Pediatric Nephrology

, Volume 28, Issue 6, pp 855–862

Cardorenal syndrome: an emerging problem in pediatric critical care

Authors

    • The Heart Institute, Cincinnati Children’s Hospital Medical CenterUniversity of Cincinnati College of Medicine
  • Stuart L. Goldstein
    • Center for Acute Care Nephrology, Cincinnati Children’s Hospital Medical CenterUniversity of Cincinnati, College of Medicine
Review

DOI: 10.1007/s00467-012-2251-4

Cite this article as:
Jefferies, J.L. & Goldstein, S.L. Pediatr Nephrol (2013) 28: 855. doi:10.1007/s00467-012-2251-4

Abstract

The cardiorenal syndrome (CRS) refers to a complex pathophysiologic state in which heart and kidney dysfunction coexist. Although a robust amount of adult literature exists, limited reports have been made regarding CRS in pediatric patients. However, CRS is increasingly being recognized as an impactful clinical problem that can have important implications regarding the need for treatment and prognosis. Although wide acceptance of a unified definition of CRS is lacking, a general consensus exists that CRS can be either primarily caused by cardiac disease with secondary effects on the kidney, or vice versa, as well as systemic conditions in which cardiac and renal disease are both considered to be secondary. Convincing data in the pediatric perioperative population have been reported, but there is a paucity of information in acute and chronic heart failure (HF), as well as acute kidney injury (AKI) and chronic kidney disease (CKD). Herein, we briefly report on the adult literature and summarize the current pediatric experience.

Keywords

Acute kidney injuryHeart failureChildren

Introduction

Defining heart failure and kidney injury

Heart failure (HF) is a significant health care concern for children and adults worldwide. More than five million American adults have HF, with limited data existing regarding prevalence in children [1, 2]. In recent years, HF has been characterized appropriately as a clinical syndrome including complex relationships with multiple organ systems, including the kidney. The term cardiorenal syndrome (CRS) refers to the pathophysiologic conditions in which heart and kidney dysfunction coexist. Increasing evidence suggests that a greater understanding of CRS offers a unique and previously unrecognized opportunity to make favorable clinical interventions and offer prognostic information in patients of all ages. Herein, we will further review definitions and classifications of CRS, existing pediatric and pertinent adult data, and describe current care of CRS patients in our institution.

Heart failure is a clinical syndrome

The scope of pediatric HF with respect to prevalence and cost remains largely unknown. However, HF affects 2.4 % of the adult population [3]. The estimated cost in the United States for management of HF is currently ∼35 billion dollars [4]. Although the cost in the pediatric population is not known, recent reports suggest that there has been a substantial increase in costs associated with care of pediatric heart transplant patients [5].

Instruments designed to estimate mortality in the adult HF population have identified over 100 variables associated with hospitalization and mortality [6, 7]. Many of these models rely on demographic data, functional status, hemodynamic and cardiac function data, as well as cardiac biomarkers. However, the biomarkers used are quite variable, with many calculations failing to include any assessment of kidney function. Of the four most frequently used models for prognosis in hospitalized patients, only two incorporate serum blood urea nitrogen (BUN) and only one, the ADHERE model, uses serum creatinine in calculating risk [6, 810].

The opportunity to accurately predict risk is of great importance in the management of critically ill ICU patients, especially those with need for advanced HF therapies. In patients with the clinical picture of a low cardiac output state, as reflected by poor perfusion and end-organ dysfunction, early intervention in the form of mechanical circulatory support (MCS) may be a life-saving therapy. MCS may function as a bridge to recovery, bridge to a long-term support strategy, or a bridge to cardiac transplantation.

The heart and the kidneys—a bidirectional influence

The term cardiorenal syndrome (CRS) is increasingly found in the literature. However, a widely accepted definition remains inconsistent. Ronco et al. proposed the most widely quoted description, which helps to define both acute and chronic bidirectional interplay between the heart and the kidneys [11]. The proposed classification describes five subtypes in the cardiorenal syndrome: (1) CRS type 1 would occur in the setting of acute myocardial dysfunction leading to acute kidney injury (AKI) (e.g., myocardial injury, acute decompensated heart failure (ADHF); (2) CRS type 2 describes chronic myocardial dysfunction resulting in chronic kidney disease (CKD) (e.g., chronic heart failure); (3) CRS type 3 is characterized by an acute change in kidney function leading to acute cardiac dysfunction (e.g., AKI from acute glomerular nephritis); (4) CRS type 4 refers to chronic kidney disease (CKD) resulting in myocardial dysfunction (chronic glomerular disease); and (5) CRS type 5 describes the presence of cardiac and kidney dysfunction due to systemic disorders (sepsis). We will further describe each CRS type in the following paragraphs and highlight the current understanding in children.

CRS type 1

CRS type 1 is characterized by an acute worsening of cardiac function that results in AKI. In adult populations, CRS type 1 is seen frequently given the large number of admissions for ADHF each year in the US. Renal impairment may occur in up to 40 % of adults admitted with ADHF [12]. We have registry data to suggest that a similar association exists in children. The results of this analysis are in submission at the time of this publication. ADHF may be secondary to new-onset HF from an acute event like myocardial ischemia or infarction, or an acute on chronic occurrence such as those patients living with valvular heart disease or persistent systolic or diastolic dysfunction. In pediatric populations, acute myocardial dysfunction may be seen in the setting of acquired conditions such as viral myocarditis. Perhaps more commonly, CRS type 1 is seen in the post-operative setting in children. It is in this population where novel urinary biomarkers have received the most extensive study (Table 1). The etiology behind AKI in the setting of acute cardiac dysfunction is complex and involves multiple mechanisms. Low cardiac output and decreased renal perfusion have obvious implications as a mechanism behind AKI. In addition, there is significant upregulation of the inflammatory cascade including cytokines that can have adverse effects on the kidney. Also, changes in the neurohormonal axis shift in favor of vasoconstrictive hormones including epinephrine and norepinephrine leading to deleterious end-organ effects, perhaps most significantly seen in the kidneys. Lastly, the diagnosis and treatment of HF may result in direct insult to the kidneys. Use of contrast agents, as well as treatment with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blocking agents (ARBs) may have an acute negative impact on kidney function, resulting in AKI. Diuretics are the first-line therapy for patients with volume overload but may contribute to an increase in BUN and serum creatinine levels. Interestingly, a recent report intricately ties congestive HF and worsening renal function (WRF), which was defined as an increase in serum creatinine levels of 0.3 mg/dl from baseline values obtained at admission. Metra assessed 599 consecutive admissions to a single center and found that WRF without evidence of congestion, which was defined as the persistence of 1 or more signs of volume overload, was not an independent determinant of outcomes [13]. However, WRF in conjunction with congestion had a hazard ratio of 2.44 (CI 1.24-4.18) on multivariable analysis for mortality. This study offers multiple insights into the understanding and diagnosis of CRS type 1. Acute right HF may also result in AKI. Haddad et al. recently reported that AKI is common in patients with pulmonary arterial hypertension and acute right-sided HF, and that the presence of AKI was strongly associated with 30-day mortality [14]. In a study of 145 consecutive adult admissions for acute decompensated HF, Mullens et al. identified venous congestion as the most important hemodynamic predictor of WRF, even more so than pulmonary capillary wedge pressure or cardiac index [15]. This suggests that impaired systolic function may not play as a big a role in the development of AKI as previously thought. Serum creatinine may not be the best marker for AKI, especially for predicting mortality. Furthermore, right-sided HF plays a key role in AKI, most likely through the elevated central venous pressure.
Table 1

Acute kidney injury (AKI) studies of cardiorenal syndrome (CRS) in children

Reference

Biomarker

Year

Subjects

Patient population

Price [16]

N/A

2006

73

ADHF

Zappitelli [60]

N/A

2009

390

CPB

Blinder [19]

N/A

2012

225

CPB

Mishra [18]

NGAL

2005

71

CPB

Dent [61]

NGAL

2007

120

CPB

Bennett [62]

NGAL

2008

196

CPB

Xin [63]

NGAL

2008

36

CPB

Ricci [59]

NGAL

2011

80

CPB

Parikh [64]

NGAL

2011

311

CPB

Krawczeski [20]

NGAL

2011

220

CPB

Parikh [65]

IL-18

2006

71

CPB

Xin [63]

IL-18

2008

36

CPB

Parikh [64]

IL-18

2011

311

CPB

Krawczeski [20]

IL-18

2011

220

CPB

Krawczeski [66]

Cystatin C

2010

374

CPB

Ricci [59]

Cystatin C

2011

80

CPB

Zappitelli [67]

Cystatin C

2011

288

CPB

Han [68]

KIM-1

2008

20

CPB

Krawczeski [20]

KIM-1

2011

220

CPB

Portilla [69]

L-FABP

2008

40

CPB

Krawczeski [20]

L-FABP

2011

220

CPB

The diagnosis of CRS type 1 in adult and pediatric populations often goes unrecognized secondary to poor surveillance and lack of timely biomarkers. In many centers, understanding of the importance of diagnosis and opportunity for intervention goes unrecognized. We have an ongoing prospective study at our institution to assess the importance of AKI in the setting of ADHF. Limited retrospective data suggest an increase in serum creatinine > 0.3 mg/dl is predictive of transplant, mechanical support, or death in pediatric patients admitted with ADHF [16]. The perioperative pediatric population has yielded the most significant support for CRS type 1 in children. The diagnosis of AKI following cardiopulmonary bypass (CPB) is associated with increased length of ICU stay and long-term mortality and complicates up to 40 % of cardiac surgeries [17, 18]. Blinder et al. demonstrated that severe AKI (>200 % rise in creatinine) after bypass was associated with worse LV function 30 days post-operatively [19]. We recently reported on the use of neutrophil gelatinase-associated lipocalin (NGAL), interleukin [IL]-18, liver fatty acid-binding protein (L-FABP), and kidney injury molecule [KIM]-1 for use in predicting AKI in children post-cardiopulmonary bypass [20]. AKI occurred in 27 % of our cohort. Urine NGAL levels were found to increase 2 h after CPB initiation in patients with AKI. IL-18 and L-FABP increased at 6 h and KIM-1 increased at 12 h after CPB. The sequential elevation of these biomarkers correlated with disease AKI severity and patient outcomes. More importantly, when used in combination, the biomarkers improved predictive ability in the diagnosis of AKI when added to the demographic clinical model. The high rate of post-CPB-associated AKI and resulting poor outcomes has led some, including our center, to adopt a practice of peritoneal dialysis provision in the immediate post-operative period if oliguria develops (< 0.5 to 1 ml/kg/h for 4 h) [21]. We are currently conducting a prospective randomized trial of furosemide vs. PD in this population to determine if PD will improve negative fluid balance in the 24 h post-CPB. There are no established guidelines for the treatment of WRF in the setting of ADHF. Clinically, CRS type 1 is typically managed by decreasing or discontinuing diuretic therapy in an attempt to mitigate the ongoing kidney damage. However, this results in limited symptomatic relief for the patient. The use of ultrafiltration (UF) has been proposed as an effective treatment strategy. Results of the UNLOAD (Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure) study suggest that UF, when compared with intravenous diuretics, resulted in greater weight and fluid loss in adults with ADHF [22]. However, decision-making regarding the appropriate timing of UF in these patients continues to be a point of debate. The ongoing CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) study is evaluating the efficacy and safety of UF versus stepped pharmacologic care in the treatment of persistent congestion and WRF [23]. Future evaluation of UF in pediatric HF populations may be warranted.

CRS type 2

CRS type 2 is characterized by chronic cardiac function that results in CKD. It is estimated that the prevalence of renal dysfunction in the setting of chronic HF may be as high as 25 % [24]. Worsening renal function is a strong predictor of outcomes across various stages of HF and is associated with increased length of stay, hospitalization for worsening HF, and mortality [2527]. Perhaps one of the most intriguing reports linking the importance of kidney function in chronic HF comes from a sub-study of the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) study [24]. In this study, estimated glomerular filtration rate (eGFR) was a stronger predictor of mortality than either New York Heart Association (NYHA) class or left ventricular ejection fraction (LVEF). Traditional chronic therapies targeted at relief of symptoms in patients with chronic HF continue to be centered around the use of loop diuretics [28]. However, the use of loop diuretics results in significant increases in neurohormonal activation and increased blood urea nitrogen concentrations resulting in a worse outcome [29, 30]. Furthermore, the documented, chronic lifesaving treatments offered in chronic HF management are used, in part, to reduce these neurohormonal markers. The use of loop diuretics, although helpful in mitigating symptoms, results in an unfavorable neurohormonal balance and are strongly associated with decreased survival in adult populations [26].

CRS type 3

CRS type 3 is characterized by acute worsening in kidney function, which results in a deterioration in cardiac function. Typical causes of worsening of kidney function would include kidney ischemia or glomerulonephritis (GN) resulting in myocardial dysfunction, arrhythmia, or cardiac injury. This type of CRS is not well characterized as it has been studied only to a limited degree. However, it is of significant clinical importance in the ICU setting given the frequency of AKI being possibly as high as 35 % in critically ill adults and 82 % of critically ill children [31, 32]. Olowu recently reported a retrospective review of a single-center pediatric experience with CRS. Nearly half of the cohort (47/101) had CRS [33]. CRS type 3 was identified in ten patients with several associations, acute glomerulonephritis (AGN) (7/10), captopril administration (1/10), furosemide administration (1/10), and hypovolemia (1/10), being implicated. All-cause mortality was 34.2 % with CRS type 3 and AGN being risk factors (p = 0.001 and p = 0.023, respectively).

Treatment of CRS type 3

The treatment of type 3 CRS is mainly focused on mitigating the effects of AKI on cardiac performance. Aggressive attention to blood pressure control in AGN with vasodilating agents and diuretics is the mainstay of treatment, since AGN results in a sodium- and water-retaining state. Early recognition of AKI should prompt consistent measurement of electrolytes, such as potassium and ionized calcium, which can lead to arrhythmias. Medical management with electrolyte restriction or supplementation, fluid restriction, or phosphorus and potassium binders is usually sufficient to prevent arrhythmias. However, acute dialysis may need to be provided in cases refractory to medical management.

CRS type 4

CRS type 4 categorizes the clinical scenario of chronic kidney disease, resulting in chronic changes in cardiac structure or function. CKD is a common diagnosis and is reported to occur in association with various cardiovascular pathology, including systemic hypertension and abnormal vascular stiffness, left ventricular hypertrophy (LVH), and diastolic dysfunction. Echocardiographic changes may include increasing left ventricular thickness and mass, smaller left ventricular volumes, and increased left atrial volumes, all consistent with diastolic dysfunction. Often, patients with CKD have evidence of HF symptoms without the clinical diagnosis of HF [34]. Mitsnefes recently published an excellent review of CKD-associated CVD in children [35]. Data from the Chronic Kidney Disease in Children (CKiD) study demonstrate that both traditional and uremia-related CVD risk factors are highly prevalent in children with CKD [36, 37]. It is well known that CVD is the leading cause of death in children and young adults with CKD [38, 39]. In addition, cardiovascular calcifications are highly prevalent in children with ESRD, and are associated with mineral imbalance, malnutrition, and inflammation [4043]. Given the common and strong association of HF with CKD, careful attention must be given to potential comorbid cardiac disease. A meta-analysis of more than 80,000 adult HF patients demonstrated a 7 % increase in mortality for every 10 ml/min decrease in estimated GFR, underscoring the power of the cardiorenal axis in these populations [44]. Moreover, chronic renal insufficiency, as defined as an eGFR < 60, may be a stronger predictor of outcome than WRF, as evidenced by results from the ESCAPE trial [45]. Abnormal cystatin C levels have significant clinical utility in the assessment of CKD patients but have also been shown to be an independent predictor of both systolic and diastolic HF [46]. In addition, traditional biomarkers of HF such as B-type natriuretic peptide (BNP) and NT-proBNP must be interpreted with caution in the setting of CKD, making the diagnosis more challenging [47, 48].

The implications of AKI in the pediatric population may be substantial. Changes in markers of kidney function are strong predictors of cardiovascular morbidity and mortality but may also be a harbinger of development of chronic kidney disease (CKD). Hui-Stickle et al. demonstrated in a cohort of 174 patients that over one-third of the group had reduced kidney function or were dialysis-dependent upon discharge in a single tertiary center experience [49]. Askenazi followed this cohort for 3–5 years and found two-thirds had signs of chronic kidney injury [50]. Recently, Mammen showed 10 % of survivors of a pediatric ICU AKI episode had CKD at 1-3 years [51]. Current investigation is underway to elucidate the potential transition from AKI to CKD. However, it is known that the incidence of both AKI and CKD is increasing.

Treatment of CRS type 4

No pediatric studies are currently directed at treatment of CRS type 4, but careful and consistent attention to blood pressure control, dyslipidemia, mineral metabolism, nutrition status, and inflammation is the hallmark of current therapy [35].

CRS type 5

CRS type 5 categorizes the clinical scenario of an acute or chronic systemic disorder resulting in both cardiac and kidney dysfunction. The mechanisms behind this subtype remain poorly understood. Various mechanisms are postulated, including inflammation and cytokine upregulation. Tumor necrosis factor has been implicated as one possible mediator of dysfunction in both the heart and the kidneys [52, 53]. Once acute cardiac or kidney insult occurs, as in CRS types 1 or 3, a worsening cycle of damage may ensue, resulting in increased organ dysfunction.

Treatment is centered on interventions for the underlying systemic process, such as aggressive eradication of the underlying infection with appropriate supportive measures. However, clinicians must be mindful of the accompanying cardiorenal comorbidities when treating these systemic causes. Early identification of injury utilizing existing or novel biomarkers may greatly assist clinicians in this process. Without careful attention to cardiac and kidney function beneficial supportive strategies, such as inotropic therapy for low cardiac output or continuous renal replacement therapy for kidney failure, may be overlooked, resulting in chronic disease.

AKI biomarkers

As noted above, serum creatinine rise is associated with poor outcomes in adults and children with AKI, including those with acute HF. Even small increases of 0.3 mg/dl or 50 % increase in serum creatinine are independently associated with mortality [16, 54, 55]. Since serum creatinine is a kidney function marker, and not a marker of damage per se, it is not surprising that change in serum creatinine is a late indicator of significant kidney damage. Extensive research over the past 15 years to identify earlier and more sensitive AKI biomarkers has been termed the “search for the renal troponin I” [56]. It is not within the scope of this article to review all AKI biomarker literature, as many excellent reviews already exist [57]. Conceptually, the hope for AKI biomarker discovery and validation would be to identify AKI earlier to guide interventional trials or optimize supportive therapy. The use of a risk stratification model, such as the recently proposed “renal angina” construct [58] (which includes children with heart disease and a creatinine rise of ≥0.3 mg/dl), should guide biomarker assessment and interpretation. An initial encouraging report demonstrates that intra-operative fenoldopam prevents AKI and rise in NGAL after CPB [59]. Thus, this study supports the concept of AKI biomarker-directed interventional trials in at-risk populations.

Putting it all together: importance of the cardiorenal axis in the complete care of pediatric patients

The cardiorenal axis is of significant importance to pediatric patients in both acute and chronic conditions. Early recognition of either myocardial or kidney dysfunction allows for appropriate consultation and effective multidisciplinary care that can favorably alter patient outcomes. We have developed the Center for Acute Care Nephrology (CACN) to aggressively identify and treat patients with the cardiorenal syndrome in our institution. The CACN is a unique collaboration that is comprised of physicians from Nephrology, Cardiology, and Critical Care Departments. This construct allows for the most optimal care of pediatric and adult cardiorenal patients at CCHMC with unobstructed cross-talk between disciplines and thoughtful and productive research initiatives. No such program exists elsewhere in the US in pediatric medicine. However, we recognize the need for a broad and complete approach to patients with heart and kidney disease and have devoted time and resources to this burgeoning field. Based on our current experience and increasing evidence, we have constructed institutional recommendations that are translatable to other pediatric institutions.

Specific recommendations

  1. 1.

    Pediatric patients followed for systolic or diastolic dysfunction or a history of heart failure secondary to myocardial dysfunction should be appropriately screened for kidney disease, including being evaluated by a heart failure cardiologist with noninvasive imaging such as echocardiography or MRI and appropriate serologic testing including assessment of renal function and BNP.

     
  2. 2.

    All pediatric patients followed for chronic kidney disease should be appropriately screened for myocardial disease with noninvasive imaging such as echocardiography or cardiac MRI and appropriate serologic testing.

     
  3. 3.

    Pediatric patients with evidence of acute decompensated heart failure should be monitored for acute kidney injury.

     
  4. 4.

    Early intervention should be initiated in patients with clinical evidence of cardiorenal syndrome based on its potential benefits in specific populations.

     
  5. 5.

    Consultation of pediatric cardiology and pediatric nephrology should be considered to provide a multidisciplinary assessment and approach to patients with evidence of cardiorenal syndrome.

     

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