心肾综合症-英文

Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Blood Purif 2009;27:114–126 DOI: 10.1159/000167018 The Cardiorenal Syndrome Claudio Ronco a Chang-Yin Chionh a Mikko Haapio b Nagesh S. Anavekar c Andrew House e Rinaldo Bellomo d a Department of Nephrology, Ospedale San Bortolo, Vicenza , Italy; b HUCH Meilahti Hospital, Division of Nephrology, Helsinki , Finland; c Department of Cardiology, The Northern Hospital, and d Department of Intensive Care, Austin Hospital, Melbourne , Vic., Australia; e London Health Sciences Centre, Division of Nephrology, London, Ont. , Canada disease (e.g. chronic glomerular disease) contributing to de- creased cardiac function, cardiac hypertrophy and/or in- creased risk of adverse cardiovascular events. Type V CRS re- flects a systemic condition (e.g. diabetes mellitus, sepsis) causing both cardiac and renal dysfunction. Biomarkers can help to characterize the subtypes of the CRS and to indicate treatment initiation and effectiveness. The identification of patients and the pathophysiological mechanisms underly- ing each syndrome subtype will help to understand clinical derangements, to make the rationale for management strat- egies and to design future clinical trials with accurate selec- tion and stratification of the studied population. Copyright © 2009 S. Karger AG, Basel Introduction A large proportion of patients admitted to hospital, especially in the critical care setting, have various degrees of heart and kidney dysfunction [1] . Primary disorders of one of these two organs often result in secondary dys- function or injury to the other [2] . Such pathophysiolog- ical interactions represent the pathophysiological basis for a clinical entity often referred to as the cardiorenal syndrome (CRS) [3] . Although generally defined as a con- dition characterized by the initiation and/or progression of renal insufficiency secondary to heart failure [4] , the term ‘cardiorenal syndrome’ is also often used to describe Key Words Acute kidney injury � Acute heart failure � Chronic kidney disease � Cardiorenal syndrome � Renocardiac syndrome � Heart-kidney interaction � Cardiovascular risk Abstract The term ‘cardiorenal syndrome’ (CRS) has increasingly been used in recent years without a constant meaning and a well- accepted definition. To include the vast array of interrelated derangements, and to stress the bidirectional nature of the heart-kidney interactions, the classification of the CRS today includes 5 subtypes whose etymology reflects the primary and secondary pathology, the time frame and simultaneous cardiac and renal codysfunction secondary to systemic dis- ease. The CRS can generally be defined as a pathophysiolog- ical disorder of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chron- ic dysfunction in the other organ. Type I CRS reflects an abrupt worsening of cardiac function (e.g. acute cardiogen- ic shock or decompensated congestive heart failure) leading to acute kidney injury. Type II CRS describes chronic abnor- malities in cardiac function (e.g. chronic congestive heart failure) causing progressive and permanent chronic kidney disease. Type III CRS consists in an abrupt worsening of renal function (e.g. acute kidney ischemia or glomerulonephritis) causing acute cardiac disorder (e.g. heart failure, arrhythmia, ischemia). Type IV CRS describes a state of chronic kidney Published online: January 23, 2009 Claudio Ronco, MD Ospedale San Bortolo 36100 Vicenza (Italy) Tel. +39 0444 753 650, Fax +39 0444 753 949 E-Mail cronco@goldnet.it © 2009 S. Karger AG, Basel 0253–5068/09/0271–0114$26.00/0 Accessible online at: www.karger.com/bpu The Cardiorenal Syndrome Blood Purif 2009;27:114–126 115 the negative effects of reduced renal function on the heart and circulation (more appropriately named renocardiac syndrome) [5] . Unfortunately, despite the frequent use of these terms in the literature, there is no consensus defini- tion or classification for this condition or cluster of con- ditions. The absence of a clear definition and the com- plexity of heart and kidney interactions contribute to a lack of clarity with regard to diagnosis and management [6] . This is unfortunate as recent advances in basic and clinical sciences have changed our understanding of or- gan crosstalk and interactions and have demonstrated that some therapies can have efficacy in attenuating both cardiac and renal injury [7] . All these considerations sug- gest the need for a more clearly articulated definition of the subtypes of the CRS in terms of clinical presentation, pathophysiology, diagnosis and management [5, 6] . In this article, we examine the nature of this complex clini- cal entity and discuss salient aspects of this condition and potential interventions based on a logical approach to the definition of its different clinical subtypes. CRS: A Proposed Definition The common understanding of the CRS is that a rela- tively normal kidney is dysfunctional because of a dis- eased heart [8] with the assumption that in the presence of a healthy heart, the same kidney would likely function relatively normally [9] . This concept, however, has re- cently been challenged and a more articulated definition for the CRS has been proposed [5, 6] . Heart-kidney inter- actions include a variety of conditions, either acute or chronic, where the primary failing organ can be either the heart or the kidney ( fig. 1, 2 ) [10] . For this reason, we discuss the different heart-kidney interactions, which fall under the umbrella of the CRS, using the definition struc- ture summarized in table 1 [5, 6] . Cardiovascular mortality increased by end-stage renal dysfunction Cardiovascular risk increased by kidney dysfunction Chronic HF progression due to kidney dysfunction • Uremia-related HF • Volume-related HF HF due to acute kidney dysfunction • Volume/uremia-induced HF • Renal ischemia-induced HF • Sepsis/cytokin-induced HF CKD secondary to HF AKI secondary to contrast-induced nephropathy AKI secondary to cardiopulmonary bypass AKI secondary to heart valve replacement AKI secondary to HF Fig. 1. Heart and kidney interactions. HF = Heart failure; CKD = chronic kidney disease. C-R R-C Chronic Acute Fig. 2. The bidirectional nature of the CRS and the acute or chron- ic temporal characteristics of the syndrome. C o lo r v er si o n av ai la b le o n lin e C o lo r v er si o n av ai la b le o n lin e Ronco /Chionh/Haapio /Anavekar / House /Bellomo Blood Purif 2009;27:114–126116 A major problem with previous terminology is that it does not allow clinicians or investigators to identify and fully characterize the relevant pathophysiological inter- actions. This is important because such interactions dif- fer according to the type of combined heart/kidney disorder [11] . For example, while a diseased heart has numerous negative effects on kidney function, renal in- sufficiency can also significantly impair cardiac function [10] . Thus, a large number of direct and indirect effects of each organ dysfunction can initiate and perpetuate the combined disorder of the two organs through a complex combination of neurohumoral feedback mechanisms. For this reason, a subdivision into different subtypes seems to provide a more concise and logically correct ap- proach to this condition. We will use such a subdivision to discuss several issues of importance in relation to this syndrome. CRS Type I (Acute CRS) Type I CRS or acute CRS is characterized by a rapid worsening of cardiac function, which leads to acute kid- ney injury (AKI) ( fig. 3 ). Acute heart failure (AHF) may then be divided into 4 main subtypes [12] : hypertensive pulmonary edema with preserved left ventricular systol- ic function, acute decompensated chronic heart failure (ADCHF), cardiogenic shock, and predominant right ventricular failure. Type I CRS is common. More than one million patients in the USA alone are admitted to hospital every year with either de novo AHF or with ADCHF [12] . Among patients with ADCHF or de novo AHF, premorbid chronic renal dysfunction is common and predisposes to AKI [13, 14] . The mechanisms by which the onset of AHF or ADCHF leads to AKI are mul- tiple and complex [4] . They are broadly described in a previous publication [6] . The clinical importance of each of these mechanisms is likely to vary from patient to pa- tient (e.g. acute cardiogenic shock vs. hypertensive pul- monary edema) and situation to situation (AHF second- ary to perforation of a mitral valve leaflet from acute bac- terial endocarditis vs. worsening right heart failure secondary to noncompliance with diuretic therapy). In AHF, AKI seems to be more severe in patients with im- paired left ventricular ejection fraction (LVEF) compared to those with preserved LVEF [15] and increasingly worse when LVEF is further impaired. It achieves an incidence of 1 70% in patients with cardiogenic shock [16] . Further- more, impaired renal function is consistently found as an independent risk factor for 1-year mortality in AHF pa- tients, including in patients with ST-elevation myocar- dial infarction [16, 17] . A plausible reason for this inde- pendent effect might be that an acute decline in renal function does not simply act as a marker of illness sever- ity, but also carries an associated acceleration in cardio- vascular pathobiology leading to a higher rate of cardio- vascular events both acutely and chronically, possibly through the activation of inflammatory pathways [9, 18] . The salient clinical issues of type I CRS relate to how the onset of AKI (de novo or in the setting of chronic re- nal impairment) induced by primary cardiac dysfunction impacts on diagnosis, therapy and prognosis and how its presence can modify the general approach to the treat- ment of AHF or ADCHF. The first important clinical principle is that the onset of AKI in the setting of AHF or ADCHF implies inadequate renal perfusion until proven otherwise. This should prompt clinicians to consider the diagnosis of a low cardiac output state and/or marked in- crease in venous pressure leading to kidney congestion and take the necessary diagnostic steps to either confirm or exclude the diagnosis (careful physical examination looking for ancillary signs and laboratory findings of a low cardiac output state such as absolute or relative hypo- tension, cold extremities, poor postcompressive capillary Table 1. Proposed definitions of CRS (1) CRS general definition: a pathophysiological disorder of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other or- gan (2) CRS type I (acute CRS): abrupt worsening of cardiac function (e.g. acute cardiogenic shock or decompensated congestive heart failure) leading to AKI (3) CRS type II (chronic CRS): chronic abnormalities in cardiac function (e.g. chronic congestive heart failure) causing progres- sive and permanent chronic kidney disease (4) CRS type III (acute renocardiac syndrome): abrupt worsening of renal function (e.g. acute kidney ischemia or glomerulone- phritis) causing acute cardiac disorder (e.g. heart failure, arrhyth- mia, ischemia) (5) CRS Type IV (chronic renocardiac syndrome): chronic kidney disease (e.g. chronic glomerular disease) contributing to de- creased cardiac function, cardiac hypertrophy and/or increased risk of adverse cardiovascular events (6) CRS type V (secondary CRS): systemic condition (e.g. diabetes mellitus, sepsis) causing both cardiac and renal dysfunction The Cardiorenal Syndrome Blood Purif 2009;27:114–126 117 refill, confusion, persistent oliguria, distended jugular veins, elevated or rising lactate). The second important consequence of the development of type I CRS is that it may decrease diuretic responsiveness. In a congestive state (peripheral edema, increased body weight, pulmo- nary edema, elevated central venous pressure), decreased response to diuretics can lead to failure to achieve the de- sired clinical goals. The physiological phenomena of di- uretic breaking (diminished diuretic effectiveness sec- ondary to postdiuretic sodium retention) [19] and postdi- uretic sodium retention [20] may also play an enhanced part in this setting. In addition, concerns of aggravating AKI by the administration of diuretics at higher doses or in combination are common among clinicians. Such con- cerns can also act as an additional, iatrogenic mechanism equivalent in its effect to that of diuretic resistance (less sodium removal). Accordingly, diuretics may best be giv- en in AHF patients with evidence of systemic fluid over- load with the goal of achieving a gradual diuresis. Furo- semide can be titrated according to renal function, sys- tolic blood pressure and history of chronic diuretic use. High doses are not recommended and a continuous di- uretic infusion might be helpful [21] . In parallel, mea- surement of cardiac output and venous pressure may also help ensure continued and targeted diuretic therapy. Ac- curate estimation of cardiac output can now be easily achieved by means of arterial pressure monitoring com- bined with pulse contour analysis or by Doppler ultra- sound [22–25] . Knowledge of cardiac output allows phy- sicians to develop a physiologically safer and more logical approach to the simultaneous treatment of AHF and AD- CHF and AKI. If diuretic resistant fluid overload exists despite an optimized cardiac output, removal of isotonic fluid can be achieved by ultrafiltration ( fig. 4 ). This ap- proach can be efficacious and clinically beneficial [26] . The presence of AKI with or without concomitant hyper- kalemia may also affect patient outcome by inhibiting the prescription of angiotensin-converting enzyme (ACE) inhibitors and aldosterone inhibitors (drugs that have been shown in large randomized controlled trials to in- crease survival in the setting of heart failure and myocar- dial infarction) [27] . This is unfortunate because, provid- ed there is close monitoring of renal function and potas- sium levels, the potential benefits of these interventions likely outweigh their risks even in these patients. The acute administration of � -blockers in the setting of type I CRS is generally not advised. Such therapy should wait until the patient has stabilized physiologi- cally and concerns about a low cardiac output syndrome have been resolved. In some patients, stroke volume can- not be increased and relative or absolute tachycardia sus- tains the adequacy of cardiac output. Blockade of such compensatory tachycardia and sympathetic system-de- pendent inotropic compensation can precipitate cardio- genic shock and can be lethal [28] . Particular concern applies to � -blockers excreted by the kidney such as aten- olol or sotalol, especially if combined with calcium an- tagonists [29] . These considerations should not inhibit the slow, careful and titrated introduction of appropriate treatment with � -blockers later on, once patients are he- modynamically stable. This aspect of treatment is particularly relevant in pa- tients with the CRS where evidence suggests that under- treatment after myocardial infarction is common [30] . Attention should be paid to preserving renal function, perhaps as much attention as is paid to preserving myo- cardial muscle. Worsening renal function (WRF) during admission for ST-elevation myocardial infarction is a Acute heart dysfunction Humorally mediated damage Exogenous factors Drugs AKI Hormonal factors Immunomediated damage Hemodynamically mediated damage Fig. 3. Diagram illustrating and summa- rizing the major pathophysiological inter- actions between the heart and kidney in type I CRS. C o lo r v er si o n av ai la b le o n lin e Ronco /Chionh/Haapio /Anavekar / House /Bellomo Blood Purif 2009;27:114–126118 powerful and independent predictor of in-hospital and 1-year mortality [16, 17] . In a study involving 1,826 pa- tients who received percutaneous coronary intervention, even a transient rise in serum creatinine ( 1 25% com- pared to baseline) was associated with increased hospital stay and mortality [31] . Similar findings have also been shown among coronary artery bypass graft cohorts [32] . In this context, creatinine rise is not simply a marker of illness severity but it rather represent a causative factor for cardiovascular injury acceleration through the activa- tion of hormonal, immunological and inflammatory pathways [9, 18] . Given that the presence of type I CRS defines a popu- lation with high mortality, a prompt, careful, systematic, multidisciplinary approach involving invasive cardiolo- gists, nephrologists, critical care physicians and cardiac surgeons is both logical and desirable. CRS Type II (Chronic CRS) Type II CRS or chronic CRS is characterized by chron- ic abnormalities in cardiac function (e.g. chronic conges- tive heart failure) causing progressive chronic kidney in- sufficiency ( fig. 5 ). WRF in the context of heart failure is associated with significantly increased adverse outcomes and prolonged hospitalizations [33] . The prevalence of renal dysfunction in chronic heart failure has been reported to be approxi- mately 25% [33] . Even limited decreases in estimated glo- merular filtration rate (GFR) of 1 9 ml/min appear to confer a significantly increased mortality risk [33] . Some researchers have considered WRF a marker of severity of generalized vascular disease [33] . Independent predictors of WRF include: old age, hypertension, diabetes mellitus and acute coronary syndromes. Extracorporeal ultrafiltration Art. line Ven. line Blood pump Prepump pressure Prefilter pressure Postfilter pressure Filter Ultrafiltrate Heparin Transmembrane pressure TMP = Pi – � = (Pb – Pd) – � Pb Pd � Hydrostatic Oncotic Fig. 4. Diagram presenting the technical features of ultrafiltration as applicable to patients with AHF and di- uretic-resistant fluid overload. The Cardiorenal Syndrome Blood Purif 2009;27:114–126 119 The mechanisms underlying WRF likely differ based on acute versus chronic heart failure. Chronic heart fail- ure is characterized by a relatively stable long-term situ- ation of probably reduced renal perfusion, often predis- posed by both micro- and macrovascular disease in the context of the same vascular risk factors associated with cardiovascular disease. However, although a greater pro- portion of patients with a low estimated GFR have a worse New York Heart Association class, no evidence of an as- sociation between LVEF and estimated GFR can be con- sistently demonstrated. Thus, patients with chronic heart failure and preserved LVEF appear to have a similar esti- mated GFR to patients with impaired LVEF ( ! 45%) [34] . Neurohormonal abnormalities are present with excessive production of vasoconstrictive mediators (epinephrine, angiotensin, endothelin) and altered sensitivity and/or release of endogenous vasodilatory factors (natriuretic peptides, nitric oxide). Pharmacotherapies used in the management of heart failure have been touted as contrib- uting to WRF. Diuresis-associated hypovolemia, early introduction of renin-angiotension-aldosterone system blockade, and drug-induced hypotension have all been suggested as contributing factors [4] . However, their role remains highly speculative. More recently, there has been increasing interest in the pathogenetic role of relative or absolute erythropoietin defici