Muscle mass and estimates of renal function: a longitudinal cohort study

Abstract

Background: Creatinine is the most widely used test to estimate the glomerular filtration rate (GFR), but muscle mass as key determinant of creatinine next to renal function may confound such estimates. We explored effects of 24-h height-indexed creatinine excretion rate (CER index) on GFR estimated with creatinine (eGFR_Cr ), muscle mass-independent cystatin C (eGFR_Cys ), and the combination of creatinine and cystatin C (eGFR_Cr-Cys ) and predicted probabilities of discordant classification given age, sex, and CER index.

Methods: We included 8076 adults enrolled in the PREVEND study. Discordant classification was defined as not having eGFR_Cr <60 mL/min per 1.73 m² when eGFR_Cys was <60 mL/min/1.73 m² . Baseline effects of age and sex on CER index were quantified with linear models using generalized least squares. Baseline effects of CER index on eGFR were quantified with quantile regression and logistic regression. Effects of annual changes in CER index on trajectories of eGFR were quantified with linear mixed-effects models. Missing observations in covariates were multiply imputed.

Results: Mean (SD) CER index was 8.0 (1.7) and 6.1 (1.3) mmol/24 h per meter in male and female participants, respectively (P_difference < 0.001). In male participants, baseline CER index increased until 45 years of age followed by a gradual decrease, whereas a gradual decrease across the entire range of age was observed in female participants. For a 70-year-old male participant with low muscle mass (CER index of 2 mmol/24 h per meter), predicted baseline eGFR_Cr and eGFR_Cys disagreed by 24.7 mL/min/1.73 m² (and 30.1 mL/min/1.73 m² when creatinine was not corrected for race). Percentages (95% CI) of discordant classification in male and female participants aged 60 years and older with low muscle mass were 18.5% (14.8-22.1%) and 15.2% (11.4-18.5%), respectively. For a 70-year-old male participant who lost muscle during follow-up, eGFR_Cr and eGFR_Cys disagreed by 1.5, 5.0, 8.5, and 12.0 mL/min/1.73 m² (and 6.7, 10.7, 13.5, and 15.9 mL/min/1.73 m² when creatinine was not corrected for race) at baseline, 5 years, 10 years, and 15 years of follow-up, respectively.

Conclusions: Low muscle mass may cause considerable overestimation of single measurements of eGFR_Cr . Muscle wasting may cause spurious overestimation of repeatedly measured eGFR_Cr . Implementing muscle mass-independent markers for estimating renal function, like cystatin C as superior alternative to creatinine, is crucial to accurately assess renal function in settings of low muscle mass or muscle wasting. This would also eliminate the negative consequences of current race-based approaches.

Keywords: Bias; Creatinine; Cystatin C; General population; Muscle mass; Renal function.

Figure 1

Distribution and conditional mean of height‐indexed creatinine excretion rate according to age and sex. (A) Histogram plots showing that the distribution of male participants (blue) is shifted towards the right compared with female participants (orange), indicating that male participants had a higher muscle mass at baseline (P < 0.001). The respective means are given by the dashed vertical lines. (B) Effects of age and sex on height‐indexed creatinine excretion rate (CER index). Effect estimates were obtained with a generalized least squares regression model.

Figure 2

Effects of height‐indexed creatinine excretion rate on creatinine‐based, cystatin C‐based, and creatinine‐cystatin C‐based eGFR at baseline. (A) Effects of height‐indexed creatinine excretion rate (CER index) on creatinine‐based eGFR (eGFR_Cr), cystatin C‐based eGFR (eGFR_Cys), and creatinine‐cystatin C‐based eGFR (eGFR_Cr‐Cys) for a 50‐year‐old male participant. (B) Effects of CER index on eGFR_Cr, eGFR_Cys, and eGFR_Cr‐Cys for a 70‐year‐old male participant. Effect estimates were obtained with quantile regression models for the median eGFR_Cr, eGFR_Cys, and eGFR_Cr‐Cys. The red dashed line refers to the threshold of eGFR 60 ml/min per 1.73 m² for the detection of chronic kidney disease. *Expected numerical differences between eGFR_Cr and eGFR_Cys at CER indices of 2, 4, 6, 8, 10, and 12 mmol/24 h per meter.

Figure 3

Observed percentages and expected probability of discordant classification according to age, sex, and height‐indexed creatinine excretion rate. (A) Dot plot showing the observed percentages of discordantly classified participants according to categories of age, sex, and cut‐off values of height‐indexed creatinine excretion rate (CER index). Cut‐off values were based on the 25th and 75th percentiles of CER index in male and female participants separately. The error bars about the dots represent the 95% confidence intervals. (B) Expected probability of discordant classification based on age, sex, and CER index. The lines represent the expected probability of discordant classification for any given age, sex, and CER index and were obtained with logistic regression. The shaded areas about the lines are the corresponding 95% pointwise confidence intervals. Discordant classification was defined as not having a creatinine‐based eGFR <60 mL/min per 1.73 m² when cystatin C‐based eGFR was <60 mL/min per 1.73 m².

Figure 4

Effects of annual changes in height‐indexed creatinine excretion rate on trajectories of creatinine‐based, cystatin C‐based, and creatinine‐cystatin C‐based eGFR. (A) Effects of muscle wasting on trajectories of creatinine‐based eGFR (eGFR_Cr), cystatin C‐based eGFR (eGFR_Cys), and creatinine‐cystatin C‐based eGFR (eGFR_Cr‐Cys) for a 50‐year‐old male participant. (B) Effects of steady muscle mass on trajectories of eGFR_Cr, eGFR_Cys, and eGFR_Cr‐Cys for a 50‐year‐old male participant. (C) Effects of gain of muscle on trajectories of eGFR_Cr, eGFR_Cys, and eGFR_Cr‐Cys for a 50‐year‐old male. (D) Effects of muscle wasting on trajectories of eGFR_Cr, eGFR_Cys, and eGFR_Cr‐Cys for a 70‐year‐old male participant. (E) Effects of steady muscle mass on trajectories of eGFR_Cr, eGFR_Cys, and eGFR_Cr‐Cys for a 70‐year‐old male participant. (F) Effects of gain of muscle on trajectories of eGFR_Cr, eGFR_Cys, and eGFR_Cr‐Cys for a 70‐year‐old male participant. The lines represent effect estimates for 50‐year‐old and 70‐year‐old male participants with all covariates at their median value, obtained with linear mixed‐effects models for the multivariate outcomes of eGFR_Cr, eGFR_Cys, and eGFR_Cr‐Cys. The shaded areas about the lines are the corresponding 95% pointwise confidence intervals. The three different categories of annual change in CER index (i.e. muscle wasting, steady muscle mass, and gain of muscle mass) amounted to −0.10, 0.00, and 0.05 mmol/24 h per meter, respectively. *Expected numerical differences between eGFR_Cr and eGFR_Cys at 0, 5, 10, and 15 years of follow‐up are given below the graphs. In the top right corner of each panel, the percentage difference in renal function between baseline and 15 years of follow‐up are given, which was expressed as (eGFR_0 years − eGFR_15 years)/eGFR_0 years × 100%.

Figure 5

Schematic representation of the relationship between renal function, muscle mass, creatinine, cystatin C, and GFR estimates in the circumstance of deteriorating overall health. Deteriorating overall health is a major driver of muscle wasting (path a) and often coincides with impaired renal function (path b). Given that impaired renal function adversely affects muscle mass (path c), compromised health directly leads to muscle wasting (path a), but also indirectly through impaired renal function (path b and c). As approximately 98% of circulating creatinine originates from muscle tissue (path d), both reduced muscle mass and impaired renal function (operating through reduced muscle mass) translate into reduced serum creatinine. The combination of the forgoing with the fact that impaired renal function also implies increased serum creatinine (path e) gives rise to a paradox, namely, that impaired renal function may cause a decrease, but, at the same time, also an increase in serum creatinine (paths c and e, respectively). The mechanism underlying this paradox theoretically invalidates serum creatinine as reliable estimator of renal function in circumstances wherein low muscle mass or muscle wasting prevail (path f). Cystatin C, a small protein that is freely filtered by the glomerulus, is also often used as marker of renal function (path g). As a housekeeping gene, it is produced by all nucleated cells and therefore unrelated to muscle mass. This very property makes serum cystatin C a superior alternative to serum creatinine as estimator of the GFR (path h) in settings of low muscle mass or muscle wasting.