Acute Childhood Cardiorenal Syndrome and Impact of Cardiovascular Morbidity on Survival

Cardiorenal syndrome (CRS) clinical types, prevalence, aetiology, and acute cardiovascular morbidity impact on the outcome of acute kidney function perturbation were determined. Forty-seven of 101 (46.53%) patients with perturbed kidney function had CRS. Types 3 and 5 CRS were found in 10 and 37 patients, respectively. Type 3 CRS was due to acute glomerulonephritis (AGN; n = 7), captopril (n = 1), frusemide (n = 1), and hypovolaemia (n = 1). Malaria-associated haemoglobinuria (n = 20), septicaemia (n = 11), lupus nephritis (n = 3), tumour lysis syndrome (n = 2), and acute lymphoblastic leukaemia (n = 1) caused Type 5 CRS. The cumulative mortality in hypertensive CRS was similar to nonhypertensive CRS (51.4% versus 40.9%; P = .119). Mortality in CRS and non-CRS was similar (45.7% versus 24.5%; P = .053). Type 5 survived better than type 3 CRS (66.7% versus 12.5%; P = .001). Risk factors for mortality were Type 3 CRS (P = .001), AGN-associated CRS (P = .023), dialysis requiring CRS (P = .008), and heart failure due to causes other than anaemia (P = .003). All-cause-mortality was 34.2%. Preventive measures aimed at the preventable CRS aetiologies might be critical to reducing its prevalence.


Introduction
The cardiorenal syndrome (CRS) is a disorder of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other [1,2]; it is a recognized morbidity and mortality multiplier in critically ill children [3]. While heart failure (HF) is a clinical syndrome in which heart disease reduces cardiac output, increases venous pressures, and is accompanied by molecular abnormalities that cause progressive deterioration of the failing heart and premature myocardial cell death [4], acute kidney injury (AKI) is an abrupt clinical and/or laboratory manifestation of kidney dysfunction usually within 48 hours of bilateral kidney insult of any kind. Failure of both organs commonly coexists in critically ill children [5][6][7]. Congestive HF is a highly prevalent AKI comorbidity and a major indication for acute dialysis in children [5]. Recently, the 7th Acute Dialysis Quality Initiative (ADQI) workgroup classified CRS into five distinct clinical types, [1,2] namely: acute CRS (Type 1)-acute worsening of heart function leading to kidney injury and/or dysfunction; chronic CRS (Type 2)-chronic abnormalities in heart function leading to kidney injury and/or dysfunction; acute renocardiac syndrome (Type 3)-acute worsening of kidney function (AKI) leading to heart injury and/or dysfunction; chronic renocardiac syndrome (Type 4)-chronic kidney disease leading to heart injury, disease, and/or dysfunction, and secondary CRS (Type 5)-systemic conditions leading to simultaneous injury and/or dysfunction of heart and kidney. While a lot of data have been published on chronic kidney disease as risk factor for cardiovascular morbidity and mortality in both children and adults (reviewed in [1][2][3]), there is paucity of specific data on acute cardiac dysfunction leading to AKI and vice versa in children especially [8]; in this study, an attempt was made to determine the prevalence, aetiology, clinical types of CRS, and impact of acute cardiovascular morbidity on the outcome of childhood acute kidney injury.

Patients and Methods
Clinical charts of patients managed for AKI-associated HF and acute glomerulonephritis (AGN)-associated HF in our paediatric nephrology and hypertension unit were reviewed. It was a retrospective case-control study; patients who had either AKI or AGN without HF served as control (non-CRS). The objectives were to determine the prevalence, aetiology, clinical types of CRS, and impact of acute cardiovascular morbidity on the outcome of childhood AKI. The study period ranged between January 2005 and December 2009. Our hospital's Ethics and Research Committee approved the research protocol. The study conformed to the provisions of the revised Declaration of Helsinki, Edinburg, 2000.
Analyzed data were age, gender, anthropometry, vital signs, admission diagnosis, time of onset of HF and AKI, final AKI stage, hospitalization period, follow-up duration, urine output, and management outcome. Relevant laboratory investigations including serum creatinine (Scr) both at baseline and at followup were reviewed.

Definitions.
AKI was diagnosed based on the acute kidney injury network (AKIN) criteria [9] as an absolute increase in serum creatinine (Scr) level within 48 hours of bilateral kidney insult by ≥0.3 mg/dL (≥26.4 µmol/L) or a 50% (1.5-fold) increase or more in Scr from the baseline. AKI was staged using the creatinine criteria of the AKIN workgroup [9]-Stage 1 AKI (AKI-1): rise in Scr by ≥0.3 mg/dL (26.4 µmol/L) or an increase of >150-200% (1.5-to 2-fold increase) from the baseline; Stage 2 AKI (AKI-2): rise in Scr by >200-300% (>2-to 3-fold increase) from baseline; Stage 3 AKI (AKI-3): rise in Scr by >300% (>3-fold) from the baseline or Scr ≥ 4.0 mg/dL (≥354 µmol/L) with an acute rise of at least 0.5 mg/dL (44 µmol/L). Nonoliguric AKI was defined as urine output that was persistently >0.5 mL/kg/hour in the setting of an abnormal Scr level. Anuric AKI was defined as the urine output that was <0.039 mL/kg/hr for 12 hr or more in the absence of an obstructive uropathy. AKI was staged based on the peak Scr (pScr) level. pScr was the highest Scr level reached in any patient either before death or before gradual return to normal. Those who were initially diagnosed AKI-1 or AKI-2 but later required dialyses were upgraded to AKI-3 as recommended [9]. The predictive eGFR equation with corrections for age, gender, and race derived by the Modification of Diet in Renal Disease (MDRD) [10] study group was used to determine the baseline Scr for patients who do not have baseline Scr as recommended by the 2nd ADQI workgroup [11]. For such patients, the 2nd ADQI recommended that normal estimated glomerular filtration rate (eGFR) ranging from 75 to 100 mL/min per 1.73 m 2 should be used. In this study, all AKI patients without baseline measure of renal function were assumed to have eGFR value of 100 mL/min/1.73 m 2 . By the MDRD equation, [10].
Heart failure was diagnosed based on a combination of dyspnoea, tachycardia (heart rate >160, >150, >140, >120, and >100 beats/min for infants, children aged 1-3, 4-5, 6-12, and above 12 years, resp.), tachypnoea (respiratory rate >60, >40, >34, >30, and >20 breathes/min for infants, children aged 1-3, 4-5, 6-12, and above 12 years, resp.), tender hepatomegaly, and feeding difficulty with or without chest X-ray evidence of cardiomegaly (abnormal cardiothoracic ratio >60% in under fives and >55% in older children). HF severity was assessed and classified according to the modified Ross heart failure classification for children [12]-Class I heart failure: asymptomatic; Class II heart failure: mild tachypnoea or diaphoresis with feeding in infants or dyspnoea on exertion in older children; Class III heart failure: marked tachypnoea or diaphoresis with feeding in infants, marked dyspnoea on exertion, and prolonged feeding times with growth failure; Class IV heart failure: symptoms such as tachypnoea, retractions, grunting, or diaphoresis at rest. Hypertension was diagnosed based on the update of the 1987 Task Force Report on High Blood Pressure in Children and Adolescents [13]. CRS was classified based on the 7th ADQI consensus conference report [2].
The inclusion criteria were patients with acute perturbation of kidney function (AKI or AGN or both) with or without HF. Patients with chronic renal failure or acute-onchronic renal failure were excluded. To determine the impact of HF on survival, mortality was compared between CRS (AKI + HF and AGN + HF) and non-CRS patients. The cumulative all-cause-mortality and CRS-specific mortality rates were determined.

Results
A total of 101 patients with acute perturbation of kidney function, namely, AKI and AGN were reviewed. There were 7 and 94 acute glomerulonephritis (AGN) and AKI patients, respectively. Forty seven of 101 (46.53%) patients with abnormal kidney function had HF-cardiorenal syndrome. HF was of the severest class (Class IV) in all the CRS patients. Age, gender, and blood pressure data are summarized in Table 1. Median age of 5.0 years (0.06-15.0) for controls was similar to that for CRS, P = .689. Types 3 and 5 CRS were found in 10 (21.3%) and 37 (78.7%) patients, respectively. Table 2 shows the relationship between the two CRS types in this study and their aetiologies. Two of 7 patients whose CRS was due to AGN had no associated AKI (AGN-AKI) while the remaining 5 had associated AKI. The pScr was 6.11 ± 4.0 (0.95-17.32) mg/dL. AKI-1, AKI-2, and AKI-3 accounted for 4 (8.50%), 5 (10.60%), and 36 (76.60%) CRS cases, respectively, while AGN-AKI accounted for the rest. Twenty-two (46.80%) of the CRS patients had oliguric AKI while nonoliguric and anuric AKI were seen in 11 (23.40%) and 14 (29.80%) patients, respectively. Oliguria duration in both CRS and controls was 6.9 ± 5.54 days and 7.5 ± 4.75 days, respectively (P = .654).

Discussion
This study revealed CRS as a highly prevalent clinical event in acute perturbation of kidney function with hypertension as a common cardiovascular comorbidity. Given the spectrum of CRS aetiology in this study, hypertension was probably the result of intravascular congestion brought about by oliguria seen in 76.6% of the patients on one hand, and activation of the renin-angiotensin-aldosterone-system following renal hypoperfusion secondary to acute proliferative changes of AGN on the other hand. Interestingly, hypertension was found not to be a significant risk factor for mortality in this study (HR: 0.476, 95% CI: 0.183-1.240).
The acute nature of the CRS and the accompanying hypertension, as well as, prompt response to antihypertensive treatment, and vascular decongestion following diuretic phase onset could be responsible for this. Left ventricular hypertrophy and congestive HF are common in childhood AGN and CKD with high mortality rate [7,[14][15][16]. In this study, HF was highly prevalent and mortality rate from CRS was equally high but was not significantly different from controls; this is not withstanding the fact that the HF was of the severest class (Class IV). Anaemia is a highly prevalent comorbidity in both AKI [5,6,17] and CKD [18]; it has been associated with increased severity of congestive HF, increased hospitalization, worse cardiac function and functional class, the need for higher doses of diuretics, progressive worsening of renal function, and reduced quality of life [19]. Anaemia occurred in 91.5% of our patients with anaemia-specific mortality rate of 38.6%. Nonanaemic CRS patients were, however, 4.6 times more likely to die than their anaemic counterparts (95% CI: 1.496-14.370). This is because the majority of the anaemic cases were due to malaria that responded rapidly to treatment; the acute nature of the accompanying congestive anaemic HF that responded promptly to blood transfusion also contributed to better survival in the anaemic CRS compared to nonanaemic CRS that was largely due to poor outcome septicaemia and AGN. While AKI stage and type did not influence the outcome in this study, Type 5 CRS was found to protect against mortality. The positive impact of Type 5 CRS on survival was due to the fact that the majority of the patients in this class had MAH that was significantly associated with the highest survival rate compared to Type 3 CRS in which majority of the patients had AGN that was significantly associated with very low survival rate. The fact that CRS patients who required no dialysis survived better than those who required dialysis (HR: 0.28; 95% CI: 0.106-0.765) could mean more severe structural kidney pathology and dysfunction in those needing dialysis. This was particularly more evident when CRS was stratified for CRS types and outcome.
It is concluded that CRS was a very common clinical event with high mortality rate in critically ill children. Compared to controls, CRS mortality rate was not significantly higher; risk factors for mortality in CRS were CRS Type 3, AGN-associated CRS, dialysis-requiring CRS, and heart failure not associated with anaemia. Preventive measures aimed at some of the preventable aetiologies of CRS might be critical to reducing its prevalence.