There is growing evidence that protein modification by urea (carbamylation) contributes to uremic cardiomyopathy and mortality. We recently developed an assay for carbamylated albumin (C-Alb), a blood test similar to ?hemoglobin A1c for uremia.? We have shown that C-Alb values are predictive of risk of heart failure and death from cardiac causes in patients on hemodialysis and that amino acid deficiencies are critical determinants of carbamylation, and C-Alb can be reduced by amino acid scavenger therapy. Moreover, hypercarbamylation by urea in mice is sufficient to induce cardiac dysfunction in mice. This proposal seeks to investigate whether C-Alb also predicts outcomes in patients with chronic kidney disease prior to initiation of dialysis therapy in order to extend the clinical applications of this test to patients in the earlier stages of disease, when changes in treatment have a chance to prevent disease progression. Second, we want to prove the specific toxicity of urea on the heart and investigate its mechanisms in mouse models of CKD and oxidative stress- associated cardiomyopathy.
AIM 1 will test the HYPOTHESIS that C-Alb is a prognostic biomarker associated with mortality, morbidity, progression to dialysis, and protein energy wasting in non-dialyzed patients with stages 2-5 chronic kidney disease.
Aim 1 will further compare the risk associated with C-Alb to that of standard clinical indicators of uremia in order to probe whether C-Alb may be a superior indication of early initiation of dialysis, and will test the hypothesis that high C-Alb is associated with deficiencies of specific amino acids and other essential nutrients which represent candidates for targeted nutritional therapies.
AIM 2 will seek to develop well controlled mouse models of urea-induced cardiomyopathy in order to prove the direct toxicity of urea on the heart and to study potential mechanisms. Our HYPOTHESIS is that inducing isolated increases in circulating urea by feeding urea to mice with reduced kidney function or to mice with sensitivity to cardiac mitochondrial oxidative stress will produce cardiomyopathy and heart failure similar to that seen in patients with chronic kidney disease.
Aim 2 (a) will utilize the 5/6 nephrectomy and podocyte-specific COSMC-deficient mouse models of kidney failure mice which will be fed urea in their diet to test the effects of hyperuremia superimposed upon renal insufficiency. Animals will be monitored by echocardiography for differences in cardiac function, and studied for differences in myocardial signaling pathways which mediate urea?s toxicity.
Aim 2 (b) will utilize a mouse model with a cardiac- specific deficiency of PGC-1? coactivator. These animals suffer from increased cardiac mitochondrial oxidative stress and are prone to stress-induced cardiomyopathy. Feeding urea to these animals will test the contribution of urea to cardiac oxidative stress and myopathy in an animal with normal kidney dysfunction, further isolating the effect of urea on the heart.

Public Health Relevance

Chronic kidney disease affects an estimated 5%-10% of adults, and the vast majority of these patients die of cardiovascular disease even before they ever require hemodialysis. The discoveries of an assay for carbamylated albumin and a role for free amino acids as inhibitors of carbamylation provide tools that may be used to predict mortality in these patients, and could be used to determine which of these patients may benefit from early initiation of dialysis or amino acid supplementation therapy. Studying the toxic effects of urea on the heart in animal models of kidney failure and cardiomyopathy will further elucidate the intrinsic toxicity of urea on the heart, and provide a tools for investigating mechanisms of uremic cardiomyopathy and testing novel therapies for chronic kidney disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Pathobiology of Kidney Disease Study Section (PBKD)
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Desvigne-Nickens, Patrice
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Cedars-Sinai Medical Center
Los Angeles
United States
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Kalim, Sahir; Wald, Ron; Yan, Andrew T et al. (2018) Extended Duration Nocturnal Hemodialysis and Changes in Plasma Metabolite Profiles. Clin J Am Soc Nephrol 13:436-444