McCullough PA, Ahmad A. Cardiorenal syndromes. World J Cardiol 2011; 3(1): 1-9
Corresponding Author of This Article
Peter A McCullough, MD, MPH, Department of Medicine, Cardiology Section, St. John Providence Health System, Providence Park Hospital, Institute, 47601 Grand River Avenue, Suite B-125, Novi, MI 48374, United States. email@example.com
Article-Type of This Article
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Cardiol. Jan 26, 2011; 3(1): 1-9 Published online Jan 26, 2011. doi: 10.4330/wjc.v3.i1.1
Peter A McCullough, Aftab Ahmad
Peter A McCullough, Aftab Ahmad, Department of Medicine, Cardiology Section, St. John Providence Health System, Providence Park Hospital, Novi, MI 48374, United States
ORCID number: $[AuthorORCIDs]
Author contributions: All authors contributed equally to this work.
Correspondence to: Peter A McCullough, MD, MPH, Department of Medicine, Cardiology Section, St. John Providence Health System, Providence Park Hospital, Institute, 47601 Grand River Avenue, Suite B-125, Novi, MI 48374, United States. firstname.lastname@example.org
Telephone: +1-248-4655485 Fax: +1-248-4655486
Received: October 28, 2010 Revised: December 3, 2010 Accepted: December 10, 2010 Published online: January 26, 2011
Cardiorenal syndromes (CRS) have been subclassified as five defined entities which represent clinical circumstances in which both the heart and the kidney are involved in a bidirectional injury and dysfunction via a final common pathway of cell-to-cell death and accelerated apoptosis mediated by oxidative stress. Types 1 and 2 involve acute and chronic cardiovascular disease (CVD) scenarios leading to acute kidney injury or accelerated chronic kidney disease. Types 2 and 3 describe acute and chronic kidney disease leading primarily to heart failure, although it is possible that acute coronary syndromes, stroke, and arrhythmias could be CVD outcomes in these forms of CRS. Finally, CRS type 5 describes a simultaneous insult to both heart and kidneys, such as sepsis, where both organs are injured simultaneously. Both blood and urine biomarkers are reviewed in this paper and offer a considerable opportunity to enhance the understanding of the pathophysiology and known epidemiology of these recently defined syndromes.
Both cardiac and renal diseases commonly present in the same patient and have been associated with increased costs of care, complications, and mortality[1,2]. Cardiorenal syndromes (CRS), describing the dynamic inter-relationship between heart and kidney malfunction have been defined in a recent consensus process by the Acute Dialysis Quality Initiative (ADQI). This has generated five distinct syndromes upon which the epidemiology of CRS can be described. This paper will review this new classification and give concrete examples of each CRS, and discuss the available data on incidence and risk predictors. Finally, a succinct review of promising biomarkers will be presented that are very likely to change the described CRS epidemiological literature as we know it, based largely upon the measurement of a single blood biomarker-serum creatinine.
CLASSIFICATION OF CARDIORENAL SYNDROMES
The term cardiorenal syndromes suggests the presence of multiple syndromes with subtypes denoted by dysfunction of the principal organ (cardiac or renal or both) as well as the relative acuity of the condition. Both organs must have or develop pathological abnormalities to fulfill the criteria for definition. The umbrella term “cardiorenal syndromes” 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 subcategories of CRS are given below. Proposed pathophysiological mechanisms are described in Figure 1 for each syndrome.
Figure 1 Pathophysiology and definitions of the five subtypes of cardiorenal syndromes.
CVP: Central venous pressure; GFR: Glomerular filtration rate; BNP: Brain natriuretic peptide; ANP: Atrial natriuretic peptide; RAAS: Renin-angiotensin-aldosterone system ; ADHF: Acute decompensated heart failure; ACS: Acute coronary syndrome; CKD: Chronic kidney disease; CVD: Cardiovascular disease; ATN: Acute tubular necrosis; CI-AKI: Contrast-induced acute kidney injury; CSA-AKI: Cardiac surgery-associated AKI; CHF: Chronic heart failure; LVH: Left ventricular hypertrophy; EPO: Erythropoietin; LPS: Lipopolysaccharide.
POORLY LIGANDED, LABILE, CATALYTIC IRON AS THE BASIS OF OXIDATIVE STRESS REACTIONS
As shown in Figure 1, it has been recently determined that the process of oxidative stress resulting in cell dysfunction, accelerated apoptosis, and cell death is reliant on the cytosolic and extracellular presence of labile or catalytic iron. There are several steps in generation of reactive oxygen species (ROS). Oxygen may be reduced to form superoxide anion, which can then either dismutate or go through another reduction reaction by superoxide dismutase to form hydrogen peroxide which itself can then be reduced through several pathways. Overall, the net Fritz-Haber reaction is slow and in the presence of reduced transition metals such as ferric iron (Fe3+), a Haber-Weiss reaction results in the formation of the highly damaging hydroxyl radical from the superoxide anion. Then in the presence of ferrous iron (Fe2+), a Fenton-type reaction converts hydrogen peroxide to the highly damaging hydroxyl radical. Further reduction of the hydroxyl radical finally ends in the formation of water. It has been theorized that a common element to all forms of oxidative stress in the heart and kidneys involves the availability of unbound iron. The body has an intricate management system for iron metabolism keeping it bound in transport proteins, heme, and cellular organelles for normal functioning[5,6]. If small amounts of iron are released from adjacent injured cells and not bound, this poorly liganded (labile or catalytic) iron in either the ferric or ferrous states, can facilitate the rapid generation of oxygen free radicals and the propagation of oxidative stress and injury across regions of vascular tissue. Thus, it is possible that the fundamental pathophysiological basis for CRS is the loss of control over normal iron management after insults to either the heart or the kidneys in the form of hypoxia, chemotoxicity, or inflammation.
It has been interesting to note that intravenous infusions of iron in the form of iron dextran, iron sucrose, iron gluconate, and iron dextrin (polymaltose) have been proposed as a treatment for anemia in patients with heart failure. While in general the trials have demonstrated improvement in either anemia, symptoms, or both, there are as yet no published outcomes data. Several studies have demonstrated that intravenous infusions of iron in normal volunteers and hemodialysis patients have resulted in a transient 3-4 fold rise in systemic levels of catalytic iron[9-11]. The clinical consequences of iron infusions and catalytic iron in heart failure (HF) patients, if any, are unknown at this time.
CATEGORIES OF SYNDROMES
The broad and most important concepts of CRS include the following: (1) bidirectional organ injury or malfunction; (2) an inciting event for acute CRS; and (3) a precipitous decline in function for acute or chronic CRS.
Acute cardiorenal syndrome
Acute cardiorenal syndrome (CRS Type 1): acute decompensation of cardiac function leading to acute renal failure. This is a syndrome of worsening renal function that frequently complicates acute decompensated heart failure (ADHF) and acute coronary syndrome (ACS). Seven observational studies have reported on the frequency and outcomes of CRS Type 1 in the setting of ADHF and five in ACS. Depending on the population, 27%-40% of patients hospitalized for ADHF develop acute kidney injury (AKI) as defined by an increase in serum creatinine of ≥ 0.3 mg/dL[12,13]. Risk predictors for this complication include reduced baseline renal function, diabetes, and prior HF. These patients experience more complicated hospital courses, longer inpatient stays, and higher mortality. In the Prospective Outcomes Study in Heart Failure (POSH) study, only in those with ADHF and a hospital course complicated by circulatory shock, hypotension, cardiac arrest, sepsis or ACS, a rise in serum creatinine did confer a higher 6-mo mortality. Conversely, those with an increase in serum creatinine of ≥ 0.3 mg/dL but no other complications did not have higher mortality in the hospital, at 30 or 180 d. Thus, much of CRS Type 1 mortality is confounded by a complicated course and AKI. Importantly, it has been noted that CRS Type 1 in ADHF rarely occurs in the prehospital phase, and is observed after hospitalization, implying that some factor associated with hospitalization, namely diuresis, precipitates CRS. The use of loop diuretics, probably by further activation of the renin-angiotensin system and possibly worsening intra-renal hemodynamics, have been identified as one of the modifiable in-hospital determinants of CRS Type 1. Testani et al have recently shown in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial that the use of higher doses of loop diuretics, causing hemoconcentration, resulted in a 5-fold increased rate of worsening renal function. However, in this prospective trial of hemodynamic monitoring, aggressive diuresis was associated with a 69% reduction in mortality at 180 d. Several studies have now linked the presence of an elevated central venous pressure and renal venous congestion to the development of CRS Type 1, thus, the relative balance of venous and arterial tone and congestion of the kidney appear to be important in the drop in renal filtration that occurs during hospitalized treatment of ADHF.
The other major clinical scenario where CRS Type 1 develops is in the setting of urgent or elective coronary revascularization for acute or chronic coronary disease. Acute contrast-induced and cardiopulmonary bypass surgery-associated AKI occur in 15% and 30% of patients, respectively[18,19]. Importantly, iodinated contrast which causes renal vasoconstriction and direct cellular toxicity to renal tubular cells is an important pre-existing factor in the few days before cardiac surgery. Cardiac surgery exposes the kidneys to hypothermic, pulseless reduced perfusion for 30-90 min, and thus represents a superimposed ischemic injury in the setting of a pro-inflammatory state. It is possible that the extracorporeal circuit used in cardiopulmonary bypass surgery activates systemic factors that further induce AKI; however, attempts to limit this exposure have not resulted in significantly reduced rates of AKI. Thus, these two scenarios are tightly linked, since almost every cardiac surgery patient operated upon in the urgent setting undergoes coronary angiography in the hours to days before surgery. As with ADHF, CRS Type 1 in acute and chronic coronary disease has a confounded relationship with outcomes. In those with complications, CRS Type 1 appears to be independently associated with a 3 to 4-fold increase in mortality despite the availability of dialysis in the hospital[23,24]. In all forms of CRS Type 1, there is a risk of advancing to higher stages of CKD and ultimately the need for chronic renal replacement strategies. The incremental and cumulative risk of these renal outcomes according to the clinical scenarios described above for an individual patient are unknown. Thus the important points concerning the epidemiology of CRS Type 1 are: (1) the mortality risk appears to be confounded by other non-renal complications occurring during the hospitalization; (2) intravascular iodinated contrast alone, and in cases where cardiac surgery follows coronary angiography, direct cellular toxicity from the contrast itself results in an observed rise in serum creatinine predominately in those with baseline reductions in renal filtration with additional risk factors, including diabetes, heart failure, older age, and larger contrast volumes; and (3) in the setting of ADHF, superimposed use of iodinated contrast or other cardiac procedures is associated with longer lengths of stay and higher mortality which is possibly in part, attributable to CRS Type 1[26-28].
Chronic cardiorenal syndrome
Chronic cardiorenal syndrome (CRS Type 2): chronic abnormalities in myocardial function leading to worsened chronic kidney disease (CKD). This subtype implies that chronic CVD can contribute to the development of CKD. Six observation studies have reported on CRS Type 2, with a minority of reports reporting on CVD contributing to an excess risk of CKD. It is recognized that the risk factors for atherosclerosis, namely diabetes, hypertension, and smoking are independently associated with the development of CKD. In addition, chronic abnormalities in systolic and diastolic myocardial performance can lead to alterations in neurohormonal activation, renal hemodynamics, and a variety of adverse cellular processes leading to apoptosis and renal fibrosis. Approximately 30% of those with chronic cardiovascular disease (CVD) meet a definition of CKD, and multiple studies have demonstrated the independent contribution of CVD to the worsening of CKD. An important component of CRS Type 2 epidemiology is that CKD appears to accelerate the course of atherosclerosis and result in premature CVD events including myocardial infarction and stroke[32,33]. Importantly, CKD and its metabolic milieu work to cause advanced calcific atherosclerosis through CKD mineral and bone disorder characterized by phosphate retention, relative vitamin D and calcium availability, and secondary hyperparathyroidism. Of these factors, phosphate retention appears to be the critical pathophysiological component stimulating the conversion of vascular smooth muscle cells to osteoblastic-like cells which, via the Pit-1 receptor, are stimulated to produce extracellular calcium hydroxyapatite crystals in the vascular smooth muscle layer of arteries[35,36]. Thus, patients as a part of CRS type 2, more commonly have vascular calcification, less vascular compliance, and a higher degree of chronic organ injury related to blood pressure elevation and shear stress. Despite these mechanisms specific to CRS, CRS Type 2 remains heavily confounded by the “common soil” of atherosclerosis and CKD. The cardiometabolic syndrome and neurohormonal activation affect both organ systems; thus, it is difficult to tease out the temporal sequence of pathophysiological events for most individuals which are occurring over the period of decades.
Studies have shown that 45.0%-63.6% of patients with chronic HF have evidence of CKD defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min per 1.73 m2. Multiple studies have demonstrated that CKD is closely linked to more frequent hospitalizations and complications from pump failure and arrhythmias[40,41]. In addition, patients with CKD and end-stage renal disease have higher defibrillation thresholds and may not have the protective benefit of implantable cardio defibrillators as those with normal renal function. Increased degrees of left ventricular hypertrophy and cardiac fibrosis are believed to be the biologic basis for these electrophysiological findings.
Acute renocardiac syndrome
Acute renocardiac syndrome (CRS Type 3): acute worsening of renal function leading to cardiac events. The most common scenario for CRS Type 3 is the development of AKI that results in volume overload, sodium retention, neurohormonal activation, and the development of clinical HF with the cardinal features of pulmonary congestion and peripheral edema. Volume overload alone has been shown to induce cardiac failure and reflect CRS Type 3 most clearly in the pediatric population. However, in adults, when acute on chronic disease is a common occurrence, it is difficult to identify clear cases where AKI lead to cardiac decompensation. It is also possible that CRS Type 3 could precipitate in an acute coronary syndrome, stroke, or other acute cardiac event. Thus the epidemiology of this CRS subtype is not well defined for individual CVD events such as ACS, stroke, cardiac rehospitalization, arrhythmias, pump failure, and cardiac death.
Chronic renocardiac syndrome
Chronic renocardiac syndrome (CRS Type 4): chronic renal disease leading to the progression of cardiovascular disease. Over the past several decades there has been recognition of a graded and independent association between the severity of CKD and incidence as well as prevalence of CVD. In a meta-analysis of 39 studies (1 371 990 participants), there was a clear relationship between the degree of renal dysfunction and the risk for all-cause mortality. The unadjusted relative risk of mortality in participants with reduced kidney function was in excess of the reference group in 93% of cohorts. Fourteen of the 39 studies described the risk of mortality from reduced kidney function, after adjustment for other established risk factors. Although adjusted relative hazard ratios were on average 17% lower than unadjusted relative risks, they remained significantly greater than unity in 71% of cohorts. The overall mortality was influenced greatly by excess cardiovascular deaths, which constituted over 50% of cases. Thirteen studies have been identified as specifically reporting on CRS Type 4, most of which were in populations with end-stage renal disease. It should also be recognized, that CKD contributes to CVD outcomes in CRS Type 4 by complicating pharmacological and interventional treatment[46,47]. For example, azotemia and hyperkalemia restrict the use of drugs that antagonize the renin-angiotensin system, thus fewer patients with CKD enjoy the cardiovascular benefits of angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, and aldosterone receptor blockers[48,49]. It has been shown that CKD also worsens the presentation, severity, response to treatment, and cardiorenal outcomes in acute and chronic hypertension[50,51]. In addition, the perceived risks of AKI lead patients with CKD towards conservative management strategies which have been associated with poor outcomes in the setting of both acute and chronic coronary artery disease. Finally, a recent study of silent brain injury (asymptomatic cerebral infarctions by magnetic resonance imaging) has been associated with a rapid decline in renal function in approximately 30% of patients. This suggests the possibility that cerebrovascular disease could in some way contribute to more rapid progression of CKD.
Secondary cardiorenal syndrome
Secondary cardiorenal syndrome (CRS Type 5): systemic illness leading to simultaneous heart and renal failure. It is recognized that a systemic insult, particularly in a younger patient with no prior heart or kidney disease, can lead to simultaneous organ dysfunction. This is almost always in the setting of critical illness such as sepsis, multiple trauma, or burns. There are limited data on the incidence and determinants of CRS Type 5, in part because of confounders such as hypotension, respiratory failure, liver failure, and other organ injury beyond the cardiac and renal systems. This results in a difficult human model for investigation. Sepsis as a precipitator of CRS Type 5 is common and its incidence is increasing, with a mortality estimated at 20%-60%[54,55]. Approximately 11%-64% of septic patients develop AKI that is associated with a higher morbidity and mortality. Abnormalities in cardiac function are also common in sepsis including wall motion abnormalities and transient reductions in left ventricular ejection fraction. Observational data have found approximately 30%-80% of individuals with sepsis have measurable blood troponin I or T that are above the 99th detection limits. These elevated cardiac biomarkers have been associated with reduced left ventricular function and higher mortality even in patients without known coronary disease[59-61]. Importantly, volume overload as a result of aggressive fluid resuscitation appears to be a significant determinant of CRS Type 5. Among 3147 patients enrolled in the Sepsis Occurrence in Acutely Ill Patients (SOAP), there was a 36% incidence of AKI, and volume overload was the strongest predictor of mortality. Iatrogenic volume overload appears to play an important additional role, possibly along the lines described for CRS Type 1 and passive venous congestion of the kidney, in the pathogenesis of AKI. At the same time, volume overload increases left ventricular wall tension and likely contributes to cardiac decompensation in those predisposed to both systolic and diastolic HF. In summary for CRS Type 5, both AKI and markers of cardiac injury followed by volume overload are common in sepsis, with each being associated with increased mortality. However, there is a current lack of integral information on the incidence of bidirectional organ failure and its pathophysiological correlates in a variety of acute care settings.
BIOMARKERS OF CARDIORENAL SYNDROMES
There is considerable interest in blood and urine biomarkers to detect CRS. For decades, the rise in serum creatinine has been the only detectable sign of a reduction in glomerular filtration. Creatinine has had the disadvantages of being linked to creatine and overall body muscle mass, hence varying according to body size in addition to the rate of renal elimination. Furthermore, the kidney both filters and secretes creatinine. Finally, the assays used to measure creatinine have not be standardized across laboratories, therefore studies reporting values from multiple centers have inherent variation in values attributed to differences in measurement technique. Hence, there is a clear need for better laboratory markers of renal filtration. An ideal marker would be independent of muscle mass, reflect actual renal filtration at the time of measurement, and be sensitive to changes in actual GFR in order to alert clinicians to a meaningful change shortly after it occurs.
Unlike cardiac biomarkers indicating myocardial injury and overload (troponin, creatine kinase myocardial band, natriuretic peptides), the field of nephrology has been devoid of approved blood or urine markers of AKI. Thus the current paradigm is that when renal injury occurs, clinicians must wait to observe a reduction in GFR before AKI is inferred. The concept of measuring markers of the acute injury process is crucial to the early upstream identification of AKI before there is serious loss of organ function. Table 1 is a summary of relatively novel renal markers and what is known about them in acute cardiac and renal injury. Their use in the years to come will undoubtedly influence the epidemiology of CRS.
Table 1 Novel biomarkers of acute cardiac and renal injury.
Mechanism of action
Potential therapeutic approaches
Catalytic (labile, poorly-liganded) iron
Leads to generation of the hydroxyl radical, the most destructive of ROS; released into the blood in patients with ACS; thought to be involved in oxidative organ damage also in AKI; local cellular and tissue availability of catalytic iron are likely to determine the degree and severity of organ injury in the setting of most hypoxic and other toxic insults
In patients with ACS, the appearance of catalytic iron precedes the rise in serum troponin and detects acute myocardial infarction with an area under the ROC curve of > 90%
Detection of non-transferrin-bound iron in blood by the bleomycin assay
Use of iron chelators to diminish oxidative injury
NGAL (lipocalin-2, siderocalin)
Natural siderophore produced by renal tubular cells that reduces the availability of catalytic iron, thus limiting oxidative damage and limiting bacterial growth
One of the earliest kidney markers of cardiac and renal injury in animals; detected in humans shortly after AKI and predicts need for in-hospital dialysis
Overexpression reduces oxidative stress in ischemic injury
Cysteine protease inhibitor (housekeeping protein) produced by all nucleated cells that is freely filtered by the glomerulus and reabsorbed in the proximal tubule; no tubular secretion
Not dependent on muscle mass; better predictor of risk of adverse events in patients with CVD than creatinine or eGFR
Detection in blood
Transmembrane glycoprotein not normally detected in urine; detected in urine early after ischemic or nephrotoxic injury to cells of the proximal tubule
Highly specific for AKI caused by systemic illnesses such as sepsis and not for pre-renal azotemia or drug-induced renal injury; May be elevated before histologic evidence of proximal tubular cell death
Detection in urine
Large lysosomal brush-border enzyme found in cells of the proximal tubule, not normally filtered by the glomerulus; elevated concentrations found in urine in the setting of AKI, CKD, diabetes mellitus, hypertension and heart failure
Marker of the degree of tubular damage
Detection in urine
Pro-inflammatory cytokine found in urine after acute ischemic damage to proximal tubules; associated with AKI-related mortality, although not organ-specific; might be involved in myocardial cell damage in the setting of ACS
Sensitive and specific to detect ischemic AKI with an area under the ROC curve of 0.78; levels rise 48 h before those of creatinine
Detection in urine
Inhibitors expressed in stem cells are protective in models of myocyte injury
Selectively binds free unsaturated fatty acids and products of lipid oxidation in cells in the setting of hypoxic tissue injury; detected in the urine in the setting of AKI
Might predict dialysis-free survival in patients with AKI
Detection in urine
Several enzymes, such as gamma glutamyl transpeptidase, alkaline phosphatase, lactate dehydrogenase, and α and π glutathione S-transferases are released from tubular cells[76-78]
A combination of measures of enzyme levels could potential indicate the presence and location of kidney injury
Cardiorenal syndromes as described in this paper are not spontaneous or primary conditions that arise in free-living populations. Acute CRS appears to occur once hospitalization and its associated care have occurred. Thus, there are determinants and clear precipitants to these syndromes that are potentially controllable by clinicians. Improved education and awareness concerning the risk factors and presence of CKD holds great promise for patients and clinicians to avoid contributors to CRS such as excess sodium intake, and use of intensive loop diuretics, non-steroidal anti-inflammatory agents, thiazolidinediones, and iodinated contrast. The National Kidney Foundation Kidney Early Evaluation Program is a nationwide and now global community-based screening program that evaluates volunteers for CKD and its risk factors, with effective education for participants and their physicians. This program, as it evolves and broadens, has a considerable opportunity to lessen the frequency of avoidable CRS in the future by spurring community awareness and clinical appreciation for CKD. Finally, the most important public health question concerning this field is wether or not a lessening of the frequency or severity of AKI will reduce hospital length of stay, cardiovascular, renal, and all-cause morbidity and mortality. Large scale clinical trials of preventive therapies that consign broad composite primary endpoints with biomarkers as secondary endpoints are needed to answer this pivotal question.
The ADQI consensus on CRS has yielded a framework for a better understanding of the epidemiology of the five subtypes of CRS. A description of the epidemiology of the heart-kidney interaction is critical to our understanding of the overall disease burden associated with these specific CRS subtypes, and will guide future investigations into their pathophysiology, diagnosis, prognosis, and management. Recent studies have identified and characterized several novel biomarkers for HF and AKI. These advances will herald better understanding, diagnosis, and treatment of CRS. It is anticipated that these biomarkers will help make an earlier diagnosis of CRS possible, as well as identify the specific type of CRS. It is hoped that some of these new biomarkers will either provide sufficient risk prediction or early diagnosis of all patients for novel preventive and treatment strategies to ameliorate the course of CRS, and subsequently, the long-term outcome.
Peer reviewers: Ferruh Artunc, MD, Facharzt für Innere Medizin, Medizinische Klinik IV, Sektion Nieren-und Hochdruckkrankheiten, Otfried-Müller Str. 10, 72076 Tübingen, Germany; Adam Whaley-Connell, DO, MSPH, FAHA, FACP, FASN, Assistant Professor of Medicine, Department of Internal Medicine, Division of Nephrology and Hypertension, University of Missouri-Columbia School of Medicine, CE417, DC043.0, Five Hospital Dr, Columbia, MO 65212, United States
McCullough PA. Why is chronic kidney disease the "spoiler" for cardiovascular outcomes?J Am Coll Cardiol. 2003;41:725-728.
Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL, McCullough PA, Kasiske BL, Kelepouris E, Klag MJ. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention.Circulation. 2003;108:2154-2169.
Ronco C, McCullough P, Anker SD, Anand I, Aspromonte N, Bagshaw SM, Bellomo R, Berl T, Bobek I, Cruz DN. Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative.Eur Heart J. 2010;31:703-711.
Shah SV. Oxidants and iron in chronic kidney disease.Kidney Int Suppl. 2004;S50-S55.
Walker BL, Tiong JW, Jefferies WA. Iron metabolism in mammalian cells.Int Rev Cytol. 2001;211:241-278.
Richardson DR, Lane DJ, Becker EM, Huang ML, Whitnall M, Rahmanto YS, Sheftel AD, Ponka P. Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol.Proc Natl Acad Sci USA. 2010;107:10775-10782.
Balla J, Vercellotti GM, Jeney V, Yachie A, Varga Z, Jacob HS, Eaton JW, Balla G. Heme, heme oxygenase, and ferritin: how the vascular endothelium survives (and dies) in an iron-rich environment.Antioxid Redox Signal. 2007;9:2119-2137.
Jelani QU, Katz SD. Treatment of anemia in heart failure: potential risks and benefits of intravenous iron therapy in cardiovascular disease.Cardiol Rev. 2010;18:240-250.
Kooistra MP, Kersting S, Gosriwatana I, Lu S, Nijhoff-Schutte J, Hider RC, Marx JJ. Nontransferrin-bound iron in the plasma of haemodialysis patients after intravenous iron saccharate infusion.Eur J Clin Invest. 2002;32 Suppl 1:36-41.
Zanen AL, Adriaansen HJ, van Bommel EF, Posthuma R, Th de Jong GM. 'Oversaturation' of transferrin after intravenous ferric gluconate (Ferrlecit(R)) in haemodialysis patients.Nephrol Dial Transplant. 1996;11:820-824.
Bagshaw SM, Cruz DN, Aspromonte N, Daliento L, Ronco F, Sheinfeld G, Anker SD, Anand I, Bellomo R, Berl T. Epidemiology of cardio-renal syndromes: workgroup statements from the 7th ADQI Consensus Conference.Nephrol Dial Transplant. 2010;25:1406-1416.
Forman DE, Butler J, Wang Y, Abraham WT, O'Connor CM, Gottlieb SS, Loh E, Massie BM, Rich MW, Stevenson LW. Incidence, predictors at admission, and impact of worsening renal function among patients hospitalized with heart failure.J Am Coll Cardiol. 2004;43:61-67.
Cowie MR, Komajda M, Murray-Thomas T, Underwood J, Ticho B. Prevalence and impact of worsening renal function in patients hospitalized with decompensated heart failure: results of the prospective outcomes study in heart failure (POSH).Eur Heart J. 2006;27:1216-1222.
Metra M, Nodari S, Parrinello G, Bordonali T, Bugatti S, Danesi R, Fontanella B, Lombardi C, Milani P, Verzura G. Worsening renal function in patients hospitalised for acute heart failure: clinical implications and prognostic significance.Eur J Heart Fail. 2008;10:188-195.
Testani JM, Chen J, McCauley BD, Kimmel SE, Shannon RP. Potential effects of aggressive decongestion during the treatment of decompensated heart failure on renal function and survival.Circulation. 2010;122:265-272.
Tang WH, Mullens W. Cardiorenal syndrome in decompensated heart failure.Heart. 2010;96:255-260.
Bellomo R, Auriemma S, Fabbri A, D'Onofrio A, Katz N, McCullough PA, Ricci Z, Shaw A, Ronco C. The pathophysiology of cardiac surgery-associated acute kidney injury (CSA-AKI).Int J Artif Organs. 2008;31:166-178.
Elahi MM, Battula NR, Hakim NS, Matata BM. Acute renal failure in patients with ischemic heart disease: causes and novel approaches in breaking the cycle of self-perpetuating insults abrogated by surgery.Int Surg. 2005;90:202-208.
Diez C, Haneya A, Brünger F, Philipp A, Hirt S, Ruppecht L, Kobuch R, Keyser A, Hilker M, Puehler T. Minimized extracorporeal circulation cannot prevent acute kidney injury but attenuates early renal dysfunction after coronary bypass grafting.ASAIO J. 2009;55:602-607.
Ranucci M, Ballotta A, Kunkl A, De Benedetti D, Kandil H, Conti D, Mollichelli N, Bossone E, Mehta RH. Influence of the timing of cardiac catheterization and the amount of contrast media on acute renal failure after cardiac surgery.Am J Cardiol. 2008;101:1112-1118.
McCullough PA, Wolyn R, Rocher LL, Levin RN, O'Neill WW. Acute renal failure after coronary intervention: incidence, risk factors, and relationship to mortality.Am J Med. 1997;103:368-375.
Del Duca D, Iqbal S, Rahme E, Goldberg P, de Varennes B. Renal failure after cardiac surgery: timing of cardiac catheterization and other perioperative risk factors.Ann Thorac Surg. 2007;84:1264-1271.
Newsome BB, Warnock DG, McClellan WM, Herzog CA, Kiefe CI, Eggers PW, Allison JJ. Long-term risk of mortality and end-stage renal disease among the elderly after small increases in serum creatinine level during hospitalization for acute myocardial infarction.Arch Intern Med. 2008;168:609-616.
McCullough PA, Stacul F, Becker CR, Adam A, Lameire N, Tumlin JA, Davidson CJ. Contrast-Induced Nephropathy (CIN) Consensus Working Panel: executive summary.Rev Cardiovasc Med. 2006;7:177-197.
Smith GL, Lichtman JH, Bracken MB, Shlipak MG, Phillips CO, DiCapua P, Krumholz HM. Renal impairment and outcomes in heart failure: systematic review and meta-analysis.J Am Coll Cardiol. 2006;47:1987-1996.
Philbin EF, McCullough PA, Dec GW, DiSalvo TG. Length of stay and procedure utilization are the major determinants of hospital charges for heart failure.Clin Cardiol. 2001;24:56-62.
Kundhal K, Lok CE. Clinical epidemiology of cardiovascular disease in chronic kidney disease.Nephron Clin Pract. 2005;101:c47-c52.
Chinnaiyan KM, Alexander D, McCullough PA. Role of angiotensin II in the evolution of diastolic heart failure.J Clin Hypertens (Greenwich). 2005;7:740-747.
McCullough PA, Jurkovitz CT, Pergola PE, McGill JB, Brown WW, Collins AJ, Chen SC, Li S, Singh A, Norris KC. Independent components of chronic kidney disease as a cardiovascular risk state: results from the Kidney Early Evaluation Program (KEEP).Arch Intern Med. 2007;167:1122-1129.
Yerkey MW, Kernis SJ, Franklin BA, Sandberg KR, McCullough PA. Renal dysfunction and acceleration of coronary disease.Heart. 2004;90:961-966.
McCullough PA, Li S, Jurkovitz CT, Stevens L, Collins AJ, Chen SC, Norris KC, McFarlane S, Johnson B, Shlipak MG. Chronic kidney disease, prevalence of premature cardiovascular disease, and relationship to short-term mortality.Am Heart J. 2008;156:277-283.
McCullough PA, Sandberg KR, Dumler F, Yanez JE. Determinants of coronary vascular calcification in patients with chronic kidney disease and end-stage renal disease: a systematic review.J Nephrol. 2004;17:205-215.
Tintut Y, Demer LL. Recent advances in multifactorial regulation of vascular calcification.Curr Opin Lipidol. 2001;12:555-560.
McCullough PA, Agrawal V, Danielewicz E, Abela GS. Accelerated atherosclerotic calcification and Monckeberg's sclerosis: a continuum of advanced vascular pathology in chronic kidney disease.Clin J Am Soc Nephrol. 2008;3:1585-1598.
Guérin AP, Pannier B, Métivier F, Marchais SJ, London GM. Assessment and significance of arterial stiffness in patients with chronic kidney disease.Curr Opin Nephrol Hypertens. 2008;17:635-641.
Ahmed A, Rich MW, Sanders PW, Perry GJ, Bakris GL, Zile MR, Love TE, Aban IB, Shlipak MG. Chronic kidney disease associated mortality in diastolic versus systolic heart failure: a propensity matched study.Am J Cardiol. 2007;99:393-398.
Soman SS, Sandberg KR, Borzak S, Hudson MP, Yee J, McCullough PA. The independent association of renal dysfunction and arrhythmias in critically ill patients.Chest. 2002;122:669-677.
Jenkins K, Kirk M. Heart failure and chronic kidney disease: an integrated care approach.J Ren Care. 2010;36 Suppl 1:127-135.
Wase A, Basit A, Nazir R, Jamal A, Shah S, Khan T, Mohiuddin I, White C, Saklayen M, McCullough PA. Impact of chronic kidney disease upon survival among implantable cardioverter-defibrillator recipients.J Interv Card Electrophysiol. 2004;11:199-204.
Glassock RJ, Pecoits-Filho R, Barberato SH. Left ventricular mass in chronic kidney disease and ESRD.Clin J Am Soc Nephrol. 2009;4 Suppl 1:S79-S91.
Bagshaw SM, Cruz DN. Fluid overload as a biomarker of heart failure and acute kidney injury.Contrib Nephrol. 2010;164:54-68.
Tonelli M, Wiebe N, Culleton B, House A, Rabbat C, Fok M, McAlister F, Garg AX. Chronic kidney disease and mortality risk: a systematic review.J Am Soc Nephrol. 2006;17:2034-2047.
Shlipak MG. Pharmacotherapy for heart failure in patients with renal insufficiency.Ann Intern Med. 2003;138:917-924.
McCullough PA, Berman AD. Percutaneous coronary interventions in the high-risk renal patient: strategies for renal protection and vascular protection.Cardiol Clin. 2005;23:299-310.
McCullough PA, Sandberg KR, Yee J, Hudson MP. Mortality benefit of angiotensin-converting enzyme inhibitors after cardiac events in patients with end-stage renal disease.J Renin Angiotensin Aldosterone Syst. 2002;3:188-191.
McCullough PA. Chronic kidney disease: tipping the scale to the benefit of angiotensin-converting enzyme inhibitors in patients with coronary artery disease.Circulation. 2006;114:6-7.
Kalaitzidis R, Li S, Wang C, Chen SC, McCullough PA, Bakris GL. Hypertension in early-stage kidney disease: an update from the Kidney Early Evaluation Program (KEEP).Am J Kidney Dis. 2009;53:S22-S31.
Szczech LA, Granger CB, Dasta JF, Amin A, Peacock WF, McCullough PA, Devlin JW, Weir MR, Katz JN, Anderson FA Jr. Acute kidney injury and cardiovascular outcomes in acute severe hypertension.Circulation. 2010;121:2183-2191.
Keeley EC, Kadakia R, Soman S, Borzak S, McCullough PA. Analysis of long-term survival after revascularization in patients with chronic kidney disease presenting with acute coronary syndromes.Am J Cardiol. 2003;92:509-514.
Kobayashi M, Hirawa N, Morita S, Yatsu K, Kobayashi Y, Yamamoto Y, Saka S, Toya Y, Yasuda G, Umemura S. Silent brain infarction and rapid decline of kidney function in patients with CKD: a prospective cohort study.Am J Kidney Dis. 2010;56:468-476.
Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care.Crit Care Med. 2001;29:1303-1310.
Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000.N Engl J Med. 2003;348:1546-1554.
Bagshaw SM, Lapinsky S, Dial S, Arabi Y, Dodek P, Wood G, Ellis P, Guzman J, Marshall J, Parrillo JE. Acute kidney injury in septic shock: clinical outcomes and impact of duration of hypotension prior to initiation of antimicrobial therapy.Intensive Care Med. 2009;35:871-881.
Lopes JA, Jorge S, Resina C, Santos C, Pereira A, Neves J, Antunes F, Prata MM. Acute renal failure in patients with sepsis.Crit Care. 2007;11:411.
Zanotti-Cavazzoni SL, Hollenberg SM. Cardiac dysfunction in severe sepsis and septic shock.Curr Opin Crit Care. 2009;15:392-397.
Favory R, Neviere R. Significance and interpretation of elevated troponin in septic patients.Crit Care. 2006;10:224.
Ammann P, Maggiorini M, Bertel O, Haenseler E, Joller-Jemelka HI, Oechslin E, Minder EI, Rickli H, Fehr T. Troponin as a risk factor for mortality in critically ill patients without acute coronary syndromes.J Am Coll Cardiol. 2003;41:2004-2009.
Mehta NJ, Khan IA, Gupta V, Jani K, Gowda RM, Smith PR. Cardiac troponin I predicts myocardial dysfunction and adverse outcome in septic shock.Int J Cardiol. 2004;95:13-17.
Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, Moreno R, Carlet J, Le Gall JR, Payen D. Sepsis in European intensive care units: results of the SOAP study.Crit Care Med. 2006;34:344-353.
Chinnaiyan KM, Alexander D, Maddens M, McCullough PA. Curriculum in cardiology: integrated diagnosis and management of diastolic heart failure.Am Heart J. 2007;153:189-200.
Myers GL, Miller WG, Coresh J, Fleming J, Greenberg N, Greene T, Hostetter T, Levey AS, Panteghini M, Welch M. Recommendations for improving serum creatinine measurement: a report from the Laboratory Working Group of the National Kidney Disease Education Program.Clin Chem. 2006;52:5-18.
Stevens LA, Stoycheff N. Standardization of serum creatinine and estimated GFR in the Kidney Early Evaluation Program (KEEP).Am J Kidney Dis. 2008;51:S77-S82.
Soni SS, Ronco C, Katz N, Cruz DN. Early diagnosis of acute kidney injury: the promise of novel biomarkers.Blood Purif. 2009;28:165-174.
McCullough PA, Vassalotti JA, Collins AJ, Chen SC, Bakris GL. National Kidney Foundation's Kidney Early Evaluation Program (KEEP) annual data report 2009: executive summary.Am J Kidney Dis. 2010;55:S1-S3.
Mishra J, Ma Q, Prada A, Mitsnefes M, Zahedi K, Yang J, Barasch J, Devarajan P. Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury.J Am Soc Nephrol. 2003;14:2534-2543.
Nickolas TL, O'Rourke MJ, Yang J, Sise ME, Canetta PA, Barasch N, Buchen C, Khan F, Mori K, Giglio J. Sensitivity and specificity of a single emergency department measurement of urinary neutrophil gelatinase-associated lipocalin for diagnosing acute kidney injury.Ann Intern Med. 2008;148:810-819.
Mori K, Lee HT, Rapoport D, Drexler IR, Foster K, Yang J, Schmidt-Ott KM, Chen X, Li JY, Weiss S. Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury.J Clin Invest. 2005;115:610-621.
Parikh CR, Devarajan P. New biomarkers of acute kidney injury.Crit Care Med. 2008;36:S159-S165.
Liangos O, Tighiouart H, Perianayagam MC, Kolyada A, Han WK, Wald R, Bonventre JV, Jaber BL. Comparative analysis of urinary biomarkers for early detection of acute kidney injury following cardiopulmonary bypass.Biomarkers. 2009;14:423-431.
Portilla D, Dent C, Sugaya T, Nagothu KK, Kundi I, Moore P, Noiri E, Devarajan P. Liver fatty acid-binding protein as a biomarker of acute kidney injury after cardiac surgery.Kidney Int. 2008;73:465-472.
McMahon BA, Koyner JL, Murray PT. Urinary glutathione S-transferases in the pathogenesis and diagnostic evaluation of acute kidney injury following cardiac surgery: a critical review.Curr Opin Crit Care. 2010;Epub ahead of print.
Branten AJ, Mulder TP, Peters WH, Assmann KJ, Wetzels JF. Urinary excretion of glutathione S transferases alpha and pi in patients with proteinuria: reflection of the site of tubular injury.Nephron. 2000;85:120-126.
Walshe CM, Odejayi F, Ng S, Marsh B. Urinary glutathione S-transferase as an early marker for renal dysfunction in patients admitted to intensive care with sepsis.Crit Care Resusc. 2009;11:204-209.
Westhuyzen J, Endre ZH, Reece G, Reith DM, Saltissi D, Morgan TJ. Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive care unit.Nephrol Dial Transplant. 2003;18:543-551.