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.

Grant Number: 5R01AR077042-05
NIH Institute/Center: NIH
Principal Investigator: Matthew Abramowitz