Beyond Hemodynamics: Uremic Toxins, Post-Translational Modifications, and Inflammatory-Metabolic Remodeling in Uremic Cardiomyopathy.
- 1Cardiovascular Research Center, Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
- 2Department of Internal Medicine B, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
- 3Cardiovascular Research Center, Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel. Electronic address: [email protected].
Abstract
Uremic cardiomyopathy has traditionally been attributed to pressure overload, volume overload, hypertension, and neurohormonal activation in chronic kidney disease. However, growing experimental and clinical evidence indicates that nonhemodynamic mechanisms also contribute to myocardial remodeling in uremia. These mechanisms include retention of uremic toxins and protein-bound solutes, mediators of mineral metabolism, gut-derived metabolites, inflammatory signaling, mitochondrial dysfunction, and post-translational protein modifications. In this review, we discuss uremic cardiomyopathy as a systemic inflammatory-metabolic disorder in which kidney failure reshapes myocardial structure and function through interacting biochemical and interorgan pathways. We first define the major classes of uremic toxins, including small water-soluble solutes, middle molecules, protein-bound uremic toxins, and reactive chemical intermediates. We then focus on post-translational modifications, particularly urea-derived cyanate-mediated carbamylation, a well-characterized uremia-associated mechanism that can alter collagen, extracellular matrix turnover, plasma proteins, lipoproteins, and potentially long-lived cardiac proteins. Additional injury pathways, including oxidative modifications, ferroptosis, fibroblast growth factor 23/Klotho imbalance, aryl hydrocarbon receptor activation by indoxyl sulfate, gut-derived adrenergic metabolites, endotoxemia, and inflammasome signaling, are discussed as complementary and partially overlapping mechanisms. Because much of the current mechanistic evidence comes from preclinical models, circulating biomarkers, or associative human studies, we distinguish established evidence from plausible mechanistic hypotheses throughout the review. Finally, we discuss therapeutic implications, including enhanced toxin removal, sodium-glucose cotransporter 2 inhibitors, mineralocorticoid receptor antagonists, glucagon-like peptide 1 receptor agonists, and future strategies targeting uremic toxins, proteostasis, ferroptosis, inflammasome activation, and toxin-induced post-translational modifications.
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BibTeX
@article{parnasa2026beyond,
title = {{Beyond Hemodynamics: Uremic Toxins, Post-Translational Modifications, and Inflammatory-Metabolic Remodeling in Uremic Cardiomyopathy.}},
author = {Elchanan Parnasa and Yair Rokach and Suzan Abedat and Offer Amir and Iddo Z Ben-Dov and Rabea Asleh},
journal = {JACC. Basic to translational science},
year = {2026},
month = oct,
doi = {10.1016/j.jacbts.2026.101677},
url = {https://europepmc.org/article/MED/42879827},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Beyond Hemodynamics: Uremic Toxins, Post-Translational Modifications, and Inflammatory-Metabolic Remodeling in Uremic Cardiomyopathy.
AU - Elchanan Parnasa
AU - Yair Rokach
AU - Suzan Abedat
AU - Offer Amir
AU - Iddo Z Ben-Dov
AU - Rabea Asleh
PY - 2026
DA - 2026/10/15
JO - JACC. Basic to translational science
DO - 10.1016/j.jacbts.2026.101677
UR - https://europepmc.org/article/MED/42879827
AB - Uremic cardiomyopathy has traditionally been attributed to pressure overload, volume overload, hypertension, and neurohormonal activation in chronic kidney disease. However, growing experimental and clinical evidence indicates that nonhemodynamic mechanisms also contribute to myocardial remodeling in uremia. These mechanisms include retention of uremic toxins and protein-bound solutes, mediators of mineral metabolism, gut-derived metabolites, inflammatory signaling, mitochondrial dysfunction, and post-translational protein modifications. In this review, we discuss uremic cardiomyopathy as a systemic inflammatory-metabolic disorder in which kidney failure reshapes myocardial structure and function through interacting biochemical and interorgan pathways. We first define the major classes of uremic toxins, including small water-soluble solutes, middle molecules, protein-bound uremic toxins, and reactive chemical intermediates. We then focus on post-translational modifications, particularly urea-derived cyanate-mediated carbamylation, a well-characterized uremia-associated mechanism that can alter collagen, extracellular matrix turnover, plasma proteins, lipoproteins, and potentially long-lived cardiac proteins. Additional injury pathways, including oxidative modifications, ferroptosis, fibroblast growth factor 23/Klotho imbalance, aryl hydrocarbon receptor activation by indoxyl sulfate, gut-derived adrenergic metabolites, endotoxemia, and inflammasome signaling, are discussed as complementary and partially overlapping mechanisms. Because much of the current mechanistic evidence comes from preclinical models, circulating biomarkers, or associative human studies, we distinguish established evidence from plausible mechanistic hypotheses throughout the review. Finally, we discuss therapeutic implications, including enhanced toxin removal, sodium-glucose cotransporter 2 inhibitors, mineralocorticoid receptor antagonists, glucagon-like peptide 1 receptor agonists, and future strategies targeting uremic toxins, proteostasis, ferroptosis, inflammasome activation, and toxin-induced post-translational modifications.
SN - 2452-302X
ER -