Cardiorenal Syndrome

Etiology

There are 5 subtypes of cardiorenal syndrome; each type has its unique pathophysiology, with unique management strategies and varying prognoses.[3][4] Cardiorenal syndrome type 1 is the most common and most analyzed.[5]

• Type 1: A sharp decline in cardiac function that results in an acute decrease in renal function
• Type 2: Chronic cardiac dysfunction that results in a sustained reduction in renal function
• Type 3: A sharp decline in renal function that results in an acute reduction in cardiac function
• Type 4: A chronic decline in kidney function that results in chronic cardiac dysfunction
• Type 5: Systemic diseases that result in both cardiac and renal dysfunction

Epidemiology

The 2007 report on the 118,465 patients admitted with acutely decompensated heart failure in the Acute Decompensated Heart Failure National Registry database showed that 9% of patients had normal renal function on admission whereas 27.4% had mild renal dysfunction (defined as glomerular filtration rate [GFR] 60–89 mL/min/1.73m²), 43.5% had moderate renal dysfunction (GFR 30–59 mL/min/1.73m²), 13.1% had severe renal dysfunction (GFR 15–29 mL/min/1.73m²), and 7.0% had a GFR less than 15 mL/min/1.73m² or were on chronic dialysis.[6][7] Other large databases have shown that the prevalence of cardiac or renal dysfunction increases the incidence of the other.

Pathophysiology

Type 1 cardiorenal syndrome occurs when there is acute decompensation of cardiac function leading to a decrease in glomerular filtration. Researchers have previously proposed that a decline in cardiac output, accompanied by decreased renal perfusion, is the leading underlying cause of worsening kidney function in cardiorenal syndrome types 1 and 2. However, results from recent studies have postulated that increased central venous pressures are a more critical factor.[1] When patients develop fluid overload due to worsening cardiac function, venous pressures increase and are transmitted back to the efferent arterioles, resulting in a net decrease in glomerular filtration pressure and renal injury. The classical renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system act together to link heart and kidney damage. Continued overactivity of RAAS and the sympathetic nervous system leads to additional heart dysfunction due to heightened levels of oxidative stress, inflammation, and fibrotic extracellular matrix remodelling.[2][8] Notably, the release of angiotensin II and the production of aldosterone promote cardiac fibrosis and cardiac myocyte hypertrophy, as does the subsequent production of monocytes and cytokines.[2] 

Other factors involved in the pathogenesis of types 1 and 2 cardiorenal syndromes include elevated intraabdominal pressures and increased inflammatory damage to the kidney related to heart failure.[9][10] There is also increased activation of the arginine vasopressin secretion.[11] The hormonal changes lead to increased salt and water retention, thereby worsening the preload. Targeting this cycle is the mainstay of therapy for type 1 cardiorenal syndrome. Types 3 and 4 cardiorenal syndromes are more likely to result from volume overload from renal dysfunction, abnormal cardiac function in the setting of metabolic disturbances (such as acidemia), and neurohormonal changes that accompany renal disease.[12] Some of these neurohormonal mediators include natriuretic peptide, brain natriuretic peptide, C-type natriuretic peptide, and urodilatin.[2] Patients can develop type 5 cardiorenal syndrome in the setting of sepsis, systemic lupus erythematosus, diabetes mellitus, decompensated cirrhosis, or amyloidosis; all of these disorders can lead to disease in both the heart and kidneys.[13]

History and Physical

The patient’s history and physical exam can help clinicians differentiate between acute and chronic decompensation as well as between primarily cardiac or renal causes. Examples of helpful historical information would include if the patient presents with an acute myocardial ischemic event that can be triggering for severe cardiac dysfunction, which subsequently results in renal injury or recent-onset diarrhea and vomiting, causing acute renal injury, which might lead to a sharp decline in heart function. Other historical clues, such as medication use and prior laboratory values (eg, creatinine), may be helpful. Although the clinical examination may not help differentiate the different types of cardiorenal syndrome, many patients will have evidence of volume overload with signs, including the following:

• Elevated jugular venous pressure
• Generalized swelling and edema with “third spacing” presenting as pleural effusion(s), ascites, or peripheral edema
• Crackles or rales on lung auscultation
• Patients may also demonstrate manifestations of decreased cardiac output with hypotension, fatigue, diminished peripheral pulses, and abnormal heart rates (either tachycardia or bradycardia)[1]

Other possible signs indicating a primary renal cause of cardiorenal syndrome may include the following:

• Pallor from anemia
• Oliguria or anuria preceding cardiac dysfunction
• Signs and symptoms of uremia

Evaluation

The initial history and physical examination tailor the clinician's approach to the appropriate investigation for determining the underlying etiology. The initial laboratory workup should include a complete blood count, complete metabolic panel, urine studies (urinalysis with microscopy, urine protein-to-creatinine ratio, urine sodium), brain natriuretic peptide, and troponin. The estimated glomerular filtration rate is calculated from the creatinine level to help determine the degree of renal impairment. In recent years, biomarkers of renal tubular injury, such as neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, have been studied as their levels begin to rise even before serum creatinine levels increase.[14] In patients with possible cardiorenal syndrome type 5, further investigations, including blood and urine cultures, lupus serologies (antinuclear antibody, anti-double-stranded deoxyribonucleic acid, serum complement levels [C3, C4]), and a procalcitonin test, may be useful.

An electrocardiogram and cardiac monitoring should be included in the initial evaluation to evaluate for any underlying arrhythmias that may be contributing to or resulting from the cardiorenal syndrome. A transthoracic echocardiogram is invaluable in evaluating wall motion abnormalities, obtaining measurements such as the left ventricular ejection fraction, and determining whether a pericardial effusion is present. A renal ultrasound can help evaluate kidney size and function. Smaller kidney size and increased renal echogenicity are consistent with chronic kidney disease.[10] A magnetic resonance image (MRI) or blood oxygen level–dependent MRI is also a reasonable alternative to evaluate cardiac and renal parameters and blood flow.[2] Bioimpedance devices, along with  N-terminal pro–B-type natriuretic peptide, have also been proven useful in measuring hydration status in patients on hemodialysis.[15]

Treatment / Management

Although no therapies have been demonstrated to improve outcomes in patients with cardiorenal syndrome, treatment is generally directed at the underlying etiology and aimed at mitigating the syndrome's complications. As most patients with cardiorenal syndrome have volume overload, the primary treatment targets are typically fluid removal, either with diuretics or ultrafiltration.[1] Loop diuretics, including furosemide, torsemide, and bumetanide, are the most potent diuretic class. They can be used alone or in conjunction with other types of diuretics. Patients with type 1 cardiorenal syndrome are often especially diuretic-resistant and may require high doses of diuretics.[2] There are 2 strategies for diuresis: either a continuous infusion dose or the use of intravenous boluses.

Creatinine clearance can be used to help determine the dosage. For example, treatment can start with a loading dose of 40 mg intravenous furosemide, followed by 10 mg/h if the creatinine clearance is between 25 and 75 mL/min. In contrast, one can start with 80 mg to 160 mg of intravenous furosemide as the maximum dose, which can be repeated several times a day to achieve a desirable response, given the same creatinine clearance.[1][7] Definitive clinical evidence is still lacking to support either strategy over the other. However, using the continuous infusion strategy gives clinicians more opportunities to evaluate the response to therapy. Also, adding a thiazide diuretic can help overcome diuretic resistance in some cardiorenal patients via achieving sequential nephron blockade. Metolazone is typically used and is considered one of the most common combinations with loop diuretics.

Ultrafiltration can be useful in refractory cases. Still, results from recent studies have shown that diuretic therapy is better than ultrafiltration for symptom control and creatinine level decline in the initial approach towards achieving euvolemia. Inotropes can be used for patients with low cardiac output; however, the American College of Cardiology/American Heart Association guidelines recommend against the use of inotropes in patients without low cardiac output, as they can be pro-arrhythmic. No conclusive data support using dobutamine, dopamine, or milrinone as well.[2][10] Importantly, in acute cardiorenal syndrome, the serum creatinine can either increase, remain stable, or decrease with decongestive therapy. A rise in serum creatinine in these patients generally indicates effective decongestion, rather than a true renal injury.[16] Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers can be used with careful monitoring, particularly once volume depletion has been addressed. Results from many studies have shown an improvement in all-cause mortality with their use.[7][17][7] The treatment of cardiorenal syndrome types 3 and 4 focuses on addressing the underlying kidney disease and minimizing the use of nephrotoxic medications and contrast agents. Ultimately, addressing the underlying systemic conditions is crucial for effectively managing type 5 cardiorenal syndrome.  (A1)

Differential Diagnosis

Sometimes, it can be challenging to determine the etiology of cardiorenal syndrome at initial presentation in many patients, as they may present without all the classic features, making the diagnosis difficult. A history of a recent increase in diuretic doses, diarrhea, vomiting, skin or throat infection, heatstroke, fever, or recent extensive workout use could help towards a hypovolemic etiology leading to renal dysfunction. Also, other causes of kidney injury (such as obstruction or tubulointerstitial disease ) should be considered in any patient with heart failure presenting with kidney injury.

Pertinent Studies and Ongoing Trials

Some preliminary evidence supports the use of sacubitril-valsartan, which has shown benefits in cardiac remodeling, creating significant interest in natriuretic peptide analogues.[18][19][20] Sodium-glucose cotransporter 2 inhibitors have also shown significant promise when used in patients with and without diabetes.[21][22]

Prognosis

Acute kidney injury in patients with heart failure is associated with increased risk of mortality.[23] Patients with heart failure who develop chronic kidney disease (CKD) have a higher mortality than those who do not have CKD.[24] Also, in patients with heart failure, a greater variability of kidney function is associated with increased risk of death.[25] There are multiple mortality and readmission predictor calculators available to predict an individual patient’s prognosis further. They use multiple variables to predict in-hospital mortality and readmission rate, including the blood urea nitrogen, systolic blood pressure, serum creatinine, brain natriuretic peptide, and response to diuretics.[26][27][28]

Complications

The following complications are associated with CRS:

• Liver failure
• Respiratory failure requiring invasive and noninvasive ventilation
• Worsening renal failure requiring dialysis (either temporarily or permanently)