Cardiorenal Syndrome: An Overview

It is well established that a large number of patients with acute decompensated heart failure present with various degrees of heart and kidney dysfunction usually primary disease of heart or kidney often involve dysfunction or injury to the other. The term cardiorenal syndrome increasingly had been used without a consistent or well-accepted definition. To include the vast array of interrelated derangements and to stress the bidirectional nature of heart-kidney interactions, a new classification of the cardiorenal syndrome with 5 subtypes that reflect the pathophysiology, the time frame, and the nature of concomitant cardiac and renal dysfunction was proposed. Cardiorenal syndrome can generally be defined as a pathophysiological disorder of the heart and kidneys, in which acute or chronic dysfunction of one organ may induce acute or chronic dysfunction to the other. Although cardiorenal syndrome was usually referred to as acute kidney dysfunction following acute cardiac disease, it is now clearly established that impaired kidney function can have an adverse impact on cardiac function. It is well established that a large number of patients with acute decompensated heart failure present with various degrees of heart and kidney dysfunction usually primary disease of heart or kidney often involve dysfunction or injury to the other. The term cardiorenal syndrome increasingly had been used without a consistent or well-accepted definition. To include the vast array of interrelated derangements and to stress the bidirectional nature of heart-kidney interactions, a new classification of the cardiorenal syndrome with 5 subtypes that reflect the pathophysiology, the time frame, and the nature of concomitant cardiac and renal dysfunction was proposed. Cardiorenal syndrome can generally be defined as a pathophysiological disorder of the heart and kidneys, in which acute or chronic dysfunction of one organ may induce acute or chronic dysfunction to the other. Although cardiorenal syndrome was usually referred to as acute kidney dysfunction following acute cardiac disease, it is now clearly established that impaired kidney function can have an adverse impact on cardiac function. Clinical Summary•Definition of cardiorenal syndrome.•Meaning of heart and kidney cross-talk.•Exploring the role of the newest risk factors for cardiorenal interactions.•Summarizing therapeutic approaches to cardiorenal syndrome patients. •Definition of cardiorenal syndrome.•Meaning of heart and kidney cross-talk.•Exploring the role of the newest risk factors for cardiorenal interactions.•Summarizing therapeutic approaches to cardiorenal syndrome patients. An effective classification of cardiorenal syndrome (CRS) has been proposed in a Consensus Conference by the Acute Dialysis Quality Group1Ronco C. The cardiorenal syndrome: basis and common ground for a multidisciplinary patient-oriented therapy.Cardiorenal Med. 2011; 1: 3-4Google Scholar, 2Ronco C. House A.A. Haapio M. Cardiorenal syndrome: refining the definition of a complex symbiosis gone wrong.Intensive Care Med. 2008; 34: 957-962Crossref PubMed Scopus (183) Google Scholar in 2008 (Table 1). This classification essentially divides CRS in 2 main groups, cardiorenal and renocardiac CRS, based on the primum movens of disease (cardiac or renal). Both cardiorenal and renocardiac CRS are then divided into acute and chronic types according to the onset and duration of the underlying organ dysfunction. CRS type 5 (CRS-5) integrates all cardiorenal involvements induced by systemic disease.Table 1Classification of Cardiorenal SyndromeTypeDenominationDescriptionExample1Acute cardiorenalHeart failure leading to AKDAcute coronary syndrome leading to acute heart and kidney failure2Chronic cardiorenalChronic heart failure leading to kidney failureChronic heart failure3Acute nephrocardiacAKD leading to acute heart failureUremic cardiomyopathy AKD-related4Chronic nephrocardiacCKD leading to heart failureLeft ventricular hypertrophy and diastolic heart failure because of kidney failure5SecondarySystemic disease leading to heart and kidney failureSepsis, vasculitis, diabetes mellitusAbbreviation: AKD, acute kidney disease. Open table in a new tab Abbreviation: AKD, acute kidney disease. The interactions and feedback mechanisms involved in heart and kidney failure are more complex than previously thought. The classic understanding of kidney dysfunction in heart failure was that low renal plasma flow signals the kidneys to retain sodium and water leading to refilling and improved perfusion to vital organs.3Hillege H.L. Girbes A.R.J. de Kam P.J. et al.Renal function, neurohormonal activation, and survival in patients with chronic heart failure.Circulation. 2000; 102: 203-210Crossref PubMed Scopus (856) Google Scholar However, now it is becoming clear that hemodynamic adaptations of the kidney and related pathophysiological mechanisms can be independent of cardiac hemodynamics (Fig 1). The renal hemodynamic response to chronic heart failure is initially characterized by low renal plasma flow and relative preservation of the glomerular filtration rate (GFR) resulting in an increased filtration fraction. The GFR is preserved until cardiac function is severely impaired because of an increase in efferent arteriolar resistance and glomerular capillary hydrostatic pressure.3Hillege H.L. Girbes A.R.J. de Kam P.J. et al.Renal function, neurohormonal activation, and survival in patients with chronic heart failure.Circulation. 2000; 102: 203-210Crossref PubMed Scopus (856) Google Scholar In addition to these changes in GFR, enhanced sodium reabsorption in the loop of Henle also appears to play a significant role in the CRS together with multiple neurohormonal factors as represented by activation of the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS). Neurohormonal activation, increased arginine vasopressin release, and endothelin release result in systemic vasoconstriction, preservation of GFR, and salt and water retention.3Hillege H.L. Girbes A.R.J. de Kam P.J. et al.Renal function, neurohormonal activation, and survival in patients with chronic heart failure.Circulation. 2000; 102: 203-210Crossref PubMed Scopus (856) Google Scholar This is an initial compensatory response to preserve or optimize cardiac output, arterial blood pressure, and GFR.3Hillege H.L. Girbes A.R.J. de Kam P.J. et al.Renal function, neurohormonal activation, and survival in patients with chronic heart failure.Circulation. 2000; 102: 203-210Crossref PubMed Scopus (856) Google Scholar In patients with heart failure, however, because of neurohormonal response, a congestive state with peripheral edema develops. Inappropriate activation of the RAAS also leads to activation of nicotinamide adenine dinucleotide phosphate (reduced) oxidase by angiotensin II, leading to the formation of reactive oxygen species (ROS).4Giam B. Kaye D.M. Rajapakse N.W. Role of renal oxidative stress in the pathogenesis of the cardiorenal syndrome.Heart Lung Circ. 2016; 25: 874-880Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 5Iwata K. Matsuno K. Murata A. et al.Up-regulation of NOX1/NADPH oxidase following drug-induced myocardial injury promotes cardiac dysfunction and fibrosis.Free Radic Biol Med. 2018; 120: 277-288Crossref PubMed Scopus (21) Google Scholar The critical role that RAAS plays in the CRS suggests the possibility of a treatment paradox: angiotensin-converting enzyme (ACE) inhibitor therapy in patients with chronic heart failure and CKD is associated with long-term benefits, but hypothetically may acutely exacerbate the CRS. However, this is not necessarily true in clinical practice. ACE inhibitors are not associated with worsening kidney function in patients hospitalized for management of heart failure, and the mild worsening of kidney function because of the CRS does not constitute an indication to stop ACE inhibitor therapy in patients already on ACE inhibitor treatment.6Buggey J. Mentz R.J. DeVore A.D. Velazquez E.J. Angiotensin receptor neprilysin inhibition in heart failure: mechanistic action and clinical impact.J Card Fail. 2015; 21: 741-750Abstract Full Text Full Text PDF Scopus (28) Google Scholar Nitric oxide (NO) system activation represents a major issue in the pathophysiology of the CRS because it is involved in vasodilation, natriuresis, and desensitization of the tubuloglomerular feedback mechanism.4Giam B. Kaye D.M. Rajapakse N.W. Role of renal oxidative stress in the pathogenesis of the cardiorenal syndrome.Heart Lung Circ. 2016; 25: 874-880Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 5Iwata K. Matsuno K. Murata A. et al.Up-regulation of NOX1/NADPH oxidase following drug-induced myocardial injury promotes cardiac dysfunction and fibrosis.Free Radic Biol Med. 2018; 120: 277-288Crossref PubMed Scopus (21) Google Scholar It also inhibits several components of atherogenesis and smooth muscle cell proliferation, and increases angiogenesis by ensuring delivery of vascular endothelial growth factor.4Giam B. Kaye D.M. Rajapakse N.W. Role of renal oxidative stress in the pathogenesis of the cardiorenal syndrome.Heart Lung Circ. 2016; 25: 874-880Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 5Iwata K. Matsuno K. Murata A. et al.Up-regulation of NOX1/NADPH oxidase following drug-induced myocardial injury promotes cardiac dysfunction and fibrosis.Free Radic Biol Med. 2018; 120: 277-288Crossref PubMed Scopus (21) Google Scholar Therefore, NO system activation inhibits platelet aggregation, endothelial adhesion molecule expression, and leukocyte-endothelial cell interaction.4Giam B. Kaye D.M. Rajapakse N.W. Role of renal oxidative stress in the pathogenesis of the cardiorenal syndrome.Heart Lung Circ. 2016; 25: 874-880Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 5Iwata K. Matsuno K. Murata A. et al.Up-regulation of NOX1/NADPH oxidase following drug-induced myocardial injury promotes cardiac dysfunction and fibrosis.Free Radic Biol Med. 2018; 120: 277-288Crossref PubMed Scopus (21) Google Scholar In kidney failure, the balance between NO and ROS is shifted because a relative deficiency of NO is observed. Decreased NO and increased oxidative stress in patients with kidney failure lead to increased risk for cardiac events also because of accelerated atherosclerosis.4Giam B. Kaye D.M. Rajapakse N.W. Role of renal oxidative stress in the pathogenesis of the cardiorenal syndrome.Heart Lung Circ. 2016; 25: 874-880Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 6Buggey J. Mentz R.J. DeVore A.D. Velazquez E.J. Angiotensin receptor neprilysin inhibition in heart failure: mechanistic action and clinical impact.J Card Fail. 2015; 21: 741-750Abstract Full Text Full Text PDF Scopus (28) Google Scholar C-reactive protein (CRP) has numerous proinflammatory and proatherogenic effects and is thought to have a role in the pathogenesis of atherosclerosis in cardiorenal patients.7Martinez B.K. White C.M. The emerging role of inflammation in cardiovascular disease.Ann Pharmacother. 2018; 52: 801-809Google Scholar It is increased in ESRD and probably has a synergistic role in the progression of renal and cardiovascular disease.7Martinez B.K. White C.M. The emerging role of inflammation in cardiovascular disease.Ann Pharmacother. 2018; 52: 801-809Google Scholar The SNS stimulates the release of renin by sympathetic neurons. Catecholamines produce hemodynamic changes in the glomerulus similar to those of angiotensin II (increased systemic vascular resistance and sodium retention).8Senni M. D'Elia E. Emdin M. Vergaro G. Biomarkers of Heart Failure with Preserved and Reduced Ejection Fraction.in: Bauersachs J. Butler J. Marsh N. Heart Failure. Springer International Publishing, Cham, Switzerland2016: 79-108Google Scholar Peripheral sympathetic nerve activity increases in ESRD, but corrects when the diseased kidneys are removed.8Senni M. D'Elia E. Emdin M. Vergaro G. Biomarkers of Heart Failure with Preserved and Reduced Ejection Fraction.in: Bauersachs J. Butler J. Marsh N. Heart Failure. Springer International Publishing, Cham, Switzerland2016: 79-108Google Scholar The complex interactions involved in acute renal disease eventually lead to a compensatory response that involves several natriuretic factors, such as atrial natriuretic factor, brain natriuretic factor, and urodilatin.9Travessa A.M. Menezes Falcão L. Vasodilators in acute heart failure—evidence based on new studies.Eur J Intern Med. 2018; 51: 1-10Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar CRS type 1 (CRS-1) (acute cardiorenal) is characterized by acute worsening of cardiac function leading to acute kidney injury (AKI). CRS-1 usually presents in the setting of an acute cardiac disease such as acute decompensated heart failure (ADHF), often after an ischemic (acute coronary syndrome, cardiac surgery complications) or nonischemic heart disease (valvular disease, pulmonary embolism). CRS-1 occurs in about 25% of patients hospitalized for ADHF10Bagshaw S.M. Cruz D.N. Aspromonte N. et al.Epidemiology of cardio-renal syndromes: workgroup statements from the 7th ADQI Consensus Conference.Nephrol Dial Transplant. 2010; 25: 1406-1416Crossref PubMed Scopus (158) Google Scholar, 11Damman K. Navis G. Voors A.A. et al.Worsening renal function and prognosis in heart failure: systematic review and meta-analysis.J Card Fail. 2007; 13: 599-608Abstract Full Text Full Text PDF PubMed Scopus (472) Google Scholar; among these patients, pre-existent CKD is common and contributes to AKI in 60% of all cases studied. AKI can be considered an independent mortality risk factor in patients with ADHF, including those with ST-segment elevation myocardial infarction and/or reduced left ventricular ejection fraction.12McCullough P.A. Cardiorenal syndromes: pathophysiology to prevention.Int J Nephrol. 2010; 2011: 762590PubMed Google Scholar An acute heart failure syndrome (AHFS) may be defined as heart failure with a relatively rapid onset of signs and symptoms, resulting in hospitalization, or emergency room or unplanned office visits. AHFS can result from a variety of different pathophysiological conditions, although approximately 70% of cases result from worsening of chronic heart failure. Other causes of AHFS include new-onset heart failure caused by an acute coronary event such as a myocardial infarction and end-stage or refractory heart failure not responsive to therapy. Clinical presentation may vary, encompassing worsening congestion, worsening chronic heart failure, pulmonary edema, hypertensive crisis, or cardiogenic shock.13Ronco C. Cicoira M. McCullough P.A. Cardiorenal syndrome type 1: pathophysiological crosstalk leading to combined heart and kidney dysfunction in the setting of acutely decompensated heart failure.J Am Coll Cardiol. 2012; 60: 1031-1042Crossref PubMed Scopus (282) Google Scholar In all forms of heart failure, the kidney responds in a similar manner, retaining sodium and water despite expansion of the extracellular fluid volume.13Ronco C. Cicoira M. McCullough P.A. Cardiorenal syndrome type 1: pathophysiological crosstalk leading to combined heart and kidney dysfunction in the setting of acutely decompensated heart failure.J Am Coll Cardiol. 2012; 60: 1031-1042Crossref PubMed Scopus (282) Google Scholar Obesity and metabolic syndrome can also contribute to both heart and kidney disease. In obesity, growth of adipocytes and increase in fatty acid content can be involved in vascular inflammation as it occurs in the epicardial coronary arteries.13Ronco C. Cicoira M. McCullough P.A. Cardiorenal syndrome type 1: pathophysiological crosstalk leading to combined heart and kidney dysfunction in the setting of acutely decompensated heart failure.J Am Coll Cardiol. 2012; 60: 1031-1042Crossref PubMed Scopus (282) Google Scholar Obesity-related glomerulopathy has been described as a condition of hyperfiltration in obese individuals without diabetes mellitus that leads to CKD and predisposes to CRS-1.13Ronco C. Cicoira M. McCullough P.A. Cardiorenal syndrome type 1: pathophysiological crosstalk leading to combined heart and kidney dysfunction in the setting of acutely decompensated heart failure.J Am Coll Cardiol. 2012; 60: 1031-1042Crossref PubMed Scopus (282) Google Scholar Combined disorders of heart and kidney are also likely to develop in the presence of some degree of cachexia and sarcopenia.13Ronco C. Cicoira M. McCullough P.A. Cardiorenal syndrome type 1: pathophysiological crosstalk leading to combined heart and kidney dysfunction in the setting of acutely decompensated heart failure.J Am Coll Cardiol. 2012; 60: 1031-1042Crossref PubMed Scopus (282) Google Scholar Hemodynamic mechanisms play a major role in CRS-1 in the presence of ADHF leading to decreased renal arterial flow and GFR decline (Fig 2). Four different hemodynamic profiles have been proposed in patients with acute heart failure: cold/warm and dry/wet.14Stevenson L.W. The limited reliability of physical signs for estimating hemodynamics in chronic heart failure.JAMA. 1989; 261: 884-888Crossref PubMed Scopus (750) Google Scholar In “cold” pattern patients, a reduction in extracellular fluid volume represents the main hemodynamic change together with a decrease in renal blood flow related to the RAAS and systemic nervous system activation causing efferent vasoconstriction. Patients who present with a “wet” hemodynamic profile display increased pulmonary and/or systemic congestion. In these patients, high central venous pressure directly affects renal vein and kidney perfusion pressure.15Mullens W. Abrahams Z. Francis G.S. et al.Importance of venous congestion for worsening of renal function in advanced decompensated heart failure.J Am Coll Cardiol. 2009; 53: 589-596Crossref PubMed Scopus (1060) Google Scholar, 16Uthoff H. Breidthardt T. Klima T. et al.Central venous pressure and impaired renal function in patients with acute heart failure.Eur J Heart Fail. 2011; 13: 432-439Crossref PubMed Scopus (83) Google Scholar Increase in central venous pressure also results in increased interstitial pressure with tubular collapse and progressive decline in the GFR.17Braam B. Cupples W.A. Joles J.A. Gaillard C. Systemic arterial and venous determinants of renal hemodynamics in congestive heart failure.Heart Fail Rev. 2012; 17: 161-175Crossref PubMed Scopus (66) Google Scholar As previously mentioned, nonhemodynamic mechanisms involve SNS, RAAS activation, chronic inflammation, and imbalance in the proportion of ROS/NO production.4Giam B. Kaye D.M. Rajapakse N.W. Role of renal oxidative stress in the pathogenesis of the cardiorenal syndrome.Heart Lung Circ. 2016; 25: 874-880Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar Diagnosis of CRS-1 focuses on clinical and laboratory findings, ultrasonography, and other radiological tests. Early diagnosis of AKI in CRS-1 (such as in type 3) still remains a challenge18Han W.K. Bonventre J.V. Biologic markers for the early detection of acute kidney injury.Curr Opin Crit Care. 2004; 10: 476-482Crossref PubMed Scopus (169) Google Scholar; classic biomarkers, such as creatinine levels, which increase when kidney injury is already established and prevention fails. New frontiers are represented by novel biomarkers such as serum and urinary neutrophil gelatinase–associated lipocalin, cystatin –C, kidney injury molecule 1, interleukin 18 (IL-18), and liver-type fatty acid-binding protein.19Hekmat R. Mohebi M. Comparison of serum creatinine, cystatin C, and neutrophil gelatinase-associated lipocalin for acute kidney injury occurrence according to risk, injury, failure, loss, and end-stage criteria classification system in early after living kidney donation.Saudi J Kidney Dis Transpl. 2016; 27: 659-664Google Scholar, 20Vaidya V.S. Ramirez V. Ichimura T. Bobadilla N.A. Bonventre J.V. Urinary kidney injury molecule-1: a sensitive quantitative biomarker for early detection of kidney tubular injury.Am J Physiol Renal Physiol. 2006; 290: F517-F529Crossref PubMed Scopus (531) Google Scholar Ultrasonography can provide further useful information for diagnosis of CRS-1. Typical findings on echocardiography reveal abnormal myocardial kinetics (indicating an ischemic condition) and left ventricular hypertrophy, valvular stenosis, and/or regurgitation (particularly in case of rapid deterioration, such as valvular endocarditis or valvular rupture), pericardial effusions, normal inspiratory collapse of the inferior vena cava (excluding severe hypervolemia), and aortic aneurysms or dissection.21Di Lullo L. Floccari F. Granata A. et al.Ultrasonography: Ariadne's thread in the diagnosis of the cardiorenal syndrome.Cardiorenal Med. 2012; 2: 11-17Crossref PubMed Google Scholar Ultrasound evaluation of the kidney usually shows normal or large-sized kidneys with preserved cortical-medullary ratio; color Doppler evaluation shows regular intraparenchymal blood flow, often associated with increased resistance index (>0.8 cm/s).21Di Lullo L. Floccari F. Granata A. et al.Ultrasonography: Ariadne's thread in the diagnosis of the cardiorenal syndrome.Cardiorenal Med. 2012; 2: 11-17Crossref PubMed Google Scholar CRS type 2 (CRS-2) is characterized by chronic abnormalities in cardiac function leading to kidney injury or dysfunction. Literature data show that chronic heart and kidney disease often coexist but large cohort studies assessed the onset of one disease (eg, chronic heart failure) while describing the prevalence of the other (CKD).22Hebert K. Dias A. Delgado M.C. et al.Epidemiology and survival of the five stages of chronic kidney disease in a systolic heart failure population.Eur J Heart Fail. 2010; 12: 861-865Crossref PubMed Scopus (50) Google Scholar, 23Heywood J.T. Fonarow G.C. Costanzo M.R. Mathur V.S. Wigneswaran J.R. Wynne J. High prevalence of renal dysfunction and its impact on outcome in 118,465 patients hospitalized with acute decompensated heart failure: a report from the ADHERE database.J Card Fail. 2007; 13: 422-430Abstract Full Text Full Text PDF PubMed Scopus (606) Google Scholar In this situation, it is difficult to establish which of the 2 disease states is primary (or secondary). CKD has been observed in 45% to 63% of chronic heart failure patients,22Hebert K. Dias A. Delgado M.C. et al.Epidemiology and survival of the five stages of chronic kidney disease in a systolic heart failure population.Eur J Heart Fail. 2010; 12: 861-865Crossref PubMed Scopus (50) Google Scholar, 23Heywood J.T. Fonarow G.C. Costanzo M.R. Mathur V.S. Wigneswaran J.R. Wynne J. High prevalence of renal dysfunction and its impact on outcome in 118,465 patients hospitalized with acute decompensated heart failure: a report from the ADHERE database.J Card Fail. 2007; 13: 422-430Abstract Full Text Full Text PDF PubMed Scopus (606) Google Scholar, 24Cruz D.N. Bagshaw S.M. Heart-kidney interaction: epidemiology of cardiorenal syndromes.Int J Nephrol. 2010; 2011: 351291PubMed Google Scholar but it is unclear how to classify these patients as often some patients may have had preceding CRS-1. It is not always easy to differentiate these patients from CRS type 4 (CRS-4).25Palazzuoli A. Silverberg D.S. Iovine F. et al.Effects of β-erythropoietin treatment on left ventricular remodeling, systolic function, and B-type natriuretic peptide levels in patients with the cardiorenal anemia syndrome.Am Heart J. 2007; 154: 645.e9-645.e15Crossref Scopus (129) Google Scholar Pathophysiology of CRS-2 includes renal congestion and hypoperfusion together with increased right atrial pressure, which represent a cornerstone in renal dysfunction of chronic heart failure patients (Fig 3).26Nohria A. Hasselblad V. Stebbins A. et al.Cardiorenal interactions: insights from the ESCAPE trial.J Am Coll Cardiol. 2008; 51: 1268-1274Crossref PubMed Scopus (444) Google Scholar More recently, there is an increasing interest in the role of erythropoietin deficiency contributing to a more pronounced degree of anemia than what kidney disease alone could explain.27Jie K.E. Verhaar M.C. Cramer M.-J.M. et al.Erythropoietin and the cardiorenal syndrome: cellular mechanisms on the cardiorenal connectors.Am J Physiol Renal Physiol. 2006; 291: F932-F944Google Scholar In some studies, erythropoiesis-stimulating agent therapy in patients with heart failure, CKD, and anemia has led to improved cardiac function with reduction in left ventricle size and volume, whereas diuretic therapy improves fluid retention and patients' New York Heart Association scores.25Palazzuoli A. Silverberg D.S. Iovine F. et al.Effects of β-erythropoietin treatment on left ventricular remodeling, systolic function, and B-type natriuretic peptide levels in patients with the cardiorenal anemia syndrome.Am Heart J. 2007; 154: 645.e9-645.e15Crossref Scopus (129) Google Scholar However, a large (n = 2278) randomized double-blind trial, the Reduction of Events by Darbepoetin Alfa in Heart Failure (RED-HF) (using darbepoetin to target hemoglobin level of 13 g/dL or placebo), in patients with systolic heart failure and mild-to-moderate anemia (hemoglobin 9-12 g/dL) treated with darbepoetin alfa did not find any difference in the primary outcomes (composite of death from any cause or hospitalization for worsening heart failure).28Swedberg K. Young J.B. Anand I.S. et al.Treatment of anemia with darbepoetin alfa in systolic heart failure.N Engl J Med. 2013; 368: 1210-1219Crossref PubMed Scopus (376) Google Scholar CRS type 3 (CRS-3) or acute renocardiac CRS occurs when AKI contributes and/or precipitates to the development of acute cardiac injury. AKI may directly or indirectly produce an acute cardiac event. This can be associated with volume overload, metabolic acidosis, and electrolyte disorders (ie, hyperkalemia and/or hypocalcemia); coronary artery disease, left ventricular dysfunction, and fibrosis also have been described in patients with AKI with direct deleterious effects on cardiac outcomes.29Kingma Jr., J.G. Vincent C. Rouleau J.R. Kingma I. Influence of acute renal failure on coronary vasoregulation in dogs.J Am Soc Nephrol. 2006; 17: 1316-1324Crossref PubMed Scopus (42) Google Scholar, 30Prabhu S.D. Cytokine-induced modulation of cardiac function.Circ Res. 2004; 95: 1140-1153Crossref PubMed Scopus (292) Google Scholar Defining incidence and prevalence of CRS-3 is difficult because of lack of epidemiologic data. In a northern Scotland population-based study, the incidences of AKI and acute-on-chronic kidney failure were 1811 and 336 per million population, respectively.31Ali T. Khan I. Simpson W. et al.Incidence and outcomes in acute kidney injury: a comprehensive population-based study.J Am Soc Nephrol. 2007; 18: 1292-1298Crossref PubMed Scopus (664) Google Scholar Another prospective, multicenter, community-based study in 748 AKI patients reported common causes of death in AKI: infections (48%), hypovolemic shock (45.9%), respiratory distress (22.2%), heart disease (15%), disseminated intravascular coagulation (6.3%), gastrointestinal bleeding (4.5%), and stroke (2.7%).32Liano F. Pascual J. Epidemiology of acute renal failure: a prospective, multicenter, community-based study. Madrid Acute Renal Failure Study Group.Kidney Int. 1996; 50: 811-818Abstract Full Text PDF PubMed Scopus (807) Google Scholar, 33Liano F. Junco E. Pascual J. Madero R. Verde E. The spectrum of acute renal failure in the intensive care unit compared with that seen in other settings. The Madrid Acute Renal Failure Study Group.Kidney Int Suppl. 1998; 66: S16-S24PubMed Google Scholar In a more recent retrospective study of AKI after trauma, cardiac arrest was reported as a cause of death in 20% of patients. Other causes of death included cerebrovascular accidents (46%), sepsis (17%), multiple organ dysfunction syndrome (7.3%), and respiratory insufficiency (3.2%).34de Abreu K.L.S. Júnior G.B.S. Barreto A.G. et al.Acute kidney injury after trauma: prevalence, clinical characteristics and RIFLE classification.Indian J Crit Care Med. 2010; 14: 121-128Crossref PubMed Scopus (45) Google Scholar Pathophysiological interactions between kidney and heart during AKI have been referred to as “cardiorenal connectors,”35Bongartz L.G. Cramer M.J. Doevendans P.A. Joles J.A. Braam B. The severe cardiorenal syndrome: ‘Guyton revisited’.Eur Heart J. 2004; 26: 11-17Google Scholar like including the activation of immune (ie, release of proinflammatory and anti-inflammatory cytokines and chemokines) and SNS, activation of the RAAS, and coagulation cascades. Oliguria can lead to sodium and water retention with consequent fluid overload and development of edema, volume overload, hypertension, pulmonary edema, and myocardial injury. Electrolyte disturbances (primarily hyperkalemia) can contribute to risk of fatal arrhythmias and sudden death, whereas uremia-related metabolic acidosis can affect myocyte metabolism and produce pulmonary vasoconstriction, increased right ventricular afterload and negative inotropic effect (Fig 4).36Scheuer J. The effects of uremic compounds on cardiac function and metabolism.J Mol Cell Cardiol. 1973; 5: 287-300Abstract Full Text PDF PubMed Scopus (46) Google Scholar Ultrasound evaluation of the kidney and heart in patients with CRS-3 can be helpful. Without prior knowledge of baseline kidney function, kidney size and echogenicity provide primary features to discern between acute and CKD.37Ozmen C.A. Akin D. Bilek S.U. Bayrak A.H. Senturk S. Nazaroglu H. Ultrasound as a diagnostic tool to differentiate acute from chronic renal failure.Clin Nephrol. 2010; 74: 46-52PubMed Google Scholar, 38Licurse A. Kim M.C. Dziura J. et al.Renal ultrasonography in the evaluation of acute kidney injury.Arch Intern Med. 2010; 170: 1900-1907Crossref