I. Cardiorenal Syndrome: What every physician needs to know.

The term cardiorenal syndrome (CRS) refers to a condition in which either renal impairment occurs as a result of cardiac dysfunction, or heart structure and function are negatively affected by renal disorders. The damage/dysfunction can be produced in either the heart or the kidney by an acute or chronic disease of the other organ, or abnormal heart and kidney functions occur simultaneously as a result of a systemic disease.

For example, acute heart failure (HF) decompensation can both cause acute renal injury and predispose to the development of chronic kidney disease (CKD) as the result of activation of the sympathetic nervous system (SNS), the renin-angiotensin-aldosterone system (RAAS), and mediators of inflammation and fibrosis. Conversely, acute kidney injury (AKI) can provoke HF due to inflammation-mediated impairment of contractility and myocyte death.

CKD independently increases the risk of cardiovascular (CV) disease by promoting myocardial hypertrophy, coronary atherosclerosis, and fluid overload. Finally, highly prevalent conditions, such as diabetes and hypertension, and less common ones, including autoimmune diseases, amyloidosis, pulmonary arterial hypertension, and sepsis, can simultaneously damage the heart and kidneys.

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Based on these facts, the CRS has recently been classified according to five types as follows:

Type I: acute cardiorenal syndrome

Abrupt worsening of cardiac function (e.g., acute cardiogenic shock or acutely decompensated heart failure) leading to acute kidney injury.

Type II: chronic cardiorenal syndrome

Chronic abnormalities in cardiac function (e.g., chronic heart failure) causing progressive and potentially permanent chronic kidney disease.

Type III: acute renocardiac syndrome

Abrupt worsening of renal function (e.g., acute kidney ischemia or glomerulonephritis) causing acute cardiac disorder (e.g., heart failure, arrhythmia, ischemia).

Type IV: chronic renocardiac syndrome

Chronic kidney disease (e.g., chronic glomerular or interstitial disease) contributing to decreased cardiac function, cardiac hypertrophy, and/or increased risk of adverse cardiovascular events.

Type V: secondary cardiorenal syndrome

Systemic condition (e.g., diabetes mellitus, sepsis) causing both cardiac and renal dysfunction.

II. Diagnostic Confirmation: Are you sure your patient has Cardiorenal Syndrome?

In patients with CV diseases, the accurate diagnosis of underlying renal abnormalities is critically important for the implementation of effective preventive and therapeutic strategies for patients with CRS. The presence of CKD is characterized by structural or functional abnormalities of the kidney lasting for at least 3 months and revealed by either kidney damage, as indicated by persistent albuminuria, or a decreased glomerular filtration rate (GFR) (<60 ml/min/1.73 m2).

In many patients CKD remains undetected because renal function measures, such as blood urea nitrogen (BUN) and serum creatinine (sCr) often do not identify patients with mild to moderate reduction in GFR, and albuminuria is not routinely examined. The most accurate method to determine kidney function, measurement of GFR with iothalamate or similar markers, is time-consuming, costly, difficult to perform, and seldom available.

The use of the sCr for the estimation of GFR is limited by the individual variations in the rates of Cr production due to differences in muscle mass. Women and the elderly often have deceptively low sCr levels, despite substantial reductions in GFR. Because the relationship between the sCr level and GFR is not linear, small increases in sCr are erroneously dismissed as clinically insignificant.

Compared to sCr, cystatin C, a serine protease inhibitor released at a relatively constant rate by all cells and freely filtered by the glomerulus, has a closer correlation with GFR and greater ability to predict the development of congestive HF in elderly patients. The specificity of cystatin C as a reliable indicator of GFR is reduced by the influence on its production of age, gender, weight, height, smoking, serum C-reactive protein levels, steroid therapy, and connective tissue diseases.

The estimation of GFR by calculation of creatinine clearance (CrCl) from urine produced over a 24-hour period is no longer recommended because of unacceptable error rates due to inaccurate urine collection. It is therefore preferable to estimate GFR with validated equations that use easily obtainable clinical and laboratory data (Table 1).

Table 1.n

Equations for the Estimation of Creatinine Clearance and Glomerular Filtration Rate

The Cockcroft-Gault method uses sCr, gender, age, and ideal weight. Inaccurate weight measurements reduce the accuracy of this method. The formula developed from the Modification of Diet in Renal Disease (MDRD) study is currently the best validated method to estimate GFR in adults.

The simplified MDRD study equation requires only demographic data and sCr levels, and produces GFR estimates very similar to those of the complete formula. Both versions of the MDRD can be automatically generated and displayed in laboratory reports.

Online calculators for the MDRD eGFR equation are available from the National Kidney Foundation at www.kidney.org and from the National Kidney Disease Education Program (NKDEP) of the National Institutes of Health at www.nkdep.nih.gov. Both MDRD equations may overestimate the presence of CKD in patients with normal or only slightly diminished renal function.

Albuminuria (>30 mg urinary albumin excretion per 24 hours or spot urinary values >30 mg albumin/g Cr) is associated with an increased risk for cardiovascular disease (CVD) and may be a manifestation of generalized endothelial dysfunction. Due to increased albumin excretion with infections and HF, screening for albuminuria should be done in the absence of intercurrent illnesses.

The sensitivity of the albumin-to-Cr ratio in a spot urine sample may be reduced in patients treated with an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). However, persistent albuminuria in these patients still confirms the presence of CKD.

Combined screening for microalbuminuria and estimation of GFR with the MDRD equation are recommended for all adult patients with CV disease, including those with coronary artery disease (CAD), HF, diabetes, and hypertension. Screening should be repeated at 3 months if either test is abnormal. Abnormalities lasting 3 months should prompt appropriate evaluation and treatment of CKD.

A. History Part 1: Prevalence:

Prevalence of the Cardiorenal Syndrome

Renal impairment in HF patients is common and independently associated with increased morbidity and mortality (Table 2). In the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) study, the level of renal dysfunction was a powerful independent predictor of death or hospitalization for HF.

Table 2.n

Prevalence of Chronic Kidney Disease by Stage

The Acute Decompensated Heart Failure National Registry (ADHERE), a large U.S. database of 105,388 hospitalized HF patients, reported that 30% had CKD. Approximately 20% of patients had sCr >2.0 mg/dl, 9% had Cr >3.0 mg/dl, and 5% were treated with dialysis. A meta-analysis of 16 studies spanning 60 years and including 80,098 HF patients with variably defined renal impairment showed that 63% of patients had any renal impairment, and 29% had moderate to severe impairment.

Adjusted all-cause mortality was significantly increased in patients with any renal impairment. Mortality worsened incrementally across the range of renal dysfunction, with 15% increased risk for every 0.5-mg/dl increase in sCr and 7% increased risk for every 10 ml/min decrease in eGFR.

Among 6,440 HF patients hospitalized between 1987 and 2002, age and admission sCr increased, and eGFR and hemoglobin decreased over the 16-year period analyzed. The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial showed that, compared to historical data, episodes of ADHF were more commonly associated with renal dysfunction and the requirement of higher diuretic doses at discharge.

Thus cardiorenal failure in patients hospitalized for HF is becoming more frequent and severe, and equally frequent in patients with preserved or decreased left ventricular ejection fraction (LVEF). Several studies have documented that, during hospitalization for HF, >70% of patients will experience some increase in sCr, with approximately 20% to 30% having increments >0.3 mg/dl.

Worsening renal function (WRF ): Occurs early in the course of the hospitalization and is independently associated with longer hospitalizations, greater costs, and higher short- and long-term mortality. Nonetheless, it remains unclear whether the WRF itself contributes to the increased mortality or whether it represents more advanced disease. Rates of WRF during hospitalization are similar in patients with decreased or preserved LVEF.

It is estimated that approximately 30% of HF patients develop diuretic resistance, defined as persistent pulmonary and peripheral congestion with or without WRF despite attempts at diuresis. Patients with underlying renal disease are at an especially high risk for developing diuretic-induced WRF before euvolemia can be achieved.

The common risk factors of hypertension, diabetes mellitus, and atherosclerosis explain the high prevalence of coexistent cardiac and renal dysfunction. On average, persons developing WRF are older and more often have prior HF, renal dysfunction, diabetes, and hypertension.

Cox regression analysis in 1004 diverse HF patients permitted the development of a risk score for predicting which patients with ADHF would develop WRF. With the allocation of one point each to HF history, diabetes, and systolic blood pressure (BP) >60 mm Hg at admission; two points to sCr 1.5 to 2.4 mg/dl; and three points to sCr ≥2.5mg/dl, 35% of the patients had a score of ≥ 3 and a 43% likelihood of WRF. In summary, renal dysfunction is common in HF patients, portends a poor prognosis, and poses complex therapeutic challenges.

B. History Part 2: Competing diagnoses that can mimic Cardiorenal Syndrome

The most frequent diagnostic challenge in patients arriving to the emergency department (ED) with dyspnea and renal insufficiency is to establish whether this presentation is consistent with ADHF or with other diagnoses, including acute coronary syndromes, pneumonia, exacerbation of chronic obstructive pulmonary disease (COPD), or pulmonary embolism.

Point of care measurement of B-type natriuretic peptide (BNP )or NT-proBNP levels can help to confirm or exclude the presence of ADHF. BNP levels <100 pg/ml or NT-proBNP levels <300 pg/ml generally exclude ADHF.

Low NP levels can occur in the setting of ADHF when pulmonary edema develops rapidly due to acute mitral regurgitation or a hypertensive crisis, or when there is increased NP degradation due to obesity. Imaging modalities, such as a chest x-rays (CXR), ventilation perfusion scan, and/or high resolution computed tomography (CT) scan, are used to determine whether pulmonary infiltrates, emboli, or bronchospasms are the sole or contributing causes of dyspnea.

In the chronic setting, when patients present with swelling of the lower extremities and concomitant renal insufficiency, it is important to determine whether peripheral edema is due to HF-related fluid overload or to other conditions such as venous insufficiency, lymphedema, liver disease, nephrotic syndrome, or medications (corticosteroids and calcium channel blockers).

When jugular venous pressure JVP cannot be evaluated or the echocardiogram does not permit estimation of cardiac filling pressures, particularly if LV systolic function is preserved, invasive hemodynamic monitoring may be appropriate to distinguish HF-related peripheral edema from extracardiac causes of lower extremity swelling.

C. Physical Examination Findings

The principal goals of the physical examination in HF failure patients at risk of CRS are to evaluate volume and perfusion status. The following variables are especially important:

Weight: Measured in kilograms or pounds (1 kg = 2.2 lb). Values also expressed in terms of body mass index (BMI) in kg/m or lb/m. BMI <18.5: underweight; 18.5 to 24.9: normal; 25 to 29.9: overweight; ≥30: obese. Weight should be measured with the patient unsupported, in bare feet or slippers, and each day with the same scale.

Advantages : Weight is easily monitored. An increase of 2 lb or more overnight or 5 lb or more over 7 days is indicative of fluid retention.

Disadvantages: Measurements often inconsistent (different scales or patient conditions); weight may change due to causes unrelated to fluid excess (increase caloric intake or cachexia).

Relevance to the CRS: The Weight Monitoring in Heart Failure (WHARF) trial showed that in-home daily weight monitoring with the AlereNet system did not decrease HF hospitalizations but was associated with mortality benefit. Observations from the Chronicle Offers Management to Patients with Advanced Signs and Symptoms of Heart Failure (COMPASS-HF) trial showed that filling pressure can rise in the absence of a weight increase.

Blood pressure (BP): Measured in millimeters of mercury (mm Hg). Normal value in individuals 18 years or older are <120/80 mm Hg; for details on proper BP measurements go to nhlbi.nih.gov/hbp/direct/tips.htm.

Advantages: BP is easily monitored. Low BP may indicate low CO and hypoperfusion, and it must be evaluated in conjunction with other symptoms and signs of hypoperfusion.

Disadvantages: Measurements often inconsistent (different instruments and patient’s conditions; low BP not necessarily reflective of hypovolemia (medications, etc.).

Relevance to the CRS:The BP is an independent predictor of outcomes in ADHF, regardless of LVEF. Hypertension (HTN) is a major risk factor for HF (70%). HTN may mediate ADHF. HTN mediates both cardiac and renal damage. Many ADHF studies have shown that the lower the baseline BP, the poorer the outcomes.

Heart rate (HR): Measured in beats per minute (bpm); normal values range between 60 to 100 bpm. HR calculated from the count of beats per minute at the apical, carotid, or radial positions.

Advantages: Easily measured, helpful in detecting brady- and tachyarrhythmias that can affect cardiac output (CO) and/or precipitate ADHF. Increased HR may be present with hypovolemia.

Disadvantages: HR influenced by factors other than volume status (activity level, fitness status, air temperature, body position, emotions, body size, medications, etc.).

Relevance to the CRS: Regardless of etiology, CKD severity is associated with increased atrial fibrillation rates. Up to 60% of hemodialysis (HD) patients die of sudden cardiac death.

Temperature (T): Measured in degrees, Fahrenheit or Celsius [C × 9/5 +32=F; (F-32) × 5/9 = C]. Normal T is 37.0 °C or 98.6 °F. Oral and rectal T correlate with core T.

Advantages: T is easily measured. Elevated body T may suggest infection, which can mediate hemodynamic changes and/or precipitate ADHF. In hospitalized HF patients, hypothermia (<35.8 °C) is an independent predictor of 60 day mortality. Hypothermia can be associated with a high BUN/sCr, narrow pulse pressure and LV dysfunction. Hypothermia may precipitate AKI and exacerbate CKD.

Disadvantages: Measurement may be inconsistent. Value of T in the outpatient setting and that of repeated measurements is unknown. T is influenced by many factors unrelated to volume status and kidney function.

Relevance to the CRS: Hypothermic ADHF patients are 3.9 times more likely to die in 60 days. Body T may be higher in HD patients due to AV fistulas.

Jugular Venous Pressure (JVP): Measured in centimeters. Normal values are 6 to 8 cm. Calculated by adding 5 cm to the oscillation point of the right internal jugular (RIJ) vein.

Advantages: Reflects central venous pressure (CVP). J VP is sensitive and specific for the assessment of volume status.

Disadvantages: JVP is not consistently or correctly assessed by health care providers. There may be anatomic limitations to JVP assessment.

Relevance to the CRS: An increased JVP independently predicts hospitalization risk, death or hospitalization for HF, or death from pump failure. An increased CVP predicts WRF in acute and chronic HF more than CI, systolic BP and PCWP.

Third Sound (S3): Presence or absence assessed by cardiac auscultation.

Advantages: S3 reflects ventricular dysfunction and volume overload.

Disadvantages: Liver span is seldom measured. Liver enlargement may be due to causes other than congestion. Liver congestion may be difficult to detect in patients with reduced liver size due to cirrhosis.

Pulmonary Rales: Presence or absence assessed by chest auscultation. Rales are interrupted, explosive respiratory sounds during inspiration.

Advantages: Presence of rales may indicate increased lung water content.

Disadvantages: May be absent in 30% of patients with fluid overload. Rales are a late sign of pulmonary congestion or may be due to causes other than pulmonary edema.

Ascites: Detected by abdominal exam and likely to be present when flanks bulging shifting dullness and a fluid wave are observed.

Advantages: When ascites is present, it indicates the presence of an elevated intraabdominal pressure, which has been shown to be correlated with WRF. Detection of ascites should prompt evaluation of right ventricular (RV) function, tricuspid regurgitation, and pulmonary arterial hypertension.

Disadvantages: Often difficult to hear. May be absent despite fluid overload with chest abnormalities, lung disease and obesity.

Relevance to the CRS: Similarly to JVP, S3 is an independent predictor of hospitalization risk, death or hospitalization for HF or death from pump failure.

Peripheral Edema: Under normal circumstances edema is absent. Lower extremity edema is measured on a four-point scale (1+ to 4+). Both scale and height of edema should be reported.

Advantages: Peripheral edema reflects an elevated CVP in HF patients.

Disadvantages: Severity of peripheral edema may be disproportionate to CVP elevation depending upon immobility, posture, and venous insufficiency. Peripheral edema lacks specificity because it may be due to many conditions other than fluid overload (venous insufficiency, lymphedema) and to medications (corticosteroids, calcium channel blockers, etc.)

Hepatomegaly: Detected by percussion and palpation of the abdomen.

Advantages: Hepatomegaly may indicate the presence of liver congestion due to fluid overload and may reflect right ventricular (RV) dysfunction.

Disadvantages: Liver span is seldom measured. Liver enlargement may be due to causes other than congestion. Liver congestion may be difficult to detect in patients with reduced liver size due to cirrhosis.

D. What diagnostic tests should be performed?

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Blood Tests

Blood Urea Nitrogen (BUN):Measured in serum in mg/dl or mmol/L. Normal values are 5 to 20 mg/dl or 1.8 to 7.1 mmol/L.

Advantages: Measurement is simple and readily available. BUN reflects GFR. Determination of BUN level is valuable as a screening test for renal function and useful in following the progression of renal disease.

Disadvantages: BUN levels vary by protein intake, endogenous protein catabolism, hydration status, hepatic urea synthesis, renal urea excretion. The relationship of BUN to GFR is not linear but parabolic, and levels may remain normal until 50% of renal function is lost. From this point on, doubling of BUN means a 50% fall in GFR.

Relevance to the CRS: In HF patients with CRS BUN reflects elevation of CVP and degree of neurohormonal activation. BUN is an independent and strong predictor of outcomes in HF patients. The reabsorption of filtered urea increases as renal blood flow (RBF) decreases. Vasopressin increases permeability of collecting tubules to urea, and therefore an increased BUN may reflect increased nonosmotic vasopressin release.

Serum Creatinine (sCr): Measured in mg/dl or mmol/L. Normal values are 0.5 to 1.2 mg/dl or 53 to 106 mmol/L in adult males and 0.5 to 1.1 mg/dl or 44 to 97 mmol/L in adult females.

Advantages: sCr reflects lean body mass and GFR. Unlike urea, creatinine is freely filtered by the glomerulus, not reabsorbed or affected by urine flow.

Disadvantages: Cr levels are influenced by body weight, muscle mass, race, age gender, total body volume, drugs, muscle metabolism, and protein intake. In patients with decreased muscle mass, a low sCr may under estimate the severity of renal impairment. Example: the CrCl in a 75-year-old female weighing 60 kg and with an sCr of 1.2 mg/dl is only 38 ml/min. It is not clear whether an increase in sCr per se increases mortality or whether it represents a more advanced stage of HF and/or CRS.

BUN to sCr Ratio (BUN/sCr): Normal values are 10 to 20:1, high >20:1; low <10:1.

Advantages: In HF patients with the CRS, a BUN/sCr >20:1 is generally due to enhanced proximal tubular reabsorption of urea, which can be due to hypovolemia and/or increased CVP in volume overloaded HF patients.

Disadvantages: BUN/sCr can be influenced by GI bleeding (hypovolemia due to blood loss) and advanced age (decrease in muscle mass).

Estimated Glomerular Filtration Rate (eGFR): eGFR is measured in ml/min/1.73 m2 and it is calculated according to various equations (Cokroft-Gault, MDRD-1, MDRD-2) to define stages of CKD.

Advantages: GFR reflects the number of functioning nephrons. The MDRD equation is the best validated method to estimate GFR in adults. The simplified MDRD equation (MDRD-2) produces GFR estimates very similar to the complete formula. Online calculators are available (www.kidney.org and www.nkdep.nih.org).

Disadvantages: Inaccurate sCr measurements reduce the accuracy of the Cokroft-Gault method. Both MDRD equations may overestimate the presence of CKD inpatients with normal or slightly reduced renal function. eGFR is accurate only when calculated in patients with stable renal function, and not in patients with acute illnesses, including ADHF.

Relevance to the CRS: eGFR is an independent predictor of outcomes in HF patients both in patients with reduced, and in those with preserved, LVEF.

Sodium Level (Na): Na is measured in mEq/L or mmol/L. Normal values are 136 to 145 mmol/L. Values between 121 and 135 mmol/L define mild to moderate hyponatremia and values <121 mmol/L define severe hyponatremia.

Advantages: Measurement simple and available. Na is the primary cation in extracellular fluid (ECF) in humans and the primary determinant of ECF volume. In HF patients with the CRS hyponatremia reflects nonosmotic release of vasopressin stimulated by activation of the sympathetic and RAAS systems.

Relevance to the CRS: Hyponatremia is classified as dilutional if due to hypervolemic or euvolemic HF and as depletional if associated with hypovolemia. It is present in 15% to 28% of hospitalized patients. Hyponatremia can be multifactorial: decreased RBF, neurohormonal activation, increased vasopressin release, use of diuretics, especially thiazide diuretics.

Hyponatremia has been consistently proven to predict a poor prognosis in HF. However, it remains unclear whether correction of hyponatremia improves prognosis.

Potassium level (K): K is measured in mg/dL or mmol/L. Normal values are 3.5 to 5.0 mmol/L.

Advantages: Measurement simple and available. K monitoring is mandated by AHA/ACCHF guidelines due to the detrimental effects of both hypokalemia (usually due to loop diuretics use) and hyperkalemia (related to the severity of renal impairment and/or use of ACEIs and aldosterone antagonists).

Relevance to the CRS: Increased K levels are due to ACEI use in 10% to 38% of patients hospitalized for hyperkalemia. Increased K levels are present in 10% of ambulatory patients taking ACEI. The risk of hyperkalemia is higher in older patients and in those with diabetes and impaired renal function.

Hemoglobin (Hgb): Measured in g/dL. Normal values vary with gender and age. Normal adult males: 14 to 18; Normal adult females: 12 to 16; Post-middle-age males:12.4 to 14.9; Post-middle-age females 11.7 to 13.8.

Advantages: Monitoring is easy and uniformly available. Anemia is common in both HF and CKD, and therefore it is a serious concern in patients with CRS. Hemoglobin levels are strongly associated with outcomes, regardless of underlying disease. In HF patients, it is important but challenging to determine whether decreased hemoglobin is due to true anemia or to hemoglobin dilution due to hypervolemia.

Disadvantages: Hemoglobin values alone do not provide clues as to the cause of anemia. To identify the cause(s) of anemia, other laboratory tests must be obtained, including hematocrit, complete blood count (CBC), iron level and saturation, total iron binding capacity (TIBC), ferritin level ,and renal function values.

Relevance to the CRS: Although the reported prevalence and incidence of anemia in the CRS is highly variable, it is reasonable to estimate that anemia is present in approximately 50% of CRS patients. Anemia is a powerful and independent predictor of outcomes.

Even small decreases in hemoglobin predict poor outcomes. Renal impairment and proinflammatory cytokines contribute to anemia in most CRS patients, resulting in inappropriate erythropoietin production and defective iron utilization. In CKD, anemia is associated with higher CV morbidity and mortality. In non-HD patients, targeting hemoglobin level higher than 12.5 g/dl is no benefit and may be harmful.

Albumin: Measured in g/dl. Normal values range between 3.5 and 5.4 g/dl.

Advantages: Measurement is easy and uniformly available. Albumin accounts for 75% to 80% of plasma oncotic pressure and for 50% of plasma protein content. In HF patients’ low serum albumin levels may be due to an increased volume of distribution and inflammation.

Disadvantages: Hypoalbuminemia may be due to causes other than CRS, including liver disease, nephrotic syndrome, and acute and chronic inflammatory illnesses.

Relevance to the CRS: Hypoalbuminemia is associated with an increased risk of HF in elderly patients in a time-dependent manner, independent of inflammation and CAD events. ADHF patients with albumin levels <3.4 g/dl have a higher frequency of renal dysfunction and 1-year mortality.


The information on measurement of biomarkers levels is limited to aspects relevant to the evaluation and treatment of HF patients with the CRS.

Natriuretic peptides (BNP and NT-proBNP): Measured in pg/ml. Normal values are <100 pg/ml for BNP and < 300 pg/ml for NT-proBNP.

Advantages: Point-of-care assays make measurement of NP levels easy and widely available. NP levels are correlated with cardiac filling pressure, HF severity and outcomes.

Disadvantages: Individual values of BNP and NT-proBNP are not interchangeable due to different half-life, modes of degradation, ranges, and cut-off values. “Baseline” NP levels in individual patients are frequently unknown.

Noncardiorenal pathology may be associated with increased NP levels (i.e., pulmonary embolism). In patients with GFR <60 ml/min, NP levels reflect both a counterregulatory response of the heart to the kidney and reduced renal clearance of NPs. Therefore the cut point of NP level used to detect HF must be raised in patients with GFR <60 ml/min.

However, high BNP levels should not be ignored in the setting of renal impairment, because CV disease is likely to be present. In obese patients, any given NP level should be doubled due to increased degradation of NPs by adipose tissue.

Relevance to the CRS: In ADHF patients, NP levels substantially higher than prehospitalization values (>50%) usually reflect volume overload and increased cardiac filling pressure (“wet” versus “dry” NP levels). Worsening azotemia from excessive diuresis may contribute to increasing NP levels in hospitalized ADHF patients. Therefore NP levels should always be interpreted together with measures of renal function. Predischarge NP values are the levels most predictive of rehospitalization and death.

Urine tests

Urine osmolality and specific gravity: Normal values: minimum of 50 to 100 mOsmol/kg without ADH to maximum of 900 to 1,200 mOsmol/kg with greatest ADH action.

Advantages: Urine osmolality is a measure of the kidney’s concentrating ability. In most cases, the urine specific gravity increases by 0.001 for every 35 to 40 mOsmol/kg increase in osmolality. Specific gravity in the Bowman’s capsule is between 1.007 and 1,010.

Higher values indicate dehydration and lower values overhydration. Specific gravity values <1.022 after 2 hours of fasting indicate impaired renal concentrating ability. Values >1.035 may indicate contamination with glucose, contrast dye, or certain antibiotics. To determine nonglucose urinary solute concentration, 0.004 must be subtracted for every 1% of glucose.

Urinary protein (albumin): Urinary protein concentration is measured in mg/dl in a 24-hour urine collection or random urine sample. Normal values are <150 mg/day or <10 mg/100 ml in a single specimen. Severity of proteinuria is measured on a 5-point scale where Trace = 150/24 hr, 1+ = 200 to 250 mg/24 hr, 2+ = 0.5- to.5 g/24 hr, 3+ = 2.5 mg/24 hr and 4+ =/> 7g/24 hr. Another method to stratify the severity proteinuria is the 6-point scale sulfosalicylic acid (SSA) test: 0 = 0 mg/dl, Trace = 1 to 10 mg/dl,1 + 15 to 30 mg/dl, 2+ = 40 to 100 mg/dl, 3+ = 150 to 300 mg/dl and 4+= >500 mg/dl.

Advantages: Albuminuria, defined as >30 mg urinary albumin secretion in 24 hr or > 30 mg of albumin per gram of creatinine, is associated with an increased risk of CV disease.

Disadvantages: Screening can only be done in the absence of intercurrent illness. Sensitivity of albumin to creatinine ratio is decreased in patients receiving ACEI or ARB.

However, persistence of proteinuria still confirms the presence of CKD. Relevance to the CRS: Combined screening for microalbuminuria and eGFR by the MDRD equation is recommended for all adult patients with CKD, HF, DM ,and HTN. Screening should be repeated every 3 months. Persistence of albuminuria >3 months warrants further evaluation and screening for CKD.

Urinary sodium: Urinary Na is measured in mmol/L or mEq/L.

Advantages: Measurement simple and widely available. In normal subjects, urinary Na+ excretion roughly equals average dietary intake. Therefore urinary Na should be <100 mEq/day if patients adhere to the recommended dietary Na restriction. A urinary Na <20 mEq/day suggests hypovolemia, whereas values >40 mEq/day are seen in syndrome of inappropriate anti-diuretic hormone secretion (SIADH) and renal failure.

Disadvantages: Urinary Na is influenced by urine volume.

Fractional excretion of sodium (FeNa): Advantages: FeNa eliminates the confounding factor of variation in urine volume. FeNa is useful in differentiating prerenal from intrinsic or postrenal causes of renal impairment.

Relevance to the CRS: In ADHF, a FeNa >4% more than 6 hours after a diuretic dose predicts WRF and a complicated hospital course (Table 3).

Table 3.n

Assessment of Renal Impairment by Urinary Sodium and FeNa

Other biomarkers relevant to the cardiorenal system

Cardiac troponin (cTNI): Measured in ng/ml. Detection levels are 0.01 ng/ml for standard assays and <0.001 ng/ml for high sensitivity assays.

Advantages: There is a consistent association between cTNI elevation and outcomes in both acute and chronic HF. In the AHA/ACC HF guidelines, determination of cTNI levels in hospitalized ADHF patients is a Class I, Level C recommendation.

Disadvantages: Incidence of positive cTNI levels depends on the sensitivity of the assay used. The clinical application of cTNI levels remains poorly defined. It is still unclear whether an elevated cTNI levels in HF patients is related to frank acute coronary system (ACS) or not.

Relevance to the CRS: cTNI provides incremental prognostic information on top of standard prognostic information and other laboratory values. The prognostic value of cTNI levels is independent of NP levels. cTNI levels provide insight into the transition from chronic compensated HF to ADH.

Cystatin C: Measured in mg/L. Normal values are 0.53 to 0.95 mg/L.

Advantages: Cystatin C is freely filtered by the renal glomeruli and metabolized by the proximal tubules. Cystatin C values are independent of age, sex, race, and lean body mass. Cystatin C has been proposed as a substitute for sCr in the estimation of GFR.

Disadvantages: Although measurement of Cystatin C has been approved by the FDA for diagnostic use, the assay is seldom performed and not yet widely available.

Relevance to the CRS: Cystatin C may identify renal impairment in high-risk patients with normal sCr levels and therefore it may detect CKD before any increase in sCr levels. In ADHF, Cystatin C levels may rise 24 to 48 hours before those of sCr. Patients with the highest levels of cystatin C have twice the risk of all-cause death and CV death, and a 50% higher risk of myocardial infarction (MI) and stroke compared with patients with normal or lower levels.

Neutrophil gelatinase-associated lipocalin (NGAL): Measured in ng/ml in plasma or urine. Normal values are <150 ng/ml.

Advantages: NGAL is a marker of tubular damage in acute and chronic HF. NGAL is an early biomarker of AKI because NGAL levels increase 24 to 48 hours before any increase in sCr due to renal reserve and renal secretion of creatinine.

Disadvantages: NGAL plasma levels are influenced by CKD, chronic HTN, systemic infection, or inflammation. Urine NGAL levels are influenced by CKD, nephritis, and urinary tract infection (UTI).

Relevance to the CRS: ADHF patients with supernormal admission NGAL levels have a greater likelihood of developing WRF.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

This discussion is not meant as an exhaustive description of the modalities that will be mentioned, but rather as a summary of aspects pertinent to the CRS.

Chest radiogram (CXR):

Advantages: The CXR demonstrates or excludes the presence of cardiomegaly (cardiothoracic ratio >0.5), RV enlargement, aorta or pulmonary artery enlargement, pulmonary vascular redistribution, Kerley B lines, and pleural effusions. The presence of parenchymal infiltrates, changes consistent with COPD, decreased vascular markings in the periphery and elevation of the diaphragm helps to identify causes of dyspnea unrelated or contributing to HF and volume overload.

Disadvantages: The CXR lacks sensitivity and specificity for the diagnosis of fluid overload as indicated by the finding that radiographic pulmonary congestion is absent in one third of patients with invasively measured elevated cardiac filling pressure.

Echocardiogram: Two-dimensional and Doppler echocardiography enables evaluation of ventricular size, global and regional systolic function, diastolic function, valvular disease, and pericardial disease. The CO can be estimated by pulsed-wave Doppler from the LV outflow tract.

Echocardiography also enables estimation of right atrial pressure, pulmonary artery pressure, and PCWP. Doppler peak tricuspid regurgitation (TR) velocity can be used to estimate pulmonary artery systolic pressure. Inferior vena cava (IVC) diameter and collapsibility can be used to estimate CVP and fluid excess.

Renal ultrasound:

Advantages: Excludes urinary tract obstruction and establishes the cause of hydronephrosis. Because urinary tract obstruction is easily diagnosed and reversible when treated early, renal ultrasound should be performed in all patients presenting with renal failure of unknown etiology.

Renal ultrasound is useful in the initial detection of a renal mass and to screen for polycystic kidney disease. Renal ultrasound evidence of decreased kidney size suggests the presence of irreversible kidney damage.

Doppler renal ultrasonography can be used to evaluate renal vascular flow in conditions such as renal vein thrombosis, renal infarction, and renal artery stenosis. A Doppler-derived resistive index [(Peak Systolic Velocity – End Diastolic Velocity)/ Peak systolic velocity] >0.7 may indicate intrarenal vascular disease or arteriosclerosis, but may also occur with acute tubular necrosis or obstructive uropathy.

Disadvantages: Renal ultrasound is less sensitive than CT in the detection of renal masses.

Echocardiographic measurements that may be useful in patients with the cardiorenal syndrome

The PCWP can be estimated via the ratio (E/Ea or E/E’) of tissue Doppler of early mitral inflow velocity (E) to early diastolic velocity of the mitral annulus (Ea or e’). An E/e’ ratio >15 suggests a PCWP >15 mm Hg where e’ is the mean of medial and lateral mitral annulus early diastolic velocities.

The ratio of TR velocity (m/sec) to velocity-time integral [VTI (m)] is useful for the estimation of pulmonary vascular resistance (PVR): TR velocity/VTI >016 predicts a PVR >2 Wood Units with 91% sensitivity and 100% specificity; in HF patients, TR velocity/VTI >0.15 predicts HF hospitalizations, mortality, and CV adverse events. The tricuspid annular plane systolic excursion (TAPSE) reflects RV function. A TAPSE >2 suggests normal RV function.

III. Management.

See Figure 1. Algorithm for the Management of the Cardiorenal Syndrome.

Figure 1.

Algorithm for the Management of the Cardiorenal Syndrome


In symptomatic HF patients, diuretics are effective in treating the symptoms and signs of pulmonary and peripheral congestion. However, diuretic therapy in some HF patients may lead to deterioration of renal function.

Therefore the optimal management of volume overloaded HF patients requires in-depth knowledge of the pharmacology of diuretics and of the factors responsible for the development of resistance to diuretic therapy. In the relationship between dietary Na intake, urinary Na excretion and mean arterial pressure, diuretics shift the renal function curve to the left, permitting Na excretion to increase at a constant mean arterial pressure.

Aspects of diuretic therapy especially relevant to patients with HF and renal impairment are outlined below:

  • Loop diuretics can increase Na excretion by a maximum of 25% of the filtered Na. Regardless of route of administration, loop diuretics increase urine output only if they achieve a critical intratubular concentration. The repeated administration of loop diuretics doses insufficient to achieve such concentration will not effectively increase diuresis. Therefore, if a given IV loop diuretic dose does not produce the expected increase in urine output, the subsequent dose should be doubled.

  • In edematous conditions such as HF, this dose-response curve is shifted downward and to the right, indicating that achievement of natriuresis requires loop diuretic doses higher than those that effectively increase urinary NaCl excretion in normal individuals. A rightward shift of the dose-response curve also occurs with renal insufficiency, indicating that compared to normal renal function, higher diuretic doses are needed to achieve the same FeNa (Table 4).

  • Considering that a furosemide dose >240 mg produces only a modest additional natriuresis, but is associated with considerable toxicity, it is currently recommended that such dose not be exceeded in HF patients. Importantly most patients can correctly identify which diuretic dose produces a significant increase in urine output within 4 hours of ingestion. In the absence of increased diuresis, it is reasonable to double the diuretic dose.

  • Different loop diuretics have similar bioavailability when given IV. In contrast, bioavailability and half-life vary between loop diuretics when these drugs are given orally.

    Although in HF loop diuretics’ half-lives are lengthened, they remain ≤ 6 hours. Thus, after a period of natriuresis, the diuretic concentration in the renal tubular fluid declines below the diuretic threshold and renal Na reabsorption resumes (postdiuretic NaCl retention). Therefore the net daily effect of a diuretic is the Na excretion occurring while NaCl reabsorption is inhibited minus the Na retention persisting until the next diuretic dose achieves sufficient tubular concentration to trigger natriuresis.

    If dietary NaCl intake is excessive, postdiuretic NaCl retention can overcome initial natriuresis and a negative salt balance cannot be achieved. Thus daily dietary salt restriction (≤2 g or 86 mEq of Na) is critically important to preserve the effectiveness of diuretics. To minimize postdiuretic Na retention, loop diuretics should be given at least twice daily.

  • When loop diuretics effectively decrease ECF volume, the NaCl balance gradually returns to neutral despite continued diuretic administration. Thus the magnitude of natriuresis decreases after each diuretic dose (“braking phenomenon”).

    The greater the contraction of the ECF volume, the greater is the decline in natriuresis with subsequent diuretic doses, because the amount of filtered NaCl is reduced and the amount of reabsorbed NaCl is increased. Thus, during chronic diuretic treatment, inhibition of NaCl transport along the distal nephron (the predominant site of thiazide action) is counterbalanced by a reduction in distal NaCl delivery. Under these conditions, urinary NaCl equals dietary NaCl intake because enhanced proximal NaCl absorption equals inhibited distal NaCl absorption.

  • Because their half-life is longer than that of loop drugs, collecting tubule (DCT) diuretics may attenuate postdiuretic NaCl retention by continuing to inhibit NaCl reabsorption after the action of the loop diuretic ceases. By inhibiting carbonic anhydrase, DCT diuretics also inhibit salt transport in the proximal tubule, thereby enhancing NaCl and fluid delivery to the loop of Henle, which in turn leads to increased NaCl delivery to the DCT.

    The weak carbonic anhydrase inhibitors, such as acetazolamide, can be effective when added to loop diuretics. Chronic administration of loop diuretics produces a threefold increase in hypertrophy and hyperplasia of distal tubular cells that mediate an increase in distal NaCl reabsorption.

    Because DCT diuretics inhibit distal NaCl reabsorption, the combination of low-dose loop and DCT diuretics may be more effective than higher doses of a single diuretic type. In general, when a second diuretic is added, the loop diuretic dose should not be modified, because the shape of the steep dose-response curve for loop diuretics is not altered by the addition of other diuretics.

    Metolazone is often the DCT diuretic of choice because it remains effective at low GFRs and has a longer half-life. Although DCT diuretics may be added in full doses (50 to 100 mg/day hydrochlorothiazide or 10 mg/day metolazone) when a rapid and robust response is needed, such an approach may lead to complications without close monitoring to prevent excessive fluid and electrolyte depletion, which can occur in up to two thirds of the patients.

    One reasonable approach to combination therapy is to achieve control of ECF volume by initially adding full daily doses of DCT diuretics and then to maintain control by reducing DCT diuretic dosing to three times weekly. A limited course of combination diuretic therapy may be as effective as and perhaps safer than more prolonged courses.

    Thus, in the outpatient setting, either a small dose of DCT diuretic, such as 2.5 mg/day metolazone, or a limited course of a higher dose (metolazone 10 mg daily for 3 days) may be effective and safer. Because DCT diuretics are absorbed more slowly than loop diuretics, it may be reasonable to administer the DCT diuretic 0.5 to 1 hour prior to the loop diuretic.

  • Although acutely not as effective as DCT diuretics, collecting duct drugs, such as amiloride and spironolactone, can be added to loop diuretics. Aldosterone antagonists also have important roles in preventing hypokalemia and hypomagnesemia while maintaining renal Na excretion and they have been shown to prolong life.

  • In the inpatient setting, IV loop diuretics can be given either as bolus injections or as continuous infusions. These two therapeutic modalities have similar efficacy and safety. Low (1x oral dose) or high (2.5x oral dose) also yield similar results. In the hospital setting chlorothiazide (500 to 1,000 mg once or twice daily) and acetazolamide (250 to 375 mg up to four times daily) are available for IV administration to supplement loop diuretics.

Table 4.n

Pharmacokinetics of Loop Diuretics

(See Figure 2, Figure 3, and Figure 4)

Figure 2.

Percentage of sodium reabsorbed in different segments of the nephron and site of action of diuretics

Figure 3.

Dose-response Curves for Loop Diuretics in Normal Individuals and Patients with Chronic Renal Failure and Congestive Heart Failure

Figure 4.

Effects of diuretics on urinary sodium excretion and extracellular fluid volume.

Other pharmacologic therapies for Cardiorenal Syndrome

Angiotensin-converting enzyme inhibitors and beta-blockers

A description of the benefits of ACEI, ARB, and beta-blockers in HF patients is beyond the scope of this discussion. In the setting of the CRS, it is important to stress that ACEI, ARB, and beta-blockers are renoprotective.

Indeed the benefit of ACEI is greater in patients with renal impairment than in those without renal impairment. Therefore every effort should be made to continue these life-saving drugs in patients with HF and renal impairment.

In addition, inhibition of the sympathetic and RAAS activation decreases Na retention by the proximal tubule, where 65% to 70% of Na is reabsorbed and where increased reabsorption is neurohormonally mediated. However ACEIs and ARBs may worsen renal function by blocking A II-induced vasoconstriction of the efferent arteriole of the kidney, which reduces glomerular hydrostatic pressure and thus GFR and perpetuates Na retention and volume overload.

The HF patients most susceptible to this effect are those with an abnormal renal function who are treated with loop diuretics. In general, if vasodilation is not balanced by adequate improvement of CO, the resulting reduction in RPP will be associated with increased tubular Na reabsorption.

In patients with systolic BP <80 to 90 mmHg, sCr >3 mg/dl, K >5.2 mmol/L, or diabetes, renal function and electrolytes should be assessed ≤1 week after initiation of ACEI and closely monitored thereafter. The sCr levels often rise after initiation of ACEI in HF patients regardless of baseline renal function and slowly return to baseline values even in the absence of ACEI dose adjustment.

Measures to reduce renal complications include initiation of lower ACEI doses, avoidance NSAIDs, and avoidance of volume depletion by reduction of diuretic doses. Patients with severe HF who develop intolerance to ACEI due to symptomatic hypotension and/or renal limitations have an especially poor prognosis and should be evaluated for advanced HF therapies.


Nitrates are the most frequently used vasodilators. Nitroglycerin reduces cardiac filling pressure through venodilatation. At higher doses, the drug may increase CO by lowering afterload and increasing CO.

In patients without symptomatic hypotension, IV nitroglycerin added to IV diuretics therapy may result in rapid improvement in symptoms and signs of pulmonary congestion. Therapy with high dose IV nitrates plus low dose IV furosemide is associated with better outcomes than use of low dose IV nitrates plus high dose IV furosemide.

Although tachyphylaxis can occur within hours of IV administration of high doses of nitroglycerin, intermittent use of IV nitrates is not recommended due to potentially adverse hemodynamic effects. Hypotension and headaches may occur with IV nitroglycerine.

Use of phosphodiesterase (PDE-5) inhibitor should be excluded before initiation of IV nitrates. Initial IV nitroglycerin doses are 5 to 10 mcg/min. These doses can be increased every 3 to 5 minutes up to maximum doses of 200 mcg/min.


In patients with ADHF therapy, nesiritide is associated with a modest reduction in dyspnea, increased rates of hypotension, and similar rates of death or 30-day rehospitalization compared to usual care. Nesiritide was not associated with increased rates and severity of WRF compared to standard care.

Given these results and the high cost of the drug, the use of nesiritide is recommended only in selected nonhypotensive patients who remain symptomatic despite usual care. Nesiritide has a longer half-life than nitroglycerin or nitroprusside, and therefore hypotension may persist longer.

Nesiritide is usually given as an initial 2 mcg/kg IV bolus, followed by a continuous infusion of 0.01 mcg/kg/min, with subsequent dose adjustment if appropriate. The bolus should not be used in patients with a systolic BP <110 mmHg. Close monitoring of hemodynamics, urine output, and renal function is strongly recommended.


Nitroprusside is a potent arterial and venous vasodilator that rapidly decreases preload and afterload. This drug is especially useful in hypertensive crises, acute aortic or mitral regurgitation, or acute ventricular septal rupture.

The initial dose of 5 to 10 mcg/min can be uptitrated to maintain a systolic BP >90 mmHg or mean BP >65 mmHg. Nitroprusside administration requires continuous BP and HR monitoring for early detection of hypotension and tachycardia.

Rebound vasoconstriction may occur upon discontinuation of nitroprusside. The most feared complication of nitroprusside is thiocyanate toxicity, which is more likely to occur at doses >400 mcg/min and can be fatal.

Arginine Vasopressin Antagonists

In HF patients, nonosmotic release of vasopressin is stimulated by increased sympathetic and angiotensin II activity. In the distal nephron, binding of vasopressin to its V2 receptor upregulates aquaporin channels thereby increasing free water reabsorption that results in dilutional hyponatremia.

Oral administration of the V2 selective vasopressin antagonist tolvaptan in ADHF patients is associated with a significant decrease in dyspnea, edema, and weight and an increase in serum Na. However, these benefits do not translate into improvement in the long-term outcomes of cardiovascular death or hospitalization for HF, and quality of life.

Tolvaptan is FDA approved for the treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum Na <125 mEq/L or less marked hyponatremia that is symptomatic and refractory to fluid restriction), as can be seen in patients with HF, cirrhosis, and syndrome of inappropriate antidiuretic hormone secretion (SIADH). It is recommended that tolvaptan be initiated only in the hospital where serum Na can be closely monitored.

Too rapid correction of hyponatremia (>12 mEq/L/24 hr) can cause osmotic demyelination (dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, and death) especially in patients with severe malnutrition, alcoholism, or advanced liver disease, in whom slower rates of correction are recommended.

Contraindications to the use of tolvaptan include the urgent need to raise serum Na, impaired response to thirst, hypovolemic hyponatremia, concomitant use of strong CYP 3A inhibitors, and anuria. Serum K levels should be closely monitored in patients with a serum K >5 mEq/L and in those receiving drugs that increase serum K levels.

In adults, tolvaptan dose is 15 mg orally once daily without regard to meals. The daily dose can be increased to 30 mg after at least 24 hours, and to a maximum of 60 mg as needed to achieve the desired level of serum Na.

The dual V1/V2 vasopressin antagonist conivaptan is indicated in hospitalized patients for the treatment of euvolemic hyponatremia (SIADH, hypothyroidism, adrenal insufficiency, pulmonary disorders, etc.). The safety of conivaptan in HF patients has not been established.

Conivaptan should be initiated with a loading dose of 20 mg IV infused over 30 minutes, followed by a continuous IV infusion of 20 to 40 mg/day for a maximum of 4 days.

Inotropic Agents

The IV inotropic agents dobutamine (beta-agonist) and milrinone (phosphodiesterase inhibitor) are recommended in selected patients with severe LV systolic dysfunction and low CO syndrome (diminished peripheral perfusion and end-organ dysfunction) in whom the use of diuretics and vasodilators to reduce congestion is limited by a low BP (<0 mm Hg) and WRF.

Heart rhythm and BP should be frequently monitored during administration of IV inotropes and discontinuation or dose reduction of these drugs is recommended if symptomatic hypotension or worsening tachyarrhythmias occur. Inotropic agents may increase HR and myocardial oxygen consumption and thus trigger ischemia and injure hibernating myocardium, especially in patients with ischemic heart disease.

In addition, inotropic agents can increase atrial and ventricular arrhythmias. Dobutamine is usually started at doses of 2.5 mcg/kg/min and gradually increased to a maximal dose of 15 mcg/Kg/min, if appropriate and tolerated and needed. The effects of dobutamine are decreased by concomitant administration of beta-blockers.

Milrinone is used at doses of 0.375 to a maximum of 0.750 mcg/kg/min with dose adjustment required in the presence of renal insufficiency, hypotension, or arrhythmias. A loading dose of milrinone (50 mcg/kg over 10 minutes) is seldom used.


Dopamine increases Na excretion by reducing Na reabsorption in the proximal tubule and, to a lesser extent, in the collecting tubules. At low doses (0.5 to 3 mcg/kg/min), dopamine dilates both the afferent and efferent renal arterioles, resulting in a relatively large increase in RBF without a significant change in GFR.

These effects have led to the use of low-dose, “renal-dose” dopamine to increase the urine output and to preserve renal function in oliguric patients at risk for postischemic acute tubular necrosis. In patients with moderate to severe HF, dopamine at doses of 5 to 10 mcg/kg/min also causes significant increases in CO, but the proportionate increase in RBF was greater than that of CO.

The combination of low-dose dopamine plus a diuretic may reduce the risk of WRF compared to diuretic therapy alone. Renal vasoconstriction via activation of alpha-adrenergic receptors occurs with higher dopamine doses (>5 mcg/kg/min). The use of these doses to support BP in hypotensive patients with sepsis is occasionally complicated by marked natriuresis and polyuria (300 to 500 ml/hr) despite renal hypoperfusion.

Extracorporeal fluid removal, with focus on simplified isolated veno-venous ultrafiltration (aquapheresis)

It is estimated that at least 30% of ADHF patients have diuretic resistance, defined as persistence of signs and symptoms of pulmonary and peripheral congestion despite therapy with adequate doses of IV loop diuretics. Patients with ADHF and diuretic refractoriness may benefit from extracorporeal fluid removal.


Ultrafiltration consists of the transport of plasma water across a semipermeable membrane in response to a transmembrane pressure gradient (TMP). Solute transport occurs by convection. Because of the membrane sieving capacity, the produced ultrafiltrate contains crystalloids but not cells or colloids and it is therefore iso-osmotic to plasma water.

Vascular access and extracorporeal circuit

With UF, blood is extracted from the patient after cannulation of a vessel, it is moved through the extracorporeal circuit (EC) and then returned to patient’s circulation. With current simplified UF devices, cannulation of a large central (femoral) vein is no longer required. A small central vein (right internal jugular), a large peripheral (basilic) vein, or a combination of the two, are adequate as the vascular access for simplified isolated UF.

Ultrafiltration equipment and therapy

In the U.S., simplified equipment (Aquadex System 100; CHF Solutions Brooklyn Park, MN) permits to accomplish UF with very low blood flows (20 to 100 ml/min) and a total extracorporeal blood volume of 30 ml. Peripheral or small central vein access can provide UF rates of 10 to 500 ml/hr.

Contemporary UF devices provide data on the pressure being generated in the blood withdrawal line, the filter itself, and the blood return line, thus allowing early detection of filter dysfunction and access-related issues (Figure 5).

Figure 5.

Aquadex System 100 Ultrafiltration Device

To prevent line thrombosis, heparin should be infused in the arterial line to achieve a local aPTT of 72 to 105 seconds. Direct thrombin inhibitors can be used in patients with heparin allergies. Contemporary UF circuits also include a hematocrit sensor that provides an estimate of changes in blood volume and adequacy of intravascular refilling.

The safety and efficacy of UF depend upon the ability to remove fluid without causing hemodynamic instability and/or worsening renal function. To achieve this goal, the amount and rate of fluid removal must be clearly established.

If UF rates are too high, hemodynamic instability occurs because the refilling of the intravascular space from the interstitium cannot keep pace with the reduction in intravascular volume. Lower UF rates give rise to gradual intravascular refilling from the interstitial space that reduces extracellular fluid without inducing intravascular volume depletion.

In practice, UF should initially be prescribed at low UF rates (100 to 200 ml/hr). After assessment of the hemodynamic response higher rates can be tried in the absence of symptomatic hypotension and/or WRF.

In general extracorporeal fluid removal is better tolerated when conducted with low UF rates over a prolonged period of time, whereas aggressive UF performed with intermittent methods may result in severe hemodynamic instability, which can compromise short- and long-term renal function. Edematous ADHF patients treated with Aquapheresis have a plasma refill rate PRR >500 ml/hr for an average of 9 hours.

After removal of 4 L of fluid, the PRR drops but still exceeded 400 ml/hour. Theoretically, if UF is within the PRR, the difference between pretreatment and posttreatment hematocrit should = 0. However, because multiple factors, including change in body position, can significantly alter hematocrit values, physical and laboratory assessments are typically relied upon to determine the appropriate rates of UF.

Rates of UF exceeding 250 ml/hr are no longer recommended. Patients with predominantly right sided HF or patients with HF and preserved systolic function indicate that these patients are especially susceptible to intravascular volume depletion and may only tolerate UF rates of 100 to 150 ml/hr.

Therefore, every patient should be carefully evaluated and clinical status monitored while undergoing UF. Careful monitoring is especially important during the first hours of treatment.

As the patient’s fluid excess is reduced, PRR usually decreases, so that UF rates should be reduced as well. Fluid reduction therapy using UF should continue until resolution of congestion, defined as JVP <8 cm, with no orthopnea and with trace peripheral edema or no edema.

Rates of UF can be slowed or stopped completely for transient episodes of hypotension and worsening renal function. However, UF can be restarted if the patient has not successfully achieved the treatment goal.

Practical recommendations regarding the use of ultrafiltration in heart failure(Figure 6)

Figure 6.n

Example of Ultrafiltration Orders

  • Which degree of congestion should be treated with UF rather than IV diuretics?

    A recent consensus statement proposes that congestion be graded according to a combination of clinical and laboratory parameters. The expert consensus suggests that a congestion grade >12, together with low urine output (<1,000 ml/24 hr), should trigger the use of extracorporeal fluid removal.

  • Which degree of renal impairment requires blood cleansing (i.e., dialysis) in addition to fluid removal by UF?

    In the absence of data from controlled clinical trials, it is reasonable to use UF alone in patients with sCr levels ≤3 mg/dl and blood cleansing therapies in those with sCr levels >3 mg/dl.

  • How does one determine how much fluid should be removed and how fast?

    A frequently used practical approach is to estimate fluid excess by comparing the patient’s current weight with that measured in the absence of signs and symptoms of congestion, and remove at least 50% to 60% of this excess fluid without causing WRF or hemodynamic instability.

    It is reasonable to define resolution of congestion as a JVP ≤8 cm, absence of pulmonary rales and trace or no edema.

    Online hematocrit sensors for the continuous estimation of blood volume, available in contemporary UF systems, can be programmed so that fluid removal is stopped if the increase in hematocrit exceeds the threshold set by the treating physician (3% to 7%). It can be resumed when the hematocrit value falls below the prespecified limit, which indicates that adequate refilling of the intravascular volume from the interstitial space has occurred.

  • Should diuretics be adjusted during UF?

    It is strongly recommended that all diuretics be stopped during UF. After discontinuation of the therapy, diuretics can be resumed at half the dose given before initiation of UF and subsequently adjusted according to the patient’s volume status.

  • Does UF affects long-term outcomes of ADHF patients?

    The effects of UF on long-term outcomes are unknown, because patients treated with this modality have not been followed beyond 6 months. Available evidence suggests that, compared to IV loop diuretics, UF is associated with lower 90-day HF rehospitalization rates.

  • Which patients should not be treated with UF?

    Patients should not be considered for UF if the following conditions exist: venous access cannot be obtained; there is a hypercoagulable state; systolic BP is <85 mm Hg or there are signs or symptoms of cardiogenic shock; patients require intravenous pressors to maintain an adequate BP; or there is end-stage renal disease, as documented by a requirement for dialysis approaches.

    Ultrafiltration can be carried out in patients with hematocrit levels >40% only if it can be proven that hypovolemia is absent.

  • Should patients undergoing UF receive systemic IV anticoagulation, even if already taking warfarin or other oral anticoagulants?

    Yes, to avoid filter clotting, given the low blood flow rates used with UF.

Practice guidelines recommendations regarding the use of ultrafiltration in heart failure

European and North American practice guidelines state that UF is reasonable for patients with refractory congestion not responding to medical therapy and assign to this recommendation a Class IIa, Level of Evidence: B. In patients with severe renal dysfunction or edema refractory to standard care, UF may be needed to achieve adequate control of fluid retention.

The guidelines further acknowledge that in these patients, UF can produce clinical benefits, may restore responsiveness to conventional doses of loop diuretics, and correct hyponatremia. Neither practice guidelines nor clinical trial data provide guidance as to which clinical variables should trigger initiation of extracorporeal therapies.

Challenges in the treatment of the cardiorenal syndrome in the setting of acutely decompensated heart failure

Optimal therapy of ADHF patients with renal impairment requires careful determination of the patient’s fluid status, cardiac output, and severity of intrinsic renal disease.

Assessment of fluid status is critical, as volume status can be easily manipulated with the appropriate interventions. Patients can develop hypovolemia during intensive treatment for HF with IV diuretics or UF or because of intercurrent illness.

Overly aggressive fluid removal with either IV diuretics or UF can decrease CO because of an excessive reduction in preload. Diuretics also decrease GFR independently of their effect on CO.

Hypotension induced by fluid removal therapies must be reversed with fluids before irreversible renal damage occurs. Thus, when HF and renal insufficiency coexist, it is critically important to determine if the patient is hypovolemic.

In this regard careful physical examination or echocardiographic estimation of right atrial pressure is especially helpful. In some cases, invasive hemodynamic monitoring may be necessary to monitor cardiac filling pressure.

If the patient is euvolemic or hypervolemic, the adequacy of renal performance should be determined. If the patient is hypotensive, pressor agents should be used to keep systolic blood pressure >80 mm Hg, with a mean systolic blood pressure ≤60 mm Hg.

In the absence of hypotension, knowledge of CO is helpful in directing therapy. The patient with cold extremities, low CO, and increased systemic vascular resistance is excessively vasoconstricted and often responds very favorably to vasodilation.

When such a patient has renal insufficiency, ACEI are often withdrawn in an attempt to improve renal function; however, such patients are the ones who truly benefit from vasodilator therapy, first acutely and later with ACEI. Renal function may actually improve as CO and, consequently, renal perfusion increase.

Systolic BP of 80 to 90 mmHg should be tolerated as long as renal function does not worsen. More problematic is the treatment of patients with hypotension, normal CO, low systemic vascular resistance, and WRF. This hemodynamic picture, typically seen with sepsis, can also occur in patients with severe HF and is termed “vasodilatory shock.”

In such cases either BP is too low to support adequate renal perfusion, or blood is shunted away from the kidneys. This intense vasodilation is often refractory to NE and A II.

Infusion of vasopressin at a dose of 0.01 to 0.04 units/min may increase BP and allow a reduction in pressor medication dose in patients with hypotension and low system vascular resistance. Early recognition and appropriate therapy for this form of CRS is vital because it is associated with a high mortality.

In patients who are eligible for cardiac transplantation, insertion of a ventricular assist device can reverse renal insufficiency and allow successful transplantation. Intrinsic renal disease is frequent in patients with the CRS and should be suspected when hypovolemia has been excluded or corrected, and CO and systemic vascular resistance are normal.

These patients are especially susceptible to the development of diuretic resistance and may require extracorporeal fluid removal therapies.

Monitoring of fluid removal therapies in heart failure patients

Monitoring of fluid removal can be based on clinical judgment, chemical biomarkers, and physical parameters. The information resulting from this combined approach may help to determine the fluid status of the patient and to judge when fluid removal should be initiated, how it should be carried out, and when it should be discontinued.

Clinical Variables: Conventional indicators of hydration status and tissue perfusion are systemic blood pressure, heart rate, body weight, jugular venous pressure, and presence or absence of pulmonary and/or peripheral congestion. The clinical assessment of volume status may be hindered by many physiologic and therapeutic variables, such as mechanical ventilation.

Central venous pressure (CVP) and pulmonary artery wedge pressure (PAWP) accurately reflect preload, but their elevation does not necessarily exclude intravascular volume depletion. In mechanically ventilated patients, stroke volume variation in response to fluid administration is used to determine a patient’s hydration status.

Echocardiography may permit estimation of filling pressure and assessment of respiratory diameter excursions of the inferior vena cava. A chest radiogram may reveal cardiomegaly, interstitial pulmonary edema, and vascular congestion. All these methods do not have adequate sensitivity and specificity, and should not be the sole determinants of the patient’s volume status.

Biomarkers: Rarely do chronic HF patients with the CRS have normal NP levels, even when euvolemic. These abnormally high NP levels further increase during ADHF and have been shown to correlate with both HF severity and response to treatment.

HF patients may have a “dry” and a “wet” NP levels, both of which vary within the same individual over time and clinical evolution. As PAWP falls, BNP levels decrease at a rate of approximately 30 to 50 pg/ml/hr.

Therefore NP levels can be used to assess whether therapy is adequate or whether it should be intensified, particularly if NP levels have not been appreciably lowered in 24 to 48 hours. It is recommended that BNP levels be measured in ADHF patients on admission, 24 hours after initiation or change in therapy, and at discharge.

Patients in whom NP levels fail to decline >30% during hospitalization have a higher risk of death and/or re-hospitalization. Higher NP levels are consistently observed in HF patients with CKD due to coexisting cardiac disease and/or reduced renal clearance of the NPs.

Hematocrit Sensors: The hematocrit is the ratio of the volume occupied by packed red blood cells to the volume of the whole blood. Since red cell mass does not change in the short term unless bleeding is present, changes in hematocrit reflect changes in plasma volume and therefore they can be used to estimate changes in intravascular volume.

Relative increases in hematocrit indicate volume contraction. Hematocrit sensors are sometimes used online with UF devices to permit continuous estimation of blood volume.

Such equipment can be programmed to stop fluid removal if the increase in hematocrit exceeds a set threshold (5% to 7%) and resumed when the hematocrit value falls below the prespecified limit, indicating an adequate refilling of the intravascular volume from the interstitial space.

Bioelectrical impedance for the monitoring of fluid removal therapies in heart failure

Bioelectrical Impedance: The principle of bioimpedance vector analysis (BIVA) is based on the whole body’s resistance and conductance to the passage of an electrical current. Measurements can be made in vivo with the application of relatively high frequency alternating microcurrents (most commonly at 50 kHz) using a well-established tetrapolar system (Cardio-EFG, EFG-Dublin, Ireland).

The impedance to the alternating current results from the electrical characteristics of the complex network of resistive and capacitive conductors arranged in parallel and in series within living soft tissues which, in turn, reflect the amount of intracellular and extracellular fluid.

Data on age, gender, and height of 1,800 Caucasian subjects have been used to develop nomograms of resistance and reactance, which permit to determine whether a subject is euvolemic, dehydrated, or fluid overloaded. In overhydrated patients, bioimpedence vector analysis (BIVA) can be used to guide UF and target overall volume of fluid removal. The BIVA system is being studied, but it is not yet approved for clinical use in the U.S.

Common Pitfalls and Side-Effects of Management

Potential adverse effects of diuretics

Worsening renal function

The use of high IV loop diuretic doses has been linked to the development of WRF in several studies. One possibility is that a subgroup of HF patients refractory to diuretics, and therefore requiring higher doses of these drugs during HF decompensation, are especially susceptible to the development of WRF, particularly if admission sCr levels are elevated and combination diuretic therapy (loop + thiazide) is required.

The combination of IV nitrates or low-dose dopamine with low-dose IV furosemide may decrease the risk of WRF compared to the use of high furosemide doses alone. The possibility that the administration of higher doses of furosemide is a consequence, rather than a cause, of more advanced HF and coexistent renal failure cannot be excluded, making high diuretic doses only a marker rather than a cause of poor outcomes.

Other complications

The most common complications of loop diuretics are related to the hypokalemia, hyponatremia, and hypotension that can occur because of excessive fluid and electrolyte losses.

Hyperkalemia can be a serious complication of therapy with aldosterone antagonists, particularly in elderly and diabetic patients and in those already receiving an ACEI and/or ARB.

Potential adverse effects of ultrafiltration

Overly aggressive UF in ADHF patients can convert nonoliguric renal dysfunction into oliguric failure by increasing neurohormonal activation and decreasing renal perfusion pressure (RPP), which may lead to dialysis dependence.

Simplified isolated veno-venous UF appears to be safe. According to the Manufacturer and User Facility Device Experience (MAUDE) FDA website, 8 adverse events, all unrelated to the device, have been reported to date in approximately 33,000 treatments conducted with the Aquadex System 100.

The reason for the paucity of adverse events is the presence of safety features in contemporary UF devices. Air emboli are prevented by the air detector sensor and alarm.

Line disconnection, and pump or tubing malfunctions are detected by the pressure sensors, which stop the therapy until the mechanical problem has been addressed and corrected. Hemolysis and hemorrhage are <1%.

Despite the safety simplified veno-venous UF, it is critically important to remain vigilant about the occurrence of potential adverse events. These include compromise of the venous access site, infiltration of the IV line, catheter-related infection, and bleeding due to systemic anticoagulation.

What's the Evidence for specific management and treatment recommendations?

Smith, GL, Lichtman, JH, Bracken, MB. “Renal impairment and outcomes in heart failure: Systematic review and meta-analysis”. J Am Coll Cardiol. vol. 47. 2006. pp. 1987-96.

Krumholz, HM, Chen, YT, Vaccarino, V. “Correlates and impact on outcomes of worsening renal function in patients ≥ 65 years of age with heart failure”. Am J Cardiol. vol. 85. 2000. pp. 1110-3.

Costanzo, MR, Mebaaza, A, Gheorghiade, M, Zannad, FM, Parrillo, JE. “Management of volume overload in acute heart failure: diuretics and ultrafiltration”. 2008. pp. 503-18.

Gottlieb, SS, Abraham, W, Butler, J. “The prognostic importance of different definitions of worsening renal function in congestive heart failure”. J Card Fail. vol. 8. 2002. pp. 136-41.

Ellison, DH. “Diuretic therapy and resistance in congestive heart failure”. Cardiology. vol. 96. 2001. pp. 132-43.

Drazner, MH, Rame, JE, Stevenson, LW, Dries, DL. “Prognostic importance of elevated jugular venous pressure and a third heart sound in patients with heart failure”. N Engl J Med. vol. 345. 2001. pp. 574-81.

Heywood, JT, Fonarow, GC, Costanzo, MR, Mathur, VS, Wigneswaran, JR, Wynne, J. “High prevalence of renal dysfunction and its impact on outcome in 118,465 patients hospitalized with acute decompensated heart failure: a report from the ADHERE database”. J Card Fail. vol. 13. 2007. pp. 422-30.

Ronco, C, Haapio, M, House, A, Anavekar, N, Bellomo, R. “Cardiorenal syndrome”. J Am Coll Cardiol.. vol. 52. 2008. pp. 1527-39.

Felker, GM, Lee, KL, Bull, DA. “Diuretic strategies evaluation in patients with acute decompensated heart failure”. N Engl J Med. vol. 364. 2011. pp. 797-805.

Ronco, C, Bellomo, R. “Continuous renal replacement therapies: the need for a standard nomenclature”. Contrib Nephrol. vol. 116. 1995. pp. 28-33.

Anwaruddin, A, Lloyd-Jones, DM, Baggish, A. “Renal function, congestive heart failure, and amino-terminal Pro-Brain Natriuretic Peptide”. J Am Coll Cardiol. vol. 48. 2006. pp. 1060-1.

Valle, R, Aspromonte, N, Ronco, C. “Optimizing fluid management in patients with acute decompensated heart failure (ADHF): The emerging role of combined measurement of body hydration status and brain natriuretic peptide (BNP) levels”. Heart Fail Rev. vol. 16. 2011. pp. 519-29.

Agostoni, PG, Marenzi, GC, Lauri, GF. ” Sustained improvement in functional capacity after removal of body fluid with isolated ultrafiltration in chronic cardiac insufficiency: failure of furosemide to provide the same result”. Am J Med. vol. 96. 1994. pp. 191-9.

Costanzo, MR, Guglin, ME, Saltzberg, MT. “Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure”. J Am Coll Cardiol.. vol. 49. 2007. pp. 675-83.

Konstam, MA, Gheorghiade, M, Burnett, JC. “Effects of oral tolvaptan in patients hospitalized for worsening heart failure. The EVEREST outcome trial”. JAMA. vol. 297. 2007. pp. 1319-31.

Abdallah, JG, Schreier, RW, Edelstein, C. “Loop diuretic infusion increases thiazide-sensitive Na+/Cl–cotransporter abundance: role of aldosterone”. J Am Soc Nephrol. vol. 12. 2001. pp. 1335-41.

He, XR, Greenberg, S, Briggs, J, Schnermann, J. “Effects of furosemide and verapamil on the NaCl dependency of macula densa-mediated secretion”. Hypertension. vol. 26. 1995. pp. 137-42.

Mullens, W, Abrahams, Z, Francis, GS. “Importance of venous congestion for worsening of renal function in advanced decompensated heart failure”. J Am Coll Cardiol. vol. 53. 2009. pp. 589-96.

Jessup, M, Costanzo, MR. “The cardiorenal syndrome: Do we need a change of strategy or a change of tactics?”. J Am Coll Cardiol. vol. 53. 2009. pp. 597-9.

Jessup, M, Abraham, WT, Casey, DE. “2009 Focused update: ACCF/AHA guidelines for the diagnosis and management of heart failure in adults: A report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines”. Circulation. vol. 119. 2009. pp. 1977-2016.

Howlett, JG, McKelvie, RS, Costigan, J. “The 2010 Canadian Cardiovascular Society guidelines for the diagnosis and management of heart failure update: Heart failure in ethnic minority populations, heart failure and pregnancy, disease management, and quality improvement/assurance programs”. Can J Cardiol. vol. 26. 2010. pp. 185-202.

Dickstein, K, Cohen-Solal, A, Filippatos, G. “ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: The task force for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology”. Eur Heart J. vol. 29. 2008. pp. 2388-442.

Gheorghiade, M, Follath, F, Ponikowski, P. “Assessing and grading congestion in acute heart failure: a scientific statement from the acute heart failure committee of the heart failure association of the European Society of Cardiology and endorsed by the European Society of Intensive Care Medicine”. Eur J Heart Fail. vol. 12. 2010. pp. 423-33.

Guiotto, G, Masarone, M, Paladino, F. “Inferior vena cava collapsibility to guide fluid removal in slow continuous ultrafiltration: a pilot study”. Intensive Care Med. vol. 36. 2010. pp. 692-6.

C. DRG Codes and Expected Length of Stay.

ICD-9 and DRGs Codes (Table 5)

404 Hypertensive heart and chronic kidney disease


-Cardiorenal disease

-Cardiovascular renal

-Any condition classifiable to 402 with any condition classifiable to 403

Use additional code to specify type of heart failure (428.0-428.43), if known

The following fifth-digit subclassification is for use with category 404:

0 – Without heart failure and with chronic kidney disease stage I through stage IV, or unspecified

Use additional code to identify the stage of chronic kidney disease (585.1-585.4, 585.9)

1 – With heart failure and with chronic kidney disease stage I through stage IV, or unspecified

Use additional code to identify the stage of chronic kidney disease (585.1-585.4, 585.9)

2 – Without heart failure and with chronic kidney disease stage V or end stage renal disease

Use additional code to identify the stage of chronic kidney disease (585.5, 585.6)

3 – With heart failure and chronic kidney disease stage V or end stage renal disease

Use additional code to identify the stage of chronic kidney disease (585.5, 585.6)

ICD-9-CM Procedure Code

    99.78 Aquapheresis**

    Plasma water removal

    Ultrafiltration (for water removal)


    Hemodiafiltration (39.95)

    Hemodialysis (39.95)

    Therapeutic plasmapheresis (99.71)

**New ICD-9-CM Procedure Code issued by CMS Coordination & Maintenance Committee – fy2005