Muscle fibrosis and maladaptation occur progressively in CKD and are rescued by dialysis.

Camille R Brightwell,Thomas H Hostetter,Jaclyn B Perkins,Meredith Hawkins,William Paredes,Yan Tang,Matthew K Abramowitz,Kehao Zhang,Rupinder S Buttar,Knubian J Gatlin,Jeffrey E Pessin,Christopher S Fry,Rima Pai,Ameya S Kulkarni,Bushra Zaidi,Hina Farooq,Matthew Custodio,Michal L Melamed

doi:10.1172/jci.insight.150112

Abstract

BACKGROUNDSkeletal muscle maladaptation accompanies chronic kidney disease (CKD) and negatively affects physical function. Emphasis in CKD has historically been placed on muscle fiber–intrinsic deficits, such as altered protein metabolism and atrophy. However, targeted treatment of fiber-intrinsic dysfunction has produced limited improvement, whereas alterations within the fiber-extrinsic environment have scarcely been examined.METHODSWe investigated alterations to the skeletal muscle interstitial environment with deep cellular phenotyping of biopsies from patients with CKD and age-matched controls and performed transcriptome profiling to define the molecular underpinnings of CKD-associated muscle impairments. We examined changes in muscle maladaptation following initiation of dialysis therapy for kidney failure.RESULTSPatients with CKD exhibited a progressive fibrotic muscle phenotype, which was associated with impaired regenerative capacity and lower vascular density. The severity of these deficits was strongly associated with the degree of kidney dysfunction. Consistent with these profound deficits, CKD was associated with broad alterations to the muscle transcriptome, including altered ECM organization, downregulated angiogenesis, and altered expression of pathways related to stem cell self-renewal. Remarkably, despite the seemingly advanced nature of this fibrotic transformation, dialysis treatment rescued these deficits, restoring a healthier muscle phenotype. Furthermore, after accounting for muscle atrophy, strength and endurance improved after dialysis initiation.CONCLUSIONThese data identify a dialysis-responsive muscle fibrotic phenotype in CKD and suggest the early dialysis window presents a unique opportunity of improved muscle regenerative capacity during which targeted interventions may achieve maximal impact.TRIAL REGISTRATIONNCT01452412FUNDINGNIH, NIH Clinical and Translational Science Awards (CTSA), and Einstein-Mount Sinai Diabetes Research Center

Highlights

Chronic kidney disease (CKD) affects nearly 700 million people, approximately 1 in 11 individuals, worldwide [1]
Age and sex were similar between the CKD and control groups (Table 1)
DPI was similar between CKD patients and controls, whether assessed by food frequency questionnaire (FFQ) or 24-hour urine collection

Summary

Introduction

Chronic kidney disease (CKD) affects nearly 700 million people, approximately 1 in 11 individuals, worldwide [1]. Common in CKD, is a major risk factor for these outcomes [3–5]. Previous studies have established muscle fiber–intrinsic deficits (e.g., alterations in protein metabolism, mitochondrial impairments) [9, 10], but to date interventions targeting these deficits have demonstrated marginal success at improving physical function [11–13]. Greater interrogation of muscle fiber–extrinsic alterations in patients with CKD may offer novel therapeutic directions to preserve or enhance muscle function [14] critical to independent living. Skeletal muscle maladaptation accompanies chronic kidney disease (CKD) and negatively affects physical function. Emphasis in CKD has historically been placed on muscle fiber– intrinsic deficits, such as altered protein metabolism and atrophy. Targeted treatment of fiber-intrinsic dysfunction has produced limited improvement, whereas alterations within the fiberextrinsic environment have scarcely been examined

Methods

Results

Conclusion