Preserving physical function in patients with kidney disease

Project Summary/Abstract Skeletal muscle dysfunction contributes to frailty, disability, and mortality in patients with chronic kidney disease (CKD). This proposal seeks to determine if muscle dysfunction in CKD can be alleviated by dialysis (blood filtration for kidney failure). We recently discovered that patients with CKD experience progressively worsening muscle fibrosis, and that greater severity of fibrosis is associated with reduced muscle strength and physical function. In patients with severe CKD, fibrotic changes are extensive. However, despite the seemingly advanced nature of this fibrotic transformation, patients starting dialysis experienced marked improvement in fibrosis. This suggests that, in patients with severe CKD and muscle fibrosis, the initiation of dialysis could improve physical function. Therefore, this proposal tests the highly innovative hypothesis that the initiation of dialysis in patients with severe CKD reverses muscle fibrosis and improves physical function. We will accomplish this objective using a translational approach that integrates clinically relevant functional endpoints with state-of-the-art methods including muscle tissue mechanics, quantitative magnetic resonance imaging (qMR), and transcriptomic and proteomic studies of human skeletal muscle. The proposed human studies will (1) define the effect of dialysis initiation on muscle fibrosis by examining changes in muscle collagen content, collagen cross-linking, tissue passive stiffness, and qMR measures; (2) determine the extent to which regression of fibrosis after dialysis initiation translates into functional improvements by testing the association of alterations in the structural parameters from Aim 1 with changes in muscle strength, endurance, and lower extremity performance; and (3) identify molecular and cellular predictors of the resolution of fibrosis using transcriptomic and proteomic analyses of skeletal muscle. If our hypotheses are correct: (1) muscle fibrosis could be an indicator for physicians to start dialysis therapy; and (2) this proposal will identify an intervention to alleviate muscle dysfunction in patients with CKD.