Biomarkers of Kidney Function: Creatinine

Optimal Takeaways

Creatinine is a byproduct of muscle metabolism involving creatine and creatine phosphate. Production of creatinine reflects muscle mass. However, it is a waste product and must be eliminated by the kidneys. Elevated levels occur with kidney dysfunction, dehydration, muscle injury or breakdown, excess exercise, myocardial infarction, some medications, and atherosclerosis that affects blood flow to the kidney. Low creatinine levels are associated with low muscle mass, debilitation, muscular dystrophies, and increased risk for type 2 diabetes.

Conventional Lab Range: 0.40 – 1.50 mg/dL (35.36 – 132.60 umol/L)

The ODX Range: 0.80 – 1.10 mg/dL (70.72 – 97.24 umol/L)

Low creatinine levels are associated with debilitation, decreased muscle mass, muscular dystrophy, and myasthenia gravis (Pagana 2021). A low serum creatinine associated with reduced muscle mass may increase the risk of type 2 diabetes (Harita 2009, Hu 2019).

High creatinine levels are associated with kidney disorders, reduced blood flow to the kidney (e.g., caused by dehydration, shock, congestive heart failure, and atherosclerosis), diabetic nephropathy, rhabdomyolysis, muscle damage (including excess exercise, injury, and myocardial infarction), acromegaly, gigantism, and nephrotoxic drugs (Pagana 2021). Modest elevations in creatinine are associated with significantly increased complications and mortality following cardiac surgery (O’Brien 2002) and heart failure (Smith 2003). Cooked red meat is high in creatinine, and excess intake may cause an acute increase in serum levels (Kashani 2020).

Overview

Creatinine is a byproduct of creatine and creatine phosphate metabolism in muscle and reflects lean body mass (Hosten 1990). The kidney must continuously excrete creatinine to avoid toxic buildup. Serum creatinine increases as renal function decreases and should be assessed alongside BUN and estimated glomerular filtration rate. A doubling of creatinine in the blood usually represents a 50% reduction in glomerular filtration rate. Increased serum creatinine is associated with kidney disorders such as glomerulonephritis, pyelonephritis, acute tubular necrosis, diabetic nephropathy, and reduced renal blood flow that can occur with dehydration, shock, congestive heart failure, and atherosclerosis. Elevated levels can also be seen with rhabdomyolysis, i.e., muscle damage that can occur with direct trauma, heavy exercise, or myocardial infarction. Some medications can increase creatinine, including ACE inhibitors, cimetidine, aminoglycosides, heavy-metal chemotherapy, and other nephrotoxic drugs. Decreased levels are associated with debilitation, and reduced muscle mass, especially in conditions such as muscular dystrophy and myasthenia gravis (Pagana 2021).

In one study of 252 healthy 18–74-year-olds, a healthy reference interval for serum creatinine was determined to be 0.72—1.18 mg/dL (63.65-104.31 umol/L) for males and 0.55-1.02 (48.62-90.17 umol/L) for females (Junge 2004).

Increasing serum creatinine suggests renal dysfunction, and levels can mirror the degree of impairment. Using 1 mg/dL as a healthy baseline, serum creatinine of 2 mg/dL (176 umol/L) may represent a 50% reduction in GFR, 3 mg/dL (265.2 umol/L) indicating a 70-85% reduction in GFR, and 8 mg/dL (707.2 umol/L) representing a 90-95% reduction in GFR (Shahbaz 2022).

Low serum creatinine is also associated with health risks and may indicate malnutrition or debilitation. A serum creatinine below 0.6 mg/dL (53.04 umol/L) likely reflects lower muscle mass and is associated with increased severity of illness and longer ICU length of stay (Kashani 2020).

Skeletal muscle, a significant source of creatine and, therefore, creatinine, is a primary target of insulin. One prospective cohort study of non-diabetic men investigated the relationship between skeletal muscle insulin resistance, low muscle mass, and serum creatinine; Results revealed that the lowest serum creatinine of 0.4-0.6 mg/dL (35.36-53.04 umol/L) was independently associated with increased risk of type 2 diabetes. Researchers recommend resistance training to increase muscle mass for those at increased risk of diabetes (Harita 2009).

Subsequent research confirmed the association between low serum creatinine and type 2 diabetes in a prospective study of 31,343 males 20-64 years old. The highest risk was in those maintaining serum creatinine below 0.7 mg/dL (61.88 umol/L), a finding consistent with results from several clinical studies.

Previous research had found a significantly increased risk of type 2 diabetes in men with a creatinine of 0.7 mg/dL (61.88 umol/L) or below and 0.5 mg/dL (44.2 umol/L) or below in women. Additional research notes an increased risk of progressing from prediabetes to diabetes when serum creatinine is low (Hu 2019).

References

Harita, Nobuko et al. “Lower serum creatinine is a new risk factor of type 2 diabetes: the Kansai healthcare study.” Diabetes care vol. 32,3 (2009): 424-6. doi:10.2337/dc08-1265

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.

Hu, Huanhuan et al. “Low serum creatinine and risk of diabetes: The Japan Epidemiology Collaboration on Occupational Health Study.” Journal of diabetes investigation vol. 10,5 (2019): 1209-1214. doi:10.1111/jdi.13024

Junge, Wolfgang et al. “Determination of reference intervals for serum creatinine, creatinine excretion and creatinine clearance with an enzymatic and a modified Jaffé method.” Clinica chimica acta; international journal of clinical chemistry vol. 344,1-2 (2004): 137-48. doi:10.1016/j.cccn.2004.02.007

Kashani, Kianoush et al. “Creatinine: From physiology to clinical application.” European journal of internal medicine vol. 72 (2020): 9-14. doi:10.1016/j.ejim.2019.10.025

O'Brien, Maureen M et al. “Modest serum creatinine elevation affects adverse outcome after general surgery.” Kidney international vol. 62,2 (2002): 585-92. doi:10.1046/j.1523-1755.2002.00486.x

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

Shahbaz, Hassan. and Mohit Gupta. “Creatinine Clearance.” StatPearls, StatPearls Publishing, 25 July 2022.

Smith, Grace L et al. “Worsening renal function: what is a clinically meaningful change in creatinine during hospitalization with heart failure?.” Journal of cardiac failure vol. 9,1 (2003): 13-25. doi:10.1054/jcaf.2003.3