Kidney Week

Abstract: FR-OR122

Skeletal Muscle Inflammation and Fibrosis Contribute to Weakness in Patients with CKD

Session Information

• Translational Advances in Nutrition and Metabolism
  October 26, 2018 | Location: 7B, San Diego Convention Center
  Abstract Time: 04:30 PM - 04:42 PM

Category: Health Maintenance, Nutrition, and Metabolism

• 1302 Health Maintenance, Nutrition, and Metabolism: Clinical

Authors

• Abramowitz, Matthew K., Albert Einstein College of Medicine, New York, New York, United States

Matthew K. Abramowitz, MD, MS

Matthew Abramowitz, M.D., M.S. completed his medical education at the Albert Einstein College of Medicine and internal medicine residency at Montefiore Medical Center, where he was a Chief Resident. He remained at Einstein/Montefiore for nephrology fellowship and earned a Master’s in Clinical Research through Einstein’s Clinical Research Training Program. He is currently Associate Professor of Medicine (Nephrology) at Einstein. Dr. Abramowitz’s research focuses on understanding the causes of impaired physical function in patients with chronic kidney disease, including skeletal muscle pathology, metabolic acidosis, and gait disturbances. His research has been funded by the Einstein/Montefiore Institute for Clinical and Translational Research, the American Society of Nephrology, and the National Institutes of Health.

• Paredes, William, Albert Einstein College of Medicine, New York, New York, United States

William Paredes,

• Zhang, Kehao, Einstein Medical School, Bronx, New York, United States

Kehao Zhang,

• Brightwell, Camille, University of Texas Medical Branch, Galveston, Texas, United States

Camille Brightwell,

• Newsom, Julia N., University of Texas Medical Branch, Galveston, Texas, United States

Julia N. Newsom,

• Kwon, Hyokjoon, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, United States

Hyokjoon Kwon,

• Custodio, Matthew, Albert Einstein College of Medicine, New York, New York, United States

Matthew Custodio,

• Buttar, Rupinder singh, Jacobi medical center, Belmont, New York, United States

Rupinder singh Buttar,

• Farooq, Hina, Louis A. Weiss Memorial Hospital, Chicago, Illinois, United States

Hina Farooq,

• Zaidi, Bushra, BronxCare Health System, Bronx, New York, United States

Bushra Zaidi,

• Pai, Rima N., Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

Rima N. Pai,

• Pessin, Jeffrey E., Albert Einstein College of Medicine, New York, New York, United States

Jeffrey E. Pessin,

• Hawkins, Meredith, Albert Einstein College of Medicine, New York, New York, United States

Meredith Hawkins,

• Fry, Christopher, University of Texas Medical Branch, Galveston, Texas, United States

Christopher Fry,

Background

Muscle dysfunction is an important cause of morbidity among patients with chronic kidney disease (CKD). Although muscle fibrosis is present in a CKD rodent model, its existence in humans and its impact on physical function are currently unknown. In animal models of muscle injury, TNF-α secreted by macrophages prevents muscle fibrosis by limiting the expansion of fibro/adipogenic progenitor cells (FAPs).

Methods

We examined isometric leg extension strength and measures of skeletal muscle fibrosis and inflammation in vastus lateralis muscle from CKD patients (n=10, stage 4 and 5 CKD) and healthy, sedentary controls of similar age (n=10). Histochemistry and immunohistochemistry were used to assess muscle collagen and macrophage and FAP cell populations, and RT-qPCR was used to assess muscle-specific inflammatory marker expression.

Results

Muscle collagen content was significantly greater in CKD compared with control (18.8 ± 6.7% vs. 11.7 ± 2.0% collagen area, p=0.008), as was staining for collagen I, pro-collagen I, and a novel collagen-hybridizing peptide that binds remodeling collagen. Muscle collagen was inversely associated with leg extension strength in CKD (r= -0.74, p=0.01) but not control (r=0.40, p=0.28). FAP abundance was increased in CKD, was highly correlated with muscle collagen (r=0.84, p<0.001), and was inversely associated with TNF-α expression (r= -0.65, p=0.003). TNF-α, CD68, CCL2, and CCL5 mRNA were significantly lower in CKD than control, despite higher serum TNF-α and IL-6. Immunohistochemistry confirmed fewer CD68+ and CD11b+ macrophages in CKD muscle.

Conclusion

Skeletal muscle collagen content is increased in humans with CKD and is functionally significant. Muscle fibrosis correlated with increased FAP abundance resulting from insufficient macrophage-mediated TNF-α secretion. These data provide a foundation for future research elucidating the mechanisms responsible for this newly identified human muscle pathology.

Funding

• NIDDK Support