Evidence-Based Review of Renal Injury Risks in Cardiothoracic Surgery


Complete author affiliations and disclosures are at the end of this activity.


Release Date: September 27, 2007

Patient History and Introduction

 

AJ is a 63-year-old obese black man with a history of type 2 diabetes mellitus for 15 years, hypertension for 34 years, and coronary artery disease for 8 years. He presented with an acute myocardial infarction 2 days ago. Cardiac catheterization was performed, the results of which showed a 90% occluding left anterior descending lesion, a 70% occluding obtuse marginal lesion, and an 80% occluding circumflex lesion; the patient also had moderate mitral regurgitation. Left ventricular ejection fraction was 35%. Following the procedure, the patient was stabilized and admitted to the coronary care unit. Echocardiogram showed moderate left ventricular dilatation, grade 3 mitral regurgitation, and a structurally normal mitral valve. Pulmonary artery pressure was elevated at 48 mm Hg systolic.

Medications prior to admission include metoprolol, ramipril, hydrochlorothiazide, glyburide/metformin, atorvastatin, and aspirin. Pertinent vital signs and laboratory values are as follows:

Weight: 126 kg
Height: 173 cm
Blood pressure: 110/64 mm Hg
Heart rate: 88 beats/min
Respirations: 18/min
Temperature: 101.7? F
Serum creatinine: 149 mcmol/L (53-106 mcmol/L)
Blood urea nitrogen (BUN): 1.8 mmol/L (1.2-3.0 mmol/L)
Glomerular filtration rate (GFR): 140 mL/min
Potassium: 4.4 mmol/L (3.5-5.0 mmol/L)
Chloride: 102 mmol/L (95-105 mmol/L)
Bicarbonate: 24 mmol/L (22-28 mmol/L)
Glucose: 7.8 mmol/L (< 6.6 mmol/L)
Total cholesterol: 7 mmol/L (3.6-6.5 mmol/L)
Hemoglobin: 43%
Hematocrit: 2.28 mmol/L (2.09-2.71 mmol/L)
White blood cells (WBC): 13.2 x 106/L (4.5-11.0 x 106/L)
Platelets: 280 x 109/L (150-400 x 109/L)
Glycosylated hemoglobin (Hb A1c): 9%

The patient was pain free in the coronary care unit and was treated with the addition of furosemide. A frank discussion was held with him and his family regarding the need for coronary artery bypass graft (CABG) and mitral valve repair or replacement. The estimated risks for mortality and morbidity -- in particular for renal dysfunction postoperatively -- were discussed. Surgery was scheduled for 3 days later to allow his fever to abate.

The population of patients undergoing CABG surgery is diverse; overall, patients are older and have more comorbidities. The STS National Adult Cardiac Database is the largest voluntary clinical database in medicine and contains the most comprehensive information available regarding the demographics and outcomes of patients undergoing CABG surgery (http://www.sts.org/sections/stsnationaldatabase).

Ferguson and colleagues provided important information about patient risk and mortality rates from the STS National Cardiac Database from 1990 through 1999, during which time 1,154,486 patient records were harvested for isolated CABG procedures performed at 522 STS participant sites in the United States and Canada. The investigators used statistical modeling techniques that permitted a longitudinal time-trend analysis of the change in surgical risk over time based on preoperative risk factors. During the study period, patients who underwent isolated CABG were older, had more comorbidities, and were considered higher surgical risk. The mean age increased (from 63.7 years in 1990 to 65.1 years in 1999; P < .0001), as did the percentage of women (25.7% vs 28.7%; P < .0001).

The frequency of comorbid conditions (eg, smoking, diabetes, renal failure, hypertension, preoperative stroke, chronic obstructive pulmonary disease, cardiogenic shock, New York Heart Association functional class IV, and triple-vessel disease) increased significantly (P < .0001). Up to one third of patients' predicted relative risk for operative mortality increased by 30%, from 2.6% in 1990 to 3.4% in 1999 (P < .0001 for the time trend). Despite this, there was a decrease in re-operations and a decrease in operative mortality rates from 3.9% to 3.0%, representing a 23.1% reduction (P < .0001 for the time trend). Risk-adjusted operative mortality also decreased significantly from 4.8% to 2.9%. A Medicare-aged subset (n = 629,174) showed similar increases in risk and decreases in mortality (Ferguson, 2002). Updated data from the STS showed that CABG patients' acuity continued to increase in 2005 (STS, 2006); however, operative mortality continued to decrease in 2005 (Figure 1) (STS, 2006).

These factors should be considered when the surgical plan is developed for an individual undergoing CT surgery. The type of operation is also an important consideration; a patient undergoing first-time CABG has different risk factors than an elderly patient undergoing CABG with mitral valve repair. The patient's specific risk factors must be considered and specific evidence-based measures taken to ensure optimal surgical outcomes and minimize the risk for complications.


The spectrum of renal injury following cardiopulmonary bypass (CPB) ranges from subclinical injury to established renal failure that ultimately requires dialysis (Abu-Omar, 2006). Despite advances in surgical and anesthetic techniques, renal dysfunction is a relatively frequent and serious complication of CT surgery. The incidence varies depending on factors such as the study population, exclusion criteria, and especially criteria for defining renal dysfunction (Kuitunen, 2006).

In a recent review, Stafford-Smith found that after CABG surgery, 1% to 5% of patients require dialysis, 8% to 16% have moderate renal injury, and 80% to 90% have more subtle renal dysfunction (Stafford-Smith, 2007).

Antunes and colleagues from Portugal evaluated the incidence of postoperative renal dysfunction in 2445 consecutive patients who had no pre-existing renal disease (creatinine ≤ 2.0 mg/dL, without dialysis) and who had isolated CABG with CPB between July 1996 and December 2001. The main outcome measure, postoperative renal dysfunction, was defined as a postoperative serum creatinine level ≥ 2.1 mg/dL with a preoperative-to-postoperative increase of ≥ 0.9 mg/dL. Cardiopulmonary bypass was conducted using nonpulsatile flow and mild hypothermia (32? C). The systemic perfusion pressure was electively maintained at 55 to 65 mm Hg. The mean CPB time was 61.3 ? 20.1 minutes. A bloodless prime was used in > 95% of cases when the preoperative hematocrit was > 35%. Blood products were not administered unless the hematocrit fell below 20% to 22% during CPB. Collected mediastinal shed blood was reinfused during the first 6 postoperative hours. The incidence of postoperative renal dysfunction was 5.6% (136/2122 patients). Higher preoperative creatinine levels were predictive of postoperative renal dysfunction (Antunes, 2004).

Yates showed that patterns of change in serum creatinine after heart transplant, minimally invasive direct CAB, and CABG with CPB varied enormously; each had its own fingerprint suggestive of differing mechanisms of renal injury (Yates, 2006).

Renal injury, evidenced by increases in serum creatinine, usually becomes apparent within a few days after surgery, even if the procedure is uncomplicated. Changes in creatinine may lag behind reductions in GFR. Depending on the degree of damage, renal dysfunction may remain subclinical or evolve into renal failure requiring some form of replacement therapy (Swaminathan, 2003).

There is variability in normal serum creatinine based on age, body weight, nutritional status, ethnicity, gender, and the presence of anemia. Patients > 65 years of age may have GFR < 60 mL/min despite a normal serum creatinine level. Since creatinine is derived from muscle, patients with low body weight and/or poor nutritional status may have deceptively low serum creatinine levels. This may also be true in women (CKD Guidelines). The GFR can be estimated using 1 of several methods and is considered more reliable than serum creatinine alone.

The inverse relation between serum creatinine level and GFR can confound straightforward interpretation. For example, in a 30-year-old man with an initial serum creatinine level of 1.0 mg/dL (88. 4 mmol/L), an increase in his creatinine level to 2.0 mg/dL (176.8 mmol/L) would indicate a 50% decrease in GFR. When his creatinine level exceeds 10.0 mg/dL (884.0 mmol/L), only then will his GFR approach 0. Physicians often misinterpret the initial small changes as clinically insignificant (Hostetter, 2004).

A calculator to determine GFR is available at the National Kidney Disease Education Program website and is suitable for downloading to a handheld personal digital assistant (PDA) (http://nkdep.nih.gov/professionals/index.htm).

Clinical laboratories can automatically perform the calculation with simple adjustments of their information systems so that the clinician receives an estimate of a patient's GFR along with his or her creatinine level. Many laboratories have already begun to provide this service. These calculations assume a body weight of 72 kg and are corrected to a body surface area of 1.72 m2 (Hostetter, 2004).

A major problem with determining the incidence of acute renal failure in patients undergoing CT surgery is the lack of a standardized definition. The spectrum of definitions includes severe acute renal failure requiring dialysis to relatively modest observable increases in serum creatinine (≥ 25 %) or decreases in calculated GFR (Kuitunen, 2006).

Shah and Mehta recently summarized emerging trends in our knowledge of renal dysfunction and noted the following: "Studies describe acute renal failure depending on serum creatinine changes, absolute levels of serum creatinine, or the need for dialysis. Issues of nomenclature, definition, classification, and assessment of severity have long been recognized as problematic. A major limitation in this regard has been the lack of common standards for diagnosing and classifying the disease. Most definitions of acute renal failure have common elements, including the use of serum creatinine and, often, urine output, probably because these are the only functions that are routinely and easily measured and are unique to the kidney. In the absence of a universally accepted definition for acute renal failure, and in recognizing that acute renal failure actually includes a spectrum of clinical conditions from subclinical injury to complete failure of the organ, the AKIN group has recommended using the term acute kidney injury (AKI) to reflect the entire spectrum of the syndrome" (Shah, 2006). They commented that several groups are working on a standardized definition and this, along with the application of emerging biomarkers for renal function, will improve the care of these patients.

This can be compared to the diagnosis of myocardial infarction. Multiple elements, chest pain, electrocardiographic changes, and enzyme changes are sensitive and specific. The severity of the signs and symptoms allow gradation of the condition from angina and acute coronary syndrome through to infarction (Mehta, 2003).

Currently, physicians use an increase in serum creatinine of various levels to estimate postoperative renal function, ranging from 0.5 mg/dL (44.2 mcmol/L) to 2 mg/dL (176.8 mcmol/L), or an increase of 25%, from baseline (Kuitunen, 2006; Antunes, 2004; Karkouti, 2006).

The GFR is the most accurate measure of renal function. However, direct measurement of GFR requires meticulous urine collection and use of markers such as inulin. There are several formulas for estimating GFR based on serum creatinine. The GFR is accepted as the best measure of overall kidney function in both healthy patients and those with medical conditions. Normal GFR varies according to age, gender, and body size, and it normally declines with age. Normal GFR in young adults is approximately 120 to 130 mL/min/1.73 m2. A GFR < 60 mL/min/1.73 m2 represents loss of half or more of the adult level of normal kidney function, below which there is an increasing prevalence of complications of chronic kidney disease (CKD) (NKF Guidelines, 2004). Recent guidelines recommend estimating the GFR using prediction equations (estimating equations) based on serum creatinine, age, sex, race, and body size. Commonly used equations in adults and children are shown in Table 1.


The MDRD study formula is less influenced by non-kidney determinants of serum creatinine, and the NKF has advocated its use to determine GFR from serum creatinine measurements in clinical laboratories. However, healthy persons were not included in the development of the MDRD equation, which overestimates kidney function when GFR is > 60 mL/min per 1.73 m2 (Rule, 2004; Stafford-Smith, 2007).

Table 2 lists the range of values of serum creatinine that correspond to an estimated GFR of 60 mL/min/1.73 m2. Note that these values depend on age, gender, and race. It is critical to note that a patient with a serum creatinine level in the normal range can have CKD, and that minor elevations of serum creatinine concentration may be consistent with substantial reduction in GFR. Therefore, GFR should be estimated using one of the equations listed in Table 1 (NKF Guidelines, 2004).

The Acute Dialysis Quality Initiative Workgroup has outlined a consensus, known as RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease), for classification of acute renal impairment. This classification has been validated in patients undergoing cardiac surgery procedures. The classification system is divided into 3 levels based on either plasma creatinine level or urine output (Table 3) (Kuitunen, 2006). There was a linear relationship of outcomes (eg, mortality in patients) to their RIFLE classification in this study.

Table 3. The RIFLE* Classification for Acute Renal Failure

  GFR Criteria Urine Output Criteria
Risk Increased plasma creatinine x 1.5 or GFR decrease > 25% < 0.5 mL ? kg-1?h-1 x 6 hours
Injury Increased plasma creatinine x 2 or GFR decrease > 50% < 0.5 mL ? kg-1?h-1 x 12 hours
Failure Increased plasma creatinine x 3 or acute plasma creatinine ≥ 350 mcmol/mL or acute rise ≥ 44 mcmol/L < 0.3 mL ? kg-1?h-1 x 24 hours or anuria x 12 hours
Loss Persistent acute renal failure=complete loss of kidney function > 4 weeks  
ESKD End-stage kidney disease (.3 months)  

*Acronym for Risk, Injury, Failure, Loss, and End-stage kidney disease.
GFR: glomerular filtration rate; ESKD: end-stage kidney disease.
From Kuitunen, Ann Thorac Surg., 2006.

The medical community is not sure how to define acute renal failure, but most clinicians agree that a change in serum creatinine up to a certain level, along with changes in BUN, serum potassium, alterations in acid/base balance, and decreased urine output in a postoperative patient should be investigated and measures to attenuate any further renal toxicity should be initiated (Sear, 2005).

Novel markers for earlier detection of renal failure and renal injury are being evaluated. Neutrophil gelatinase-associated lipocalin (NGAL) was studied in a pediatric cardiac surgery population by Mishra and associates. As early as 2 hours following the procedure, NGAL was able to detect acute renal failure. A sustained elevation of NGAL permitted late diagnosis of acute renal failure. As yet, tests such as this are not mature enough to support rapid diagnosis (Mishra, 2005).

Factors associated with an increased risk of postoperative renal dysfunction include increased age and pre-existing medical conditions such as diabetes, peripheral vascular disease, hypertension, impaired left ventricular function, baseline renal failure, and renal artery disease (Abu Omar, 2006; Swaminathan, 2003). Most patients who present for the surgical correction of vascular disease have some degree of either latent or overt renal insufficiency. Therefore, the importance of obtaining a good preoperative history from patients scheduled to undergo cardiac surgery cannot be overemphasized.

Intraoperative factors associated with postoperative renal dysfunction should also be considered. Patients undergoing redo procedures, those undergoing aneurysm operations, those undergoing emergency surgery, and patients of older age undergoing multiple procedures are also at high risk for developing postoperative renal dysfunction (Abu Omar, 2006).

In the study by Antunes and colleagues that evaluated 2445 consecutive patients with no pre-existing renal disease (serum creatinine ≤ 2.0 mg/dL, without dialysis) and who underwent isolated coronary surgery under CPB, the following variables were independent predictors of postoperative renal dysfunction:

Blauth demonstrated the impact of macroscopic and microscopic emboli of gas, biologic aggregates (eg, cholesterol), and inorganic debris that can occur during cardiac operations with CPB, leading to end-organ ischemia and direct toxicity in the brain and kidneys. Many of these emboli are generated from manipulation of the atherosclerotic ascending aorta; these patients are at increased risk for postoperative renal dysfunction (Blauth, 1995).

Hammon and colleagues demonstrated improved outcomes in patients undergoing isolated CABG surgery with modified surgical techniques including increased use of a single cross-clamp technique, venting of the left ventricle, and transesophageal and epiaortic ultrasound scanning to locate atherosclerotic plaques and avoiding cannulation in these areas. Specifically, these patients had a significant decrease in the neurobehavioral event rate compared with patients undergoing standard surgical procedures (69% vs 60%, P < .05). There was also a significant decrease in postoperative neurobehavioral deficits at 1 week and 1 month postoperatively (29% vs 18%, P < .01). The stroke rate was < 2% in both groups (P = NS) (Hammon, 1997, 2003). Atheroembolism has been implicated as a causative agent in renal impairment after cardiac surgery.

There are several medications that are commonly used in the operative setting that may lead to renal dysfunction in patients undergoing surgery through alterations in renal hemodynamics and/or direct toxicity. If these agents are used preoperatively, the risk for postoperative renal dysfunction is increased due to combined effects of the drugs and CPB. Although drug-induced renal dysfunction is important, it is an often overlooked cause of acute renal failure in this patient population. Commonly used medications that may lead to changes in serum creatinine and/or renal insufficiency include albumin, aminoglycosides, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), antifibrinolytics (lysine analogs) aprotinin, cephalosporins, ionic contrast media, penicillins, vancomycin, and volatile anesthetics (Boldt, 2003; Taber, 2006). Cyclosporine, a common immunosuppressant used in heart transplant patients, is a potent source of renal impairment.

Karkouti and colleagues reported on patients who received prophylactic antifibrinolytic (aprotinin and tranexamic acid) drugs for high-transfusion-risk cardiac surgery. By use of propensity scoring, the investigators matched 449 of 586 patients receiving aprotinin (high-risk cases) to 449 of 10,284 patients receiving tranexamic acid (low-risk cases). The results showed no differences in transfusion rates or other clinical outcomes (myocardial infarction, stroke, or death), except for a higher proportion of patients with increased creatinine. There was no difference in the incidence of renal dialysis (Karkouti, 2006).

In an observational study (n = 4374) comparing patients who were taking aprotinin or either of 2 antifibrinolytic drugs (aminocaproic acid or tranexamic acid) or were not treated with any blood conservation drugs, Mangano and colleagues (Mangano, 2006) reported an association between aprotinin and increased thrombotic risk, especially renal dysfunction, after cardiac procedures. Concerns about methodological problems with the study have been raised (Ferraris, 2006).

In an earlier report, Mora Mangano for the same group reported on risk factors associated with renal dysfunction. The Multicenter Study for Perioperative Ischemia (McSPI) database was created from 69 centers in 17 countries. Data were collected for < 2% of patients undergoing surgery at many of the hospitals (Bidstrup, 2006).

The authors "minimized the risk associated with blood transfusion and recommended use of antifibrinolytic drugs that are either not approved for use in the USA or Europe (tranexamic acid and aminocaproic acid) or not approved for this indication (aminocaproic acid)" (Ferraris, 2006).

In addition, the findings are at variance with those of Karkouti and coworkers, as well as other reports, many of which have been summarized in 2 meta-analyses (Henry, 2001; Sedrakyan, 2004). The review by Sedrakyan included data from 35 trials involving 3879 patients (1988-2001) undergoing CABG. These authors found that aprotinin compared to placebo decreased transfusion requirements (RR 0.61, 95% confidence interval [CI], 0.58-0.66); had no effect on mortality, myocardial infarction, or renal failure; and decreased the risk of stroke (RR 0.53, 95% CI, 0.31-0.90).

In a more recently published paper from the McSPI 2 database and the Ischemia Research Foundation, Aronson and colleagues examined data from 4810 patients undergoing CABG. The demography did not report on the use of antifibrinolytic drugs. The risk factors for achieving the endpoint were age, congestive heart failure, previous myocardial infarction, pre-existing renal disease, use of intraoperative inotropes, intra-aortic balloon pump, and CBP > 2 hours (Aronson, 2007).

The studies discussed above raise important questions: "Should we alter our practice in cardiac surgery? We will be damned if we do (increased bleeding, blood use, and take backs) and possibly damned if we don't. Each patient deserves the best chance he or she can be given. In the high-risk scenario, this requires judgment based on all the known factors. Each piece of evidence should be considered and weighted according to its strengths and weaknesses" (Bidstrup, 2006).

Both preoperative and postoperative renal dysfunction are independent predictors of adverse outcomes. Acute renal failure after surgery alters prognosis enormously --mortality rates of up to 90% have been reported, especially if dialysis is required.

Alex and colleagues prospectively collected and analyzed data from 3120 consecutive patients who had elective CABG to identify patient profile, cost, outcome, and predictors of those readmitted to the intensive care unit (ICU). They showed that renal dysfunction, among other risk factors, was a predictor of readmission to the ICU. Despite a 4-fold increase in cost of care, the mortality rate (32.4%) of patients readmitted to intensive care was 23-times higher than that of routine patients (1.4%) (Alex, 2005).

In the study by Antunes and colleagues, 2445 consecutive patients without pre-existing renal disease underwent isolated CABG with CPB. The mortality rate for patients who experienced postoperative renal dysfunction was 8.8 vs 0.1% for patients who did not (P < .001). Patients with postoperative renal dysfunction had an increased length of hospital stay by 3.4 days (7.6 vs 11.0 days; P < .001). Patients who required hemodialysis (11%) had a perioperative mortality rate of 33.3% and a mean hospital length of stay of 16 days (Antunes, 2004).

Mora-Mangano found that postoperative renal dysfunction was associated with an almost 60% mortality rate, as well as an increase in ICU stay, hospital stay, and extended care (Figure 2) (Mora-Mangano, 1998). A separate study examined 183 patients who underwent aortic or thoracoabdominal surgery with deep hypothermic circulatory arrest between 1992 and 2000. The objective of the study was to determine preoperative variables associated with renal dysfunction in this population. Renal dysfunction was defined as a 25% reduction in creatinine clearance. Based on this definition, 38% (70 of 183) of patients had postoperative renal dysfunction (Mora-Mangano, 2001).

These adverse outcomes in patients with renal dysfunction likely reflect the underlying severity of their medical condition. Sicker patients are more likely to experience renal failure and are more likely to undergo complicated procedures, which are associated with longer bypass times and can lead to renal injury and ultimately renal dysfunction. Patients who develop renal failure are also more likely to develop multiorgan failure (Alex, 2005).

Renal dysfunction (azotemia) can be caused by prerenal, postrenal, and intrinsic renal factors. Prerenal causes are usually due to a decrease in renal blood flow, which leads to a reduction in GFR. Prerenal dysfunction is the most common form of acute renal failure in surgery and ICUs, leading to approximately 65% of renal dysfunction in the setting of cardiac surgery (Boldt, 2003). Factors that predispose an individual to prerenal dysfunction include:

Laboratory abnormalities that may help diagnose this condition include:

Postrenal azotemia causes include obstruction of the urinary outflow tract caused by calculi, neoplasms, blood clots, strictures, or tumors. Signs may include anuria (no urine) if the obstruction is total or oliguria (small volume) if partial. Postrenal causes account for < 5% of cases of postoperative renal dysfunction. This is usually easily reversible (Nolan, 1998).

Patients requiring CT surgery often undergo imaging procedures in which radiographic contrast media is used. Contrast-induced nephropathy is defined as a worsening of renal function after administration of radiocontrast media. As for postoperative renal dysfunction, a change in serum creatinine over baseline by 48 hours, such as ≥ 25% above baseline or an absolute increase of
> 0.25 or 0.5 mg/dL, is indicative of CIN (Schweiger, 2007). However, this definition can vary.

Contrast-induced nephropathy is the third leading cause of all cases of hospital-acquired renal failure. Chronic kidney disease is the primary predisposing factor for CIN. An estimated GFR of
< 60 mL/min/1.73 m2 represents significant renal dysfunction and is used to define the patient at high risk for developing CIN. Table 4 lists the most common modifiable and nonmodifiable risk factors for CIN.

Table 4. Clinical Risk Factors for Contrast-Induced Nephropathy

Modifiable Risk Factors Nonmodifiable Risk Factors
Contrast volume Diabetes
Hydration status Chronic kidney disease
Concomitant nephrotoxic agents Shock/hypotension
Recent contrast administrations Advanced age (> 75 years)
  Advanced congestive heart failure

From Schweiger, Cath Cardiovasc Int., 2007.

To minimize the risk of CIN, the patient's medications should be reviewed carefully and, if clinically appropriate, potentially nephrotoxic drugs (eg, aminoglycoside antibiotics, anti-rejection medications, nonsteroidal anti-inflammatory drugs) should be withheld (Levy, 1999).

Optimizing volume status is also essential. Treatment with ACEIs should be continued but should not be initiated, and the dose should not be changed until that patient is safely past the risk period for CIN. In many institutions, cardiac surgery is scheduled after the patient has received contrast media. Since patients undergoing CT surgery are at high risk for renal dysfunction, consideration should be given to scheduling elective surgery after the risk for CIN has passed. This is also true for other nephrotoxins. The potential for CIN is an important consideration in evaluating the potential etiology of renal failure in cardiac surgery (Sear, 2005).

Appropriate intravascular volume replacement is a fundamental component of critical care management. There is controversy as to whether crystalloids or colloids are preferred for intravascular volume replacement. All colloids, including hyperoncotic human albumin (HA; 20% or 25%) and synthetic colloids (eg, dextran [DEX] or different hydroxyethyl starch [HES] solutions), may be associated with acute renal dysfunction by increasing the plasma colloid osmotic pressure. Patients with dehydration who receive considerable amounts of hyperoncotic colloids without additional crystalloids are especially at risk for renal dysfunction. Boldt and Preibe recently reviewed data regarding the effects of synthetic colloids on renal function. They noted that there is relatively incomplete data on the influence of different volume replacement strategies on renal function. The investigators concluded the following:

Anemia is associated with an increased risk for postoperative renal dysfunction; however, in patients who are treated with erythropoietin, anemia should be resolved prior to elective CT surgery (Boldt , 2003).

Multiple intraoperative factors are associated with an increased risk of postoperative renal dysfunction, including volume shifts, hypotension, hemodilution, and the need for inotropes or a balloon pump. The use of nonpulsatile blood flow in CPB may increase the risk of postoperative renal dysfunction; the use of pulsatile blood flow is more physiologic and has been associated with a decreased risk of renal dysfunction in high-risk patients (Abu-Omar, 2006).

The need for inotropes and/or a balloon pump after bypass usually indicates poor cardiac performance, which decreases renal perfusion pressure and predisposes the patient to renal injury. Hemodilution leads to the need for intraoperative transfusion, which is associated with a significant risk of postoperative renal dysfunction (Mora Mangano, 1998). A high degree of hemodilution during CPB is a risk factor for postoperative renal dysfunction; however, its detrimental effects may be reduced by increasing oxygen delivery with an adequately increased pump flow (Abu-Omar, 2006).

The major mechanisms of renal injury in CT surgery are ischemia and inflammation. Although the kidney receives 20% of the cardiac output, the high energy requirements of the renal medulla occur in an environment of low oxygen tension (2-3 Kpa) and a high extraction ratio of 80%. The blood supply to the medulla is carefully regulated by paracrine systems (renin-angiotensin, nitric oxide). This delicate balance can be disturbed by the inflammatory response seen during CPB. Cytokines (eg, TNF-alpha, IL6) are generated both systemically and within the kidney. This alters the microcirculation with an imbalance of oxygen supply and demand, leading to tubular injury (Figure 3).

These protective mechanisms can exacerbate renal injury in the face of persisting ischemia. Initially, afferent arteriolar constriction reduces blood supply and GFR, thus attempting to reduce medullary oxygen consumption. If the insult is prolonged, efferent vasoconstriction attempts to restore the glomerular perfusion, but autoregulation may be overcome, resulting in ischemic injury. Further insults (eg, nephrotoxins and atheroembolism) compound these responses.

Intrinsic renal injury accounts for approximately 35% to 40% of postoperative renal dysfunction cases. Intrinsic causes of acute renal failure may be classified according to the primary site of injury including the tubules, interstitium, glomerulus, and intrarenal vessels. Acute injury to the renal tubules leading to acute tubular necrosis is common and is due to ischemia and/or direct nephrotoxicity. Sear described a classification based on etiology (Sear, 2005):

Intrarenal edema, endothelial dysfunction, and tubular cellular injury further alter blood flow and urine flow. The reduction in GFR is sustained for a varying period, resulting in acute renal failure requiring metabolic and possibly dialytic support. Recovery may occur with no resultant reduction in GFR. Figure 4 shows the sequence of events leading to renal failure and possible recovery.

There are 2 strategies for renal protection: minimizing the renal insult before it occurs, and attenuation of renal injury after it has occurred.

Minimizing the renal insult before it occurs. This approach includes risk stratification, procedure modification, and optimization (eg, minimizing cross-clamping, minimizing CPB time); maintaining optimal hydration and hemodynamic parameters (adequate preload and adequate CPB flow rates); avoiding excessive hemodilution (eg, hematocrit > 20%); avoiding transfusion; use of appropriate fluid replacement (HES may cause hypersensitivity reactions that can affect the kidney); maintaining tight glucose control; and possibly use of pulsatile flow (Sear, 2005; Nakamura, 2004).

There is some evidence to suggest that minimized extracorporeal circuits may not be as proinflammatory as conventional bypass circuits. These circuits have a closed miniaturized bypass circuit that features a significantly reduced tubing set, an integrated pump, and an air removal system without a cardiotomy reservoir. Abdel-Rahman and colleagues showed that compared to conventional CPB, a minimized extracorporeal circuit was associated with significant suppression of activation of coagulation and fibrinolytic cascades, suggesting that these circuits may be a step toward reduced imbalance of hemostasis in cardiac surgery (Abdel-Rahman, 2006).

Attenuation of renal injury after it has occurred. This approach includes maintenance of adequate renal blood pressure and renal perfusion, avoiding nephrotoxins postoperatively (eg, aminoglycoside antibiotics, nonsteroidal anti-inflammatory drugs), and administration of renoprotective pharmacologic agents (Stafford-Smith, 2005).

Renal-dose dopamine has been used for decades to preserve renal function because it activates mesenteric dopamine receptors nonselectively and leads to increased renal blood flow, decreased renal vascular resistance, and enhanced diuresis and natriuresis. However, evidence from numerous double-blind trials and several meta-analyses does not support the use of dopamine as a renoprotective agent. The Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trial Group studied 328 patients from 23 hospitals and found no benefit from dopamine on the occurrence of renal failure in patients following cardiac surgery. Despite this evidence, the drug is still commonly used. It may lead to adverse effects including impairment of hepatosplanchnic metabolism and cardiac arrthymias (Bellomo, 2000).

Fenoldopam mesylate, a selective dopamine-1 receptor antagonist approved by the US Food and Drug Administration (FDA) as an antihypertensive, has shown promise as an agent to prevent CIN, but there is no evidence that it has benefit in the setting of CT surgery. Bove reported a randomized trial in 80 patients considered at high risk for renal dysfunction and found no renoprotective benefit from fenoldopam (Bove, 2005).

The theory behind the proposed renoprotective effects of diuretics such as furosemide is that increasing tubular solute flow through injured renal tubules will maintain tubular patency, thus avoiding some of the consequences of tubular destruction, oliguria, or anuria, and possibly the need for dialysis (Stafford-Smith, 2005). In animal models, loop diuretics have been shown to increase oxygen levels in the renal medulla (possibly by reducing oxygen consumption by tubular active transport) and to provide protection from renal tubular damage after ischemia-reperfusion and nephrotoxins. However, several clinical studies have shown no benefit and possibly even harm (increased serum creatinine and increased postoperative complications) from perioperative loop diuretic therapy in patients following CT surgery (Stafford-Smith, 2005, Lassnigg, 2000). Routine use of diuretics cannot be supported other than to maintain fluid balance in selected patients. A recent study evaluated high dose N-acetyl cysteine in 60 high renal risk patients and found no benefit in reducing either cystatin-C excretion or other renal indices (Haase, 2007).

Renal failure can present quickly after CT surgery, or several days after surgery, especially if there is a trigger event such as a late bleed and/or hypotension, as in this case. It is important to closely monitor clinical parameters to detect early changes in renal function. Clinical parameters to monitor include body weight to evaluate for fluid retention, fluid intake, and urine output. Laboratory values should also be carefully monitored to identify increases in serum creatinine and potassium, as well as pH changes. In many cases, there is a transient increase in serum creatinine following CT surgery; therefore, it is critical that other parameters are followed closely and the entire picture is evaluated (Nolan, 1998). It is important to continue to maintain fluid balance; in the case of acute renal failure, fluid restriction may be necessary. Potentially nephrotoxic drugs should be avoided. A rise in creatinine may be delayed as it lags behind a true change in GFR.

Patients may need renal replacement therapy with continuous venovenous hemodialysis. Peritoneal dialysis may also be used, but should be used cautiously due to the potential for complications during catheter insertion, the potential for infection, and the need to maintain meticulous fluid balance.

Due to the resiliency of the kidneys, the most appropriate strategy may be to wait until acute renal failure takes its course, while continuing to manage fluid status and avoid any further insults to the kidneys. Most patients with acute renal dysfunction will recover, especially following acute tubular necrosis. The kidney has a unique capability for regeneration of tubular epithelium, and it may take some weeks for the recovery phase to begin (Gupta, 2002).

Nephrotoxic and ischemic insults to the kidney lead to acute renal failure and most often manifest as acute tubular necrosis.The kidney is one of the few organs that can tolerate such acute injury and recover fully. Recovery of renal function following acute tubular necrosis requires the replacement of necrotic tubular cells with functional tubular epithelium, which is thought to be derived from resident renal tubular cells (Gupta, 2002). This regeneration process takes time. The maintenance phase of acute renal failure generally lasts about 10 days, followed by a recovery phase that begins after the maintenance phase. This will be manifested by improved clinical and laboratory measures of renal function.

The ischemia reperfusion injury model in the kidney is different from that seen in the heart. If adequately reperfused, the ischemic kidney can recover. Therefore, many of the strategies for preventing renal dysfunction after CT surgery are directed at renal protection following injury (Stafford-Smith, 2005).

Supported by an independent educational grant from Bayer Healthcare Pharmaceuticals.


References

  1. Abdel-Rahman U, Martens S, Risteski P, et al. The use of minimized extracorporeal circulation system has a beneficial effect on hemostasis--a randomized clinical study. Heart Surg Forum. 2006;9(1):E543-E548.
  2. Abu-Omar Y, Ratnatunga C. Cardiopulmonary bypass and renal injury. Perfusion. 2006;21:209-213.
  3. Alex J, Shah R, Griffin SC, et al. Intensive care unit readmission after elective coronary artery bypass grafting. Asian Cardiovasc Thorac Ann. 2005 Dec;13(4):325-329.
  4. Antunes PE, Prieto D, Ferr? de Oliveira J, Antunes MJ. Renal dysfunction after myocardial revascularization. Eur J Cardiothorac Surg. 2004:597-604.
  5. Aronson S, Fontes ML, Miao Y, Mangano D, et al, for the Investigators of the Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation. Risk index for perioperative renal dysfunction/failure: critical dependence on pulse pressure hypertension. Circulation. 2007;115(6): 733-742.
  6. Baker RC, Armstrong MA, Allen SJ, McBride WT. Role of the kidney in perioperative inflammatory responses. Br J Anaesth. 2002 Mar 88(3):330-4.
  7. Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J, for the Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Lancet. 2000;356(9248):2139-2143.
  8. Bidstrup B. Aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery [letter]. Transfusion. 2006;46:2208.
  9. Blauth CI. Macroemboli and microemboli during cardiopulmonary bypass. Ann Thorac Surg. 1995;59(5):1300-1303.
  10. Boldt J, Priebe H. Intravascular volume replacement therapy with synthetic colloids: is there an influence on renal function? Anesth Analg. 2003;96:376-382.
  11. Bove T, Landoni G, Calabr?MG, et al. Renoprotective action of fenoldopam in high-risk patients undergoing cardiac surgery: a prospective, double-blind, randomized clinical trial. Circulation. 2005;111(24):3230-3235.
  12. CKD guidelines. 2000. Available at: http://www.kidney.org/professionals/kdoqi/guidelines_ckd/p5_lab_g4.htm). Accessed August 2007.
  13. Ferguson TB, Hammill BG, Peterson ED, DeLong ER, Grover FL, for the STS National Database Committee. A decade of change -- risk profiles and outcomes for isolated coronary artery bypass grafting procedures, 1990-1999: a report from the STS National Database Committee and the Duke Clinical Research Institute. Ann Thorac Surg. 2002;73:480-490.
  14. Ferraris VA, Bridges CR, Anderson RP. Aprotinin in cardiac surgery (Letter to the Editor). New Engl J Med. 2006;354(18):1953-1954.
  15. GFR calculator Available at: (http://nkdep.nih.gov/professionals/index.htm).
  16. Gupta S, Verfaillie C, Chmielewski D, et al. A role for extrarenal cells in the regeneration following acute renal failure. Kidney International. 2002;62:1285-1290.
  17. Haase M, Haase-Fielitz A, Bagshaw SM. Phase II, randomized, controlled trial of high-dose N-acetylcysteine in high-risk cardiac surgery patients. Crit Care Med. 2007;35(5):1324-1331.
  18. Hammon JW Jr, Edmunds LH Jr. Extracorporeal circulation: Organ damage. In: Cohn LH, Edmunds LH Jr, eds. Cardiac Surgery in the Adult. New York: McGraw-Hill, 2003:361388. Available at: http://cardiacsurgery.ctsnetbooks.org/cgi/content/full/2/2003/361?ck=nck#Assessment. Accessed May 2007.
  19. Hammon JW, Stump DA, Kon ND, et al. Risk factors and solutions for the development of neurobehavioral changes after coronary artery bypass grafting. Ann Thorac Surg. 1997;63:1613-1618.
  20. Henry DA, Moxey AJ, Carless PA, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2001;(1):CD001886.
  21. Hostetter TH. Chronic kidney disease predicts cardiovascular disease. N Engl J Med. 2004;351:1344-1346.
  22. Karkouti K, Beattie WS, Dattilo KM, et al. A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery. Transfusion. 2006;46:327-338.
  23. Kuitunen A, Vento A, Suojaranta-Ylinen R, et al. Acute renal failure after cardiac surgery: evaluation of the RIFLE classification. Ann Thorac Surg. 2006;81:542-546.
  24. Lassnigg A, Donner E, Grubhofer G, Presterl E, Druml W, Hiesmayr M. Lack of renoprotective effects of dopamine and furosemide during cardiac surgery. J Am Soc Nephrol. 2000;11(1):97-104.
  25. Levy JH. Adverse Drug Reactions in Hospitalized Patients. 1999. Available at: www.anaphylaxisweb.com. Accessed April 2007.
  26. Mangano DT, Tudor IC, Dietzel C. The risk associated with aprotinin in cardiac surgery. N Engl J Med. 2006;354:353-365.
  27. Mehta RL. Outcomes research in acute renal failure. Semin Nephrol. 2003;23(3):283-294.
  28. Mishra J, Dent C, Tarabishi R. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet. 2005;365(9466):1231-1238.
  29. Mora Mangano C, Diamondstone LS, Ramsay JG, Aggarwal A, Herskowitz A, Mangano DT, for the Multicenter Study of Perioperative Ischemia Research Group. Renal dysfunction after myocardial revascularization: risk factors, adverse outcomes, and hospital resource utilization. Ann Intern Med. 1998;128:194-203.
  30. Mora Mangano CT, Neville MJ, Hsu PH, et al. Aprotinin, blood loss, and renal dysfunction in deep hypothermic circulatory arrest. Circulation. 2001;104(suppl I):I276-I281.
  31. Nakamura, K., Harasaki H, et al. Comparison of pulsatile and non-pulsatile cardiopulmonary bypass on regional renal blood flow in sheep. Scandinavian Cardiovascular Journal 2004;38(1): 59-63.
  32. National Kidney Foundation (NKF). K/DOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease, 2004. Available at: http://www.kidney.org/PROFESSIONALS/kdoqi/guidelines_bp/guide_2.htm. Accessed March 2007.
  33. Nolan C R, Anderson RJ. Hospital-acquired acute renal failure. J Am Soc Nephrol 1998;9(4): 710-718.
  34. Rule AD, Larson TS, Bergstrah EJ. Using serum creatinine to estimate glomerular filtration rate: accuracy in good health and in chronic kidney disease. Ann Intern Med. 2004;141:929-937.
  35. Schweiger MJ, Chambers CE, Davidson CJ, et al. Prevention of contrast-induced nephropathy: recommendations for the high-risk patient undergoing cardiovascular procedures. Cath Cardiovasc Int. 2007;69:135-140.
  36. Sear JW. Kidney dysfunction in the postoperative period. Br J Anaesth 2005;95(1): 20-32.
  37. Sedrakyan A, Treasure T, Elefteriades JA. Effect of aprotinin on clinical outcomes in coronary artery bypass graft surgery: a systematic review and meta-analysis of randomized clinical trials. J Thorac Cardiovasc Surg. 2004;128:442-448.
  38. Shah SH, Mehta RL. Acute kidney injury in critical care: time for a paradigm shift? Curr Opin Nephrol Hypertens. 2006;15(6):561-565.
  39. Society of Thoracic Surgeons Executive Summary, Fall 2006. Available at: http://www.sts.org/sections/stsnationaldatabase/publications/executive/article.html. Accessed May 2007.
  40. Stafford-Smith M. Evidence-based renal protection in cardiac surgery. Semin Cardiothorac Vasc Anesth. 2005;9(1):65-76.
  41. Stafford-Smith M. Acute Kidney Injury in Cardiac Surgery: Filtering the Data and Strategies for Protection. Symposium on Evaluation and Management of Risk in Cardiac Surgery : Improving Outcomes. Whistler, British Columbia, Canada. March 20, 2007.
  42. Swaminathan M, Stafford-Smith M. Renal dysfunction after vascular surgery. Curr Opin Anesthesiol. 2003;16:45-51.
  43. Taber SS, Mueller BA. Drug-associated renal dysfunction. Crit Care Clin. 2006;22(2):357-374.
  44. US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Summary Minutes of the Cardiovascular and Renal Drugs Advisory Committee Meeting for September 21, 2006. Available at: http://www.fda.gov/OHRMS/DOCKETS/ac/06/minutes/2006-4234m-FinalMinutes.pdf. Accessed May 2007.
  45. Yates RB, Stafford-Smith M. The genetic determinants of renal impairment following cardiac surgery." Semin Cardiothor Vasc Anesth. 2006;10(4): 314-326.



Authors and Disclosures

Author

Benjamin P. Bidstrup, FRACS, FRCSEd, FEBTCS

  Clinical Associate Professor, The Tweed Hospital, Tweed Heads, New South Wales, Australia

Disclosure: Dr. Bidstrup has disclosed that he has received honoraria from Bayer HealthCare Pharmaceuticals.