Inhibition of urea transporter ameliorates uremic cardiomyopathy in chronic kidney disease

Abstract Chronic kidney disease is highly prevalent, affecting 10% to 15% of the adult population worldwide and is associated with increased cardiovascular morbidity and mortality. As chronic kidney disease worsens, a unique cardiovascular phenotype develops characterized by heart muscle disease, increased arterial stiffness, atherosclerosis, and hypertension. Cardiovascular risk is multifaceted, but most cardiovascular deaths in patients with advanced chronic kidney disease are caused by heart failure and sudden cardiac death. While the exact drivers of these deaths are unknown, they are believed to be caused by uremic cardiomyopathy: a specific pattern of myocardial hypertrophy, fibrosis, with both diastolic and systolic dysfunction. Although the pathogenesis of uremic cardiomyopathy is likely to be multifactorial, accumulating evidence suggests increased production of fibroblast growth factor‐23 and αKlotho deficiency as potential major drivers of cardiac remodeling in patients with uremic cardiomyopathy. In this article we review the increasing understanding of the physiology and clinical aspects of uremic cardiomyopathy and the rapidly increasing knowledge of the biology of both fibroblast growth factor‐23 and αKlotho. Finally, we discuss how dissection of these pathological processes is aiding the development of therapeutic options, including small molecules and antibodies, directly aimed at improving the cardiovascular outcomes of patients with chronic kidney disease and end‐stage renal disease.

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Defining the Natural History of Uremic Cardiomyopathy in Chronic Kidney Disease

JACC Cardiovascular Imaging ◽

10.1016/j.jcmg.2013.09.025 ◽

2014 ◽

Vol 7 (7) ◽

pp. 703-714 ◽

Cited By ~ 45

Author(s):

Nicola C. Edwards ◽

William E. Moody ◽

Colin D. Chue ◽

Charles J. Ferro ◽

Jonathan N. Townend ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Natural History ◽

Uremic Cardiomyopathy ◽

History Of

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Ischemic preconditioning protects the heart against ischemia-reperfusion injury in chronic kidney disease in both males and females

Biology of Sex Differences ◽

10.1186/s13293-021-00392-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Márta Sárközy ◽

Fanni Magdolna Márványkövi ◽

Gergő Szűcs ◽

Zsuzsanna Z. A. Kovács ◽

Márton R. Szabó ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Infarct Size ◽

Ischemic Preconditioning ◽

Molecular Mechanisms ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Cardiomyocyte Hypertrophy ◽

Uremic Cardiomyopathy ◽

Males And Females

Abstract Background Uremic cardiomyopathy is a common cardiovascular complication of chronic kidney disease (CKD) characterized by left ventricular hypertrophy (LVH) and fibrosis enhancing the susceptibility of the heart to acute myocardial infarction. In the early stages of CKD, approximately 60% of patients are women. We aimed to investigate the influence of sex on the severity of uremic cardiomyopathy and the infarct size-limiting effect of ischemic preconditioning (IPRE) in experimental CKD. Methods CKD was induced by 5/6 nephrectomy in 9-week-old male and female Wistar rats. Two months later, serum and urine laboratory parameters were measured to verify the development of CKD. Transthoracic echocardiography was performed to assess cardiac function and morphology. Cardiomyocyte hypertrophy and fibrosis were measured by histology. Left ventricular expression of A- and B-type natriuretic peptides (ANP and BNP) were measured by qRT-PCR and circulating BNP level was measured by ELISA. In a subgroup of animals, hearts were perfused according to Langendorff and were subjected to 35 min global ischemia and 120 min reperfusion with or without IPRE (3 × 5 min I/R cycles applied before index ischemia). Then infarct size or phosphorylated and total forms of proteins related to the cardioprotective RISK (AKT, ERK1,2) and SAFE (STAT3) pathways were measured by Western blot. Results The severity of CKD was similar in males and females. However, CKD males developed more severe LVH compared to females as assessed by echocardiography. Histology revealed cardiac fibrosis only in males in CKD. LV ANP expression was significantly increased due to CKD in both sexes, however, LV BNP and circulating BNP levels failed to significantly increase in CKD. In both sexes, IPRE significantly decreased the infarct size in both the sham-operated and CKD groups. IPRE significantly increased the phospho-STAT3/STAT3 ratio in sham-operated but not in CKD animals in both sexes. There were no significant differences in phospho-AKT/AKT and phospho-ERK1,2/ERK1,2 ratios between the groups. Conclusion The infarct size-limiting effect of IPRE was preserved in both sexes in CKD despite the more severe uremic cardiomyopathy in male CKD rats. Further research is needed to identify crucial molecular mechanisms in the cardioprotective effect of IPRE in CKD.

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Is uremic cardiomyopathy a direct consequence of chronic kidney disease?

Expert Review of Cardiovascular Therapy ◽

10.1586/14779072.2014.879040 ◽

2014 ◽

Vol 12 (2) ◽

pp. 127-130 ◽

Cited By ~ 6

Author(s):

Shanmugakumar Chinnappa ◽

Sandeep S Hothi ◽

Lip-Bun Tan

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Direct Consequence ◽

Uremic Cardiomyopathy

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Cardiotoxicity of Uremic Toxins: A Driver of Cardiorenal Syndrome

Toxins ◽

10.3390/toxins10090352 ◽

2018 ◽

Vol 10 (9) ◽

pp. 352 ◽

Cited By ~ 24

Author(s):

Suree Lekawanvijit

Keyword(s):

Risk Factors ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Heart Rhythm ◽

Cardiorenal Syndrome ◽

Uremic Toxins ◽

Excretory Function ◽

Heart Rhythm Disorders ◽

Increased Risk ◽

Uremic Cardiomyopathy

Cardiovascular disease (CVD) is highly prevalent in the setting of chronic kidney disease (CKD). Such coexistence of CVD and CKD—the so-called “cardiorenal or renocardiac syndrome”—contributes to exponentially increased risk of cardiovascular (CV) mortality. Uremic cardiomyopathy is a characteristic cardiac pathology commonly found in CKD. CKD patients are also predisposed to heart rhythm disorders especially atrial fibrillation. Traditional CV risk factors as well as known CKD-associated CV risk factors such as anemia are insufficient to explain CV complications in the CKD population. Accumulation of uremic retention solutes is a hallmark of impaired renal excretory function. Many of them have been considered inert solutes until their biological toxicity is unraveled and they become accepted as “uremic toxins”. Direct cardiotoxicity of uremic toxins has been increasingly demonstrated in recent years. This review offers a mechanistic insight into the pathological cardiac remodeling and dysfunction contributed by uremic toxins with a main focus on fibroblastic growth factor-23, an emerging toxin playing a central role in the chronic kidney disease–mineral bone disorder, and the two most investigated non-dialyzable protein-bound uremic toxins, indoxyl sulfate and p-cresyl sulfate. Potential therapeutic strategies that could address these toxins and their relevant mediated pathways since pre-dialysis stages are also discussed.

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New Insights into the Role of FGF-23 and Klotho in Cardiovascular Disease in Chronic Kidney Disease Patients

Current Vascular Pharmacology ◽

10.2174/1570161118666200420102100 ◽

2020 ◽

Vol 19 (1) ◽

pp. 55-62 ◽

Cited By ~ 1

Author(s):

Evangelos Memmos ◽

Aikaterini Papagianni

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Prognostic Value ◽

Fibroblast Growth Factor 23 ◽

Mortality Rates ◽

Vascular Lesions ◽

Biochemical Abnormality ◽

Uremic Cardiomyopathy ◽

Fgf 23

Alterations of fibroblast growth factor 23 (FGF-23) and Klotho levels are considered to be the earliest biochemical abnormality of chronic kidney disease – mineral and bone disease (CKDMBD) syndrome. Moreover, emerging data suggests that the dysregulated FGF-23 and Klotho axis has many effects on the cardiovascular (CV) system and contributes significantly to the increased CV morbidity and mortality rates of CKD patients. This review examines recent evidence on the role of FGF-23 and Klotho in the development and progression of CV complications of uremia namely cardiac hypertrophy, uremic cardiomyopathy, and atherosclerotic and arteriosclerotic vascular lesions. Moreover, the available evidence on their associations with adverse clinical outcomes are summarized. Undoubtedly, more studies are needed to further elucidate the effects of FGF-23 and Klotho on the heart and vessels and to gain insights into their prognostic value as CV risk factors. Finally, large prospective studies are required to test the hypothesis that modification of their levels would have a favourable impact on the unacceptably high mortality rates of these patient populations.

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