Circulating follistatin in patients with chronic kidney disease: implications for muscle strength, bone mineral density, inflammation, and survival

Abstract

Background and objectives: Follistatin mediates muscle growth and bone mineralization. At present, it is unknown whether circulating follistatin levels are altered in chronic kidney disease (CKD) or links to CKD risk factors and outcomes.

Design, setting, participants, & measurements: Plasma follistatin levels were cross-sectionally analyzed in relation to protein-energy wasting (PEW), handgrip strength (HGS), bone mineral density (BMD), and inflammatory markers in 280 CKD stage 5 patients, 32 CKD stage 4 patients, 16 CKD stage 3 patients, and 32 control subjects. In CKD stage 5 patients survival was prospectively investigated during a follow-up period of up to 5 years.

Results: The plasma follistatin concentration was not higher in CKD stage 5 patients than in other CKD stages or controls. In CKD stage 5 patients, circulating follistatin positively correlated with age, high-sensitivity C-reactive protein (hsCRP), and IL-6; negatively correlated with HGS, serum creatinine, and BMD; and was increased in patients with PEW. In a multivariate logistic regression model, lower HGS, lower BMD, and higher hsCRP independently correlated with higher follistatin levels. In a Cox regression model, follistatin levels were not associated with all-cause mortality.

Conclusions: Circulating follistatin levels were neither elevated nor predicted outcome in patients with CKD. However, increased follistatin levels occurred together with increased inflammation, reduced muscle strength, and low BMD, suggesting an involvement of a mechanism including follistatin in the uremic wasting process.

Figure 1.

Plasma follistatin concentrations in 32 control subjects, 16 CKD stage 3 patients, 32 CKD stage 4 patients, and 280 incident dialysis patients. GFR was calculated by the mean of urea and creatinine clearances in incident dialysis patients and estimated using the Modification of Diet in Renal Disease study equation in CKD stage 3 to 4 subjects and controls.

Figure 2.

Plasma follistatin concentrations in relation to the nutritional status as assessed by SGA in incident dialysis patients. Nonwasted, SGA = 1 (n = 195); wasted, SGA ≥ 2 (n = 85).

Figure 3.

Restricted spline curve showing on the left axis the age- and sex-adjusted hazard ratios and 95% CIs (dashed lines) for all-cause mortality associated with circulating follistatin levels in 261 incident dialysis patients. The model is plotted as restricted cubic splines with two knots. On the right y-axis, the distribution of patients (counts) across the follistatin spectrum is shown. For the analysis presented here, we excluded 19 patients considered as outliers (follistatin levels > 3.11 ng/ml). Log HR, log-transformed hazard ratio; 95% CI, lower and upper 95% CIs, respectively.