Cardiorenal Syndrome

Sandeep Soman, M.D.
Chandrika Chitturi, M.D.

Basic Information

Definition

The term cardiorenal syndrome (CRS) refers to disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other. Another definition proposed by the National Heart, Lung, and Blood Institute (NHLBI) is one in which therapy to relieve congestive symptoms of heart failure is limited by progressive renal insufficiency. There are five types of CRS (Fig. E1).

This section focuses on CRS types 1 and 2.

Synonym

ICD-10CM CODES
I13	Hypertensive heart and renal disease
I13.0	Hypertensive heart and renal disease with (congestive) heart failure
I13.2	Hypertensive heart and renal disease with both (congestive) heart failure and renal failure
I17.8	Other renal failure

Epidemiology & Demographics

•
CKD is present in 20% to 67% of patients with congestive heart failure (CHF).
1. 1.
  
  Women, the elderly, Caucasians, and patients with diabetes mellitus or systolic blood pressure >160 mm Hg have an increased incidence.
2. 2.
  
  In general, mortality is increased in patients with heart failure and reduced glomerular filtration rate (GFR).
3. 3.
  
  Patients with CKD have an increased risk of atherosclerotic heart disease and heart failure.
4. 4.
  
  Cardiovascular disease is responsible for up to 50% of deaths in patients with CKD.
•
20% to 30% of patients treated for acute or chronic CHF will develop acute kidney injury (AKI).
1. 1.
  
  In patients with acute CHF, the severity of AKI is increased with decreased left ventricular systolic function and baseline CKD.
2. 2.
  
  Only 9% of patients hospitalized with acute heart failure in the ADHERE trial had normal renal function with GFR >90 ml/min/1.73 m² on admission.
•

Patients with acute heart failure experienced the highest occurrence rate of CRS, but the impact on mortality was greatest in patients who developed CRS in the setting of cardiac surgery.

Physical Findings & Clinical Presentation

•
Acute/subacute decompensated heart failure (ADHF)
1. 1.
  Clinical symptoms:
  1. 1.
    
    Dyspnea with exertion or at rest
  2. 2.
    
    Orthopnea
  3. 3.
    
    Paroxysmal nocturnal dyspnea
  4. 4.
    
    Right upper quadrant pain
2. 2.
  Vital signs:
  1. 1.
    
    Sinus tachycardia
  2. 2.
    
    Hypertension or hypotension
  3. 3.
    
    Elevated respiratory rate
  4. 4.
    
    Narrow pulse pressure
  5. 5.
    
    Pulsus alternans: poor prognostic indicator
3. 2.
  Physical exam findings:
  1. 1.
    
    Elevated jugular venous pressures
  2. 2.
    
    Peripheral edema
  3. 3.
    
    Third heart sound (S3)
  4. 4.
    
    Respiratory crackles
  5. 5.
    
    Abdominal ascites
  6. 6.
    
    Hepatomegaly and splenomegaly
•
Chronic heart failure
1. 1.
  Clinical symptoms:
  1. 1.
    
    Dyspnea
  2. 2.
    
    Fatigue
  3. 3.
    
    Anorexia: poor prognostic indicator
2. 2.
  Vital signs:
  1. 1.
    
    Similar to ADHF, but sinus tachycardia may not be present, and hypotension may be present with a low cardiac output state.
  2. 2.
    
    Physical exam findings:
    
    1.
    
    Similar to ADHF, but rales may be absent, reflecting the rapidity of the collection of fluid. In chronic heart failure, the pulmonary vasculature may store large fluid volumes in alveoli rather than the total body intravascular volume.
•

These findings of heart failure will be associated with laboratory findings of kidney disease (discussed later); in extreme cases, physical exam findings of severe kidney disease such as asterixis, uremic frost, uremic smell, and uremic pericarditis may be present.

Etiology

The etiology of CRS can be divided into four mechanisms (Figs. E2 and E3):

FIG.E2

Integrated pathways of the cardiorenal syndrome in HF.

From Damman K, et al.: The cardiorenal syndrome in heart failure, *Prog Cardiovasc Dis* 54:144–153, 2011.

FIG.E3

Pathophysiology of type 1 cardiorenal syndrome or worsening renal function after hospitalization for acutely decompensated heart failure.

*ADH*, antidiuretic hormone; *ANP/BNP*, atrial natriuretic protein/B-type natriuretic protein; *BNP*, B-type natriuretic peptide; *EPO*, erythropoietin; LV, left ventricular; *NSAIDS*, nonsteroidal anti-inflammatory drugs; *TNF*, tumor necrosis factor.

From Herzog CA, et al.: Cardiovascular disease in chronic kidney disease: a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO), *Kidney Int* 80:572, 2011.

•
Increased renal venous pressure
1. 1.
  
  Occurs secondary to elevated central venous pressure or elevated intraabdominal pressure.
2. 2.
  
  Frequency of worsening kidney function is lowest in patients with CVP <8 mm Hg.
3. 3.
  
  GFR increase may occur following diuretic therapy, which is most likely mediated by a reduction in renal venous pressure and/or a reduction in right ventricular dilation.
•
Reduced renal perfusion
1. 1.
  
  Common cause of CRS type 1 (acute CHF results in AKI).
2. 2.
  
  Loop diuretic therapy can reduce ventricular preload and reduce cardiac output by as much as 20%.
•
Right ventricular dilation and dysfunction
1. 1.
  
  Increases central venous pressure that increases renal venous pressure and reduces GFR.
2. 2.
  
  Right ventricular dilation and dysfunction reduce left ventricular filling and renal blood flow.
•
Neurohormonal
1. 1.
  
  Activation of the renin-angiotensin-aldosterone system, sympathetic nervous system, antidiuretic hormone, and endothelin-1 increases salt and water retention, and systemic vasoconstriction decreases renal perfusion.
2. 2.
  
  Activation of the above systems overrides vasodilatory effects of natriuretic peptides, nitric oxide, prostaglandins, and bradykinin.

Diagnosis

Differential Diagnosis

•
Before establishing the diagnosis of CRS, rule out other causes of kidney failure:
1. 1.
  Prerenal causes
  1. 1.
    
    Volume depletion (overdiuresis, gastrointestinal losses, or vomiting)
  2. 2.
    
    Fluid overload states besides CHF (cirrhosis, nephrotic syndrome)
2. 2.
  Intrinsic renal disease
  1. 1.
    
    Acute tubular necrosis
  2. 2.
    
    Glomerular disease
•
Nephrotic and nephritic syndromes
1. 1.
  Postrenal causes
  1. 1.
    
    Obstruction

Workup

•

Medical history is consistent with CHF symptoms and includes dyspnea, orthopnea, paroxysmal nocturnal dyspnea, edema, increasing abdominal girth, or weight gain. Laboratory results will show signs of kidney injury.
•

Diagnostic workup includes chest radiograph, echocardiogram, kidney ultrasound, and laboratory tests.

Laboratory Tests

•
Serum creatinine
1. 1.
  Patients with CRS had a mortality odds ratio of 1.48 for even mild increases in serum creatinine levels (0.3-0.5 mg/dl), with higher odds ratio for mortality with increases in serum creatinine >0.5 mg/dl.
  1. •
    
    For serum creatinine level increases of >0.5 mg/dl, the odds ratio for mortality increases to 3.22.
•
Glomerular filtration rate (GFR)
1. 1.
  
  Evaluation of GFR using estimated GFR (eGFR) or calculated GFR as appropriate
•
Blood urea nitrogen
1. 1.
  
  Admission levels >43 mg/dl are associated with a higher in-hospital mortality rate.
•
Cystatin C
1. 1.
  
  GFR calculations are moderately less accurate than cystatin C assays.
•
Brain natriuretic peptide (BNP)
1. 1.
  
  Initial admission values >480 pg/ml are associated with a 51% chance of death, hospital readmission, or an emergency department visit within 6 months compared to patients whose levels were <230 pg/ml.
•

It may be difficult to distinguish between CKD and impaired kidney function due to cardiorenal syndrome, especially if prior renal function is unknown. Some patients have both underlying CKD and CRS. Findings that support underlying CKD include significant proteinuria (>1000 mg/day), urine sediment with hematuria and/or pyuria, cellular casts, and/or small echogenic kidneys on ultrasound.

Imaging Studies

•
Chest radiograph
1. 1.
  
  May demonstrate signs of fluid overload, including pulmonary edema, effusions, or fluid in the fissures
•
Echocardiogram
1. 1.
  
  Determines if there is underlying systolic or diastolic dysfunction and/or significant valvular disease present
•
Kidney ultrasound
1. 1.
  
  Distinguishes between acute and chronic kidney disease and determines whether obstruction may be worsening kidney function

Treatment

Nonpharmacologic Therapy

•

Sodium and fluid restriction
•
Hemodialysis/ultrafiltration
1. ▪
  
  Used when there is insufficient response to pharmacologic treatment or when pharmacologic agents are limited by hemodynamics or worsening laboratory values
•
Left ventricular assist device/cardiac resynchronization therapy (CRT)
1. ▪
  
  Improves cardiac output and reverses cardiac dyssynchrony. CRT improves ejection fraction by 7% and CHF symptoms in patients with NYHA class II–IV heart failure with ejection fractions ≤35% and left bundle branch block morphology and QRS duration >150 msec.

Acute General Rx

No medical treatment directly improves GFR in the setting of CRS, but improving cardiac function improves kidney function by alleviating any of the mechanisms of CRS listed previously.

•
Diuretics
1. 1.
  
  Extracellular fluid volume reduction returns hemodynamics to a more optimal position on the Frank-Starling curve.
2. 2.
  
  Reducing volume overload improves renal perfusion pressure by decreasing central venous pressure, renal venous pressure, and right ventricular dilation, which improves right ventricular function and left ventricular performance.
3. 3.
  
  Twice-daily intravenous furosemide that is 2.5 times the daily oral furosemide equivalent dose is a reasonable starting point.
4. 4.
  
  High-dose intravenous bolus loop diuretic therapy improves cardiopulmonary congestion more effectively than low-dose loop diuretics. Continuous loop diuretic infusions are not more effective than frequently administered bolus loop diuretic regimens.
5. 5.
  
  Diuretic resistance is common, and a combination of diuretics with different sites of action may optimize treatment (e.g., furosemide and metolazone).
•
Inhibitors of the renin-angiotensin-aldosterone system
1. 1.
  Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, aldosterone receptor antagonists, and direct renin inhibitors
  1. 1.
    
    Use is limited by worsening kidney function, especially when serum creatinine is greater than 2.5 mg/dl.
  2. 2.
    
    Permits reduced diuretic dosages.
  3. 3.
    
    Efficacy of anti-renin-angiotensin-aldosterone system therapy in the management of decompensated heart failure (HF) is established, but its role in CRS is unproven.
•
Vasodilators
1. 1.
  Includes nitroglycerin and nitroprusside
  1. 1.
    
    Increase renal perfusion pressure by improving Frank-Starling relationships and cardiac output
•
Inotropic agents
1. 1.
  
  Include dobutamine, dopamine, and milrinone.
2. 2.
  
  Improve cardiac output and renal perfusion by vasodilation. Used to treat cardiogenic shock and low cardiac output states with normal blood pressure.
3. 3.
  
  Dobutamine and milrinone may lower systemic blood pressure, limiting therapeutic efficacy.
•

Mechanical fluid removal such as extracorporeal ultrafiltration (UF) may be required to achieve control of fluid retention, particularly in patients resistant to diuretic therapy. UF removes plasma salt and water isotonically by convection through a highly permeable filter in an extracorporeal circuit and typically requires central venous catheterization. Newer technologies permit vascular access via peripheral veins. With slow continuous UF, the intravascular fluid volume remains stable as fluid shifts from the extravascular to intravascular space without inducing hypotension. UF may be indicated in highly refractory HF with diuretic resistance.
•

Serelaxin, a recombinant human relaxin-2, has recently generated enthusiasm for the treatment of ADHF and CRS.

Disposition

Based on improvements in heart failure and kidney function.

Referral

Consultations by a cardiologist and nephrologist are recommended

Ferri – Cardiorenal Syndrome