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Cardiorenal Syndrome: An Overview
ACKD
Cardiorenal Syndrome: An Overview Claudio Ronco, Antonio Bellasi, and Luca Di Lullo 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. Q 2018 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Cardiorenal syndrome (CRS), Risk factors, Diagnosis, Outcomes and treatment
DEFINITION OF CARDIORENAL SYNDROME An effective classification of cardiorenal syndrome (CRS) has been proposed in a Consensus Conference by the Acute Dialysis Quality Group1,2 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. CARDIORENAL AXIS 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.3 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.3 In addition to these changes in GFR, enhanced sodium reabsorption in the From the International Renal Research Institute, S. Bortolo Hospital, Vicenza, Italy; Department of Nephrology and Dialysis, ASST Lariana, S. Anna Hospital, Como, Italy; and Department of Nephrology and Dialysis, L. Parodi - Delfino Hospital, Colleferro, Italy. Financial support: None. Financial disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Luca Di Lullo, MD, PhD, Department of Nephrology and Dialysis L. Parodi - Delfino Hospital, Piazza Aldo Moro, 100034 Colleferro, Roma, Italy. E-mail: [email protected] Ó 2018 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 https://doi.org/10.1053/j.ackd.2018.08.004
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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.3 This is an initial compensatory response to preserve or optimize cardiac output, arterial blood pressure, and GFR.3 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).4,5 The critical role that RAAS plays in the CRS suggests the possibility of a treatment paradox: angiotensinconverting 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.6 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.4,5 It also inhibits several components of atherogenesis and smooth muscle cell proliferation, and increases angiogenesis by ensuring delivery of vascular endothelial growth factor.4,5 Therefore, NO system activation inhibits platelet aggregation, endothelial adhesion molecule expression, and leukocyte-endothelial cell interaction.4,5 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.4,6 C-reactive protein (CRP) has numerous proinflammatory Adv Chronic Kidney Dis. 2018;25(5):382-390
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and proatherogenic effects and is thought to have a role in the pathogenesis of atherosclerosis in cardiorenal patients.7 It is increased in ESRD and probably has a synergistic role in the progression of renal and cardiovascular disease.7 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).8 Peripheral sympathetic nerve activity increases in ESRD, but corrects when the diseased kidneys are removed.8 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.9
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viduals without diabetes mellitus that leads to CKD and predisposes to CRS-1.13 Combined disorders of heart and kidney are also likely to develop in the presence of some degree of cachexia and sarcopenia.13 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.14 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. CARDIORENAL SYNDROME TYPE 1 (ACUTE In these patients, high central venous pressure directly affects renal vein and kidney perfusion pressure.15,16 CARDIORENAL SYNDROME) Increase in central venous pressure also results in CRS type 1 (CRS-1) (acute cardiorenal) is characterized by acute worsening of cardiac function leading to acute kidincreased interstitial pressure with tubular collapse and progressive decline in the GFR.17 ney injury (AKI). CRS-1 usually presents in the setting of As previously mentioned, nonhemodynamic mechaan acute cardiac disease such as acute decompensated nisms involve SNS, RAAS activation, chronic inflammaheart failure (ADHF), often after an ischemic (acute corotion, and imbalance in the proportion of ROS/NO nary syndrome, cardiac surgery complications) or noniproduction.4 schemic heart disease (valvular disease, pulmonary Diagnosis of CRS-1 focuses embolism). on clinical and laboratory CRS-1 occurs in about 25% CLINICAL SUMMARY findings, ultrasonography, of patients hospitalized for 10,11 and other radiological tests. ; among these ADHF Definition of cardiorenal syndrome. patients, pre-existent CKD is Early diagnosis of AKI in CRS-1 (such as in type 3) common and contributes to Meaning of heart and kidney cross-talk. still remains a challenge18; AKI in 60% of all cases Exploring the role of the newest risk factors for cardiorenal classic biomarkers, such as studied. AKI can be considinteractions. creatinine levels, which inered an independent mortalcrease when kidney injury ity risk factor in patients Summarizing therapeutic approaches to cardiorenal is already established and with ADHF, including those syndrome patients. prevention fails. New fronwith ST-segment elevation tiers are represented by myocardial infarction and/or novel biomarkers such as serum and urinary neutrophil reduced left ventricular ejection fraction.12 gelatinase–associated lipocalin, cystatin –C, kidney injury An acute heart failure syndrome (AHFS) may be defined molecule 1, interleukin 18 (IL-18), and liver-type fatty as heart failure with a relatively rapid onset of signs and acid-binding protein.19,20 symptoms, resulting in hospitalization, or emergency Ultrasonography can provide further useful information room or unplanned office visits. AHFS can result from a for diagnosis of CRS-1. Typical findings on echocardiogravariety of different pathophysiological conditions, phy reveal abnormal myocardial kinetics (indicating an although approximately 70% of cases result from worsischemic condition) and left ventricular hypertrophy, ening of chronic heart failure. Other causes of AHFS valvular stenosis, and/or regurgitation (particularly in include new-onset heart failure caused by an acute corocase of rapid deterioration, such as valvular endocarditis nary event such as a myocardial infarction and end-stage or valvular rupture), pericardial effusions, normal inspiraor refractory heart failure not responsive to therapy. Clintory collapse of the inferior vena cava (excluding severe ical presentation may vary, encompassing worsening hypervolemia), and aortic aneurysms or dissection.21 congestion, worsening chronic heart failure, pulmonary 13 Ultrasound evaluation of the kidney usually shows edema, hypertensive crisis, or cardiogenic shock. In all normal or large-sized kidneys with preserved corticalforms of heart failure, the kidney responds in a similar medullary ratio; color Doppler evaluation shows regular manner, retaining sodium and water despite expansion intraparenchymal blood flow, often associated with of the extracellular fluid volume.13 Obesity and metabolic syndrome can also contribute to increased resistance index (.0.8 cm/s).21 both heart and kidney disease. In obesity, growth of adipoCARDIORENAL SYNDROME TYPE 2 (CHRONIC cytes and increase in fatty acid content can be involved in CARDIORENAL SYNDROME) vascular inflammation as it occurs in the epicardial coroCRS type 2 (CRS-2) is characterized by chronic abnormalnary arteries.13 Obesity-related glomerulopathy has been described as a condition of hyperfiltration in obese indiities in cardiac function leading to kidney injury or Adv Chronic Kidney Dis. 2018;25(5):382-390
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Table 1. Classification of Cardiorenal Syndrome Type
Denomination
Description
Example
1
Acute cardiorenal
Heart failure leading to AKD
2 3 4
Chronic cardiorenal Acute nephrocardiac Chronic nephrocardiac
Chronic heart failure leading to kidney failure AKD leading to acute heart failure CKD leading to heart failure
5
Secondary
Systemic disease leading to heart and kidney failure
Acute coronary syndrome leading to acute heart and kidney failure Chronic heart failure Uremic cardiomyopathy AKD-related Left ventricular hypertrophy and diastolic heart failure because of kidney failure Sepsis, vasculitis, diabetes mellitus
Abbreviation: AKD, acute kidney disease.
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).22,23 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,22-24 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).25 Pathophysiology of CRS-2 includes renal congestion and hypoperfusion together with increased right atrial pres-
sure, which represent a cornerstone in renal dysfunction of chronic heart failure patients (Fig 3).26 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.27 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.25 However, a large (n ¼ 2278) randomized double-blind trial, the Reduction of Events by Darbepoetin Alfa in Heart Failure (RED-HF) (using darbepoetin to
Figure 1. The cardiorenal axis (from Guyton hypothesis to actual knowledge). Abbreviations: CO, cardiac output; ECFV, extracellular fluid volume; MAP, mean arterial pressure; NO, nitric oxide; ROS, reactive oxygen species. Adv Chronic Kidney Dis. 2018;25(5):382-390
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Figure 2. Pathophysiology of cardiorenal syndrome type 1. Abbreviations: ANP, atrial natriuretic peptide; GFR, glomerular filtration rate; N-AVP, nonosmotic arginine vasopressin; RAAS, rennin-angiotensin-aldosterone system; SNS, sympathetic nervous system.
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).28 CARDIORENAL SYNDROME TYPE 3 (ACUTE RENOCARDIAC SYNDROME) 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.29,30 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 Adv Chronic Kidney Dis. 2018;25(5):382-390
million population, respectively.31 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%).32,33 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%).34 Pathophysiological interactions between kidney and heart during AKI have been referred to as “cardiorenal connectors,”35 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
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Figure 3. Pathophysiology of cardiorenal syndrome type 2.
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).36 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.37,38 A hyperechogenic renal cortex with low corticomedullary ratio is suggestive of CKD.37,38
However, cortical hyperechogenicity can also be present in acute tubular necrosis or acute glomerulonephritis.37,38 The echocardiographic pattern is not diagnostic, showing an increase in atrial volumes, pleural or pericardial effusion, and is often associated with evidence of “lung comets” on thoracic ultrasound.21 Ultrasound lung comets consist of multiple comet tails originating from water-thickened interlobular septa and fanning out from the lung surface. The technique requires ultrasound scanning of the anterior right and left chest, from the 2nd to the 5th intercostal space.39
Figure 4. Pathophysiology of cardiorenal syndrome type 3. Adv Chronic Kidney Dis. 2018;25(5):382-390
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Figure 5. Cardiovascular and renal features of cardiorenal syndrome type 4.
Over the past 5 to 10 years, a number of potential biomarkers have been proposed for the diagnosis of CRS-3. Among AKI novel biomarkers (each with pros and cons) some seem to be particularly interesting, such as neutrophil gelatinase–associated lipocalin, kidney injury molecule 1, IL-18, IL-6, cystatin C, N-acetyl-b-D-glucosamide, liver-type fatty acid-binding protein, Netrin-1, Klotho, and Midkine (neurite growth–promoting factor 2 [NEGF2]). Several cardiac biomarkers are routinely used in clinical practice: biomarkers of myocardial necrosis, such as troponins T (cTnT) and I (cTnI) and markers of heart failure as B-type natriuretic peptide and its inactive N-terminal pro B-type natriuretic peptide.40 CARDIORENAL SYNDROME TYPE 4 (CHRONIC RENOCARDIAC SYNDROME) CRS type 4 (CRS-4), also defined as chronic renocardiac, defines cardiovascular involvement in patients with CKD. A close relationship between CKD and increased risk for cardiovascular disease is clearly established: major cardiac events actually represent almost 50% of the causes of death in patients with CKD because of aging population and increasing incidence of patients with diabetes, dyslipidemia, and hypertension (Fig 5).10 The largest epidemiologic study was performed by Go and colleagues41 who estimated the longitudinal GFR among 1,120,295 adults within a large integrated health system in whom serum creatinine had been measured between 1996 and 2000 and who had not undergone dialysis or kidney transplantation. On a median follow-up of 2.8 years, the adjusted hazard ratio for cardiovascular events increased inversely with the estimated GFR. The adjusted risk of hospitalizaAdv Chronic Kidney Dis. 2018;25(5):382-390
tion with a reduced estimated GFR followed a similar pattern.41 GFR is a strong independent factor of cardiovascular morbidity and mortality, especially in patients with CKD stages 3b to 4 (according to Kidney Diseases Outcomes Quality Initiative CKD classification) and in those who have ESRD and undergoing renal replacement therapy (hemodialysis, peritoneal dialysis, or a kidney transplant).42 In patients with CKD, hyperphosphatemia and secondary hyperparathyroidism can induce the calcification of cardiac vessels and valves through “osteoblastic” transformation of vascular smooth muscle cells, whereas hypertension itself can also contribute to vascular calcification and consequent pressure overload.43,44 Chronic inflammation, insulin-resistance, hyperhomocysteinemia, and lipid dysmetabolism can also contribute to cardiovascular disease in patients with CKD with increasing accumulation of a large number of toxins (b2 microglobulin, guanidines, phenols, indoles, aliphatic amines, furans, polyols, nucleosides, leptin, parathyroid hormone, and erythropoiesis inhibitors).45,46 Kidney disease has recently been considered as an independent risk factor for sudden cardiac death because of a greater frequency of cardiac arrhythmias that may be related to volume and electrolyte disturbances occurring in patients with CKD.47,48 Serum levels of many biomarkers increase as GFR declines: troponins, asymmetric dimethylarginine, plasminogen-activator inhibitor type I, homocysteine, natriuretic peptides, CRP, serum amyloid A protein, ischemia-modified albumin, and others. The therapeutic implications of these remain to be ascertained.49,50
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Figure 6. Pathophysiological and clinical features of cardiorenal syndrome type 5.
Ultrasound examination of both heart and kidneys shows features of CKD such as a thin and hyperechogenic cortex with a reduced corticomedullary ratio together with small dilation of the urinary tract; parapelvic and subcortical cysts are also found.21 Echocardiography can demonstrate signs of volume overload, and left and right ventricular dysfunction in patients with ESRD on dialysis. Increased atrial volumes or area, pleural or pericardial effusion, and the presence of lung comets confirm volume overload.21 It is common to observe valvular calcifications (related to secondary hyperparathyroidism)21 and frequent right heart dysfunction feature such as high pulmonary artery pressure, low tricuspid annulus plane systolic excursion, or right chamber dilation.51 CARDIORENAL SYNDROME TYPE 5 CRS-5 represents simultaneous involvement of the heart and kidneys and develops in several clinical settings such as sepsis, hepatorenal syndrome, and Fabry’s disease. In the setting of sepsis, inflammation and microvasculature alterations form the basis of the pathophysiology involving the kidneys and cardiovascular system that produce cell ultrastructural alterations and organ dysfunction.52,53 Many mediators and pathways (Fig 1) have been implicated in pathogenesis of myocardial depression in sepsis; however, the precise etiopathogenetic mechanism is unclear.54 Like in AKI due to sepsis, ischemia and inflammatory mediators are the chief culprits: increased levels of prostanoids such as thromboxane and prostacyclin, which may alter coronary autoregulation and endothelial function, have been demonstrated
in patients with septic shock, together with high levels of tumor necrosis factor and IL-1.55 AKI is a common complication of patients with sepsis and carries a worse prognosis. AKI occurs in 20% of critically ill patients and in 51% of patients with septic shock and positive blood cultures.56 AKI in sepsis was considered earlier to be secondary to renal ischemia because of septic shock; global renal blood flow declines after induction of sepsis or endotoxemia, leading to acute tubular necrosis, reduction in glomerular filtration, and severe kidney failure.57,58 Current opinion suggests that the pathogenesis of septic AKI relies on hemodynamic factors and inflammatory mediators (Fig 6).57,58 Diagnosis of CRS-5 is based on the clinical setting, characteristic biomarkers, whose elevation is typical during the septic process: lipopolysaccharide-binding protein, procalcitonin, CRP, proinflammatory cytokines (IL-6, transforming growth factor-b).59 Assessment of cardiac function in CRS-5 is similar to other clinical situations where myocardial dysfunction is present. Natriuretic peptides and troponin level assays provide information about cardiac chambers (especially about left cardiac chambers) and myocardial cell damage. Echocardiography may demonstrate a high output state with abnormalities in left ventricular regional contractility together with dilation of left heart chambers.60 Diagnosis of renal involvement in CRS-5 related to sepsis can overlap with other forms of AKI with acute changes in serum creatinine levels according to Risk/Injury/Failure/Loss/Endstage (RIFLE), Acute Kidney Injury Network (AKIN), and Kidney Disease: Improving Global Outcomes (KDIGO) criteria.61 Adv Chronic Kidney Dis. 2018;25(5):382-390
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CONCLUSIONS Patients with CRS are at greater risk for mortality and morbidity than would be predicted by either disease entity alone. Renal and heart failure are synergistic, and pathophysiology involves complex mechanisms beyond hemodynamic interactions. REFERENCES 1. Ronco C. The cardiorenal syndrome: basis and common ground for a multidisciplinary patient-oriented therapy. Cardiorenal Med. 2011;1(1):3-4. 2. Ronco C, House AA, Haapio M. Cardiorenal syndrome: refining the definition of a complex symbiosis gone wrong. Intensive Care Med. 2008;34(5):957-962. 3. Hillege HL, Girbes ARJ, de Kam PJ, et al. Renal function, neurohormonal activation, and survival in patients with chronic heart failure. Circulation. 2000;102(2):203-210. 4. Giam B, Kaye DM, Rajapakse NW. Role of renal oxidative stress in the pathogenesis of the cardiorenal syndrome. Heart Lung Circ. 2016;25(8):874-880. 5. Iwata 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;120:277-288. 6. Buggey J, Mentz RJ, DeVore AD, Velazquez EJ. Angiotensin receptor neprilysin inhibition in heart failure: mechanistic action and clinical impact. J Card Fail. 2015;21(9):741-750. 7. Martinez BK, White CM. The emerging role of inflammation in cardiovascular disease. Ann Pharmacother. 2018;52(8):801-809. 8. Senni 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, eds. Heart Failure. Cham, Switzerland: Springer International Publishing; 2016:79-108. 9. Travessa AM, Menezes Falc~ao L. Vasodilators in acute heart failure—evidence based on new studies. Eur J Intern Med. 2018;51:110. 10. Bagshaw SM, Cruz DN, Aspromonte N, et al. Epidemiology of cardio-renal syndromes: workgroup statements from the 7th ADQI Consensus Conference. Nephrol Dial Transplant. 2010;25(5): 1406-1416. 11. Damman K, Navis G, Voors AA, et al. Worsening renal function and prognosis in heart failure: systematic review and meta-analysis. J Card Fail. 2007;13(8):599-608. 12. McCullough PA. Cardiorenal syndromes: pathophysiology to prevention. Int J Nephrol. 2010;2011:762590. 13. Ronco C, Cicoira M, McCullough PA. 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(12):1031-1042. 14. Stevenson LW. The limited reliability of physical signs for estimating hemodynamics in chronic heart failure. JAMA. 1989;261(6): 884-888. 15. Mullens W, Abrahams Z, Francis GS, et al. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol. 2009;53(7):589-596. 16. Uthoff 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(4):432-439. 17. Braam B, Cupples WA, Joles JA, Gaillard C. Systemic arterial and venous determinants of renal hemodynamics in congestive heart failure. Heart Fail Rev. 2012;17(2):161-175. 18. Han WK, Bonventre JV. Biologic markers for the early detection of acute kidney injury. Curr Opin Crit Care. 2004;10(6):476-482.
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39. Picano E, Frassi F, Gligorova S, Gargani L, Mottola G. Ultrasound lung comets: a clinically useful sign of extravascular lung water. J Am Soc Echocardiogr. 2006;19(3):356-363. 40. Chuasuwan A, Kellum JA. Cardio-renal syndrome type 3: epidemiology, pathophysiology, and treatment. Semin Nephrol. 2012;32(1):3139. 41. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu C-Y. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351(13):1296-1305. 42. United States Renal Data System. USRDS 2009 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases; 2009. 43. Olgaard K, Lewin E, Silver J. Calcimimetics, vitamin D and ADVANCE in the management of CKD-MBD. Nephrol Dial Transplant. 2011;26(4):1117-1119. 44. MacRae JM, Pandeya S, Humen DP, Krivitski N, Lindsay RM. Arteriovenous fistula-associated high-output cardiac failure: a review of mechanisms. Am J Kidney Dis. 2004;43(5):e17-e22. 45. Cianciolo G, De Pascalis A, Di Lullo L, Ronco C, Zannini C, La Manna G. Folic acid and homocysteine in chronic kidney disease and cardiovascular disease progression: which comes first? Cardiorenal Med. 2017;7(4):255-266. 46. Bellasi A, Di Lullo L, Di Iorio B. Vascular inflammation: a call for a specific and sensitive biomarker? Atherosclerosis. 2018;271:235-236. 47. Di Lullo L, Rivera R, Barbera V, et al. Sudden cardiac death and chronic kidney disease: from pathophysiology to treatment strategies. Int J Cardiol. 2016;217:16-27. 48. Di Lullo L, Ronco C, Cozzolino M, et al. Nonvitamin K-dependent oral anticoagulants (NOACs) in chronic kidney disease patients with atrial fibrillation. Thromb Res. 2017;155:38-47. 49. Austin WJ, Bhalla V, Hernandez-Arce I, et al. Correlation and prognostic utility of B-type natriuretic peptide and its amino-terminal fragment in patients with chronic kidney disease. Am J Clin Pathol. 2006;126(4):506-512.
50. Ronco C, Di Lullo L. Cardiorenal syndrome. Heart Fail Clin. 2014;10(2):251-280. 51. Ricci Z, Ronco C. Pathogenesis of acute kidney injury during sepsis. Curr Drug Targets. 2009;10(12):1179-1183. 52. Li X, Hassoun HT, Santora R, Rabb H. Organ crosstalk: the role of the kidney. Curr Opin Crit Care. 2009;15(6):481-487. 53. Virzì GM, Clementi A, Brocca A, de Cal M, Ronco C. Molecular and genetic mechanisms involved in the pathogenesis of cardiorenal cross talk. Pathobiology. 2016;83(4):201-210. 54. Merx MW, Weber C. Sepsis and the heart. Circulation. 2007;116(7): 793-802. 55. Reines HD, Halushka PV, Cook JA, Wise WC, Rambo W. Plasma thromboxane concentrations are raised in patients dying with septic shock. Lancet. 1982;2(8291):174-175. 56. Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP. The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. JAMA. 1995;273(2):117-123. 57. Badr KF, Kelley VE, Rennke HG, Brenner BM. Roles for thromboxane A2 and leukotrienes in endotoxin-induced acute renal failure. Kidney Int. 1986;30(4):474-480. 58. Kikeri D, Pennell JP, Hwang KH, Jacob AI, Richman AV, Bourgoignie JJ. Endotoxemic acute renal failure in awake rats. Am J Physiol. 1986;250(6 Pt 2):F1098-F1106. 59. Reinhart K, Bauer M, Riedemann NC, Hartog CS. New approaches to sepsis: molecular diagnostics and biomarkers. Clin Microbiol Rev. 2012;25(4):609-634. 60. Vignon P, Frank MB, Lesage J, et al. Hand-held echocardiography with Doppler capability for the assessment of critically-ill patients: is it reliable? Intensive Care Med. 2004;30(4):718-723. 61. Kellum JA, Lameire N, Aspelin P, et al. Kidney disease: improving global outcomes (KDIGO) acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl. 2012;2(1):1-138.
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Cardiorenal Syndrome: An Overview Claudio Ronco, Antonio Bellasi, and Luca Di Lullo 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. Q 2018 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Cardiorenal syndrome (CRS), Risk factors, Diagnosis, Outcomes and treatment
DEFINITION OF CARDIORENAL SYNDROME An effective classification of cardiorenal syndrome (CRS) has been proposed in a Consensus Conference by the Acute Dialysis Quality Group1,2 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. CARDIORENAL AXIS 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.3 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.3 In addition to these changes in GFR, enhanced sodium reabsorption in the From the International Renal Research Institute, S. Bortolo Hospital, Vicenza, Italy; Department of Nephrology and Dialysis, ASST Lariana, S. Anna Hospital, Como, Italy; and Department of Nephrology and Dialysis, L. Parodi - Delfino Hospital, Colleferro, Italy. Financial support: None. Financial disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Luca Di Lullo, MD, PhD, Department of Nephrology and Dialysis L. Parodi - Delfino Hospital, Piazza Aldo Moro, 100034 Colleferro, Roma, Italy. E-mail: [email protected] Ó 2018 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 https://doi.org/10.1053/j.ackd.2018.08.004
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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.3 This is an initial compensatory response to preserve or optimize cardiac output, arterial blood pressure, and GFR.3 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).4,5 The critical role that RAAS plays in the CRS suggests the possibility of a treatment paradox: angiotensinconverting 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.6 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.4,5 It also inhibits several components of atherogenesis and smooth muscle cell proliferation, and increases angiogenesis by ensuring delivery of vascular endothelial growth factor.4,5 Therefore, NO system activation inhibits platelet aggregation, endothelial adhesion molecule expression, and leukocyte-endothelial cell interaction.4,5 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.4,6 C-reactive protein (CRP) has numerous proinflammatory Adv Chronic Kidney Dis. 2018;25(5):382-390
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and proatherogenic effects and is thought to have a role in the pathogenesis of atherosclerosis in cardiorenal patients.7 It is increased in ESRD and probably has a synergistic role in the progression of renal and cardiovascular disease.7 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).8 Peripheral sympathetic nerve activity increases in ESRD, but corrects when the diseased kidneys are removed.8 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.9
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viduals without diabetes mellitus that leads to CKD and predisposes to CRS-1.13 Combined disorders of heart and kidney are also likely to develop in the presence of some degree of cachexia and sarcopenia.13 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.14 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. CARDIORENAL SYNDROME TYPE 1 (ACUTE In these patients, high central venous pressure directly affects renal vein and kidney perfusion pressure.15,16 CARDIORENAL SYNDROME) Increase in central venous pressure also results in CRS type 1 (CRS-1) (acute cardiorenal) is characterized by acute worsening of cardiac function leading to acute kidincreased interstitial pressure with tubular collapse and progressive decline in the GFR.17 ney injury (AKI). CRS-1 usually presents in the setting of As previously mentioned, nonhemodynamic mechaan acute cardiac disease such as acute decompensated nisms involve SNS, RAAS activation, chronic inflammaheart failure (ADHF), often after an ischemic (acute corotion, and imbalance in the proportion of ROS/NO nary syndrome, cardiac surgery complications) or noniproduction.4 schemic heart disease (valvular disease, pulmonary Diagnosis of CRS-1 focuses embolism). on clinical and laboratory CRS-1 occurs in about 25% CLINICAL SUMMARY findings, ultrasonography, of patients hospitalized for 10,11 and other radiological tests. ; among these ADHF Definition of cardiorenal syndrome. patients, pre-existent CKD is Early diagnosis of AKI in CRS-1 (such as in type 3) common and contributes to Meaning of heart and kidney cross-talk. still remains a challenge18; AKI in 60% of all cases Exploring the role of the newest risk factors for cardiorenal classic biomarkers, such as studied. AKI can be considinteractions. creatinine levels, which inered an independent mortalcrease when kidney injury ity risk factor in patients Summarizing therapeutic approaches to cardiorenal is already established and with ADHF, including those syndrome patients. prevention fails. New fronwith ST-segment elevation tiers are represented by myocardial infarction and/or novel biomarkers such as serum and urinary neutrophil reduced left ventricular ejection fraction.12 gelatinase–associated lipocalin, cystatin –C, kidney injury An acute heart failure syndrome (AHFS) may be defined molecule 1, interleukin 18 (IL-18), and liver-type fatty as heart failure with a relatively rapid onset of signs and acid-binding protein.19,20 symptoms, resulting in hospitalization, or emergency Ultrasonography can provide further useful information room or unplanned office visits. AHFS can result from a for diagnosis of CRS-1. Typical findings on echocardiogravariety of different pathophysiological conditions, phy reveal abnormal myocardial kinetics (indicating an although approximately 70% of cases result from worsischemic condition) and left ventricular hypertrophy, ening of chronic heart failure. Other causes of AHFS valvular stenosis, and/or regurgitation (particularly in include new-onset heart failure caused by an acute corocase of rapid deterioration, such as valvular endocarditis nary event such as a myocardial infarction and end-stage or valvular rupture), pericardial effusions, normal inspiraor refractory heart failure not responsive to therapy. Clintory collapse of the inferior vena cava (excluding severe ical presentation may vary, encompassing worsening hypervolemia), and aortic aneurysms or dissection.21 congestion, worsening chronic heart failure, pulmonary 13 Ultrasound evaluation of the kidney usually shows edema, hypertensive crisis, or cardiogenic shock. In all normal or large-sized kidneys with preserved corticalforms of heart failure, the kidney responds in a similar medullary ratio; color Doppler evaluation shows regular manner, retaining sodium and water despite expansion intraparenchymal blood flow, often associated with of the extracellular fluid volume.13 Obesity and metabolic syndrome can also contribute to increased resistance index (.0.8 cm/s).21 both heart and kidney disease. In obesity, growth of adipoCARDIORENAL SYNDROME TYPE 2 (CHRONIC cytes and increase in fatty acid content can be involved in CARDIORENAL SYNDROME) vascular inflammation as it occurs in the epicardial coroCRS type 2 (CRS-2) is characterized by chronic abnormalnary arteries.13 Obesity-related glomerulopathy has been described as a condition of hyperfiltration in obese indiities in cardiac function leading to kidney injury or Adv Chronic Kidney Dis. 2018;25(5):382-390
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Table 1. Classification of Cardiorenal Syndrome Type
Denomination
Description
Example
1
Acute cardiorenal
Heart failure leading to AKD
2 3 4
Chronic cardiorenal Acute nephrocardiac Chronic nephrocardiac
Chronic heart failure leading to kidney failure AKD leading to acute heart failure CKD leading to heart failure
5
Secondary
Systemic disease leading to heart and kidney failure
Acute coronary syndrome leading to acute heart and kidney failure Chronic heart failure Uremic cardiomyopathy AKD-related Left ventricular hypertrophy and diastolic heart failure because of kidney failure Sepsis, vasculitis, diabetes mellitus
Abbreviation: AKD, acute kidney disease.
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).22,23 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,22-24 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).25 Pathophysiology of CRS-2 includes renal congestion and hypoperfusion together with increased right atrial pres-
sure, which represent a cornerstone in renal dysfunction of chronic heart failure patients (Fig 3).26 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.27 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.25 However, a large (n ¼ 2278) randomized double-blind trial, the Reduction of Events by Darbepoetin Alfa in Heart Failure (RED-HF) (using darbepoetin to
Figure 1. The cardiorenal axis (from Guyton hypothesis to actual knowledge). Abbreviations: CO, cardiac output; ECFV, extracellular fluid volume; MAP, mean arterial pressure; NO, nitric oxide; ROS, reactive oxygen species. Adv Chronic Kidney Dis. 2018;25(5):382-390
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Figure 2. Pathophysiology of cardiorenal syndrome type 1. Abbreviations: ANP, atrial natriuretic peptide; GFR, glomerular filtration rate; N-AVP, nonosmotic arginine vasopressin; RAAS, rennin-angiotensin-aldosterone system; SNS, sympathetic nervous system.
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).28 CARDIORENAL SYNDROME TYPE 3 (ACUTE RENOCARDIAC SYNDROME) 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.29,30 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 Adv Chronic Kidney Dis. 2018;25(5):382-390
million population, respectively.31 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%).32,33 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%).34 Pathophysiological interactions between kidney and heart during AKI have been referred to as “cardiorenal connectors,”35 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
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Figure 3. Pathophysiology of cardiorenal syndrome type 2.
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).36 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.37,38 A hyperechogenic renal cortex with low corticomedullary ratio is suggestive of CKD.37,38
However, cortical hyperechogenicity can also be present in acute tubular necrosis or acute glomerulonephritis.37,38 The echocardiographic pattern is not diagnostic, showing an increase in atrial volumes, pleural or pericardial effusion, and is often associated with evidence of “lung comets” on thoracic ultrasound.21 Ultrasound lung comets consist of multiple comet tails originating from water-thickened interlobular septa and fanning out from the lung surface. The technique requires ultrasound scanning of the anterior right and left chest, from the 2nd to the 5th intercostal space.39
Figure 4. Pathophysiology of cardiorenal syndrome type 3. Adv Chronic Kidney Dis. 2018;25(5):382-390
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Figure 5. Cardiovascular and renal features of cardiorenal syndrome type 4.
Over the past 5 to 10 years, a number of potential biomarkers have been proposed for the diagnosis of CRS-3. Among AKI novel biomarkers (each with pros and cons) some seem to be particularly interesting, such as neutrophil gelatinase–associated lipocalin, kidney injury molecule 1, IL-18, IL-6, cystatin C, N-acetyl-b-D-glucosamide, liver-type fatty acid-binding protein, Netrin-1, Klotho, and Midkine (neurite growth–promoting factor 2 [NEGF2]). Several cardiac biomarkers are routinely used in clinical practice: biomarkers of myocardial necrosis, such as troponins T (cTnT) and I (cTnI) and markers of heart failure as B-type natriuretic peptide and its inactive N-terminal pro B-type natriuretic peptide.40 CARDIORENAL SYNDROME TYPE 4 (CHRONIC RENOCARDIAC SYNDROME) CRS type 4 (CRS-4), also defined as chronic renocardiac, defines cardiovascular involvement in patients with CKD. A close relationship between CKD and increased risk for cardiovascular disease is clearly established: major cardiac events actually represent almost 50% of the causes of death in patients with CKD because of aging population and increasing incidence of patients with diabetes, dyslipidemia, and hypertension (Fig 5).10 The largest epidemiologic study was performed by Go and colleagues41 who estimated the longitudinal GFR among 1,120,295 adults within a large integrated health system in whom serum creatinine had been measured between 1996 and 2000 and who had not undergone dialysis or kidney transplantation. On a median follow-up of 2.8 years, the adjusted hazard ratio for cardiovascular events increased inversely with the estimated GFR. The adjusted risk of hospitalizaAdv Chronic Kidney Dis. 2018;25(5):382-390
tion with a reduced estimated GFR followed a similar pattern.41 GFR is a strong independent factor of cardiovascular morbidity and mortality, especially in patients with CKD stages 3b to 4 (according to Kidney Diseases Outcomes Quality Initiative CKD classification) and in those who have ESRD and undergoing renal replacement therapy (hemodialysis, peritoneal dialysis, or a kidney transplant).42 In patients with CKD, hyperphosphatemia and secondary hyperparathyroidism can induce the calcification of cardiac vessels and valves through “osteoblastic” transformation of vascular smooth muscle cells, whereas hypertension itself can also contribute to vascular calcification and consequent pressure overload.43,44 Chronic inflammation, insulin-resistance, hyperhomocysteinemia, and lipid dysmetabolism can also contribute to cardiovascular disease in patients with CKD with increasing accumulation of a large number of toxins (b2 microglobulin, guanidines, phenols, indoles, aliphatic amines, furans, polyols, nucleosides, leptin, parathyroid hormone, and erythropoiesis inhibitors).45,46 Kidney disease has recently been considered as an independent risk factor for sudden cardiac death because of a greater frequency of cardiac arrhythmias that may be related to volume and electrolyte disturbances occurring in patients with CKD.47,48 Serum levels of many biomarkers increase as GFR declines: troponins, asymmetric dimethylarginine, plasminogen-activator inhibitor type I, homocysteine, natriuretic peptides, CRP, serum amyloid A protein, ischemia-modified albumin, and others. The therapeutic implications of these remain to be ascertained.49,50
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Figure 6. Pathophysiological and clinical features of cardiorenal syndrome type 5.
Ultrasound examination of both heart and kidneys shows features of CKD such as a thin and hyperechogenic cortex with a reduced corticomedullary ratio together with small dilation of the urinary tract; parapelvic and subcortical cysts are also found.21 Echocardiography can demonstrate signs of volume overload, and left and right ventricular dysfunction in patients with ESRD on dialysis. Increased atrial volumes or area, pleural or pericardial effusion, and the presence of lung comets confirm volume overload.21 It is common to observe valvular calcifications (related to secondary hyperparathyroidism)21 and frequent right heart dysfunction feature such as high pulmonary artery pressure, low tricuspid annulus plane systolic excursion, or right chamber dilation.51 CARDIORENAL SYNDROME TYPE 5 CRS-5 represents simultaneous involvement of the heart and kidneys and develops in several clinical settings such as sepsis, hepatorenal syndrome, and Fabry’s disease. In the setting of sepsis, inflammation and microvasculature alterations form the basis of the pathophysiology involving the kidneys and cardiovascular system that produce cell ultrastructural alterations and organ dysfunction.52,53 Many mediators and pathways (Fig 1) have been implicated in pathogenesis of myocardial depression in sepsis; however, the precise etiopathogenetic mechanism is unclear.54 Like in AKI due to sepsis, ischemia and inflammatory mediators are the chief culprits: increased levels of prostanoids such as thromboxane and prostacyclin, which may alter coronary autoregulation and endothelial function, have been demonstrated
in patients with septic shock, together with high levels of tumor necrosis factor and IL-1.55 AKI is a common complication of patients with sepsis and carries a worse prognosis. AKI occurs in 20% of critically ill patients and in 51% of patients with septic shock and positive blood cultures.56 AKI in sepsis was considered earlier to be secondary to renal ischemia because of septic shock; global renal blood flow declines after induction of sepsis or endotoxemia, leading to acute tubular necrosis, reduction in glomerular filtration, and severe kidney failure.57,58 Current opinion suggests that the pathogenesis of septic AKI relies on hemodynamic factors and inflammatory mediators (Fig 6).57,58 Diagnosis of CRS-5 is based on the clinical setting, characteristic biomarkers, whose elevation is typical during the septic process: lipopolysaccharide-binding protein, procalcitonin, CRP, proinflammatory cytokines (IL-6, transforming growth factor-b).59 Assessment of cardiac function in CRS-5 is similar to other clinical situations where myocardial dysfunction is present. Natriuretic peptides and troponin level assays provide information about cardiac chambers (especially about left cardiac chambers) and myocardial cell damage. Echocardiography may demonstrate a high output state with abnormalities in left ventricular regional contractility together with dilation of left heart chambers.60 Diagnosis of renal involvement in CRS-5 related to sepsis can overlap with other forms of AKI with acute changes in serum creatinine levels according to Risk/Injury/Failure/Loss/Endstage (RIFLE), Acute Kidney Injury Network (AKIN), and Kidney Disease: Improving Global Outcomes (KDIGO) criteria.61 Adv Chronic Kidney Dis. 2018;25(5):382-390
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CONCLUSIONS Patients with CRS are at greater risk for mortality and morbidity than would be predicted by either disease entity alone. Renal and heart failure are synergistic, and pathophysiology involves complex mechanisms beyond hemodynamic interactions. REFERENCES 1. Ronco C. The cardiorenal syndrome: basis and common ground for a multidisciplinary patient-oriented therapy. Cardiorenal Med. 2011;1(1):3-4. 2. Ronco C, House AA, Haapio M. Cardiorenal syndrome: refining the definition of a complex symbiosis gone wrong. Intensive Care Med. 2008;34(5):957-962. 3. Hillege HL, Girbes ARJ, de Kam PJ, et al. Renal function, neurohormonal activation, and survival in patients with chronic heart failure. Circulation. 2000;102(2):203-210. 4. Giam B, Kaye DM, Rajapakse NW. Role of renal oxidative stress in the pathogenesis of the cardiorenal syndrome. Heart Lung Circ. 2016;25(8):874-880. 5. Iwata 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;120:277-288. 6. Buggey J, Mentz RJ, DeVore AD, Velazquez EJ. Angiotensin receptor neprilysin inhibition in heart failure: mechanistic action and clinical impact. J Card Fail. 2015;21(9):741-750. 7. Martinez BK, White CM. The emerging role of inflammation in cardiovascular disease. Ann Pharmacother. 2018;52(8):801-809. 8. Senni 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, eds. Heart Failure. Cham, Switzerland: Springer International Publishing; 2016:79-108. 9. Travessa AM, Menezes Falc~ao L. Vasodilators in acute heart failure—evidence based on new studies. Eur J Intern Med. 2018;51:110. 10. Bagshaw SM, Cruz DN, Aspromonte N, et al. Epidemiology of cardio-renal syndromes: workgroup statements from the 7th ADQI Consensus Conference. Nephrol Dial Transplant. 2010;25(5): 1406-1416. 11. Damman K, Navis G, Voors AA, et al. Worsening renal function and prognosis in heart failure: systematic review and meta-analysis. J Card Fail. 2007;13(8):599-608. 12. McCullough PA. Cardiorenal syndromes: pathophysiology to prevention. Int J Nephrol. 2010;2011:762590. 13. Ronco C, Cicoira M, McCullough PA. 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(12):1031-1042. 14. Stevenson LW. The limited reliability of physical signs for estimating hemodynamics in chronic heart failure. JAMA. 1989;261(6): 884-888. 15. Mullens W, Abrahams Z, Francis GS, et al. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol. 2009;53(7):589-596. 16. Uthoff 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(4):432-439. 17. Braam B, Cupples WA, Joles JA, Gaillard C. Systemic arterial and venous determinants of renal hemodynamics in congestive heart failure. Heart Fail Rev. 2012;17(2):161-175. 18. Han WK, Bonventre JV. Biologic markers for the early detection of acute kidney injury. Curr Opin Crit Care. 2004;10(6):476-482.
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