secretion or urea reabsorption rather than accurately reflecting GFR 3
Clinical Assessment Strategy
When to Use Combined Measurements
At advanced kidney disease (GFR <15 mL/min/1.73 m²), the average of creatinine and urea clearances provides more accurate GFR estimation than creatinine clearance alone, which progressively overestimates GFR as kidney function declines 1, 4
When creatinine clearance falls below 15-20 mL/min, it may overestimate true GFR by nearly twofold due to increased tubular creatinine secretion 1
The 4-variable MDRD equation is currently the best prediction equation for GFR, but will overestimate residual renal function in up to 36% of cases when kidney function is significantly impaired (stages 4-5 CKD) 4
Estimation Equations vs. Direct Measurement
GFR should be estimated using prediction equations (MDRD Study equation or CKD-EPI) that incorporate serum creatinine, age, sex, race, and body size rather than relying on serum creatinine alone 1
The MDRD equation shows tighter correlation with measured GFR than 24-hour creatinine clearance and avoids collection errors inherent in timed urine samples 1
Clinical laboratories should report estimated GFR alongside serum creatinine measurements to improve detection of kidney disease 1
Critical Pitfalls and Special Circumstances
When Creatinine-Based Estimates Fail
Conditions with abnormal creatinine generation require alternative assessment methods including extremes of age and body size, severe malnutrition or obesity, skeletal muscle diseases, paraplegia/quadriplegia, vegetarian diet, and rapidly changing kidney function 1
In patients with unusually low or high creatinine generation, measure both creatinine and urea clearances rather than relying on estimating equations 1
Drugs that compete with creatinine for tubular secretion (such as cimetidine, trimethoprim) will artificially lower GFR estimates, while advanced liver disease increases tubular secretion and overestimates GFR 1
The Uremia Paradox
Uremia can occur with relatively low serum creatinine levels (4.0-4.4 mg/dL) when excessive creatinine secretion masks severely reduced GFR 3
If clinical evidence of uremia exists despite relatively low creatinine, direct GFR measurement using radioisotope methods is essential rather than relying on serum markers 3
Age-Specific Considerations
A GFR of 86 mL/min/1.73 m² represents approximately 30-35% loss of expected kidney function in a young adult (normal ~120-130 mL/min/1.73 m²), whereas the same value would be considered excellent for a 65-year-old 5
In elderly patients, serum creatinine does not reflect age-related GFR decline because concomitant muscle mass reduction decreases creatinine generation 1
Practical Algorithm for Assessment
For routine clinical assessment:
- Use estimated GFR from validated equations (MDRD or CKD-EPI) incorporating creatinine, age, sex, and race 1
- Never rely on serum creatinine alone 1
- Confirm abnormal results with repeat testing in 3 months 5
For advanced CKD (GFR <15 mL/min/1.73 m²):
- Calculate average of creatinine and urea clearances from 24-hour urine collection 1, 4
- Consider direct GFR measurement if clinical symptoms are discordant with estimated values 1, 3
For patients with abnormal muscle mass or other confounding factors: