The complex interplay between the cardiovascular and renal systems has received significant clinical, translational, and basic research attention over the past 2 decades. In both the acute and chronic care settings, dysfunction of either the heart or the kidneys can lead to dysfunction of the other organ. While this interaction has been obvious and well known in severe cases (e.g., advanced kidney failure leading to hyperkalemia and resultant cardiac dysrhythmias), recent understanding of less severe or even subclinical interactions with profound bidirectional effects have been realized.
This chapter reviews these interactions under the construct of the cardiorenal syndromes, with a focus on acute and chronic renal consequences of cardiac disease, and on potential novel diagnostic and therapeutic maneuvers to improve patient outcomes.
Classification of the Cardiorenal Syndromes
The Acute Dialysis Quality Initiative convened a consensus conference in 2008 to codify heart-kidney interactions into five distinct cardiorenal syndrome categories ( Table 78.1 ). The cardiorenal syndromes are categorized as either acute or chronic, and whether the heart or kidney is the primary organ that is injured, or whether both are injured secondary to a systemic process.
|Type||Time Course||Primary Dysfunction||Secondary Dysfunction||Clinical Syndromes|
|1||Acute||Cardiac||AKI||Acute decompensated heart failure |
Acute coronary syndrome
|2||Chronic||Cardiac||AKI or CKD||LV dysfunction |
|3||Acute||Renal||Acute heart dysfunction or injury||Cardiopulmonary bypass |
Primary acute kidney disease leading to volume overload/electrolyte disturbance
|4||Chronic||Renal||Chronic cardiac dysfunction||Chronic hypertension |
Left ventricular hypertrophy
|5||Acute/Chronic||Systemic||Both||Systemic collagen vascular disease |
Acute Cardiorenal Syndromes: Type 1 and Type 3
The acute cardiorenal syndromes present significant challenges in patient management because recognition of acute disease can be delayed, and interventions can be invasive and sometimes exacerbate the clinical problem. Development of standardized acute kidney injury (AKI) definitions and staging criteria have led to an appreciation of the association between AKI and poor outcomes in children with heart disease. The evolution of these definitions and criteria have culminated in a harmonized construct from the Kidney Disease Improving Global Outcomes (KDIGO) AKI Work Group ( Table 78.2 ). As noted above, the critical clinical and epidemiologic advance from a standardized AKI definition and staging criteria has been the realization that even the doubling of serum creatinine or 12 hours of oliguria are associated with morbidity and mortality in children.
|Serum Creatinine Criteria||Urine Output Criteria|
|Definition||Increase by ≥0.3 mg/dL within 48 h |
Increase to 1.5 times baseline, which is known or presumed to have occurred within the prior 7 days
|Urine volume <0.5 mL/kg/h for 6 h|
|Stage 1 |
|1.5–1.9 times baseline |
≥0.3 mg/dL increase
2.0–2.9 times baseline
3.0 times baseline
Increase in plasma creatinine to ≥4.0 mg/dL
Initiation of renal replacement therapy a
In patients age <18 y, a decrease in eGFR b to <35 mL/min/1.73 m 2
|<0.5 mL/kg/h for 6–12 h |
<0.5 mL/kg/h for ≥12 h
<0.3 mL/kg/h for ≥24 h
Anuria for ≥12 h
b eGFR was calculated from the original Schwartz formula, where eGFR = k × patient height (cm)/plasma creatinine (mg/dL) and k is a constant defined as 0.45 (infant <1 year), 0.55 (child or adolescent female) or 0.70 (adolescent male).
Post Cardiac Surgery
The most common and most studied acute cardiorenal syndrome seen in the pediatric setting occurs after cardiac surgery involving cardiopulmonary bypass (CPB). The focus on this population results from the clinical scenario providing a virtually unique situation in which to study AKI compared to other hospital-acquired conditions leading to, or associated with, AKI, which have been the subject of clinical and translational research ( Table 78.3 ). The fact that (1) the timing of renal insult, ischemic injury associated with the CPB procedure, is known; (2) KDIGO (or equivalent) AKI rates are high (30% to 60%) and more severe KDIGO Stage 2 or 3 rates are also high (10% to 20%) ; and (3) this population has few other comorbidities provides an ideal clinical environment for epidemiologic and clinical/translation research.
|Setting||Timing of Insult||AKI Rates||Frequency of Lab Monitoring||Urine Assessments||Translational Assessments|
|Postcardiac surgery||Known||Known (30%–40%)||At least daily||Available via indwelling catheter||Multiple biomarker studies|
|General ICU||Unknown||Known (20%–30%)||At least daily||Available via indwelling catheter||Multiple biomarker studies|
|Nephrotoxic exposure||Known||10%–20%||Variable||Not routinely available||Few single agent biomarker studies|
|Emergency center||Unknown||Unknown||Single time point||Single time point||Few single time point studies|
CPB induces AKI by mechanisms that are multifactorial and complex, but includes ischemic insult followed by a reperfusion insult, loss of pulsatile renal blood flow, renal vasoconstriction, and microemboli. The cellular biochemistry of CPB-induced AKI is also quite complex and is depicted in Fig. 78.1 . Given the high incidence of post-CPB AKI, numerous pre- and intraoperative risk factors have been identified to assist in AKI prediction ( Table 78.4 ). Of particular note, age younger than 2 years, CPB duration of greater than 90 minutes, and single ventricular physiology appear to have strong associations with the development of postoperative AKI.
|Duration of cardiopulmonary bypass|
|Young gestational age|
|Higher RACHS-1 category|
|Higher preoperative serum creatinine|
|Lower preoperative serum creatinine|
|Longer intraoperative time|
|Multiple cross clamps|
|Functional single ventricle|
|Preoperative inotropic support|
|Preoperative mechanical ventilation|
|Preoperative peritoneal dialysis|
Cardiac Surgery–Associated AKI and Outcomes
This strong association between AKI after cardiac surgery in children and patient morbidity and mortality has been demonstrated repeatedly over the past decade. Review of the largest studies, each comprising at least 400 surgeries ( Table 78.5 ), reveals mortality rates ranging from 8.9% to 54% for patients who developed AKI versus 1.2% to 6% for patients who did not develop AKI (all P values < .0001). In addition, multiple studies demonstrate that increased fluid accumulation after surgery was associated with mortality, independent of serum creatinine based AKI status, and one showed that the association between AKI and outcomes was strengthened when serum creatinine concentration was corrected for the degree of fluid overload, suggesting that fluid accumulation may mask AKI severity by diluting the serum creatinine concentration; this is a phenomenon that has been described in critically ill adults. Most strikingly, the associations observed between AKI and/or fluid overload and mortality have been controlled for underlying heart disease and operative factors, and in some studies, the associated risk for mortality is higher with AKI development than single ventricular physiology. Both AKI development and excessive positive fluid accumulation have also been associated with prolonged mechanical ventilation/delayed extubation, increased need for inotropic support, and intensive care unit length of stay.
|Study Author (Subjects)||Mortality Rates for AKI vs. No AKI||OR (95% CI) for Mortality With AKI||Ventilation Time (Median [IQR]) for AKI vs. No AKI|
|Blinder (n = 430)||11.6% vs. 2.9%||Stage 1 (1.3; 0.4–4.1) a |
Stage 2 (5.1; 1.7–15.2)
Stage 3 (9.5; 2.5–30.7)
|5 [3–7] vs. 3 [2–5] days|
|Chiravuri (n = 494)||54.4% vs. 6%||AKI-RI (6.7; 4.1–10.8) b |
AKI-F (36.9; 20–67.9)
|Toth (n = 1510)||8.9% vs. 1.2%||NA||49 [26–112] vs. 33 [15–76] hours|
b Pediatric modified RIFLE (risk, injury, failure, loss, end-stage kidney disease) criteria used for AKI. These criteria used decreases in estimated glomerular filtration rate (eGFR) to stratify AKI severity. Risk: 25% decrease; injury: 50% decrease; failure: 75% decrease or an eGFR <35 mL/min per 1.73 m 2 ; loss: persistent failure for 4 weeks; end-stage kidney disease: persistent failure for >3 months.
Given that nephrotoxic medication avoidance and fluid management represent the two modifiable risk factors for patients with, or at risk for AKI, systematic risk assessment to guide interventions is paramount. Some recommend avoidance of greater than 10% fluid (in liters) accumulation based on body weight (in kilograms) using the following formula :
Percent fluid overload=[Total fluid intake(L)−Total fluid output(L)]ICU admit weight(kg)×100%
The 10% fluid overload threshold is based on numerous studies of critically ill children with AKI who received continuous renal replacement therapy (CRRT), which observed an association between >10% and 20% fluid overload at CRRT initiation and patient mortality, independent of patient severity of illness. Three recent studies in children after cardiac surgery show that avoidance of 10% fluid overload was associated with increased survival and/or decreased days of mechanical ventilation. The strategies to limit fluid overload in the setting of AKI are fluid restriction, administration of diuretics, and initiation of renal replacement therapy.
While modified ultrafiltration during the CPB procedure is effective at minimizing fluid overload upon arrival to the cardiac intensive care unit, fluid restriction likely has little utility in the early postoperative period as patients develop capillary leak from the system inflammation caused by CPB and the surgery itself. Furthermore, fluid restriction limits the ability to provide adequate nutrition for anabolism in patients who are highly catabolic and at risk for AKI for up to 72 hours due to the low cardiac output state associated with long bypass durations. Therefore, fluid restriction alone, without escalation to diuretic administration or the initiation of renal replacement therapy, should only be considered in older pediatric patients (>1 year of age) with adequate nutritional reserves.
Diuretic, especially loop diuretic, administration is nearly ubiquitous and a “backbone” for patients with or at risk for AKI in the critical care setting with a goal of preventing or reversing fluid overload. Loop diuretics exhibit their effect by blocking sodium, potassium, and chloride resorption in the thick ascending limb of the loop of Henle. Increased urinary excretion of sodium, potassium, and fluid are beneficial in the patient with AKI, and when effective, can allow for provision of adequate nutrition-associated volumes without the development of fluid overload. Although some debate exists regarding the superiority of different loop diuretic medications (furosemide vs. ethacrynic acid ), maximum dose and administration (intermittent bolus vs. continuous infusion), a detailed discussion is beyond the scope of this chapter. However, it is critical for the clinician to establish daily goals of diuretic therapy in terms of net fluid balance given the optimal fluid, nutrition, and blood product needs of the patient, and to be firm in their assessment of diuretic resistance. Escalation of diuretic therapy to achieve these goals, including the addition of a thiazide diuretic should be made in a systematic and rational fashion, with a clear sense that diuretic resistance should not be defined by a particular urine flow rate in mL/kg per hour, but with an objective accounting of whether or not diuretics achieve the needed fluid balance. In addition, potent and increased diuretic administration is not devoid of the consequences of ototoxicity, severe electrolyte derangement, including metabolic alkalosis, hyponatremia, hypokalemia, and worsening of functional AKI leading to decreased renal perfusion.
Recently, the concept of the furosemide stress test (FST) has codified an objective metric for diuretic resistance in critically ill adults. The FST uses a standardized dose of intravenous furosemide (1 mg/kg in naive patients, 1.5 mg/kg in patients with chronic kidney disease [CKD] or who have received furosemide) and assesses urine output (UOP) in the 2 hours after administration. Patients who did not have more than 200 mL/h of UOP progressed to worsening AKI stages. A retrospective pediatric study of over 500 infants after cardiac surgery assessed a version of the FST, where UOP was assessed at 2 and 6 hours after a diuretic challenge. This study found that patients who had UOP of at least 1 mL/kg per hour were very unlikely to develop AKI. Taken together, these studies suggest that a standardized, objective assessment of diuretic responsiveness can aid in the prediction of AKI development or worsening severity.
When diuretics are unable to achieve fluid and electrolyte homeostasis, escalation to the provision of renal replacement therapy (RRT) is warranted. Determination of the optimal timing of RRT initiation has been a major focus of study in the field of critical care nephrology with conflicting outcomes, but recent studies in the pediatric cardiac surgery population have provided some positive results. However, it is important to dispel the notion that RRT itself causes irreversible kidney damage and failure. Nearly 20 years ago, one study demonstrated increased urine output after peritoneal dialysis was initiated in 20 infants after cardiac surgery. A second study randomized patients to continue versus discontinue peritoneal dialysis (PD) after a positive diuretic challenge, and found no differences in total negative fluid balance or concentrations of novel kidney damage biomarkers, and urine output continued to increase even in the patients randomized to PD continuation.
Recent studies have examined the association between PD and outcomes after cardiac surgery in children ( Table 78.6 ). In a retrospective analysis, Bojan and colleagues observed a nearly 50% decrease in patient mortality when PD was initiated on the first postoperative day versus later in the postoperative course. Two studies by Kwiatkowski and colleagues compared fluid balance, mechanical ventilation days, and electrolyte management in children who received PD catheter placement intraoperatively. In each of these studies, PD catheters were placed intraoperatively based on patient characteristics that increase the risk of postoperative AKI development ( Table 78.7 ). The first was a retrospective study of patients who received intraoperative PD catheter placement after the institution of risk-guided practice versus a matched historical cohort who did not receive a catheter prior to this practice. Patients who received a PD catheter were able to achieve negative fluid balance in the first 48 hours more often, had lower rates of 10% fluid overload, were extubated 24 hours earlier, and had fewer electrolyte derangements than those without a PD catheter. The second study was a prospective randomized study of the initiation of PD versus diuretics in patients with urine output of less than 1 mL/kg per hour for 4 consecutive hours in the first 24 hours after surgery. Patients who received PD were less likely to develop 10% fluid overload, and to have prolonged mechanical ventilation and prolonged inotrope use. Given the high incidence of AKI after cardiac surgery, these studies collectively suggest that PD catheters should be placed intraoperatively in high-risk patients to prevent severe fluid overload and to maintain electrolyte homeostasis in patients who develop oliguria and/or are diuretic resistant.