Does Serum Creatinine Reflect Muscle Mass in Patients with Kidney Failure?

In adults, 90% of body creatinine stores are contained in muscle, and with aging, a constant percentage of lean body mass is lost; men have a greater fractional loss of creatinine than women. Muscle wasting commonly occurs in patients with CKD, and muscle wasting becomes more apparent when CKD progresses to require dialysis.^1,2 Given the limitations of measuring muscle mass using routine clinical assessment tools, serum creatinine has been considered a proxy for assessing muscle mass.³

In the steady state, serum creatinine is calculated from the difference between creatinine generation in muscle plus that derived from protein intake minus the elimination rate of creatinine by kidney function plus gastrointestinal secretion. In dialysis patients with minimal residual kidney function, serum creatinine is calculated from muscle mass and dietary intake of creatinine. These relationship responses provide an opportunity to evaluate how variations in muscle mass in different races affect creatinine metabolism. This topic has not been addressed in the dialysis population. From clinical and public health perspectives, it is necessary to examine this topic because serum creatinine values are higher among Black patients, and historically, a race coefficient has been used in the calculation of eGFR to account for higher muscle mass.⁴

Delgado et al. evaluated differences in serum creatinine in a secondary analysis of the ACTIVE/ADIPOSE (A Cohort Study to Investigate the Value of Exercise in ESRD/Analyses Designed to Investigate the Paradox of Obesity and Survival in ESRD) study of patients undergoing prevalent hemodialysis (n=501, who had been treated by dialysis for at least a year).⁵ They examined associations of race and ethnicity (groups classified as Black, Asian, Non-Hispanic White, and Hispanic patients) with serum creatinine and intracellular water (ICW) using whole-body multifrequency bioimpedance spectroscopy (BIS) to serve as a proxy for the size of muscle mass.⁵ Compared with values from non-Hispanic White participants, Black, Asian, and Hispanic participants had higher levels of serum creatinine after adjusting for covariates. Although ICW was associated with serum creatinine levels, it did not differ statistically among different races or ethnic groups. All races were significantly associated with serum creatinine concentrations with and without adjusting for ICW. This suggests that there are other determinants of serum creatinine beyond skeletal muscle mass.

This secondary analysis has several strengths, including the availability of multifrequency BIS data from a diverse cohort of hemodialysis patients with minimal residual kidney function (evaluations in individual patients who had measurements after a year of dialysis treatments). However, limitations include the inability to adjust for several confounders with a relatively small sample size, lack of some key covariates, and evaluation of the generalizability of results, including for other dialysis modalities. For example, the study did not exclude results from patients taking nutritional supplements that influence serum creatinine levels. Furthermore, details of dietary intake, especially the intake of animal proteins, were not evaluated (expected to be different among different races). The report also lacked details on residual urine output and whether tubular secretion of creatinine affected serum creatinine in those with some residual function. Data pertinent to social determinants of health were not available in the report, and they are known to contribute to variations in muscle mass and protein intake. Despite these limitations, the data offers several insights to fill our knowledge gap and argues for additional studies to examine non-GFR determinants of serum creatinine and other markers.

Regarding other factors affecting serum creatinine, we evaluated creatinine metabolism in a small number of patients with advanced CKD. We measured creatinine turnover in patients with severe CKD who were being treated by dietary protein restriction.⁶ Evaluation of creatinine metabolism revealed that the total creatinine metabolism rate was positively correlated with serum creatinine: As serum creatinine rose, an increasing fraction of creatinine produced was metabolized. In addition, there was evidence of extrarenal creatinine excretion expressed as a function of total creatinine clearance that could account for approximately 31% of renal clearance in these patients. Whether there are differences in extrarenal creatinine clearance among different races of patients undergoing dialysis needs to be studied. Factors affecting creatinine metabolism and how these factors change creatinine clearance could provide insights into mechanisms that affect changes in serum creatinine.

Current clinical methodologies to estimate muscle mass include multifrequency BIS and dual energy x-ray absorptiometry. These are inexpensive and less time-consuming than computed tomography and magnetic resonance imaging scans, which are often used in clinical research. Recently, point-of-care ultrasound is being used to assess muscle mass and could help clinicians identify factors influencing patients with sarcopenia.⁷ The ACTIVE/ADIPOSE cohort had BIS assessed before the dialysis session during the mid-week. Moreover, Iorio and colleagues have reported that BIS variables fluctuate in patients undergoing hemodialysis but remain constant and highly reproducible over 120 minutes after the end of hemodialysis, especially when aiming to quantify muscle mass.⁸ Future investigations may consider other modalities of body composition assessment and their utility among different races for the hemodialysis population.

The ACTIVE/ADIPOSE study cohort included a significant proportion of Asian patients being treated by hemodialysis. In non–dialysis-dependent CKD, Asian patients have lower values of muscle mass (compared with other ethnicities).⁹ Hence, compared with other races, the finding of similar creatinine values among Asian patients (compared with non-Hispanic White participants) should be explored further. For example, the group had similar creatinine values despite lower body mass index (than other races), lower ICW, and more effective dialysis clearance, suggesting that factors other than muscle mass have to be considered. Akin to the effort by Delgado et al., a similar study in the peritoneal dialysis population would also inform us of the influence of serum creatinine and muscle mass in different races and ethnicities.

In summary, the report of Delgado et al. is a welcome attempt to generate evidence to test the assumption that higher serum creatinine in Black patients can be attributed to a higher muscle mass. While they refute some of the prevailing assumptions, additional studies to confirm these findings with other modalities of body composition techniques, among those on other forms of dialysis, and adjusting for potential confounders are needed.

Disclosures

Outside the submitted work, S.D. Navaneethan reported receiving personal fees from ACI clinical (event adjudication committee), AstraZeneca (Data safety monitoring board), Bayer, Boehringer Ingelheim/Eli Lilly, GlaxoSmithKline, Intercept (event adjudication committee), Vertex (event adjudication committee), and Vifor; and Advisory or Leadership Role: AJKD, American Journal of Nephrology, Cardiorenal Medicine, CJASN, Current Opinion in Nephrology and Hypertension, and KDIGO: Guideline writing committee member. W.E. Mitch reports Other Interests/Relationships (unpaid): National Kidney Foundation; International Society of Nephrology; American Heart Association; American Society of Nephrology; American Diabetes Association.

Funding

This work was supported by NIH/NHLBI K24 HL161414 and a Department of Veterans Affairs Health Service Research & Development Service Investigator Initiated Grant (IIR 19-069). Dr. S.D. Navaneethan is also supported by an institutional Garabed Eknoyan MD Endowed Professorship.

Author Contributions

Conceptualization: William Mitch, Sankar D. Navaneethan.

Writing – original draft: William Mitch, Sankar D. Navaneethan.

Writing – review & editing: William Mitch, Sankar D. Navaneethan.