.png)
Written by: Salar Bani-Hani, MD; S. Sudha Mannemuddhu, MD, FAAP, FASN
Infographics: Salar Bani-Hani, MD
Expert Reviewer: Alexander Kula
AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.
Introduction
The heart and kidney are inextricably linked to health and disease. Regardless of whether the disease starts in the heart or kidney, both organs will eventually be affected. Moreover, once both organs are involved, patient outcomes significantly worsen. Nephrologists and cardiologists often find themselves similarly linked to caring for patients with overlapping pathophysiology. At times this relationship seems at odds- as each specialist prioritizes the considerations and needs of their preferred organ. However, a more productive coexistence for both organs and pediatric subspecialists is possible by focusing on the shared pathology of cardiorenal syndrome.
Classification of Cardiorenal Syndrome (CRS)
Cardiorenal syndrome encompasses a wide range of clinical scenarios, and subtypes of CRS were suggested by the Acute Dialysis Quality Initiative Workgroup (ADQI) (based on the primary site of damage and acuity/chronicity) (Figure 1).
Figure 1: ADQI Classification of cardiorenal syndrome
This classification system is imperfect for the following reasons:
These classifications were developed through studies of (mostly older) adult populations. However, the sequence of events that lead to each subtype would presumably remain valid in pediatric populations.
It has been questioned whether a widely heterogeneous syndrome could be neatly categorized into these 5 categories. For example, if a patient with longstanding diabetic nephropathy develops heart failure (HF),would this phenomenon best fall under Type 4 or Type 5 CRS? Or in an adolescent who presents out of the blue with significant kidney dysfunction and heart failure, it may be very challenging to separate whether this represents Type 2, Type 4, or Type 5 CRS. For both scenarios, do treatment strategies differ depending on type? This brings up another major limitation of the classification system - determining a subtype classification is often not beneficial for treatment decisions.
Finally, after passage of time, all types of CRS become a mixture of Type 2, Type 4, and Type 5 (e.g., hypertension).
Overall, the cardiorenal subtype framework provides a useful way to conceptualize possible sequences of events leading to cardiorenal pathology, but offers little beyond that. Fortunately, pediatric nephrologists are the type to embrace complexity and take a larger perspective on issues!
Pathophysiology
The pathophysiology of CRS is immensely complex and not fully understood. CRS results from complex hemodynamic, hypoxic, hormonal, metabolic, and inflammatory interactions and effects.
Hemodynamics:
Originally, aberrant hemodynamics were believed to be the primary driver of CRS. For patients with primary heart disease, kidney dysfunction was believed to result from hypoperfusion secondary to reduced cardiac output. Recent studies have shown that the pathophysiology more complicated and multi-faceted. Central venous pressure plays a crucial role in the pathophysiology. With declining cardiac function, central venous pressures increase, thereby transmiting back to the efferent arterioles causing decreased glomerular filtration pressure and subsequent renal injury. Other critical factors in developing CRS types 1 and 2 (Figure 2) include increased intraabdominal pressure and the activation of RAAS and sympathetic nervous system. Inflammatory damage to the kidney has also been associated with worsening cardiac function.
CRS type 2 is an important cause in the pediatric population due to the relatively high prevalence of congenital structural heart disease and cardiomyopathy. Patients with single-ventricle physiology are at increased risk for cyanotic nephropathy . Moreover, dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy, and the most common etiology requiring heart transplants in children. It is worth noting that many of the risks for kidney dysfunction carry over after heart transplantation. Up to 50% of pediatric heart transplant patients demonstrate some evidence of CKD at 5 years post-transplantation.
Figure 2: Pathophysiology CRS types 1 and 2. Abbreviations: ACE-I, angiotensin-converting enzyme inhibitor; CVP, central venous pressure; IAP, intra-abdominal pressure; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system
CRS types 3 and 4, which are associated with primary renal dysfunction (oliguric or anuric kidney injury/failure), predisposes patients to cardiac dysfunction and fluid overload (Fig 3,4). Almost 80% of children on maintenance dialysis have evidence of left ventricular hypertrophy, diastolic dysfunction with depressed contractility, and reduction of myocardial blood flow at some point during their need for chronic dialysis therapy. In addition, adult patients also showed reduced peripheral arterial compliance, impaired microcirculation, and ineffective vasoregulation, leading to myocardial stunning. While clinically evident cardiovascular disease (myocardial infarction, heart failure, etc) is rare in persons <18 years, the incidence greatly increases in young adulthood, highlighting the importance of effective preventative care.
There are many proposed mechanisms linking CKD and adverse cardiovascular remodeling. Hypertension, neurohormonal activation, acidosis, anemia, altered mineral metabolism, inflammation, and metabolic derangements have all been implicated in the pathogenesis. However, untangling the web of often interrelated mechanisms has proven to be exceptionally difficult.
Figure 3: Pathophysiology CRS type 3. Abbreviations: GFR, glomerular filtration rate; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system.
Figure 4: Pathophysiology CRS type 4. Abbreviations: CaPhos, calcium phosphate; FGF, fibroblast growth factor; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system
Finally, in type 5 CRS, the heart and kidneys are victims of systemic disorders such as sepsis and immunological diseases such as lupus, diabetes mellitus, and cancer (Fig 5).
Figure 5: Pathophysiology CRS type 5. Abbreviations: CaPhos, calcium phosphate; FGF, fibroblast growth factor; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system.
Diagnosis
Clinical features and evaluation:
The past medical history and physical exam are key tools. History of chronic heart disease (Congenital Cyanotic Heart Disease, Dilated Cardiomyopathy, etc.), heart failure, chronic kidney disease (CKD), hypertension, and diabetes are all potential risk factors for the development of CRS. These patients often present with clinical features of pulmonary or systemic congestion (or both) and kidney injury.
In CKD-
A patient may exhibit a sudden drop in blood pressure while on dialysis.
Weight gain, jugular vein distension, and crackles on physical exam.
Muscle wasting with volume overload.
Pallor, shortness of breath, and orthopnea throughout the day.
Worsening extremity edema and ascites ( while accounting for the degree of proteinuria and hypoalbuminemia).
In chronic heart disease-
Hypertension, microalbuminuria, and decreased estimated glomerular filtration rate are early indicators or markers of the development of cyanotic nephropathy.
Decreased urine output despite adequate diuretic dosages.
Loss of appetite, vomiting, and altered level of consciousness may reflect uremia.
Arrhythmias could reflect electrolyte abnormalities.
In the long run, bone fractures from mineral bone disease could occur.
Systemic response to overwhelming infection or an immunological condition would manifest with fever, malaise, joint pain, rash, etc. (especially for Type V CRS).
Hypotension requiring vasopressors and oliguria/anuria (especially for CRS Types I & III) are also signs of critical disease progression
Diagnostic tests:
Assessment of hemodynamic status: Changes in vital signs, central venous pressures, and measurement of intracranial and intra-abdominal pressure changes are essential.
Renal Biomarkers: creatinine and cystatin C help assess the glomerular filtration rate and kidney function. Neutrophil gelatinase-associated lipocalin (NGAL) helps assess for AKI. NGAL changes more rapidly (hours) than serum creatinine, which is often delayed by a day or two following an insult. Parathyroid hormone levels, iron levels, vitamin D levels, calcium and phosphorus may give insight into CKD if no previous history is known.
Basic serum studies to assess blood loss, electrolyte, and acid-base disturbances.
Cardiac function biomarkers: BNP and troponin T, however, could be falsely elevated in patients with reduced renal clearance.
Imaging studies to assess cardiac status and renal-bladder anatomy.
Echocardiogram/ EKG/ POCUS to assess filling pressures and ejection fraction. Chest X-ray to evaluate cardiac silhouette and possible fluid overload.
Ultrasound of kidneys with doppler could help guide treatment therapies (e.g., reversal of flows could mean intravascular volume depletion despite edema, and scaling back on diuresis could be imperative).
Inflammatory markers such as CRP, procalcitonin, white blood cell count and neutrophils to assess infection and inflammation.
Biomarkers of cell-cycle arrest, such as urine insulin-like growth factor-binding protein-7 and tissue inhibitor of metalloproteinase-2, can identify patients at risk of developing acute CRS.
Management
The two key goals in the management of all types of CRS are 1) addressing volume overload and 2) treating the underlying etiology (heart failure, kidney injury, sepsis, lupus, etc.). Though cardiac dysfunction is the leading cause of CRS, the kidney’s response to altered volume status via autoregulation and tubuloglomerular feedback plays a significant role. Weight changes and input/output measurements are imprecise, and in response many providers have adopted a natriuresis-based estimation of diuretic response. An online natriuretic response prediction equation is available at www.cardiorenalresearch.net.
Diuretics: Mainstay and first-line treatment for volume overload in CRS. Higher doses are typically needed in the setting of AKI/CKD. Cardiologists and intensivists initiate the management in most centers with either a continuous infusion or intravenous boluses of diuretics. Nephrologists assist with dialysis mediated ultrafiltration when diuretic resistance (DR) ensues.
Several strategies like maximizing the efficacy of loop diuretics (appropriate type of loop diuretic, route, dose, and/or frequency), sequential blockade (metolazone, thiazide diuretics, SGLT2 inhibitors, etc.), vasopressin antagonists (prevents water reabsorption), and hyperdiuresis and chloride repletion (boluses of 3% saline followed by diuresis) can be used in DR.
Amiloride, mineralocorticoid antagonists, and acetazolamide promote diuresis while managing dyselectrolytrolytemias and acid-base status.
Kidney Replacement Therapy (KRT): Acute modalities including continuous kidney replacement therapy (CKRT), hemodialysis (HD), and sometimes peritoneal dialysis (PD) are utilized when diuresis fails.
Temporary (CKRT, acute HD) or chronic dialysis is almost always needed in severe cases of CRS when oliguria/anuria ensues. CKRT and HD are used to improve cardiac function, decrease venous congestion, and treat symptoms of uremia.
Aquadex and Carpediem are two of the most recent developments in KRT to achieve fluid removal in infants (neonates weighing as little as 2 Kg).
PD (often starting with continuous 24 hours in acute CRS) is utilized in children with cardiomyopathy or post-cardiac surgery.
Cardiac dysfunction: No data has shown the benefit of inotropes for CRS; however, inotropes may improve cardiac function and promote diuresis (ie. dobutamine or milrinone).
Assessment for extra corporeal membrane oxygenation (ECMO) or ventricular assist devices (VAD) if applicable, to support cardiac function in CRS type I & II.
Consider ACEis/ ARBs to prevent cardiac remodeling on CRS type IV and V.
Renal dysfunction: Mitigating the effects of AKI on cardiac performance is the primary goal of CRS type 3. Careful and consistent attention to blood pressure control, dyslipidemia, mineral metabolism, nutrition status, and inflammation is the hallmark of CRS type 4.
Mechanical ventilation is also frequently needed, particularly in fluid overload.
The clinical evidence supporting the beneficial effects of vasodilators (nitroglycerin, sodium nitroprusside, and hydralazine) is weak, particularly with hypotension being a significant side effect.
Figure 6: Management of Cardiorenal syndrome. Abbreviations: CVVH, continuous venovenous hemofiltration; CVVHD, continuous venovenous hemodialysis; CVVHDF, continuous venovenous hemodiafiltration; GFR, glomerular filtration rate.
Prognosis:
The overall prognosis of CRS is poor. Complications such as liver failure, respiratory failure, and worsening cardiac and renal failures can occur. Anticipation of CRS, early identification, and prompt management are keys to successful management. Blood urea nitrogen (BUN), systolic blood pressure, serum creatinine, brain natriuretic peptide, and response to diuretics are used in mortality and readmission predictor calculators in the adult population.
Take Home Message:
Cardiorenal syndromes (CRS) are a group of linked disorders of the heart and kidneys.
There are 5 types of CRS based on etiology and chronicity. Determining a subtype is often not beneficial for treatment decisions.
All pediatric patients with systolic/ diastolic dysfunction should be screened for kidney disease. CKD patients should be screened for myocardial disease via imaging and serologic testing.
Sudden changes in hemodynamic status and chemistries should alert to the possibility of CRS.
Diuresis, hemofiltration, and addressing the etiology are the mainstays of treatment.
AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.