Ultrasound unveiling: Decoding venous congestion in heart failure for precision management of fluid status.

This editorial discusses the manuscript by Di Maria et al, published in the recent issue of the World Journal of Cardiology. We here focus on the still elusive pathophysiological mechanisms underlying cardio-renal syndrome (CRS), despite its high prevalence and the substantial worsening of both kidney function and heart failure. While the measure of right atrial pressure through right cardiac catheterization remains the most accurate albeit invasive and costly procedure, integrating bedside ultrasound into diagnostic protocols may substantially enhance the staging of venous congestion and guide therapeutic decisions. In particular, with the assessment of Doppler patterns across multiple venous districts, the Venous Excess Ultrasound (VExUS) score improves the management of fluid overload and provides insight into the underlying factors contributing to cardio-renal interactions. Integrating specific echocardiographic parameters, particularly those concerning the right heart, may thus improve the VExUS score sensitivity, offering perspective into the nuanced comprehension of cardio-renal dynamics. A multidisciplinary approach that consistently incorporates the use of ultrasound is emerging as a promising advance in the understanding and management of CRS.

Case report: Challenging kidney transplantation in an adolescent patient with tetralogy of Fallot.

Tetralogy of Fallot is the most common cyanotic congenital heart disease. This severe disorder of cardiac physiology can impair renal function and lead to the development of cardiorenal syndrome and eventually to end-stage renal disease. Kidney transplantation may be the best option for renal replacement treatment in patients with tetralogy of Fallot, but only after correcting cardiac abnormalities and optimizing cardiac functions, all of which require a multidisciplinary approach. We report the first case of kidney transplantation in an adolescent patient with tetralogy of Fallot. Our findings confirms that kidney transplantation is a valuable treatment option in selected congenital heart disease cases.

Long-term outcomes of acute kidney injury in acute decompensated heart failure: identifying true cardiorenal syndrome and unveiling prognostic significance.

BACKGROUND: Cardiorenal syndrome (CRS) type 1 defined as acute kidney injury (AKI) in acute decompensated heart failure (ADHF), is complicated due to diverse definitions. Recently, a more precise CRS type 1 definition was proposed, mandating concurrent AKI and signs of unimproved heart failure (HF). Our study explores the incidence, predictors, and long-term outcomes of AKI in ADHF under this new definition. METHODS: A prospective observation study of ADHF patients categorized into the CRS type 1, pseudo-CRS, and non-AKI groups, followed for 12 months. CRS type 1 involved AKI with clinical congestion, while pseudo-CRS included AKI with clinical decongestion (clinical congestion score <2). The primary outcome was a 1-year composite of mortality or HF rehospitalization. RESULTS: Among 250 consecutive ADHF patients, 46.0% developed CRS type 1; chronic kidney disease (CKD) and blood urea nitrogen were significant risk factors (odds ratios, 1.37; p = 0.002 and OR, 1.05; p < 0.001, respectively). The CRS type 1 group exhibited shorter times to AKI development and peak serum creatinine than the pseudo-CRS group (1 day vs. 4 days and 2 days vs. 4 days, respectively). At 12 months, composite outcomes of mortality or HF rehospitalization and CKD progression were significantly higher in the CRS type 1 group than in the pseudo-CRS and non-AKI groups (63.5% vs. 31.7% vs. 36.1%, p < 0.001; 28.1% vs. 16.2% vs. 11.4%, p = 0.024, respectively). CONCLUSION: Distinguishing between CRS type 1 and pseudo-CRS is vital, highlighting significant disparities in short-term and longterm outcomes. Notably, pseudo-CRS exhibits comparable long-term cardiovascular and renal outcomes to those without AKI.

Red Blood Cell Distribution Width to Albumin Ratio for Predicting Type I Cardiorenal Syndrome in Patients with Acute Myocardial Infarction: A Retrospective Cohort Study.

Purpose: Red blood cell distribution width to albumin ratio (RAR) is a novel inflammatory biomarker that independently predicts adverse cardiovascular events and acute kidney injury. This study aimed to assess the predictive value of RAR for cardio-renal syndrome type I (CRS-I) risk in acute myocardial infarction (AMI) patients. Patients and methods: This study retrospectively enrolled 551 patients who were definitively diagnosed as AMI between October 2021 and October 2022 at the Affiliated Zhongda Hospital of Southeast University. Participants were divided into two and four groups based on the occurrence of CRS-I and the quartiles of RAR, respectively. Demographic data, laboratory findings, coronary angiography data, and drug utilization were compared among the groups. Logistic regression and receiver operating characteristic curve (ROC) analysis were performed to identify independent risk factors for CRS-I and evaluated the predictive value of RAR for CRS-I. Results: Among the cohort of 551 patients, 103 (18.7%) developed CRS-I. Patients with CRS-I exhibited significantly elevated RAR levels compared to those without the condition, and the incidence of CRS-I correlated with escalating RAR. Univariate and multivariate logistic regression analyses identified RAR as an independent risk factor for CRS-I. ROC curves analysis demonstrated that RAR alone predicted CRS-I with an area under the curve (AUC) of 0.683 (95% CI=0.642-0.741), which was superior to the traditional inflammatory marker C-reactive protein (CRP). Adding the variable RAR to the model for predicting the risk of CRS-I further improved the predictive value of the model from 0.808 (95% CI=0.781-0.834) to 0.825 (95% CI=0.799-0.850). Conclusion: RAR is an independent risk factor for CRS-I, and high levels of RAR are associated with an increased incidence of CRS-I in patients with AMI. RAR emerges as a valuable and readily accessible inflammatory biomarker that may play a pivotal role in risk stratification in clinical practice.

Renal Sodium Avidity in Heart Failure.

BACKGROUND: Increased renal sodium avidity is a hallmark feature of the heart failure syndrome. SUMMARY: Increased renal sodium avidity refers to the inability of the kidneys to elicit potent natriuresis in response to sodium loading. This eventually causes congestion, which is a major contributor to hospital admissions and mortality in heart failure. KEY MESSAGES: Important novel concepts such as the renal tamponade hypothesis, accelerated nephron loss, and the role of hypochloremia, the sympathetic nervous system, inflammation, the lymphatic system, and interstitial sodium buffers are involved in the pathophysiology of renal sodium avidity. A good understanding of these concepts is crucially important with respect to treatment recommendations regarding dietary sodium restriction, fluid restriction, rapid up-titration of guideline-directed medical therapies, combination diuretic therapy, natriuresis-guided diuretic therapy, use of hypertonic saline, and ultrafiltration.

Cardiovascular Consequences of Uremic Metabolites: an Overview of the Involved Signaling Pathways.

The crosstalk of the heart with distant organs such as the lung, liver, gut, and kidney has been intensively approached lately. The kidney is involved in (1) the production of systemic relevant products, such as renin, as part of the most essential vasoregulatory system of the human body, and (2) in the clearance of metabolites with systemic and organ effects. Metabolic residue accumulation during kidney dysfunction is known to determine cardiovascular pathologies such as endothelial activation/dysfunction, atherosclerosis, cardiomyocyte apoptosis, cardiac fibrosis, and vascular and valvular calcification, leading to hypertension, arrhythmias, myocardial infarction, and cardiomyopathies. However, this review offers an overview of the uremic metabolites and details their signaling pathways involved in cardiorenal syndrome and the development of heart failure. A holistic view of the metabolites, but more importantly, an exhaustive crosstalk of their known signaling pathways, is important for depicting new therapeutic strategies in the cardiovascular field.

Venous Doppler flow patterns, venous congestion, heart disease and renal dysfunction: A complex liaison.

The World Journal of Cardiology published an article written by Kuwahara et al that we take the pleasure to comment on. We focused our attention on venous congestion. In intensive care settings, it is now widely accepted that venous congestion is an important clinical feature worthy of investigation. Evaluating venous Doppler profile abnormalities at multiple sites could suggest adequate treatment and monitor its efficacy. Renal dysfunction could trigger or worsen fluid overload in heart disease, and cardio-renal syndrome is a well-characterized spectrum of disorders describing the complex interactions between heart and kidney diseases. Fluid overload and venous congestion, including renal venous hypertension, are major determinants of acute and chronic renal dysfunction arising in heart disease. Organ congestion from venous hypertension could be involved in the development of organ injury in several clinical situations, such as critical diseases, congestive heart failure, and chronic kidney disease. Ultrasonography and abnormal Doppler flow patterns diagnose clinically significant systemic venous congestion. Cardiologists and nephrologists might use this valuable, non-invasive, bedside diagnostic tool to establish fluid status and guide clinical choices.

Renal Rehabilitation: Present and Future Perspectives.

Chronic kidney disease (CKD) is a global health problem. In patients with CKD, exercise endurance is decreased, especially as renal dysfunction advances. This is due to the combined effects of protein-energy wasting, uremic acidosis, and inflammatory cachexia, which lead to sarcopenia and are aggravated by a sedentary lifestyle, resulting in a progressive downward spiral of deconditioning. Renal rehabilitation (RR) is a coordinated, multifaceted intervention designed to optimize a patient's physical, psychological, and social functioning, as well as to stabilize, slow, or even reverse the progression of renal deterioration, improving exercise tolerance and preventing the onset and worsening of heart failure, thereby reducing morbidity and mortality. This review focused on the history and benefits of RR in patients with CKD. Based on current evidence, RR is an effective, feasible, and safe secondary prevention strategy in CKD. RR is a promising model for a new field of rehabilitation. Therefore, efforts to increase RR implementation rates are urgently needed.

Assessment and management of heart failure in patients with chronic kidney disease.

Heart failure (HF) and chronic kidney disease (CKD) are two pathological conditions with a high prevalence in the general population. When they coexist in the same patient, a strict interplay between them is observed, such that patients affected require a clinical multidisciplinary and personalized management. The diagnosis of HF and CKD relies on signs and symptoms of the patient but several additional tools, such as blood-based biomarkers and imaging techniques, are needed to clarify and discriminate the main characteristics of these diseases. Improved survival due to new recommended drugs in HF has increasingly challenged physicians to manage patients with multiple diseases, especially in case of CKD. However, the safe administration of these drugs in patients with HF and CKD is often challenging. Knowing up to which values ​​of creatinine or renal clearance each drug can be administered is fundamental. With this review we sought to give an insight on this sizable and complex topic, in order to get clearer ideas and a more precise reference about the diagnostic assessment and therapeutic management of HF and CKD.

Interleukin-6, tumor necrosis factor-α, and high-sensitivity C-reactive protein for optimal immunometabolic profiling of the lifestyle-related cardiorenal risk.

OBJECTIVES: The present study aimed to identify optimal inflammatory biomarkers involved in cardiorenal risk in response to major lifestyle factors. METHODS: One hundred and twenty-nine adults aged 35-77 years participated voluntarily from 2017 to 2019 (Córdoba, Argentina) in a cross-sectional study to collect sociodemographic, clinical, and lifestyle data. Blood biomarkers (different cytokines, monocyte chemoattractant protein-1 [MCP-1], and high-sensitivity C-reactive protein [hs-CRP]) were measured using standard methods and then evaluated by principal component analysis and structural equation modeling (SEM) according to Mediterranean diet adherence, physical activity level, and waist circumference, while cardiorenal risk involved blood diastolic pressure, HDL-cholesterol, triacylglycerols, creatinine, and glycosylated hemoglobin. RESULTS: A principal component included TNF-α (tumor necrosis factor-alpha), IL-8 (interleukin-8), IL-6 (interleukin-6), hs-CRP, and MCP-1, with absolute rotated factor loadings >0.10. SEM showed that IL-6 (ß=0.38, 95 % IC=0.08-0.68), hs-CRP (ß=0.33, 95 % IC=0.17-0.48), and TNF-α (ß=0.22, 95 % IC=0.11-0.32) were the mediators that better explained an inflammatory profile positively related to waist circumference (ß=0.77, 95 % IC=0.61-0.94). Moreover, this profile was associated with an increased cardiorenal risk (ß=0.78, 95 % IC=0.61-0.94), which was well-defined by the variable used. CONCLUSIONS: Immune mediators are key elements in profiling the cardiorenal risk associated with lifestyle factors, for which the combination of hs-CRP, IL-6, and TNF-α has emerged as a robust indicator. This work reaffirms the need for biomarker optimization for early diagnosis and risk assessment.

[Diuretic resistance and heart failure: between congestion and kidney injury]. / Resistencia diurética e insuficiencia cardíaca: entre la congestión y la disfunción renal.

Nowadays, heart Failure (HF) is one of the main contributors of cardiovascular morbidity and mortality, this faces us with great challenges. The heart-kidney interaction receives particular attention due to the development of the so-called cardiorenal syndrome (CRS) and the diuretic resistance, latter is a predictor of adverse events in acute HF and is independent of the glomerular filtration rate. Development of diuretic resistance is secondary to multiple causes, so a comprehensive evaluation of all of them is required. In recent years, congestion has become relevant within the pathophysiological mechanism of CRS, as it mutually generates and perpetuates damage in these two organs. Given the importance of congestion, diuretics remain the cornerstone of treatment, although their use is largely empirical due to the limited evidence available. The evidence-based treatment paradigm is elusive in this scenario, so one question remains unanswered: Do the interventions to treat or to prevent the diuretic resistance modify the prognosis in acute HF?

Síndrome cardiorrenal: diagnóstico y tratamiento / Cardiorenal syndrome: diagnosis and treatment

Introducción: Las enfermedades cardíacas y renales coexisten con frecuencia. El síndrome cardiorrenal es una entidad compleja; en ella, la disfunción primaria cardíaca produce daño renal (tipos 1 y 2) y viceversa (tipos 3 y 4) o efecto de una enfermedad sistémica que afecta a ambos órganos (tipo 5). Objetivo: Actualizar el diagnóstico y tratamiento de los pacientes con síndrome cardiorrenal. Métodos: Se utilizan métodos teóricos y empíricos para realizar análisis del conocimiento actualizado sobre el tema. Se ha definido la existencia de un síndrome cardiorrenal que compromete a ambos órganos, con interacción bidireccional. En su detección, el diagnóstico clínico es insuficiente y requiere marcadores bioquímicos; estas herramientas, junto con la medición del sodio urinario, permite vigilar la efectividad terapéutica. Otro recurso es la ultrafiltración, según complicaciones. Conclusiones: Se debe indicar tratamiento con base en la evidencia para mejorar la calidad de vida, reducir la mortalidad y retrasar el deterioro de la función renal y cardíaca a largo plazo; el trasplante renal se debe considerar en pacientes en diálisis con disfunción ventricular severa. Idealmente, deberían recibir un trasplante combinado: cardíaco y renal, lo cual es difícil; algunos pacientes sometidos exclusivamente a trasplante renal presentan una mejoría notable en su fracción de eyección y en la sobrevida.

Introduction: heart and kidney diseases frequently coexist. Cardiorenal syndrome is a complex entity in which primary cardiac dysfunction causes a kidney damage (types 1 and 2) and vice versa (types 3 and 4) or an effect of a systemic disease that affects both organs (type 5). Objective: to update the diagnosis and treatment of patients with cardiorenal syndrome. Methods: theoretical and empirical methods are used to carry out the analysis of updated knowledge on the subject. The existence of a cardiorenal syndrome that compromises both organs has been defined with bidirectional interaction. In its detection, clinical diagnosis is insufficient and requires biochemical markers; these tools, together with the measurement of urinary sodium, allow us to monitor therapeutic effectiveness. Another resource is ultrafiltration, according to complications. Conclusions: evidence-based treatment should be indicated to improve quality of life, reduce mortality, and delay the deterioration of renal and cardiac function in the long term; kidney transplantation should be considered in dialysis patients with severe ventricular dysfunction. Ideally, they should receive a combined transplant: heart and kidney, which is difficult; some patients undergoing exclusively a renal transplantation show a notable improvement in their ejection fraction and survival.

Prognostic role of renal replacement therapy among hospitalized patients with heart failure in the Brazilian national public health system.

Introduction: Data on patients hospitalized with acute heart failure in Brazil scarce. Methods: We performed a cross-sectional, retrospective, records-based study using data retrieved from a large public database of heart failure admissions to any hospital from the Brazilian National Public Health System (SUS) (SUS Hospital Information System [SIHSUS] registry) to determine the in-hospital all-cause mortality rate, in-hospital renal replacement therapy rate and its association with outcome. Results: In total, 910,128 hospitalizations due to heart failure were identified in the SIHSUS registry between April 2017 and August 2021, of which 106,383 (11.7%) resulted in in-hospital death. Renal replacement therapy (required by 8,179 non-survivors [7.7%] and 11,496 survivors [1.4%, p < 0.001]) was associated with a 56% increase in the risk of death in the univariate regression model (HR 1.56, 95% CI 1.52 -1.59), a more than threefold increase of the duration of hospitalization, and a 45% or greater increase of cost per day. All forms of renal replacement therapy remained independently associated with in-hospital mortality in multivariable analysis (intermittent hemodialysis: HR 1.64, 95% CI 1.60 -1.69; continuous hemodialysis: HR 1.52, 95% CI 1.42 -1.63; peritoneal dialysis: HR 1.47, 95% CI 1.20 -1.88). Discussion: The in-hospital mortality rate of 11.7% observed among patients with acute heart failure admitted to Brazilian public hospitals was alarmingly high, exceeding that of patients admitted to North American and European institutions. This is the first report to quantify the rate of renal replacement therapy in patients hospitalized with acute heart failure in Brazil.

NAC Pre-Administration Prevents Cardiac Mitochondrial Bioenergetics, Dynamics, Biogenesis, and Redox Alteration in Folic Acid-AKI-Induced Cardio-Renal Syndrome Type 3.

The incidence of kidney disease is increasing worldwide. Acute kidney injury (AKI) can strongly favor cardio-renal syndrome (CRS) type 3 development. However, the mechanism involved in CRS development is not entirely understood. In this sense, mitochondrial impairment in both organs has become a central axis in CRS physiopathology. This study aimed to elucidate the molecular mechanisms associated with cardiac mitochondrial impairment and its role in CRS development in the folic acid-induced AKI (FA-AKI) model. Our results showed that 48 h after FA-AKI, the administration of N-acetyl-cysteine (NAC), a mitochondrial glutathione regulator, prevented the early increase in inflammatory and cell death markers and oxidative stress in the heart. This was associated with the ability of NAC to protect heart mitochondrial bioenergetics, principally oxidative phosphorylation (OXPHOS) and membrane potential, through complex I activity and the preservation of glutathione balance, thus preventing mitochondrial dynamics shifting to fission and the decreases in mitochondrial biogenesis and mass. Our data show, for the first time, that mitochondrial bioenergetics impairment plays a critical role in the mechanism that leads to heart damage. Furthermore, NAC heart mitochondrial preservation during an AKI event can be a valuable strategy to prevent CRS type 3 development.

Is the Benefit of Treating Iron Deficiency Greater in Acute Heart Failure with Renal Dysfunction?

BACKGROUND: This study aims to analyse whether in acute heart failure (AHF) with iron deficiency (ID), the administration of ferric carboxymaltose (FCM) produces a greater benefit in renal dysfunction. METHODS: A total of 812 consecutive patients admitted for AHF and ID were studied. Untreated (n:272) and treated (n:540) patients were compared. The six-month prevalence of a combined event (readmission for HF, all-cause death, and emergency department visit for decompensation) was analysed. Three grades of renal dysfunction (KDIGO) were compared, Group 1 (grades 1 and 2), Group 2 (grades 3a and 3b), and Group 3 (grades 4 and 5). RESULTS: There were differences in sex distribution (untreated group: males 39.7% vs. treated group: males 51.9%; p < 0.001). Sex-adjusted combined event analysis showed a greater benefit in Group 1 (OR: 0.31, 95% CI:0.19-0.5; p < 0.001) and Group 2 (OR: 0.23, 95% CI:0.14-0.38; p < 0.001), but not in Group 3 (OR: 0.51, 95% CI:0.17-0.55; p: 0.237). CONCLUSIONS: The administration of FCM in patients with AHF and ID reduces the combined event analysed. The benefit is greater when renal dysfunction is present, except in very advanced degrees where no significant benefit is obtained.

How should we treat acute kidney injury caused by renal congestion?

Decreased kidney function is associated with increased risk of cardiovascular events and mortality, and heart failure (HF) is a wellknown risk factor for renal dysfunction. Acute kidney injury (AKI) in patients with HF often is attributed to prerenal factors, such as renal hypoperfusion and ischemia as a result of decreased cardiac output. Another such factor is reduction of absolute or relative circulating blood volume, with the decrease in renal blood flow leading to renal hypoxia followed by a decrease in the glomerular filtration rate. However, renal congestion is increasingly being recognized as a potential cause of AKI in patients with HF. Increased central venous pressure and renal venous pressure lead to increased renal interstitial hydrostatic pressure and a reduction of the glomerular filtration rate. Both decreased kidney function and renal congestion have been shown to be important prognostic factors of HF, and adequate control of congestion is important for improving kidney function. Loop and thiazide diuretics are recommended as standard therapies to reduce volume overload. However, these agents are associated with worsening renal function even though they are effective for improving congestive symptoms. There is growing interest in tolvaptan, which can improve renal congestion by increasing excretion of free water and decreasing the required dose of loop diuretic, thereby improving kidney function. This review summarizes renal hemodynamics, the pathogenesis of AKI due to renal ischemia and renal congestion, and diagnosis and treatment options for renal congestion.

Cardio-renal syndrome: what's new in 2023? / Syndrome cardio-rénal : quoi de neuf en 2023 ?

Cardiac and renal pathologies lead to a high morbidity and mortality rate. The cardio-renal syndrome is characterized by the coexistence of renal and cardiac dysfunction and represents a polymorphic situation that is often complex to understand. This is a common occurrence that constitutes a real public health problem. In this review article, we propose to review the current state of knowledge on this syndrome by focusing on the main physiopathological, epidemiological, clinical and therapeutic aspects.

Les pathologies cardiaques et rénales entraînent un taux de morbi-mortalité élevé. Le syndrome cardio-rénal est caractérisé par la coexistence d'une dysfonction rénale et cardiaque et représente une situation polymorphe souvent complexe à appréhender. Il s'agit d'une conjoncture fréquente constituant une réelle problématique de santé publique. Dans cet article de revue, nous proposons de revenir sur l'état des connaissances actuelles sur ce syndrome en nous concentrant sur les principaux aspects physiopathologiques, épidémiologiques, cliniques et thérapeutiques.

CircRNA-mediated pathology: a new preliminary insight into the mechanism of type II cardio-renal syndrome.

AIM: The aim of this research was to investigate the expression of peripheral blood circular RNA (circRNA) in patients with type II cardio-renal syndrome, uncover the potential function and possible mechanisms mediated by circRNAs, and ultimately provide gene target support for the treatment of type II cardio-renal syndrome. METHODS: CircRNAs in the peripheral blood from five healthy individuals and 20 type II cardio-renal syndrome patients were collected for micro-array analysis. Another cohort study consisting of 12 normal cases and 15 type II cardiorenal syndrome patients was conducted to verify the chosen circRNA by quantitative real-time polymerase chain reaction. RESULTS: A total of 2 884 circRNAs were found to be differentially expressed in the group of patients with type II cardio-renal syndrome. Of these, 1 989 were upregulated and 895 were downregulated. One circRNA was then selected as a candidate biomarker and further validated in the second cohort. CONCLUSIONS: Differentially expressed mRNAs between patients with type II cardio-renal syndrome and healthy controls were enriched in two pathways, including haematopoietic cell lineage and cell adhesion molecules. CircRNA-mediated pathology is indispensable and plays an important role in the progress of type II cardio-renal syndrome. More importantly, hsa_cir_0001763 may be an important character in circRNA-mediated pathology.

Renal resistance index independently predicts worsening of renal function after coronary angiography.

The renal resistance index (RRI) has been demonstrated to be a useful parameter that can detect patients at a high risk of worsening of renal function (WRF). This study was designed to evaluate the role of the RRI in predicting WRF mediated by the intravascular administration of contrast media. We enrolled patients who were referred for coronary angiography. Renal arterial echo-color Doppler was performed to calculate the RRI. WRF was defined as an increase of > 0.3 mg/dL and at least 25% of the baseline value in creatinine concentration 24-48 h after coronary angiography. Among the 148 patients enrolled in this study, 18 (12%) had WRF. In the multivariate logistic analysis, the RRI was independently associated with WRF (odds ratio [OR]: 1.22; 95% confidence interval [CI]: 1.09-1.36; p = 0.001). After angiography, the RRI significantly increased in both patients with and without WRF. In the receiver operating characteristic curve analyses for WRF, the RRI at baseline and after angiography showed similar accuracy, and the best cutoff value for predicting WRF was 70%. In patients undergoing coronary angiography, the RRI is independently associated with WRF, probably because it provides more accurate information about cardiorenal pathophysiological factors and reflects kidney hemodynamic status and flow reserve.

Interleukin-33 Mediates Cardiomyopathy After Acute Kidney Injury by Signaling to Cardiomyocytes.

BACKGROUND: Acute kidney injury (AKI) is a short-term life-threatening condition that, if survived, can lead to renal insufficiency and development of chronic kidney disease. The pathogenesis of AKI and chronic kidney disease involves direct effects on the heart and the development of hypertrophy and cardiomyopathy. METHODS: We used mouse models of ischemia/reperfusion AKI and unilateral ureteral obstruction to investigate the role of IL-33 (interleukin-33) and its receptor-encoding gene Il1rl1 (also called ST2L [suppression of tumorigenicity 2]) in cardiac remodeling after AKI. Mice with cell type-specific genetic disruption of the IL-33/ST2L axis were used, and IL-33 monoclonal antibody, adeno-associated virus encoding IL-33 or ST2L, and recombinant IL-33, as well. RESULTS: Mice deficient in Il33 were refractory to cardiomyopathy associated with 2 models of kidney injury. Treatment of mice with monoclonal IL-33 antibody also protected the heart after AKI. Moreover, overexpression of IL-33 or injection of recombinant IL-33 induced cardiac hypertrophy or cardiomyopathy, but not in mice lacking Il1rl1. AKI-induced cardiomyopathy was also reduced in mice with cardiac myocyte-specific deletion of Il1rl1 but not in endothelial cell- or fibroblast-specific deletion of Il1rl1. Last, overexpression of the ST2L receptor in cardiac myocytes recapitulated induction of cardiac hypertrophy. CONCLUSIONS: These results indicate that IL-33 released from the kidney during AKI underlies cardiorenal syndrome by directly signaling to cardiac myocytes, suggesting that antagonism of IL-33/ST2 axis would be cardioprotective in patients with kidney disease.