Sindrome Cardiorena Fisio 2013

McCullough PA, Kellum JA, Mehta RL, Murray PT, Ronco C (eds): ADQI Consensus on AKI Biomarkers and Cardiorenal Syndromes. Contrib Nephrol. Basel, Karger, 2013, vol 182, pp 82–98DOI: 10.1159/000349966

Pathophysiology of the Cardiorenal Syndromes: Executive Summary from the Eleventh Consensus Conference of the Acute Dialysis Quality Initiative (ADQI)Peter A. McCullough

a · John A. Kellum

b · Michael Haase

c · Christian Müller

d · Kevin Damman

e · Patrick T. Murray

f · Dinna Cruz

g · Andrew A. House

h · Kai M. Schmidt-Ott

i · Giorgio Vescovo

j · Sean M. Bagshaw

k · Eric A. Hoste

l · Carlos Briguori

m · Branko Braam

n · Lakhmir S. Chawla

o · Maria R. Costanzo

p · James A. Tumlin

q · Charles A. Herzog

r · Ravindra L. Mehta

s · Hamid Rabb

t · Andrew D. Shaw

u · Kai Singbartl

v · Claudio Ronco

w · for the Acute Dialysis Quality Initiative (ADQI) Consensus Groupa

St. John Providence Health System, Warren, Mich., Providence Hospitals and Medical Centers, Southfield and Novi, Mich., St. John Macomb Oakland Center, Madison Heights, Mich., St. John Hospital and Medical Center, Detroit, Mich., USA; b Clinical Research, Investigation, and Systems Modeling of Acute Illness Center, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pa., USA; c Department of Nephrology, Hypertension, Diabetes and Endocrinology, Otto von Guericke University, Magdeburg, Germany; d University Hospital, Basel, Switzerland; e

Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; f

School of Medicine and Medical Science, University College Dublin, Dublin, Ireland; g Department of Nephrology Dialysis and Transplantation, San Bortolo Hospital, Vicenza, Italy; h Schulich School of Medicine and Dentistry, University of Western Ontario Division of Nephrology, University Hospital, London, Ont., Canada; i Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin, Max Delbrück Center for Molecular Medicine, Berlin, Germany; j Department of Internal Medicine, S. Bortolo Hospital, Vicenza, Italy; k Division of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alta., Canada; l Department of Intensive Care Medicine, Ghent University Hospital, Gent, Belgium; m Department of Cardiology, Clinica Mediterranea, Naples, Italy; n Department of Medicine/Division of Nephrology and Immunology, University of Alberta Hospital, Edmonton, Alta., Canada; o Department of Anesthesiology and Critical Care Medicine and Division of Renal Diseases and Hypertension, Department of Medicine, George Washington University Medical Center, Washington, D.C., USA; p Midwest Heart Foundation, Edward Heart Hospital, Naperville, Ill., USA; q Department of Medicine, College of Medicine, University of Tennessee, Chattanooga, Tenn., USA; r Hennepin County Medical Center, Minneapolis,

ADQI 11 Workgroup members are listed in Appendix 2.

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McCullough PA, Kellum JA, Mehta RL, Murray PT, Ronco C (eds): ADQI Consensus on AKI Biomarkers and Cardiorenal Syndromes. Contrib Nephrol. Basel, Karger, 2013, vol 182, pp 82–98 (DOI: 10.1159/000349966)

ADQI Consensus on ‘Pathophysiology of Cardiorenal Syndromes’ 83

AbstractCardiorenal syndromes (CRS) have been recently classified into five distinct entities, each with different major pathophysiologic mechanisms. CRS type 1 most commonly occurs in the setting of acutely decompensated heart failure where approximately 25% of patients develop a rise in serum creatinine and a reduction of urine output after the first several doses of intravenous diuretics. Altered cardiac and renal hemodynamics are believed to be the most important determinants of CRS type 1. CRS type 2 is the hastened progression of chronic kidney disease (CKD) in the setting of chronic heart failure. Accelerated renal cell apoptosis and replacement fibrosis is considered to be the dominant mechanism. CRS type 3 is acutely decompensated heart failure after acute kidney injury from inflamma-tory, toxic, or ischemic insults. This syndrome is precipitated by salt and water overload, acute uremic myocyte dysfunction, and neurohormonal dysregulation. CRS type 4 is man-ifested by the acceleration of the progression of chronic heart failure in the setting of CKD. Cardiac myocyte dysfunction and fibrosis, so-called ‘CKD cardiomyopathy’, is believed to be the predominant pathophysiologic mechanism. Type 5 CRS is simultaneous acute car-diac and renal injury in the setting of an overwhelming systemic insult such as sepsis. In this scenario, the predominant pathophysiological disturbance is microcirculatory dys-function as a result of acutely abnormal immune cell signaling, catecholamine cellular toxicity, and enzymatic activation which result in simultaneous organ injury often extend-ing beyond both the heart and the kidneys. This paper will summarize these and other key findings from an international consensus conference on the spectrum of pathophys-iologic mechanisms at work in the CRS. Copyright © 2013 S. Karger AG, Basel

The term cardiorenal syndromes (CRS) was coined by Ledoux [1] in 1951 and referred to combined heart and kidney failure. In 1997 to the present, Schrier and colleagues [2–4] in multiple papers summarized the impact of salt and water retention combined with neurohormonal activation in the pathogenesis of CRS. Brammah et al. [5] pointed out that treatment of bilateral renal arterial disease could result in improvement of both heart and kidney function. Braam and co-workers [6] in 2005 proposed that organ dysfunction in one system influences that in the other. In 2008, Ronco et al. [7] proposed five distinct CRS according to the temporal sequence of organ injury and failure as well as the clinical con-text. Later in 2008, a consensus conference was organized under the auspices of the Acute Dialysis Quality Initiative (ADQI) bringing to Venice, Italy, key opin-ion leaders and experts in the fields of nephrology, critical care, cardiac surgery, and cardiology. In series of papers and an executive summary, this group pre-

Minn., USA; s Division of Nephrology and Hypertension, Department of Medicine, University of California San Diego, San Diego, Calif., USA; t Nephrology Division, Johns Hopkins Hospital and Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md., USA; u

Department of Anesthesiology, Duke University Medical Center, Durham, N.C., USA; v Department of Critical Care Medicine, Clinical Research, Investigation, and Systems Modeling of Acute Illness Center, University of Pittsburgh, Pittsburgh, Pa., USA; w Department of Nephrology, International Renal Research Institute (IRRIV), San Bortolo Hospital, Vicenza, Italy

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84 McCullough et al.

sented the definition and classification system for the CRS, epidemiology and diagnostic criteria, prevention and therapeutic approaches, as a result of the consensus process [8]. In 2012, ADQI conducted a second consensus conference to review and summarize the rapidly developing literature on the spectrum of pathophysiologic mechanisms involved in CRS.

Methods

The ADQI process was applied using previously described methodology taking advantage of key opinion leaders in the field and identifying appropriate topics for consensus [9]. The ADQI methodology comprises a systematic search for evidence with review and evaluation of relevant literature, establishment of clinical and physiologic outcomes for comparison of different treatments, description of current practice and analysis of areas in which evidence is lacking and a specific research agenda is required. ADQI activities were divided into a pre-conference, conference, and post-conference phase. Before the conference, topics were selected and workgroups assembled. Groups identified key ques-tions and conducted a systematic literature search. During the conference, workgroups assembled in breakout sessions, as well as plenary sessions where their findings were presented, debated, and refined. Key questions were identified by the entire ADQI group, and the subgroups deliberated on these questions, bringing forth recommendations to the group as a whole. Deliberations followed three days of discussion amongst 23 attend-ees. Summary statements were then developed by the entire group and reported into the present document.

Results

Informed by previous publication records and expertise, the Steering Committee assembled a panel representing multiple disciplines from a variety of countries and scientific societies. From this plenary group, five smaller working groups were identified to examine the predominant pathophysiologic mechanism of CRS types 1–5.

Principles of Definition and Classification

It was agreed in the first ADQI consensus that a large umbrella term be pre-ferred, using the plural (Cardiorenal Syndromes), to indicate the presence of multiple syndromes (fig. 1). Subtypes would recognize the primary organ dys-function (cardiac versus renal) as well as the acute versus chronic nature of the condition (fig. 2). Both organs must have or develop structural or func-

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tional abnormalities to fulfill the criteria for definition. An additional subtype was desired to capture systemic conditions that affect both organs simultane-ously.

The umbrella term ‘Cardiorenal Syndromes’ (CRS) was defined as ‘Disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other’. Five subtypes of the syn-dromes were identified and defined as reported in figure 1. All subtypes imply that organ crosstalk is involved in the global acute and chronic pathogenesis (fig. 2) [10].

Acute Cardiorenal Syndrome (Type 1): Acute Worsening of Heart Function Leading to Kidney Injury and/or DysfunctionThis is a syndrome of worsening renal function that frequently complicates acutely decompensated heart failure (ADHF). Between 27 and 40% of patients hospitalized for ADHF develop acute kidney injury (AKI) as defined by an in-crease in serum creatinine of 0.3 mg/dl or more and fall into this clinical entity [11, 12]. These patients experience higher mortality and morbidity, and in-creased length of hospitalization.

ADHF can be phenotypically characterized in a schematic and two-by-two table as shown in figure 3 [13]. Here, the relative degree of systemic congestion and perfusion can be used to organize renal hemodynamic processes that are believed to be related to CRS type 1 [14]. Passive venous congestion influences

Cardiorenal Syndrome (CRS) General Definition:A pathophysiologic disorder of the heart and kidneys whereby acute or chronic dysfunction inone organ may induce acute or chronic dysfunction in the other organ

CRS Type I (Acute Cardiorenal Syndrome)Abrupt worsening of cardiac function (e.g. Acutely decompensated congestive heart failure)leading to acute kidney injury

CRS Type II (Chronic Cardiorenal Syndrome)Chronic abnormalities in cardiac function (e.g. chronic congestive heart failure) causingprogressive and permanent chronic kidney disease

CRS Type III (Acute Renocardiac Syndrome)Abrupt worsening of renal function (e.g. acute kidney injury) causing acute cardiac disorder(acute heart failure)

CRS Type IV (Chronic Renocardiac Syndrome)Chronic kidney disease (diabetic nephropathy) contributing to decreased cardiac function,cardiac hypertrophy, fibrosis, and/or increased risk of adverse cardiovascular events

CRS Type V (Secondary Cardiorenal Syndrome)Systemic condition (e.g. sepsis) causing both acute cardiac and renal injury and dysfunction

Fig. 1. Five subtypes of CRS as proposed by Ronco and the AQDI.

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the efferent flow from the glomerulus, the peritubular network, as well as the arcades of renal veins that coalescence the major renal vein and its accessory veins that carry blood to the inferior vena cava. Several studies have shown that renal venous congestion is an important risk predictor for the development of worsened renal filtration function in hospitalized patients [15]. Proposed patho-physiologic mechanisms include reduced transglomerular pressure, elevated re-nal interstitial pressure, myogenic and neural reflexes, baroreceptor stimulation, activation of sympathetic nervous and renin-angiotensin-aldosterone systems, non-osmotic release of arginine vasopressin, local production of endothelin, and enhanced proinflammatory pathways. When levels of sympathetic and re-nin-angiotensin system activity are further raised after one or two doses of in-travenous loop diuretics, in patients with susceptible renal hemodynamics, the CRS type 1 can be initiated and recognized over the next several hours as a re-duction in diuretic response and later a rise in serum creatinine [16]. Biomarker evidence of neurohormonal activation includes the natriuretic peptides, mid-

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regional proadrenomedullin, copeptin (C-terminal segment of preprovasopres-sin) and procalcitonin [17, 18]. In refractory patients, hyponatremia as a physi-ologic reflection of marked neurohormonal activation in CRS type 1 heralds a very poor prognosis [19]. Recent studies suggest individuals with greater levels of natriuretic peptides as baseline and evidence of pulmonary congestion, in ad-dition to increased central venous pressure, have the greatest risk for CRS type 1 [20]. The end result of these hemodynamic perturbations of the kidney result in a loss of autoregulation and the onset of worsened salt and water retention, reduction in renal filtration, and oliguria.

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Beyond hemodynamics and neurohormonal activation, abnormal patterns of cell signaling have been linked to ADHF and possibly CRS. Soluble ST-2 is a re-cently approved blood biomarker in the risk prediction of heart failure (HF) hos-pitalization and death [21, 22]. This marker appears to be complementary to the natriuretic peptides and reflects the degree of biomechanical strain and immune cell activation and cell signaling that occurs in progressive HF [23]. ST2 is the rece-ptor for interleukin (IL)-33, a cytokine with angiohypertrophic and antifibrotic effects on the myocardium [24]. Soluble ST is a circulating inhibitor of the ST2 receptor, and hence works to negate the beneficial effect of IL-33. The impact on cell signaling, the proximal tubule, and sequential effects on tubuloglomerular feedback mediated by adenosine, nitric oxide, prostaglandins and other substanc-es in the macula densa cells, are not fully understood at this time [25]. However, this line of reasoning could explain how systemic cell signaling could trigger events in the kidney in the form of maladaptive tubuloglomerular feedback which cause a transient reduction in renal filtration and a rise in serum creatinine [26, 27].

Chronic CRS (Type 2): Chronic Abnormalities in Heart Function Leading to Kidney Injury or DysfunctionThis subtype indicates a more chronic HF hastening the progression of chronic kidney disease (CKD). Approximately 63% of patients with HF meet the defini-tion of stage 3–5 CKD with an estimated glomerular filtration rate <60 ml/min/1.73 m2 [28]. There is considerable evidence to support the observation that HF is a proinflammatory state characterized by markedly elevated levels of tu-mor necrosis factor-α, upregulation of soluble receptors for tumor necrosis fac-tor, and a number of ILs including IL-1β, IL-18 and IL-6, as well as several cel-lular adhesion molecules. Multiple studies have indicated that chronic HF in-duces microalbuminuria, probably through cytokine-induced damage to the endothelial glycocalyx, and thus, creates an additional burden on the proximal tubules (megalin-cubilin complex) in terms of protein reabsorption [29–31]. This process can be the focal point for intrarenal cell signaling and inflammation that leads to progressive functional and anatomic loss of nephrons [32]. Recent-ly, HF has been shown to induce the distal renal tubular cells to upregulate the production of neutrophil gelatinase-associated lipocalin (NGAL), a reliable in-dicator of both chronic and acute kidney disease [33].

As a result of chronic volume overload and persistent hyperactivation of the neurohormonal (renin-angiotensin-aldosterone) and sympathetic nervous sys-tems, functional and structural changes occur within the kidneys. Through para-crine activation, HF is associated with activation of macrophages and secretion of galectin-3. Galectin-3 is one of a family of lectins (otherwise known as MAC-2 Ag) whose main target is myofibroblasts via intracellular signaling, which trans-

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late the transforming growth factor-β signal for increase cell cycle (cyclin D1) enabling a marked production of procollagen I which is ultimately cross-linked into mature collagen [34]. Translational studies have demonstrated that a similar process of organ fibrosis can be turned on in the kidney resulting in progressive CKD in the setting of HF, warm renal ischemia-reperfusion injury, and renal transplantation degeneration [35, 36]. Thus, in CRS type 2, HF incites a sequence of processes involving the endothelium, glycocalyx, tubules, nephron units, and fibroblasts in the skeleton of the kidney that result in progressive loss of function-ing nephrons and replacement of tissue with fibrosis (fig. 4) [37].

Acute Renocardiac Syndrome (Type 3): Acute Worsening of Kidney Function Leading to Heart Injury and/or DysfunctionLittle is known about the frequency of acute HF following AKI. It was inferred from the literature that subclinical HF or significant myocardial disease is an im-portant determinant of the phenotypic expression of this syndrome [38]. Con-versely, individuals with completely normal cardiac function rarely demonstrate HF in the setting of AKI. The mechanisms whereby AKI leads to cardiac dysfunc-tion have been proposed to include two principles: direct effects of AKI on the heart, and effects of AKI on remote organ function with indirect effects on the heart (fig. 5) [39]. AKI has been shown to cause inflammation in experimental

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Fig. 4. Pathophysiology of CRS type 2.

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renal ischemic models, which then induced cytokine expression, leukocyte infil-tration into the heart, cell death by apoptosis, and impaired cardiac function [40]. Recent studies have shown that individuals with increased proximal tubular ex-pression of kidney injury molecule-1, a marker of acute and CKD, have increased incidence of HF [41–43]. Combined with this finding are the well-known sig-nificant physiological derangements, including fluid and electrolyte imbalance and uremia that underpin remote organ failure and finally affect cardiac func-tion, which in turn causes further kidney injury. Acute salt and water retention, volume overload, and the immediate effects of uremia on the myocardium are all postulated mechanisms in precipitating ADHF in CRS type 3 [44].

Chronic Renocardiac Syndrome (Type 4): CKD Leading to Heart Injury, Disease and/or DysfunctionCKD is an accepted independent determinant for the progression of HF to hos-pitalization, pump failure death, and sudden death. In a recent meta-analysis, an exponential relation between the severity of renal dysfunction and the risk for all-cause mortality was described [45]. Overall mortality was driven by ex-cess cardiovascular deaths, which constituted over 50% of the total mortality. CKD contributes to HF by causing or worsening the three fundamental mech-anisms of cardiac failure: pressure overload, volume overload, and cardiomy-opathy (fig. 6) [46]. Multiple studies have shown that CKD worsens hyperten-

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Fig. 5. Pathophysiology of CRS type 3.

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sion and impairs the success of antihypertensive agents [47]. Chronic salt and water retention increases volume loading on the cardiac chambers and results in elevated wall tension; this is reflected by chronic elevations of the natriuretic peptides produced by the myocardium [48]. In chronic uremia, elevation of multiple factors (marinobufagenin, indoxyl sulfate, p-cresol) have been shown to impair myocardial contractility, relaxation, and change the cellular and tis-sue characteristics of the myocardium [49–51]. As a result, uremia induces both systolic and diastolic dysfunction [52]. As renal filtration function declines, a reduction in the fractional excretion of phosphorus triggers osteocytes to pro-duce fibroblast growth factor-23 (FGF-23), which stimulates FGF-23-Klotho receptor complexes in the kidneys facilitating greater degrees of fractional phosphate excretion while at the same time, having ‘off-target’ stimulating ef-fects fibroblasts and myofibroblasts in the heart [53]. Both FGF-23 and a re-

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Fig. 6. Pathophysiology of CRS type 4. CKD = Chronic kidney disease; GFR = glomerular filtration rate; RRF = residual renal function; CV = cardiovascular; LVH = left ventricular hy-pertrophy; RAAS = renin angiotensin aldosterone system; SNS = sympathetic nerveous system, mineral and bone disease; ESRD = end-stage renal disease; RRT = renal replace-ment therapy; SCD = sudden cardiac death.

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lated protein, osteoprogerin, have been linked to HF in CKD patients [54]. His-topathologic changes in the myocardium in type 4 CRS include left ventricular hypertrophy, disassembly of gap junctions, increased expression of collagen-1, fibronectin, vimentin resulting in cardiac fibrosis, decreased capillary density, and increased tissue calcification [42, 55]. These changes constitute a ‘CKD car-diomyopathy’ and have been associated with both systolic and diastolic dys-function, chronic edema, and increased rates of HF hospitalization and death (fig. 6). It is possible that given the large degree of left ventricular hypertrophy and reduction in capillary blood supply, that microvascular ischemia is a con-tributor to both symptoms and the natural history of CRS type 4. Chest pain in CKD patients has been associated with not only higher rates of acute coronary syndromes, but also the development of HF and hospitalization [56]. End-stage renal disease is the most exaggerated form of CRS type 4 and has been shown to relay added insults to the myocardium during chronic hemodialysis includ-ing myocardial stunning, tissue swelling, and marked increases in cell signaling and enzymatic activation of matrix metalloproteinase-2 [57]. The result of these changes include recruitment and activation of T cells and cardiac macrophages, which direct the cycle of cardiac myocyte apoptosis and replacement fibrosis as described above [58]. Cardiac fibrosis can be viewed as a final common sub-strate for the two major mechanisms of death in end-stage renal disease, pump failure and sudden arrhythmic death.

Secondary Cardiorenal Syndromes (Type 5): Systemic Conditions Leading to Simultaneous Injury and/or Dysfunction of Heart and KidneyAlthough this subtype does not have a primary and secondary organ dysfunc-tion, situations do arise where both organs simultaneously are targeted by sys-temic illnesses, the prototype being acute sepsis [59]. Sepsis is common and its incidence is increasing, with a mortality estimated between 20 and 60% [60]. Approximately 11–64% of septic patients develop AKI that is associated with a higher morbidity and mortality [61]. Abnormalities in cardiac function are also common in sepsis [62, 63]. Observational data have found approximately 30–80% of septic patients have elevated cardiac-specific troponin, that often corre-late with reduced left ventricular function. The predominant mechanism is be-lieved to be microcirculatory injury the results in elevations of cardiac troponin, natriuretic peptides, and evidence of left ventricular dysfunction along with var-ious degrees of other organ failure (fig. 7) [64, 65]. At the same time, the cardiac features of AKI develop including azotemia and a reduction in urine output. Toxicity from markedly elevated neurohormones, particularly catecholamines, has been suggested in cases of overwhelming injury to the heart and kidneys, particularly in those with susceptible adrenergic receptor polymorphisms [66,

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67]. When sepsis is complicated by shock, it is possible that ischemia/reperfu-sion injury occurs in both organs resulting in even further endothelial injury and impairment of microcirculatory perfusion [68, 69]. At the cellular and tissue level, abnormal cell signaling, cell cycle arrest, loss of control over oxidative re-

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Kidney Liver Gut Micro-circulation

Capillary leakedema, DIC

Loss of barrierfunction, ileus

Excretoryfailure

Oliguria/anuriaShock

Respiratorydistress

Confusion

Adaptive and effective controlNormalization of biomarker abnormalitiesResolution of organ dysfunction; recovery

Maladaptive or inadequate controlPersistence of biomarker abnormalities

Multiple organ failure; death

Pathogen-associated molecular pattern moleculesLPS, LTA, lipoproteins, peptidoglycans, bacterial DNA, etc.

Damage-associated molecular pattern moleculesHMGB-1, heat-shock protein, DNA, uric acid, etc.

Complex protein systems Vascular and tissue cells Blood and lymphatic cells

Fig. 7. Pathophysiology of CRS type 5. aPPT = Activated partial thromboplastin time; PT = pro-thrombin time; AT = activated clotting time; ELAM-1 = endothelial leukocyte adhesion mol-ecule-1; ICAM-1 = intercellular adhesion molecule-1; CRP = C-reactive protein; LBP = lipo-polysaccharide-binding protein; PCT = procalcitonin; IL = interleukin; MIF = macrophage migration inhibitory factor; HMGB1 = high mobility group box 1; sTNF = soluble tumor ne-crosis factor receptor; suPAR = soluble urokinase-type plasminogen activator receptor; sS-TREM-1 = soluble triggering receptor expressed on myeloid cells; DIC = disseminated intra-vascular coagulation.

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actions due to the liberation of catalytic iron from structural proteins (myoglo-bin) and mitochondria, acute cell death, apoptosis, and tissue necrosis can all be in the final common pathway in CRS type 5 [70]. Recently, myocardial cell Toll-like receptors (TL), particularly TL-3 on endosomes, has been implicated in the translation of cell signals in sepsis to myocyte necrosis [71]. In these cases, many other organs are often involved resulting in high in-hospital mortality [72]. In addition, if CRS type 5 survives, CKD and possibility chronic HF could be long-term outcomes of this viscous cycle [73].

Conclusions

Through the ADQI consensus on CRS, an integrative summary of leading pathophysiological considerations will lead to new thinking on novel diagnostic and therapeutic targets. There is a common need to understand acute and chronic hemodynamic mechanisms that regulate ventricular function, coronary flow, myocardial perfusion, systemic perfusion, and renal perfusion at multiple levels in the kidney. In addition, the impact of acute and chronic uremia, reten-tion of nitrogenous and other molecules, and their impact on both the cardiac and renal systems needs more fundamental research. As renal filtration function improves, both cardiac and renal parameters indicate that retained toxins must play a role in combined pathogenesis. Abnormal regulation of neurohormonal systems appears to be a fundamental component of CRS pathophysiology. The degree of maladaptation and the relative response of counterregulatory mecha-nisms both appear to be fundamental in unlocking key diagnostic and therapeu-tic targets. Finally, immune cell signaling and enzymatic activation appear to be operative in many CRS, particularly those associated with acute and or chronic inflammation such as sepsis. Because both the heart and the kidneys have ongo-ing systemic demands, shifting of workloads from diseased or non-functional units to more functional ones appears to place an even greater burden of suscep-tibility to these remaining cardiomyocytes and nephrons as they work to main-tain hemodynamic, metabolic, hormonal, nutritional, and other vital functions. As part of the final common pathway, tissue fibrosis in the heart and kidneys is apparent on histopathologic examination. Whether this is benign replacement of lost functional cells or directly pathogenic remains unknown. There are al-ready several key diagnostic and therapeutic targets in clinical use and in devel-opment in this area. In summary, the pathophysiology of CRS is a complex array of mechanisms that will require considerable investigation from the research community to understand the major determinants and best pathways for diag-nosis and management in the future.

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Acknowledgements

The 11th International ADQI Consensus Conference was funded in part by generous support in form of unrestricted educational grants from Alere, Inc., Astute Medical, Inc., Gambro, and Fresenius Medical Care, Inc. The sponsors had no input on the content of this article.

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Peter A. McCullough, MD, MPHProvidence Park Heart Institute, Providence Park Hospital47601 Grand River, B125Novi, MI 48374 (USA)E-Mail peteramccullough @ gmail.com

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Sindrome Cardiorena Fisio 2013

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