Lower Creatinine Clearance Associated with Muscle Atrophy Over Time

Chronic inflammation, protein-energy wasting, and progressive loss of muscle mass and strength are all associated with chronic kidney disease (CKD).  Adverse health outcomes resulting from reduced kidney function are “analogous to accelerated aging,” according to Baback Roshanravan, MD, MS, and colleagues. “Clinical consequences of these adverse physiologic processes associated with reduced kidney function include impaired ambulation, frailty, disability, and premature death,” they said [AJKD. 2015;65(5):737-747].

In patients with CKD and among community-dwelling older adults, lower physical performance may be associated with all-cause mortality. Previous studies of community-dwelling older adults examining the association of kidney function and skeletal muscle impairment have been limited by the absence of muscle-specific imaging, cross-sectional study design, and use of serum creatinine-based glomerular filtration rate (GFR) estimating equations, according to Dr. Roshanravan et al.

When kidney function was estimated using cystatin C level among >3000 adults from the Health ABC (Health, Aging, and Body Composition) study, there was an association between lower estimated GFR (eGFR) and decreased muscle strength and slower maximal gait speed.

This study was designed to examine associations of creatinine clearance (Clcr) with concurrent measurement of calf muscle composition, assessed by peripheral quantitative computed tomography (pQCT), and physical performance assessed by standardized testing. The study was conducted among community-dwelling older Northern Italian adults ≥65 years of age from the InCHIANTI (Invecchiare in Chianti) study. InCHIANTI examined factors that contribute to decline in mobility function in later life.

The current study sought to compare associations of Clcr with calf muscle composition and physical performance to aging, and to determine association of baseline kidney function with longitudinal changes in physical performance over 9 months.

Of the InCHIANTI participants, 826 were free of baseline activity of daily living disability and stroke/transient ischemic attack and completed assessment of baseline walking speed and had adequate urine collection. Mean age was 74 years, 56% were female, and 12% had diabetes. Mean Clcr was 78 mL/min/1.73 m2. Among the 826 participants, 183 had Clcr <60 mL/min/1.73 m2.

On average, those with lower Clcr were older, more likely to be women, and had lower levels of education and physical activity. Those with lower baseline Clcrs also had less frequent visits during the study period. Participants missing follow-up were older, less educated, and more sedentary; they also had worse kidney function.

At baseline, mean 7-m usual walking pace was 1.17 and mean 400-m fast walking pace was 1.23. Mean knee extension strength was 16.5. Following adjustment for age, sex, study site, height, weight, smoking, education, diabetes, and prevalent coronary disease, Clcr <45 mL/min/1.73 m2 was associated with an estimated 0.126 m/s slower 7-m usual walking speed and a 0.101 m/s slower 500-m fast walking speed, compared with Clcr ≥90 mL/min/1.73 m2.

There was an association between CDK, defined as Clcr <60 mL/min/1.73 m2, and a 0.068 m/s slower gait speed compared with Clcr ≥60 mL/min/1.73 m2. When modeled linearly, there was an association between each 10-mL/min/1.73 m2 decrement in Clcr and an estimated 0.010 m/s slower 7-m usual walking speed and a 0.008 m/s slower 400-m fast walking speed. There was no association between Clcr and knee extension strength. Following adjustment, each 1 year older age was associated with an equivalent 0.017 m/s slower 7-m walking speed and 400-m walk speed.

Of the 826 participants, 814 had pQCT measurements of calf muscle. Mean calf muscle cross-sectional area (CSA) and muscle density were 6177 mm2 and 71 mg/cm3, respectively. Fat CSA was correlated negatively with muscle CSA and muscle density. Following adjustment, lower Clcr was associated with lesser calf muscle CSA and muscle density.

There was an association of each 10-mL/min/1.73 m2 lower Clcr and an estimated 28 mm2 lower muscle CSA and 0.15 mg/cm3 lower muscle density, respectively. After adjustment, each additional year of age was associated with an estimated 30 mm2 lower muscle CSA and a 0.15 mg/cm3 lower muscle density. There was an association with CKD and 177 mm2 greater muscle fat CSA compared with no CKD.

There was an association of physical activity with muscle density and CSA, but not with fat CSA. Sensitivity analysis adjusting for baseline physical activity demonstrated that each 10-mL/min/1.73 m2 decrement in Clcr was associated with an estimated 0.13 mg/cm3 lower muscle density. After adjusting for baseline physical activity, the association of CKD with fat CSA was not attenuated; however, the association with calf muscle CSA was no longer significant.

During a mean follow-up of 7.1 years, each 10-mL/min/1.73 m2 lower baseline Clcr was associated with an estimated mean 0.008 m/s slower 7-m walking speed and an estimated mean 0.149 kg lower knee extension strength throughout the duration of follow-up. Each 10-mL/min/1.73 m2 lower baseline Clcr was associated with an estimated 0.0024 kg/y greater decline in knee extension strength. There was no association between Clcr and longitudinal changes in usual or fast walking speed in this cohort.

Study limitations cited by the authors included being limited by the low numbers of participants with severely decreased kidney function, only taking measurements of physical performance every 3 years, measurement of Clcr at only one time point with variable collection times, and the purposeful selection of relatively high-functioning older adults which may have attenuated estimates of association.

“In summary, we demonstrate that among community-dwelling older adults, diminished Clcr is associated with lower density and CSA of important ambulatory muscles, coinciding with diminished walking speed and longitudinal declines in knee extension strength. These findings warrant more research into understanding the determinants of lower-extremity muscle atrophy among persons with diminished kidney function. Elucidation of these determinants will help facilitate targeted intervention trials focused on reducing muscle atrophy and assessing improvement in physical performance, morbidity, and mortality in this high0risk population,” the researchers said.


Takeaway Points

  1. This study was designed to examine associations of creatinine clearance with concurrent measurement of calf muscle composition, assessed by pQCT, and physical performance assessed by standardized testing.
  2. When modeled linearly, there was an association between each 10-mL/min/1.73 m2 decrement in Clcr and an estimated 0.010 m/s slower 7-m usual walking speed and a 0.008 m/s slower 400-m fast walking speed.
  3. Among older adults, over time lower Clcr was associated with muscle atrophy, reductions in walking speed, and more rapid declines in knee extension strength.