Clinical Laboratory Strategies: May 27, 2010

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Looking Beyond BMI for Poor Outcomes in CAD
Study Finds Creatinine Excretion Rate Predicts Mortality 
By Bill Malone

Recent investigations of body mass index (BMI) in individuals with coronary artery disease have shown that individuals with the lowest BMI often have higher risk of death, leading researchers to look more carefully at each variable of body composition. This issue of Strategies examines new research that suggests creatinine excretion rate (CER)—a measure of muscle mass—is a powerful marker of risk independent of BMI. 


A basic essential for any clinical chemistry lab, measurement of urinary creatinine in timed urine specimens as an indicator of glomerular filtration rate (GFR) has fallen out of favor with physicians and is being replaced by serum-based measurement of creatinine, commonly used in estimated glomerular filtration rate (eGFR). The decline in clinical use reflects the notorious difficulty in obtaining accurate 24-hour urine collections from patients. However, the nephrology community has long recognized urinary creatinine excretion rate (CER)—the total amount of creatinine found in urine per unit time—as an accurate marker of muscle mass. Nephrologists continue to use timed urine specimens in cases where they suspect that an eGFR is not accurate because of a patient’s very low or high muscle mass.


Now CER is earning renewed interest based on new research that reported a strong linear association between CER and mortality for patients with established coronary artery disease (CAD) (Circulation 2010;121:1295–1303). The study aimed to elucidate questions about the J-shaped relationship between BMI and mortality previously reported in patients with CAD.


“CER provides an excellent tool to examine the influence of muscle mass in its relationship with death for people with heart disease,” said Joachim Ix, MD, the lead author of the study.

“This steps beyond standard measures of body composition like BMI or waist-hip ratio and looks at what contribution is coming from muscle as opposed to adiposity or other parts of body composition.” Ix is assistant professor of medicine in the division of nephrology-hypertension and department of medicine at the University of California San Diego.


The study measured urine creatinine, volume, and excretion rate in 24-hour urine collections from 903 individuals with known CAD from the Heart and Soul Study, an observational study investigating the progression of CAD. The researchers used Cox proportional-hazards models to evaluate the association of CER with mortality risk. Over a median follow-up of 6 years, 232 participants (26%) died. Compared with the highest sex-specific CER tertile, the lowest tertile was associated with a 2-fold risk of mortality (hazard ratio, 2.30) in models adjusted for age, sex, race, cystatin C–based eGFR, BMI, traditional cardiovascular disease risk factors, and C-reactive protein levels. The authors also adjusted for physical fitness, left ventricular mass, left ventricular ejection fraction, and fasting insulin and glucose levels. Despite these statistical adjustments, the association between CER and mortality retained its strength.


“The finding that creatinine excretion is still associated with mortality even when one accounts for BMI or waist-hip ratio, in addition to these other factors, suggests that there is additional information about body composition not captured using BMI or waist-hip ratio,” said Ix. “BMI is what it purports to be—it is a mass index—but it’s more than just how much fat a person has; it also includes muscle and bone.”


This finding is significant because it demonstrates that CER might help predict premature death in patients with CAD, and physicians are always on the lookout for tests that can discriminate which patients are at increased risk and need more targeted interventions, said Andrew Rule, MD, assistant professor of medicine and consultant in the division of nephrology and hypertension and in the division epidemiology at the Mayo Clinic. “Although most people would have expected that lower muscle mass would be an indicator of poor outcomes, [the researchers] found that it’s an indicator of poor outcomes above and beyond just poor cardiovascular fitness,” he said. “It seems that it’s actually the amount of muscle that’s protective and an important predictor of long-term survival.” Rule was not associated with the study.


While the authors establish a strong case for the predictive ability of CER, Ix admitted that the very reason for declining use of CER might limit the test’s application in light of its newfound significance. “The Achilles heel of creatinine excretion rate is that, not only is it tedious for the patient, but it’s fraught with collection inaccuracies,” he said. “The reason it’s not used more is that patients often under-collect or over-collect their urine and it’s very difficult to know, from a clinician’s standpoint, when it has been done accurately. This is a limitation to this strategy that has been known for decades.”


Rule noted the same challenge. “If investigators are able to get better collections than what we usually do in clinical practice, then the question is, how do we do that? We may need to change how we do urine collections from patients,” he said. “It really requires motivated patients to collect their urine carefully.”


Exactly how muscle mass itself might be protective for people with CAD is not clear. One possibility is that older, sicker people are more frail and less physically active, have less muscle mass, and so in part, CER might just be a marker of frailty, Ix explained. “We tried to evaluate that as best as we could, adjusting the models for age and performance on a treadmill to try to get at this issue, which didn’t seem to explain the relationships, but nonetheless this remains a possibility,” he said.


In the paper, the authors also speculate about other biologic mechanisms. For example, skeletal muscle serves as one of the main disposal sites for glucose. The logic behind this explanation is that less muscle mass leads to insulin resistance. However, at least based on the one-time measurements of fasting glucose and insulin available to the researchers, this theory doesn’t seem to explain the relationship either.


In the mean time, if other research confirms the strong link between CER and mortality for patients with CAD, physicians will have to balance using CER against other the established measures of muscle mass, such as a dual energy x-ray absorptiometry (DEXA) scan that assesses total body bone mineral density and soft tissue composition. “It really depends on what’s available to the clinician and what he or she intends to do with it,” said Ix. “If a clinician needed to measure muscle mass only once, and look at its relationship with outcomes, one might choose to do that with a DEXA scan. If, on the other hand, an intervention was planned with the goal of changing muscle mass, CER would be useful to assess a baseline and evaluate change over time, avoiding radiation exposure inherent with DEXA.”


CER has other advantages aside from the absence of radiation. The test is relatively inexpensive and can be performed almost anywhere, Ix noted. “Worldwide, there are many people with coronary artery disease in settings without access to a CAT scan or a DEXA scan, and yet most labs should be able to measure urine creatinine with good precision. So there might be specific advantages in resource-limited healthcare settings.”


Rule also highlighted that CER could be a valid alternative to more resource-intensive imaging techniques. “Companies have marketed scans for this purpose, because they can do better than a BMI for assessing body composition, but these scans are expensive,” he said. “With CER we also get complementary information on body composition to BMI to guide interventions, and CER is cheap and doesn’t expose people to radiation.”


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