Acute renal failure (ARF), depending on the specific definition, occurs in up to 30% of all patients who undergo cardiac surgery (1–15). ARF that requires dialysis occurs in approximately 1% (1–15). The development of kidney injury is associated with a high mortality, a more complicated hospital course, and a higher risk for infectious complications (1–15). Even minimal changes in serum creatinine that occur in the postoperative period are associated with a substantial decrease in survival (16). Furthermore, the majority of patients who develop ARF that requires dialysis (ARF-D) remain dialysis dependent, leading to significant long-term morbidity and mortality (17). Despite advances in bypass techniques, intensive care, and delivery of hemodialysis, mortality and morbidity associated with ARF have not markedly changed in the last decade (1–15). These data highlight the importance of understanding the pathophysiology of ARF associated with cardiac bypass surgery and implementing specific therapies that are based on this knowledge in well-designed clinical trials.
Incidence and Prognosis of ARF after Bypass Surgery
Depending on the definition of ARF, the incidence of ARF varies across studies, with a range of 1 to 30% (1–15). Conlon et al. (1) described a cohort of 2843 patients who underwent cardiopulmonary bypass (CPB) over a 2-yr period. ARF (defined as a rise in serum creatinine >1 mg/dl above baseline) occurred in 7.9% of patients, and ARF-D occurred in 0.7%. Other studies that used a definition of ARF as a 50% or greater rise in serum creatinine from baseline demonstrated a rate as high as 30% (2–15). Chertow et al. (15) analyzed 42,773 patients who underwent CPB and found an incidence of ARF-D of 1.1%. The incidence of ARF is dependent on the particular type of CPB surgery. Typical coronary artery bypass grafting has the lowest incidence of ARF (approximately 2.5%) and ARF-D (approximately 1%), followed by valvular surgery with an incidence of ARF of 2.8% and ARF-D of 1.7% (18,19). The highest risk group includes combined coronary artery bypass grafting/valvular surgery with an incidence of ARF of 4.6% and ARF-D of 3.3% (18,19)
Mortality associated with the development of ARF is as high as 60% in some studies but likely averages 15 to 30%, depending on the definition of ARF and the postoperative period studied (hospital discharge or 30-d mortality) (1–15). In patients who require dialysis, the mortality is uniformly high in all studies and averages 60 to 70% (1–15). Chertow et al. (15) in a multivariate analysis that adjusted for comorbid factors identified the occurrence of ARF-D as an independent determinant of the risk for death with an odds ratio of 7.9. It is interesting that even small rises in serum creatinine are associated with significant mortality. Lassnigg et al. (16) demonstrated that the 30-d mortality of patients who developed a 0- to 0.5-mg/dl and >0.5-mg/dl rise in serum creatinine was 2.77- and 18.64-fold higher, respectively, than patients without a change in serum creatinine. These results are qualitatively similar to studies by Thakar et al. (20) in which 31,677 patients who underwent cardiac surgery were analyzed. Mortality was 5.9% (P < 0.0001) when GFR declined 30% or more but did not require dialysis and 0.4% (P < 0.001) in patient with <30% decline in GFR. The development of post-CPB ARF also influences long-term mortality as identified by Loef et al. (21), who found that the hazard ratio for death at 100 mo after hospital discharge was 1.63 in patients who developed a 25% or greater rise in serum creatinine after surgery. This increase in long-term mortality was independent of whether renal function had recovered at discharge from the hospital. Lok et al. (22) also found that patients who experienced ARF after CPB had a relative risk for death at 1 yr of 4.6 as compared with patients who did not sustain renal injury.
Patients who do develop ARF-D often remain dialysis dependent. Leacche et al. (17) studied 13,847 patients who underwent CPB procedures. Of patients who developed ARF-D, 64% required permanent dialysis and the 1-yr survival was only 10%.
The link between the development of ARF and mortality likely involves numerous factors, including those directly related to hemodialysis (hemodynamic instability, catheter-related infections, ventricular ectopy, and visceral ischemia); immune dysregulation associated with ARF; platelet dysfunction; and other, less defined associations. Registry data from Liano et al. (23) demonstrated that in patients with ARF, infections were the cause of death in 40%. In patients who underwent CPB, Thakar et al. (24) also demonstrated a high risk for infections. In patients with ARF-D, the incidence of serious infections, including sepsis, was 58.5% as compared with 3.3% in all patients who underwent CPB (24).
Risk Factors Associated with ARF
Several studies have examined the risk factors associated with the development of ARF after CPB (Table 1). The particular type of surgery is important, with valvular procedures associated with a higher risk. In almost all studies, certain risk factors have been repeatedly associated with an increased risk for ARF (2,4,6–8,14,25–30). These include female gender, reduced left ventricular function or the presence of congestive heart failure, diabetes, peripheral vascular disease, preoperative use of an intra-aortic balloon pump, chronic obstructive pulmonary disease, the need for emergent surgery, and an elevated preoperative serum creatinine. This last factor is perhaps the most predictive, with the risk for ARF-D approaching 10 to 20% in patients with a baseline preoperative creatinine 2.0 to 4.0 mg/dl (25–30). In patients with a preoperative creatinine >4.0 mg/dl, the risk for ARF-D rises to 25 to 28% (25–30). Importantly, almost all of the defined risk factors relate to either impaired renal perfusion or decreased renal reserve.
Several other risk factors have been identified but are more controversial and, thus, individually they do not play as prominent a role in determining the risk for ARF. In aggregate, however, these factors may be important and potentially modifiable. These include factors specifically related to the bypass procedure itself, such as cross-clamp time (31–33), duration of CPB (31–33), pulsatile versus nonpulsatile bypass flow (34,35), normothermic versus hypothermic bypass (36–38), and on- versus off-pump coronary artery bypass (OPCAB) surgery (39–45).
One of the most controversial risk factors is OPCAB versus traditional on-pump CPB. OPCAB obviously removes the bypass circuit but can be associated with greater hemodynamic instability secondary to ventricular compression as the heart is manipulated to access the coronary arteries (42). This comparison allows separation of the risk factors specifically associated with the bypass procedure itself from other peri-, intra-, and postoperative factors. Early nonrandomized studies suggested that renal tubular injury (as assessed by urinary markers) was lessened in the group that received OPCAD (43,44). Subsequent studies have also suffered from the lack of randomization, single-site experience, and differences in patient comorbidities and baseline risk for developing ARF between the OPCAB and CPB groups. Thus, despite several large, retrospective series, the answer is still unclear, but the bulk of the data support a lower risk for ARF in patients who undergo OPCAB, especially patients with pre-existing renal insufficiency (45–48). This is further supported by a significant decrease in inflammatory markers in patients who undergo OPCAB as compared with those who undergo CPB (46,47).
CPB is associated with the generation of free hemoglobin and iron through hemolysis that typically occurs during the procedure (48). Hemolysis may be caused by cardiotomy suction, the duration of perfusion, occlusive roller pumps, turbulent flow in the oxygenator, and blood return through cell savers (48). This may contribute to oxidative stress and renal tubular injury (49). In an early study, a low preoperative serum ferritin level (potentially indicative of a reduced ability to bind free iron) was associated with an increased risk for ARF after CPB (50). However, a larger study could not validate this finding (32).
During CPB, hemodilution is induced to decrease blood viscosity in the hope of improving regional blood flow in the setting of hypoperfusion and hypothermia as well as limiting the need for blood transfusion (51,52). The resulting increase in regional blood flow is thought to offset any risk of decreased oxygen carrying capacity of the blood. However, two recent studies demonstrated that hemodilution (down to hematocrits <25%) is associated with an increased risk for renal injury as measured by changes in serum creatinine (53,54). This may be due to impairment of oxygen delivery to an already hypoxic renal medulla or to alterations in systemic inflammatory mediators caused by regional ischemia.
Predictive Scoring Systems
Several groups have developed clinical scoring systems that help to predict the risk for ARF with CPB (30,55,56). The aim is to select patients who are at high risk and then to adopt strategies that would offer renal protection. The most recent scoring system analyzed 33,217 patients with a large validation sample. A score is given on the basis of 13 preoperative factors and ranges from 0 to 17 (30) (Table 2). In the lowest risk group (score 0 to 2), the risk for ARF-D was 0.4%, whereas in the highest risk group (score 9 to 13), the risk rose to 21.5%. Chertow et al. (55) investigated the risk for developing ARF in 43,642 patients who underwent CPB. They were able to determine important preoperative clinical variables, such as patient age, preoperative creatinine clearance, use of an intra-aortic balloon pump, and left ventricular dysfunction, that predicted subsequent ARF. These clinical scoring systems require validation across several medical centers before their routine use can be adopted. Furthermore, given that these scoring systems attempt to identify a small number of high-risk patients, they will have good negative predictive power but necessarily low positive predictive power. However, they provide a very useful framework to identify patients who are at risk and may benefit from peri- or intraoperative renal protective strategies.
Pathogenesis of ARF
No systematic studies of the pathologic changes in the kidney have been undertaken in patients with ARF associated with CPB, and it is largely assumed that the pathologic lesion is acute tubular necrosis. This is usually confirmed by the presence of granular casts in the urine of patients who develop ARF. Physiologic studies by Moran and Myers (57) substantiated this in 10 patients with protracted severe ARF after CPB. It was demonstrated that the transmembrane gradient for glomerular ultrafiltration was significantly diminished, likely from intratubular obstruction and hypertension as a result of sloughing from injured tubular epithelial cells. They also demonstrated that there was significant transtubular back-leak of glomerular ultrafiltrate across the injured epithelium. These pathologic features are likely the downstream result of early events that are depicted in Figure 1 (58–63). In this schema, ARF begins with an early phase of vasomotor nephropathy in which there is associated alterations in vasoreactivity and renal perfusion leading to prerenal azotemia and eventually cellular ATP depletion and oxidative injury (initiation phase). These processes lead to activation of bone marrow–derived cells, endothelial cells, and renal epithelial cells and a resulting proinflammatory state. Inflammatory cells adhere to activated endothelium in the peritubular capillaries of the outer medulla, leading to medullary congestion and further hypoxic injury to the S3 segment of the proximal tubule (extension phase). Furthermore, elaboration of inflammatory mediators (as discussed below) leads to additional cellular injury. Tubule cells then begin the process of proliferation (maintenance phase) and re-differentiation. Ultimately, polarity and function are reconstituted (repair phase).
Clinically, the pathogenesis of ARF associated with CPB can be divided into preoperative, intraoperative, and postoperative events (Table 3). The sum of all of these various insults is ultimately reflected in the development of tubular injury that when severe enough is manifested as a rise in serum creatinine often associated with a decreased urine output.
Preoperative Events
As mentioned above, patients who enter CPB often have received minor or major renal insults. Patients have had recent myocardial infarctions or severe valvular disease with reduced left ventricular function and reduced renal perfusion. In the extreme, patients may be in cardiogenic shock and require inotropic support or an intra-aortic balloon pump. This pre-existing prerenal state may be exacerbated by the use of diuretics, nonsteroidal anti-inflammatory drugs (NSAID), angiotensin-converting enzyme inhibitors (ACEI), or angiotensin receptor blockers (ARB), which impair the autoregulation of renal blood flow (63). Furthermore, episodes of preoperative hypotension may lead to sublethal endothelial injury, which may impair the production of vasodilatory substances such as endothelial nitric oxide and promote vasoconstriction as a result of the release of endothelin, catecholamines, and angiotensin II, promoting further tubular ischemia and injury (64–66). Compounding these factors may be a lack of renal functional reserve as a result of underlying chronic kidney disease, including small- and large-vessel renovascular disease. These hemodynamic alterations in the preoperative setting may increase the vulnerability of the kidney (particularly the inner stripe of the outer medulla, where metabolic demands are high and the pO2 is between 10 and 20 mmHg) to any further ischemic or nephrotoxic insult (67,68).
There may be activation of inflammatory mediators in the preoperative period that also serve to prime the kidney for subsequent injury. Endotoxin levels have been noted to be elevated in some patients in the preoperative period, despite no evidence of active infection, and these levels have been correlated to postoperative myocardial dysfunction (69–71). The elevation in preoperative endotoxin levels may reflect the effect of poor cardiac output states’ contributing to intestinal ischemia and bacterial translocation or may be related to the preoperative care of patients (e.g., subclinical catheter infections) (72). Levels of TNF-α have also been shown to be elevated in patients with pre-existing congestive heart failure and may also play a role in stimulation of the immune system (73,74).
Nephrotoxic medications or intravenous contrast that is given in the immediate preoperative period may also lead to overt or occult tubular injury that can interact with other factors to lead to ARF. These medications include vasoactive (pressor) drugs, NSAID, ACEI, ARB, and antibiotics.
Thus, the preoperative period is a critical time when events (hemodynamic, nephrotoxic, and inflammatory) can occur and can lead to subtle renal injury that is not necessarily reflected by changes in GFR. This subtle injury is likely substantiated by the fact that the preoperative risk scoring systems all rely on factors that ultimately act to reduce renal perfusion, result in lack of renal functional reserve, or set up a proinflammatory milieu.
Intraoperative Events
The intraoperative period is a critical time when patients are exposed to anesthesia and cardiopulmonary bypass. These events lead to dramatic hemodynamic effects as well as activation of both innate and adaptive immune responses that can initiate or extend renal injury.
Hemodynamic Effects
CPB is associated with significant hemodynamic changes, and the maintenance of cardiovascular stability during CPB requires interplay between the function of the CPB machine and patient factors such as systemic vascular resistance, venous compliance, and autoregulatory capacity of various vascular beds. The ultimate goal is to maintain regional perfusion at a level that supports optimal cellular and organ function. Thus, any decrease in renal perfusion during CPB, depending on its magnitude and duration, can lead to significant cellular injury.
Minute oxygen consumption (VO2) is the major determinant of blood flow requirements normally and during CPB. Experimentally, CPB flow rates have been determined by calculating VO2 at different perfusion rates. Perfusion is increased until VO2 reaches a plateau, after which further increases in CPB flow rates do not lead to increases in oxygen consumption. In general, CPB flow rates of 1.8 to 2.2 L/min per m2 are recommended on the basis of this analysis (75,76). However, it is not known what the effect of this flow rate is on regional renal blood flow and local oxygen delivery rates.
In addition to CPB flow rates, perfusion pressure during CPB is an important determinant of adequate nutrient delivery to vascular beds. Perfusion pressure is determined by the interaction of blood flow and overall arterial resistance. Resistance, in this case, is related to actual friction resistance because of the steady, nonpulsatile nature of CPB, which negates the elastance, inertial, and reflective components of arterial resistance during normal pulsatile flow (77). Friction resistance is primarily a function of vasomotor tone and blood viscosity (which is further dependent on hematocrit and temperature). Importantly, both variables are changing during CPB (e.g., blood viscosity increases as hypothermia is induced and vasomotor tone is affected by anesthesia) and lead to associated changes in perfusion pressure. In general, a mean perfusion pressure of 50 to 70 mmHg is maintained during CPB (77).
Given hemodynamic goals of a mean perfusion pressure of 50 to 70 mmHg and CPB flow rates of 1.8 to 2.4 L/min per m2, it is not known what effect these goals have on renal perfusion and oxygen delivery. The majority of studies on autoregulation of regional blood flow during CPB has focused on the cerebral circulation and demonstrates preserved cerebral autoregulation with these parameters (78,79). Small studies have suggested that mean arterial pressures on CPB >70 mmHg lead to higher intraoperative creatinine clearances but without a change in postoperative renal function as compared with pressures between 50 and 60 mmHg (80). Thus, it is likely that renal perfusion and autoregulation are also maintained as long as these hemodynamic goals are met. However, these values are likely near the minimum blood flows that support normal organ function, and any perturbation may lead to ischemia and cellular damage. Furthermore, the effect of these parameters in patients with impaired baseline renal function is not known. In patients with pre-existing hypertension, the relationship between renal blood flow and mean arterial pressure is shifted such that falls in BP that normally would not impair renal perfusion now do so. This means that higher mean pressure may be required to maintain adequate renal perfusion in these patients (81). Furthermore, if there is any degree of pre-existing acute tubular necrosis, then autoregulatory capacity of the kidney may be lost and renal blood flow becomes linearly dependent on pressure (82).
Whether alterations of these CPB flow and pressure goals would lead to improved renal outcomes is not known. However, Gold et al. (83) reported that maintenance of higher perfusion pressures in the range of a mean perfusion pressure of 70 mmHg was associated with a reduced incidence of cardiac and neurologic complications when compared with patients whose pressures were maintained at 50 to 60 mmHg. Renal function was not assessed in this study.
Other procedural factors that likely have an impact on renal hemodynamics include hemodilution (oxygen delivery capacity), hypothermia (oxygen consumption), the absence of pulsatile perfusion, and the use of crystalloid versus colloidal prime solutions. As discussed above, with the exception of hemodilution, no deleterious effects on renal function have been found associated with alterations in body temperature or in the absence of pulsatile flow.
In total, these hemodynamic changes may lead to regional renal ischemia and cellular injury that could either initiate acute kidney injury (AKI) or extend pre-existing renal injury. Furthermore, these hemodynamic changes are potentially modifiable.
Inflammation
CPB provokes a systemic inflammatory response syndrome (SIRS; Figure 2) (84,85). Contact of blood components with the artificial surface of the bypass circuit, ischemia-reperfusion injury, endotoxemia, operative trauma, nonpulsatile blood flow, and pre-existing left ventricular dysfunction all are possible causes of SIRS in this setting (86–88). In its most severe form, a spectrum of injury that includes one or more of the following clinical manifestations may be observed: Pulmonary, renal, gastrointestinal, central nervous system, and myocardial dysfunction; coagulopathy; vasodilation and increased capillary permeability; hemolysis; pyrexia; and increased susceptibility to infection (89).
During CPB, both neutrophils and vascular endothelium are activated with upregulation of adhesion molecules such as CD11b and CD41 (89–92). Platelets also undergo activation, degranulation, and adherence to vascular endothelium (91,93). These events led to elaboration of cytotoxic oxygen-derived free radicals (94), proteases (95), cytokines (96), and chemokines (96,97). These inflammatory mediators, such as IL-6, IL-8, and TNF-α, show a considerable rise in serum levels during CPB and generally reach peak levels 2 to 4 h after termination of CPB (84).
CPB is also a potent activator of factor XII (Hageman factor) to factor XIIa (90). This process initiates the intrinsic coagulation system, the kallikrein system, and the fibrinolytic system (97). Furthermore, complement proteins are activated through both the classical and the alternative pathways (97–99). Ultimately, this humoral response amplifies the cellular response that leads to neutrophil, endothelial, and monocyte activation and further elaboration of proinflammatory cytokines (97–101). Finally, diffuse end-organ ischemia likely causes endothelial cells, circulating monocytes, and tissue-fixed macrophages to release cytokines and oxygen-derived free radicals that further drive the inflammatory response (97–101).
The end result of this generalized inflammatory response induced by CPB within the kidney is not known. It is interesting that animal models of renal ischemia-reperfusion injury have clearly demonstrated the pathologic role of interstitial inflammation and the elaboration of proinflammatory cytokines and reactive oxygen species in the production of tubular injury (100–103). This local inflammatory response in experimental models is identical to that seen on a more global scale during CPB. Thus, it is likely a safe assumption that CPB-induced inflammation has significant deleterious effects on the kidney through similar mechanisms. Despite efforts to produce a CPB system that does not produce contact activation of blood components, this goal has not been realized and CPB still remains a potent proinflammatory stimulus (104,105).
Other Events Associated with CPB
Macroscopic and microscopic emboli, both gaseous and particulate, are often generated during CPB. These emboli are temporally related to certain intraoperative events such as aortic cannulation and aortic clamp placement and release (106–109). One study demonstrated a significant correlation between the total number of Doppler-detected emboli and postoperative changes in serum creatinine (109). This suggests that embolic events to the renal circulation may be responsible in part for postoperative changes in GFR.
Aprotinin is a serine protease inhibitor and potent antifibrinolytic agent that is used to attenuate blood loss and transfusion requirements during CPB (110). Aprotinin is eliminated by glomerular filtration and is actively reabsorbed by the proximal tubules, where it is metabolized (111). Aprotinin also inhibits the production of renal kallikreins and kinins involved in vasodilatory responses (112). For these reasons, there has been concern that the use of aprotinin may lead to renal injury. Several studies in patients who underwent CPB, as well as liver transplantation, did not demonstrate any renal toxicity directly attributable to aprotinin use (113–115).
CPB exposes blood to nonphysiologic surfaces and shear forces that lead to lysis of red blood cells with release of free hemoglobin into the circulation (116). In the presence of oxidants such as hydrogen peroxide and superoxide, free low molecular mass iron is released from the heme moiety into the circulation (117). This redox active iron is able to participate in organic and inorganic oxygen radical reactions, such as stimulating lipid peroxidation and catalyzing the formation of damaging hydroxyl radicals with subsequent tissue damage (118). Normally, iron-transporting proteins such as transferrin and lactoferrin sequester this free iron and minimize its potential toxicity (119). However, in some cases, the release of free iron can be so great as to saturate the iron-binding capacity of transferrin. At this point, all iron-binding antioxidant capacity is lost and the serum displays pro-oxidant features (120). How often this occurs during CPB is not fully known, but it may be as high as 25% of cases (120,121). Reperfusion injury during CPB may exacerbate further the oxidant stress in the setting of free circulating iron. However, Tuttle et al. (32) could not find an association between low iron-binding capacity and the risk for ARF after CPB. Although deferoxamine has been demonstrated to decrease the occurrence of lipid peroxidation during CPB, no studies have investigated any protective role of iron chelation in human kidney injury (122).
Postoperative Events
The postoperative events that are critical in affecting renal function are similar to traditional causative mechanisms seen in the general intensive care setting. Thus, the use of vasoactive agents, hemodynamic instability, exposure to nephrotoxic medications, volume depletion, and sepsis/SIRS all are critical events that can lead to kidney injury. A critical factor is postoperative cardiac performance and the need for either inotropic or mechanical support. In the presence of postoperative left ventricular dysfunction, the risk for significant renal injury becomes very high as the vulnerable kidney is subjected to marginal perfusion pressures.
General Measures to Prevent AKI after Cardiac Surgery
Identification of High-Risk Patients
In patients who undergo cardiac surgery, identifying patients who are at high risk for ARF is critically important. The important risk factors and scoring systems that can be used for this identification purpose have been discussed above.
Optimization of Renal Perfusion and Avoidance of Nephrotoxins
Factors that alter renal blood flow and lead to prerenal azotemia should be identified and corrected. Treatment of volume depletion and congestive heart failure before cardiac surgery will increase cardiac output and renal perfusion. Perioperative hydration and the use of hemodynamic monitoring and inotropic agents to optimize cardiac output may be necessary. It is unknown whether intraoperative optimization of bypass flow, perfusion pressure, and oxygen delivery would affect the subsequent development of AKI, although conceptually this would seem to be a reasonable goal. Medications such as NSAID and other nephrotoxic agents should be discontinued. Whether ACEI and ARB should be discontinued before surgery is not known and is a source of some debate (123–125). If radiographic contrast is needed, then newer isosmolar contrast agents may be less toxic (126). In stable patients, cardiac surgery should be postponed in patients with contrast-induced ARF.
Pharmacologic Interventions to Prevent AKI after Cardiac Surgery
Pharmacologic interventions have been attempted with inconsistent results, and at this time, there are no known drugs that have demonstrated conclusively renal protection (Table 4). The failure of these measures to prevent ARF after cardiac surgery may be related in part to a number of factors. First, the pathophysiology of ARF after CPB is more complex than originally considered, and simple approaches to target single pathways are unlikely to succeed. Second, late pharmacologic intervention is likely to meet with failure. Third, patient populations that have been studied are often at low risk for renal dysfunction after CPB, thus potentially masking small beneficial effects of therapies. Last, most clinical trials enroll a small number of patients and are powered inadequately to detect small benefits. Most therapeutic trials in ARF after CPB have been prevention studies in which treatment was initiated before the insult and in the majority of cases have shown no significant benefits. These strategies are listed in Table 4 and reviewed briefly here.
Drugs that Increase Renal Blood Flow
In low doses (3 μg/kg per min), dopamine stimulates DA-1 and DA-2 dopamine receptors, increasing renal blood flow and inhibiting proximal tubule sodium reabsorption. Although dopamine has been used extensively, studies have failed to show its efficacy in ARF after cardiac surgery (127,128) or associated with other conditions (129). Thus, there is no role for the use of dopamine in the treatment or prevention of ARF.
Fenoldopam is a selective DA-1 agonist that has been used in the prevention of ARF with variable results. In patients who had chronic kidney disease and underwent cardiac angiography, fenoldopam failed to reduce renal dysfunction, 30-d morality, dialysis, or rehospitalization (130). However, small randomized or uncontrolled studies that used fenoldopam demonstrated a reduction of renal dysfunction in patients who underwent cardiac surgery (131–133). A potential complication is the associated systemic hypotension that occurs after administration of fenoldopam. The beneficial effect of renal vasodilation in this situation may be offset by systemic hypotension that results in an overall net reduction of blood flow to the kidney. This systemic hypotensive effect may be abrogated by local infusion of fenoldopam directly into the renal arteries using a novel vascular delivery system (Benephit catheter; FlowMedica Inc., Fremont, CA; www.flowmedica.com).
Theophylline, a nonselective adenosine antagonist, is thought to block vasoconstriction induced by A1-adenosine receptors. In a recent clinical trial, theophylline infusion in CPB was ineffective in reducing the incidence of ARF (134).
Drugs that Induce Natriuresis
Atrial natriuretic peptide (ANP) increases natriuresis by increasing GFR as well as by inhibiting sodium reabsorption by the medullary collecting duct (135). In a multicenter trial, anaritide, a 25–amino acid synthetic form of ANP was administered to critically ill patients to treat acute tubular necrosis (136). Whether patients received anaritide or not, the dialysis-free survival was the same in both groups. Although a subgroup of oliguric patients benefited from anaritide in the original study, this observation was not confirmed in a follow-up study (137). Hypotension was a complicating factor in 46% of patients who received anaritide (136,137). In a recent study, recombinant human ANP (rhANP) was used to treat ARF after cardiac surgery in patients who required inotropic support for heart failure (138). In patients who received rhANP, there was a significant reduction in the incidence of dialysis at day 21 after the start of treatment. In this trial, ANP was infused at a lower rate (50 as opposed to 200 ng/kg per min; thus lowering the incidence of hypotension) and for a more prolonged period than previous studies. These changes may explain the benefit seen in this study as opposed to earlier ones.
Diuretics may reduce the severity of ARF by preventing tubule obstruction and decreasing oxygen consumption (139). In a double-blind, randomized, controlled trial, furosemide treatment was found not to be protective as the incidence of ARF was twice that of the dopamine or placebo group (140). Similar negative results have been seen in other studies (141,142).
Mannitol has a variety of effects, including the production of an osmotic diuresis with a reduction of tubular obstruction, as well as the capability of scavenging free radicals. It is often added to the prime solution during CPB, with the thought that it may help to maintain urine output during the procedure, minimize tissue edema, and serve as a free radical scavenger (143). An early study in children who underwent cardiac surgery demonstrated than prophylactic administration of mannitol (0.5 g/kg body wt) was beneficial in the prevention of ARF (144). Fisher et al. (145) demonstrated that mannitol added to the CPB prime solution was effective at maintaining urine output at varying doses. However, several other studies did not confirm these findings, and the potential role of mannitol remains unclear (146,147). In fact, Carcoana et al. (147) showed an increased urinary excretion of β-2 microglobulin in patients who received mannitol and dopamine, suggestive of increased tubular injury in this group.
Sirivella et al. randomly assigned 100 patients with postoperative oliguric or anuric renal failure to therapy with either intermittent doses of loop diuretics or a continuous infusion of mannitol, furosemide, and dopamine (2 mg/kg per min) (148). Whereas 90% of patients who received the intermittent diuretic required dialysis, only 6.7% of the patients who received the continuous mannitol, furosemide, and dopamine infusion required dialysis. Furthermore, early therapy with this “cocktail” was associated with early restoration of renal function. Future studies are required before this approach can be broadly recommended.
Drugs that Block Inflammation
Inflammation is well documented to occur during CPB and has a prominent role in the pathogenesis of ARF and CPB (63,97). It thus is an attractive therapeutic target. Pentoxifylline, a phosphodiesterase inhibitor, blocks the activation of neutrophils by TNF-α and IL-1 (149) and TNF-α release by inflammatory cells (150). Pentoxifylline has been demonstrated to reduce cardiac dysfunction and TNF-α release in ischemia-reperfusion models (151). However, pentoxifylline did not affect renal function in elderly patients who underwent cardiac surgery (152). Dexamethasone also failed to protect against renal dysfunction after cardiac surgery (153). A recent study examined the effect of blocking complement activation in patients who underwent CPB. A single-chain antibody specific for human C5 (pexelizumab) was found to block complement activation and postoperative myocardial injury. However, renal function was not an outcome measure of this pilot study (154).
N-acetylcysteine (N-AC) has been shown to block inflammation and oxidant stress in cardiac surgery patients and thus may hold promise as a simple, nontoxic protective measure (155,156). However, N-AC has not been used in a prospective clinical trial that examines renal outcomes. N-AC has been studied most extensively in the prevention of radiocontrast-induced nephropathy. In this area, the utility of N-AC has been questioned with the publication of a meta-analysis of 16 controlled studies that demonstrated no protective benefit (157).
Other Strategies
The sympathetic nervous system is activated during and after cardiac surgery and may lead to impairment of renal function through a hemodynamic mechanism. Clonidine (an α-2 agonist) has been used to attenuate these effects, with improvement in hemodynamic stability during CPB (158). In a study of 48 normal-risk patients who underwent cardiac surgery, preoperative treatment with clonidine prevented the deterioration of renal function in this small trial, with creatinine clearances significantly higher in the clonidine-treated group 24 h after CPB (159).
Diltiazem has been used in clinical trials to prevent ARF after cardiothoracic surgery. Diltiazem has been shown to inhibit some of the inflammatory effects of CPB and is often used to prevent vasospasm of radial grafts (160,161). Although diltiazem reduced urinary excretion of markers of tubule injury (α glutathione s-transferase and N-acetyl-β-glucosaminidase) (162), its effectiveness in the prevention of renal dysfunction was inconsistent (163–165).
In patients who were at highest risk for AKI, prophylactic hemodialysis has been attempted (166). In a single study, 44 patients with a baseline serum creatinine >2.5 mg/dl were randomly assigned to either perioperative prophylactic dialysis or dialysis only when postoperative ARF that required the procedure was indicated (control). In the group that received prophylactic dialysis, mortality was 4.8 versus 30.4% in the control group. Furthermore, postoperative ARF that required dialysis was reduced from 34.8% in the control group to 4.8% in the intervention arm. These results will have to be repeated in other randomized, controlled studies before this invasive approach can be broadly recommended.
Conclusion
CPB surgery is associated with a high risk for AKI. This injury is associated further with substantial morbidity and mortality. The pathogenesis of kidney injury during CPB is complex and involves hemodynamic, inflammatory, and other mechanisms that interact at a cellular level. At present, no pharmacologic interventions have demonstrated conclusively efficacy in the prevention of renal dysfunction after cardiac surgery. Therapies such as rhANP, fenoldopam, N-AC, and clonidine have shown modestly encouraging results in small trials and need to be confirmed in larger studies that are designed appropriately to assess renal outcomes.
Ultimately, a successful therapy will utilize strategies that target these multiple pathways. This integrated strategy would target hemodynamic, inflammatory, and oxidative pathways and act both at the points of proximal cellular injury and at later downstream events, such as tubular regeneration. CPB offers an attractive model to study these pathways, because the timing of the insult is known and potentially modifiable.
Figure 1: The clinical phases of acute renal failure occur across a continuum of stereotypical pathologic changes. From Sutton
et al. (
61).
Figure 2: The inflammatory cascade activated by cardiac bypass surgery and its role in the production of acute kidney injury. Stimuli during the surgical procedure activate a host of inflammatory mediators, adhesion molecules, and proinflammatory transcription factors. These effects lead to cellular injury and acute renal failure.
Table 1: Risk factors associated with ARF a
Table 2: Cleveland Clinic Foundation Acute Renal Failure Scoring System a
Table 3: Pathophysiologic factors in ARF a
Table 4: Pharmacologic interventions for the prevention of kidney injury after CPB
This work was supported by the National Institutes of Health (DK56223, DK62324, and DK065957).
Published online ahead of print. Publication date available at http://www.cjasn.org.
References
1. Conlon PJ, Stafford-Smith M, White WD, Newman MF, King S, Winn MP, Landolfo K: Acute renal failure following cardiac surgery. Nephrol Dial Transplant 14: 1158–1162, 1999
2. Mangano CM, Diamondstone LS, Ramsay JG, Aggarwal A, Herskowitz A, Mangano DT: Renal dysfunction after myocardial revascularization: Risk factors, adverse outcomes and hospital resource utilization. Ann Intern Med 128: 194–203, 1998
3. Abel RM, Buckley MJ, Austen WG, Barnett GO, Beck CH Jr, Fischer JE: Etiology, incidence and prognosis of renal failure following cardiac operations. Results of a prospective analysis of 500 consecutive patients. J Thorac Cardiovasc Surg 71: 323–333, 1976
4. Gailiunas P Jr, Chawla R, Lazarus JM, Cohn L, Sanders J, Merrill JP: Acute renal failure following cardiac operations. J Thorac Cardiovasc Surg 79: 241–243, 1980
5. Ostermann ME, Taube D, Morgan CJ, Evans TW: Acute renal failure following cardiopulmonary bypass: A changing picture. Intensive Care Med 26: 565–571, 2000
6. Andersson LG, Ekroth R, Bratteby LE, Hallhagen S, Wesslen O: Acute renal failure after coronary surgery: A study of incidence and risk factors in 2009 consecutive patients. J Thorac Cardiovasc Surg 41: 237–241, 1993
7. Zanardo G, Michielon P, Paccagnella A, Rosi P, Calo M, Salandin V, Da Ros A, Michieletto F, Simini G: Acute renal failure in the patient undergoing cardiac operation: Prevalence, mortality rate, and main risk factors. J Thorac Cardiovasc Surg 107: 1489–1495, 1994
8. Mangos GJ, Brown MA, Chan YA, Horton D, Trew P, Whitworth JA: Acute renal failure following cardiac surgery: Incidence, outcomes and risk factors. Aust N Z J Med 25: 284–289, 1995
9. Antunes PE, Prieto D, Ferrao de Oliveira J, Antunes MJ: Renal dysfunction alter myocardial revascularization. Eur J Cardiothorac Surg 25: 597–604, 2004
10. Yeboah ED, Petrie A, Pead JL: Acute renal failure and open heart surgery. BMJ 1: 415–418, 1972
11. Bhat JG, Gluck MC, Lowenstein J, Baldwin DS: Renal failure after open heart surgery. Ann Intern Med 84: 677–682, 1976
12. Hilberman M, Myers BD, Carrie BJ, Derby G, Jamison RL, Stinson EB: Acute renal failure following cardiac surgery. J Thorac Cardiovasc Surg 77: 880–888, 1979
13. Corwin HL, Sprague SM, DeLaria GA, Norusis MJ: Acute renal failure associated with cardiac operations. A case-control study. J Thorac Cardiovasc Surg 98: 1107–1112, 1989
14. Schmitt H, Riehl J, Boseilla A, Kreis A, Putz-Stork A, Lo HB, Lambertz H, Messmer BJ, Sieberth HG: Acute renal failure following cardiac surgery: Pre- and perioperative clinical features. Contrib Nephrol 93: 98–104, 1991
15. Chertow GM, Levy EM, Hammermeister KE, Grover F, Daley J: Independent association between acute renal failure and mortality following cardiac surgery. Am J Med 104: 343–348, 1998
16. Lassnigg A, Schmidlin D, Mouhieddine M, Bachmann LM, Druml W, Bauer P, Hiesmayr M: Minimal changes of serum creatinine predict prognosis in patients after cardiothoracic surgery: A prospective cohort study. J Am Soc Nephrol 15: 1597–1605, 2004
17. Leacche M, Rawn JD, Mihaljevic T, Lin J, Karavas AN, Paul S, Byrne JG: Outcomes in patients with normal serum creatinine and with artificial renal support for acute renal failure developing after coronary artery bypass grafting. Am J Cardiol 93: 353–356, 2004
18. Abraham VS, Swain JA. Cardiopulmonary bypass and the kidney. In: Cardiopulmonary Bypass: Principles and Practice, 2nd Ed., edited by Gravlee GP, Davis RF, Kurusz M, Utley JR, Philadelphia, Lippincott Williams & Wilkins, 2000, pp 382–391
19. Grayson AD, Khater M, Jackson M, Fox MA: Valvular heart operation is an independent risk factor for acute renal failure. Ann Thorac Surg 75: 1829–1835, 2003
20. Thakar CV, Worley S, Arrigain S, Yared J-P, Paganini EP: Influence of renal dysfunction on mortality after cardiac surgery: Modifying effect of preoperative renal function. Kidney Int 67: 1112–1119, 2005
21. Loef BG, Epema AH, Smilde TB, Henning RH, Ebels T, Navis G, Stegeman CA: Immediate postoperative renal function deterioration in cardiac surgical patients predicts in-hospital mortality and long-term survival. J Am Soc Nephrol 16: 195–200, 2005
22. Lok CE, Austin PC, Wanh H, Tu JV: Impact of renal insufficiency on short- and long-term outcomes after cardiac surgery. Am Heart J 148: 430–438, 2004
23. Liano F, Pascual J: Epidemiology of acute renal failure: A prospective, multicenter, community-based study. Madrid Acute Renal Failure Study Group. Kidney Int 50: 811–818, 1996
24. Thakar CV, Yared JP, Worley S, Cotman K, Paganini EP: Renal dysfunction and serious infections after open-heart surgery. Kidney Int 64: 239–246, 2003
25. Chertow GM, Lazarus JM, Christiansen CL, Cook EF, Hammermeister KE, Grover F, Daley J: Preoperative renal risk stratification. Circulation 95: 878–884, 1997
26. Fortescue EB, Bates DW, Chertow GM: Predicting acute renal failure after coronary bypass surgery: Cross-validation of two risk-stratification algorithms. Kidney Int 57: 2594–2602, 2000
27. Frost L, Pedersen RS, Lund O, Hansen OK, Hansen HE: Prognosis and risk factors in acute, dialysis-requiring renal failure after open-heart surgery. Scand J Thorac Cardiovasc Surg 25: 161–166, 1991
28. Thakar CV, Liangos O, Yared JP, Nelson D, Piedmonte MR, Hariachar S, Paganini EP: ARF after open-heart surgery: Influence of gender and race. Am J Kidney Dis 41: 742–751, 2003
29. Thakar CV, Liangos O, Yared J-P, Nelson DA, Hariachar S, Paganini EP: Predicting acute renal failure after cardiac surgery: Validation and re-definition of a risk stratification algorithm. Hemodial Int 7: 143–147, 2003
30. Thakar CV, Arrigain S, Worley S, Yared J-P, Paganini EP: A clinical score to predict acute renal failure after cardiac surgery. J Am Soc Nephrol 16: 162–168, 2005
31. Slogoff S, Reul GJ, Keats AS, Curry GR, Crum ME, Elmquist BA, Giesecke NM, Jistel JR, Rogers LK, Soderberg JD, et al.: Role of perfusion pressure and flow in major organ dysfunction after cardiopulmonary bypass. Ann Thorac Surg 50: 911–918, 1990
32. Tuttle KR, Worrall NK, Dahlstrom LR, Nandagopal R, Kausz AT, Davis CL: Predictors of ARF after cardiac surgical procedures. Am J Kidney Dis 41: 76–83, 2003
33. Fischer UM, Weissenberger WK, Warters RD, Geissler HJ, Allen SJ, Mehlhorn U: Impact of cardiopulmonary bypass management on postcardiac surgery renal function. Perfusion 17: 401–406, 2002
34. Abramov D, Tamariz M, Serrick CI, Sharp E, Noel D, Harwood S, Christakis GT, Goldman BS: The influence of cardiopulmonary bypass flow characteristics on the clinical outcome of 1820 coronary bypass patients. Can J Cardiol 19: 237–243, 2003
35. Urzua J, Troncoso S, Bugedo G, Canessa R, Munoz H, Lema G, Valdivieso A, Irarrazaval M, Moran S, Meneses G: Renal function and cardiopulmonary bypass: Effect of perfusion pressure. J Cardiothorac Vasc Anesth 6: 299–303, 1992
36. Provenchere S, Plantefeve G, Hufnagel G, Vicaut E, De Vaumas C, Lecharny JB, Depoix JP, Vrtovsnik F, Desmonts JM, Philip I: Renal dysfunction after cardiac surgery with normothermic cardiopulmonary bypass: Incidence, risk factors and effect on clinical outcome. Anesth Analg 96: 1258–1264, 2003
37. The Warm Heart Investigators: Randomized trial of normothermic versus hypothermic coronary artery bypass surgery. Lancet 343: 559–563, 1994
38. Cook DJ: Changing temperature management for cardiopulmonary bypass. Anesth Analg 88: 1254–1271, 1999
39. Magee MJ, Edgerton JR: Beating heart coronary artery bypass: Operative strategy and technique. Sem Thorac Cardiovasc Surg 15: 83–91, 2003
40. Loef BG, Epema AH, Navis G, Ebels T, van Oeveren W, Henning RH: Off-pump coronary revascularization attenuates transient renal damage compared with on-pump coronary revascularization. Chest 121: 1190–1194, 2002
41. Ascione R, Lloyd CT, Underwood, Gomes WJ, Angelini GD: On-pump versus off-pump coronary revascularization: Evaluation of renal function. Ann Thorac Surg 68: 493–498, 1999
42. Schwann NM, Horrow JC, Strong MD, Chamchad D, Guerraty A, Wechsler AS: Does off-pump coronary artery bypass reduce the incidence of clinically evident renal dysfunction after multivessel myocardial revascularization? Anesth Analg 99: 959–964, 2004
43. Beauford RB, Saunders CR, Niemeier LA, Lunceford TA, Karanam R, Prendergast T, Shah S, Burns P, Sardari F, Goldstein DJ: Is off-pump revascularization better for patients with non-dialysis-dependent renal insufficiency? Heart Surg Forum 7: E141–146, 2004
44. Gamboso MG, Phillips-Bute B, Landolfo KP, Newman MF, Stafford-Smith M: Off-pump versus on-pump coronary artery bypass surgery and post-operative renal dysfunction. Anesth Analg 91: 1080–1084, 2000
45. Stallwood MI, Grayson AD, Mills K, Scawn ND: Acute renal failure in coronary artery bypass surgery: Independent effect of cardiopulmonary bypass. Ann Thorac Surg 77: 968–972, 2004
46. Fransen E, Maessen J, Dentener M, Senden N, Geskes G, Buurman W: Systemic inflammation present in patients undergoing CABP without extracorporeal circulation. Chest 113: 1290–1295, 1998
47. Dybdahl B, Wahba A, Haaverstad R, Kirkeby-Garstad I, Kierulf P, Espevik T, Sundan A: On-pump versus off-pump coronary artery bypass grafting: More heat-shock protein 70 is released after on-pump surgery. Eur J Cardiothorac Surg 25: 985–992, 2004
48. Wright G: Hemolysis during cardiopulmonary bypass: Update. Perfusion 16: 345–351, 2001
49. Baliga R, Ueda N, Waler PD, Shah SV: Oxidant mechanisms in toxic acute renal failure. Am J Kidney Dis 29: 465–477, 1997
50. Davis CL, Kausz AT, Zager RA, Kharasch ED, Cochran RP: Acute renal failure after cardiopulmonary bypass is related to decreased serum ferritin levels. J Am Soc Nephrol 10: 2396–2402, 1999
51. Messmer K: Hemodilution. Surg Clin North Am 55: 659–678, 1975
52. Shah D, Corson J, Karmody A, Leather R: Effects of isovolemic hemodilution on abdominal aortic aneurysmectomy in high risk patients. Ann Vasc Surg 1: 50–54, 1986
53. Swaminathan M, Phillips-Bute BG, Conlon PJ, Smith PK, Newman MF, Stafford-Smith M: The association of lowest hematocrit during cardiopulmonary bypass with acute renal injury after coronary artery bypass surgery. Ann Thorac Surg 76: 784–792, 2003
54. Karkouti K, Beattie WS, Wijeysundera DN, Rao V, Chan C, Dattilo KM, Djaiani G, Ivanov J, Karski J, David TE: Hemodilution during cardiopulmonary bypass is an independent risk factor for acute renal failure in adult cardiac surgery. J Thorac Cardiovasc Surg 129: 391–400, 2005
55. Chertow GM, Lazarus JM, Christiansen CL, Cook EF, Hammermeister KE, Grover F, Daley J: Preoperative renal risk stratification. Circulation 95: 878–884, 1997
56. Eriksen BO, Hoff KRS, Solberg S: Prediction of acute renal failure after cardiac surgery: Retrospective cross-validation of a clinical algorithm. Nephrol Dial Transplant 18: 77–81, 2003
57. Moran SM, Myers BD: Pathophysiology of protracted acute renal failure in man. J Clin Invest 76: 1440–1448, 1985
58. Heinzelmann M, Mercer-Jones MA, Passmore JC: Neutrophils and renal failure. Am J Kidney Dis 34: 384–399, 1999
59. Sheridan AM, Bonventre JV: Cell biology and molecular mechanisms of injury in ischemic acute renal failure. Curr Opin Nephrol Hypertens 9: 427–434, 2000
60. Molitoris BA: Transitioning to therapy in ischemic acute renal failure. J Am Soc Nephrol 14: 265–267, 2003
61. Sutton TA, Fisher CJ, Molitoris BA: Microvascular endothelial injury and dysfunction during ischemic acute renal failure. Kidney Int 62: 1539–1549, 2002
62. Conger JD: Vascular alterations in acute renal failure: Roles in initiation and maintenance. In: Acute Renal Failure—A Companion to Brenner and Rector’s The Kidney, edited by Molitoris BA, Finn WF, Philadelphia, Saunders, 2001, pp 13–29
63. Okusa MD: The inflammatory cascade in acute ischemic renal failure Nephron 90: 133–138, 2002
64. Goligorsky MS, Noiri E, Tsukahara H, Budzikowski AS, Li H: A pivotal role of nitric oxide in endothelial cell dysfunction. Acta Physiol Scand 168: 33–40, 2000
65. Caramelo C, Espinoza G, Manzarbeitia F, Cernadas MR, Perez Tejerizo G, Tan D, Mosquera JR, Digiuni E, Monton M, Millas I, Hernando L, Casado S, Lopez-Farre A: Role of endothelium-related mechanisms in the pathophysiology of renal ischemia/reperfusion in normal rabbits. Circ Res 79: 1031–1038, 1996
66. Kohan DE: Endothelins in the kidney: Physiology and pathophysiology. Am J Kidney Dis 22: 493–510, 1993
67. Brezis M, Rosen S: Hypoxia of the renal medulla—Its implications for disease. N Engl J Med 332: 647–655, 1995
68. Chou SY, Porush JG, Faubert PF: Renal medullary circulation: Hormonal control. Kidney Int 37: 1–13, 1990
69. Lequier LL, Nikaidoh H, Leonard SR, Bokovoy JL, White ML, Scannon PJ, Giroir BP: Preoperative and postoperative endotoxemia in children with congenital heart disease. Chest 117: 1706–1712, 2000
70. Bennett-Guerrero E, Ayuso L, Hamilton-Davies C, White WD, Barclay GR, Smith PK, King SA, Muhlbaier LH, Newman MF, Mythen MG: Relationship of pre-operative anti-endotoxin core antibodies and adverse outcomes following cardiac surgery. JAMA 277: 646–650, 1997
71. Nilsson L, Kulander L, Nystrom SO, Eriksson O: Endotoxins in cardiopulmonary bypass. J Thorac Cardiovasc Surg 100: 777–780, 1990
72. Riddington DW, Venkatesh B, Boivin CM, Bonser RS, Elliott TS, Marshall T, Mountford PJ, Bion JF: Intestinal permeability, gastric intramucosal pH, and systemic endotoxemia in patients undergoing cardiopulmonary bypass. JAMA 275: 1007–1012, 1996
73. Levine B, Kalman J, Mayer L, Fillit HM, Packer M: Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 323: 236–241, 1990
74. Torre-Amione G, Kapadia S, Benedict C, Oral H, Young JB, Mann DL: Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: A report from the studies of left ventricular dysfunction (SOLVD). J Am Coll Cardiol 27: 1201–1206, 1996
75. Parolari A, Alamanni F, Gherli T, Bertera A, Dainese L, Costa C, Schena M, Sisillo E, Spirito R, Porqueddu M, Rona P, Biglioli P: Cardiopulmonary bypass and oxygen consumption: Oxygen delivery and hemodynamics. Ann Thorac Surg 67: 1320–1327, 1999
76. Kirklin JW, Barratt-Boyes BG: Cardiac Surgery, 2nd Ed., New York, Churchill Livingstone, 1993, pp 80
77. Kurusz M, Davis RF, Conti VR: Conduct of cardiopulmonary bypass. In: Cardiopulmonary Bypass: Principles and Practice, edited by Gravlee GP, Davis RF, Kurusz M, Utley JR, Philadelphia, Lippincott Williams & Wilkins, 2000, pp 549–578
78. Rudy LW, Heymann MA, Edmunds H: Distribution of systemic blood flow during cardiopulmonary bypass. J Appl Physiol 34: 194–200, 1973
79. Harris EA, Seelye ER, Barratt-Boyes BG: On the availability of oxygen to the body during cardiopulmonary bypass in man. Br J Anaesth 46: 425–431, 1974
80. Urzua J, Troncoso S, Bugedo G, Canessa R, Munoz H, Lema G, Valdivieso A, Irarrazaval M, Moran S, Meneses G: Renal function and cardiopulmonary bypass: Effect of perfusion pressure. J Cardiovasc Vasc Anesth 6: 299–303, 1992
81. Palmer BF: Renal dysfunction complicating the treatment of hypertension. N Engl J Med 347: 1256–1261, 2002
82. Kelleher SP, Robinette JB, Conger JD: Sympathetic nervous system in the loss of autoregulation in acute renal failure. Am J Physiol 246: F379–F386, 1984
83. Gold JP, Charlson ME, Williams-Russo P, Szatrowski TP, Peterson JC, Pirraglia PA, Hartman GS, Yao FS, Hollenberg JP, Barbut D, et al.: Improvement of outcomes after coronary artery bypass; a randomized trial comparing intraoperative high versus low mean arterial pressure. J Thorac Cardiovasc Surg 110: 1302–1314, 1995
84. Cremer J, Martin M, Redl H, Bahrami S, Abraham C, Graeter T, Haverich A, Schlag G, Borst HG: Systemic inflammatory response after cardiac operations. Ann Thorac Surg 61: 1714–1720, 1996
85. Taylor K: SIRS—The systemic inflammatory response syndrome after cardiac operations. Ann Thorac Surg 61: 1607–1608, 1996
86. Hornick P, Taylor K: Pulsatile and non-pulsatile perfusion: The continuing controversy. J Cardiothorac Vasc Anesth 11: 310–315, 1997
87. Kirklin JK, Blackstone EH, Kirklin JW: Cardiopulmonary bypass: Studies on its damaging effects. Blood Purif 5: 168–178, 1987
88. Czerny M, Baumer H, Kilo J, Lassnigg A, Hamwi A, Vukovich T, Wolner E, Grimm M: Inflammatory response and myocardial injury following coronary artery bypass grafting with or without cardiopulmonary bypass. Eur J Cardiothorac Surg 17: 737–742, 2000
89. Fransen E, Maessen J, Dentener M, Senden N, Geskes G, Buurman W: Systemic inflammation present in patients undergoing CABG without extracorporeal circulation. Chest 113: 1290–1295, 1998
90. Hornick P, Taylor KM: Immune and inflammatory responses after cardiopulmonary bypass. In: Cardiopulmonary Bypass: Principles and Practice, edited by Gravlee GP, Davis RF, Kurusz M, Utley JR, Philadelphia, Lippincott Williams & Wilkins, 2000, pp 303–320
91. Asimakopoulos G, Taylor KM: Effects of cardiopulmonary bypass on leukocyte and endothelial adhesion molecules. Ann Thorac Surg 66: 2135–2144, 1998
92. Galinanes M, Watson C, Trivedi U, Chambers DJ, Young CP, Venn GE: Differential patterns of neutrophil adhesion molecules during cardiopulmonary bypass in humans. Circulation 94[Suppl 2]: 364–369, 1996
93. Zilla P, Fasol R, Groscurth P, Klepetko W, Reichenspurner H, Wolner E: Blood platelets in cardiopulmonary bypass operations. J Thorac Cardiovasc Surg 97: 379–388, 1989
94. Haga Y, Hatori N, Yoshizu H, Okuda E, Uriuda Y, Tanaka S: Granulocyte superoxide anion and elastase release during cardiopulmonary bypass. Artif Organs 17: 837–842, 1993
95. Faymonville ME, Pincemail J, Duchateau J, Paulus JM, Adam A, Deby-Dupont G, Deby C, Albert A, Larbuisson R, Limet R, et al.: Myeloperoxidase and elastase as markers of leukocyte activation during cardiopulmonary bypass. J Thorac Cardiovasc Surg 102: 309–317, 1991
96. Frering B, Philip I, Dehous M, Rolland C, Langlois JM, Desmonts JM: Circulating cytokines in patients undergoing normothermic cardiopulmonary bypass. J Thorac Cardiovasc Surg 108: 642–647, 1994
97. Paparella D, Yau TM, Young E: Cardiopulmonary bypass induced inflammation: Pathophysiology and treatment. An update. Eur J Cardiothorac Surg 21: 232–244, 2002
98. Musial J, Niewiarowski S, Hershock D, Morinelli TA, Colman RW, Edmunds LH Jr: Loss of fibrinogen receptors from the platelet surface during simulated extracorporeal circulation. J Lab Clin Med 105: 514–526, 1985
99. Kirklin JK, Westaby S, Blackstone EH, Kirklin JW, Chenoweth DE, Pacifico AD: Complement and the damaging effects of cardiopulmonary bypass. J Thorac Cardiovasc Surg 86: 845–857, 1983
100. Burne-Taney MJ, Rabb H: The role of adhesion molecules and T cells in ischemic renal injury. Curr Opin Nephrol Hypertens 12: 85–90, 2003
101. Sheridan AM, Bonventre JV: Cell biology and molecular mechanisms of injury in ischemic acute renal failure. Curr Opin Nephrol Hypertens 9: 427–434, 2000
102. Donnahoo KK, Meng X, Ayala A, Cain MP, Harken AH, Meldrum DR: Early kidney TNF-expression mediates neutrophil infiltration and injury after renal ischemia-reperfusion. Am J Physiol 277: R922–R929, 1999
103. McCoy RN, Hill KE, Ayon MA, Stein JH, Burk RF: Oxidant stress following renal ischemia: Changes in the glutathione redox ratio. Kidney Int 33: 812–817, 1988
104. Tennenberg SD, Clardy CW, Bailey WW, Solomkin JS: Complement activation and lung permeability during cardiopulmonary bypass. Ann Thorac Surg 50: 597–601, 1990
105. Jansen NJ, van-Oeveren W, Gu YJ, van Vliet MH, Eijsman L, Wildevuur CR: Endotoxin release and tumor necrosis factor formation during cardiopulmonary bypass. Ann Thorac Surg 54: 744–747, 1992
106. Blauth J: Macroemboli and microemboli during cardiopulmonary bypass. Ann Thorac Surg 59: 1300–1303, 1995
107. van der Linden J, Casimir-Ahn H: When do cerebral emboli appear during open heart operations? A transcranial Doppler study. Ann Thorac Surg 51: 237–241, 1991
108. Barbut D, Hinton RB, Szatrowski TP, Hartman GS, Bruefach M, Williams-Russo P, Charlson ME, Gold JP: Cerebral emboli detected during bypass surgery are associated with clamp removal. Stroke 25: 2398–2402, 1994
109. Sreeram GM, Grocott HP, White WD, Newman MF, Stafford-Smith M: Transcranial Doppler emboli count predicts rise in creatinine after coronary artery bypass graft surgery. J Cardiovasc Vasc Anesth 18: 548–551, 2004
110. Bidstrup BP, Royston D, Sapsford RN, Taylor KM: Reduction in blood loss and blood use after cardiopulmonary bypass with high-dose aprotinin. J Thorac Cardiovasc Surg 97: 364–372, 1989
111. Rustom R, Grime JS, Maltby P, Stockdale HR, Critchley M, Bone JM: Observations on the early renal uptake and later tubular metabolism of radiolabeled aprotinin (Trasylol) in man: Theoretical and practical considerations. Clin Sci (Colch) 84: 231–241, 1993
112. Kramer HJ, Moch T, von Sicherer L, Dusing R: Effects of aprotinin on renal function and urinary prostaglandin excretion in conscious rats after acute salt loading. Clin Sci (Colch) 56: 547–555, 1979
113. Mora Mangano CT, Neville MJ, Hsu PH, Mignea I, King J, Miller DC: Aprotinin, blood loss and renal dysfunction in deep hypothermic circulatory arrest. Circulation 104[Suppl]: I247–I255, 2001
114. Molenaar IQ, Begliomini B, Grazi GL, Ringers J, Terpstra OT, Porte RJ; EMSALT Study Group: European Multicenter Study on the Use of Aprotinin in Liver Transplantation: The effect of aprotinin on renal function in orthotopic liver transplantation. Transplantation 71: 247–252, 2001
115. Sundt TM 3rd, Kouchoukos NT, Saffitz JE, Murphy SF, Wareing TH, Stahl DJ: Renal dysfunction and intravascular coagulation with aprotinin and hypothermic circulatory arrest. Ann Thorac Surg 55: 1418–1424, 1993
116. Moat NE, Evans TE, Quinlan GJ, Gutteridge JM: Chelatable iron and copper can be released from extracorporeally circulated blood during cardiopulmonary bypass. Fed Eur Biochem Soc 328: 103–106, 1993
117. Gutteridge JMC: Iron promoters of the Fenton reaction and lipid peroxidation can be released from hemoglobin by peroxides. Fed Eur Biochem Soc Lett 201: 291–295, 1986
118. Flaherty JT, Weisfeldt ML: Reperfusion injury. Free Radic Biol Med 5: 409–419, 1988
119. Gutteridge JMC, Quinlan GJ: Antioxidant protection against organic and inorganic oxygen radicals by normal human plasma: The important primary role for iron-binding and iron-oxidizing proteins. Biochim Biophys Acta 1159: 248–254, 1992
120. Pepper JR, Mumby S, Gutteridge JMC: Sequential oxidative damage and changes in iron-binding and iron-oxidizing plasma antioxidants during cardiopulmonary bypass surgery. Free Radic Res 21: 377–385, 1994
121. Pepper JR, Mumby S, Gutteridge JMC: Blood cardioplegia increases plasma iron overload and thiol levels during cardiopulmonary bypass. Ann Thorac Surg 60: 1735–1740
122. Menasche P, Antebi H, Alcindor LG, Teiger E, Perez G, Giudicelli Y, Nordmann R, Piwnica A: Iron chelation by deferoxamine inhibits lipid peroxidation during cardiopulmonary bypass in humans. Circulation 82: IV390–IV396, 1990
123. Lazar HL: The use of angiotensin-converting enzyme inhibitors in patients undergoing coronary artery bypass graft surgery. Vascul Pharmacol 42: 119–123, 2005
124. Devbhandari MP, Balasubramanian SK, Codispoti M, Nzewi OC, Prasad SU: Preoperative angiotensin-converting enzyme inhibition can cause severe post CPB vasodilation—Current UK opinion. Asian Cardiovasc Thorac Ann 12: 346–349, 2004
125. Kwapisz MM, Muller M, Schindler E, Demir S, Veit M, Roth P, Hempelmann G: The effect of intravenous quinaprilat on plasma cytokines and hemodynamic variables during cardiac surgery. J Cardiothorac Vasc Anesth 18: 53–58, 2004
126. Aspelin P, Aubry P, Fransson SG, Strasser R, Willenbrock R, Berg KJ; Nephrotoxicity in High-Risk Patients Study of Iso-Osmolar and Low-Osmolar Non-Ionic Contrast Media Study Investigators: Nephrotoxic effects in high-risk patients undergoing angiography. N Engl J Med 348: 491–499, 2003
127. Woo EB, Tang AT, el-Gamel A, Keevil B, Greenhalgh D, Patrick M, Jones MT, Hooper TL: Dopamine therapy for patients at risk of renal dysfunction following cardiac surgery: Science or fiction? Eur J Cardiothorac Surg 22: 106–111, 2002
128. Tang AT, El-Gamel A, Keevil B, Yonan N, Deiraniya AK: The effect of ‘renal-dose’ dopamine on renal tubular function following cardiac surgery: Assessed by measuring retinol binding protein (RBP). Eur J Cardiothorac Surg 15: 717–721, 1999
129. Denton MD, Chertow GM, Brady HR: “Renal-dose” dopamine for the treatment of acute renal failure: Scientific rationale, experimental studies and clinical trials. Kidney Int 50: 4–14, 1996
130. Stone GW, McCullough PA, Tumlin JA, Lepor NE, Madyoon H, Murray P, Wang A, Chu AA, Schaer GL, Stevens M, Wilensky RL, O’Neill WW; CONTRAST Investigators: Fenoldopam mesylate for the prevention of contrast-induced nephropathy: A randomized controlled trial. JAMA 290: 2284–2291, 2003
131. Ranucci M, Soro G, Barzaghi N, Locatelli A, Giordano G, Vavassori A, Manzato A, Melchiorri C, Bove T, Juliano G, Uslenghi MF: Fenoldopam prophylaxis of postoperative acute renal failure in high-risk cardiac surgery patients. Ann Thorac Surg 78: 1332–1337, 2004
132. Caimmi PP, Pagani L, Micalizzi E, Fiume C, Guani S, Bernardi M, Parodi F, Cordero G, Fregonara M, Kapetanakis E, Panella M, Degasperis C: Fenoldopam for renal protection in patients undergoing cardiopulmonary bypass. J Cardiothorac Vasc Anesth 17: 491–494, 2003
133. Garwood S, Swamidoss CP, Davis EA, Samson L, Hines RL: A case series of low-dose fenoldopam in seventy cardiac surgical patients at increased risk of renal dysfunction. J Cardiothorac Vasc Anesth 17: 17–21, 2003
134. Kramer BK, Preuner J, Ebenburger A, Kaiser M, Bergner U, Eilles C, Kammerl MC, Riegger GA, Birnbaum DE: Lack of renoprotective effect of theophylline during aortocoronary bypass surgery. Nephrol Dial Transplant 17: 910–915, 2002
135. Light DB, Schwiebert EM, Karlson KH, Stanton BA: Atrial natriuretic peptide inhibits a cation channel in renal inner medullary collecting duct cells. Science 243: 383–385, 1989
136. Allgren RL, Marbury TC, Rahman SN, Weisberg LS, Fenves AZ, Lafayette RA, Sweet RM, Genter FC, Kurnik BR, Conger JD, Sayegh MH: Anaritide in acute tubular necrosis: Auriculin Anaritide Acute Renal Failure Study Group. N Engl J Med 336: 828–834, 1997
137. Lewis J, Salem MM, Chertow GM, Weisberg LS, McGrew F, Marbury TC, Allgren RL: Atrial natriuretic factor in oliguric renal failure. Anaritide Acute Renal Failure Study Group. Am J Kidney Dis 36: 767–774, 2000
138. Sward K, Valsson F, Odencrants P, Samuelsson O, Ricksten SE: Recombinant human atrial natriuretic peptide in ischemic acute renal failure. A randomized placebo controlled trial. Crit Care Med 32: 1310–1315, 2004
139. Jarnberg PO: Renal protection strategies in the perioperative period. Best Pract Res Clin Anaesthesiol 18: 645–660, 2004
140. 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 11: 97–104, 2000
141. Lombardi R, Ferreiro A, Servetto C: Renal function after cardiac surgery: Adverse effect of furosemide. Ren Fail 25: 775–786, 2003
142. Engelman RM, Gouge TH, Smith SJ, Stahl WM, Gombos EA, Boyd AD: The effect of diuretics on renal hemodynamics during cardiopulmonary bypass. J Surg Res 16: 268–276, 1974
143. Cooper JR, Giesecke NM: Hemodilution and priming solutions. In: Cardiopulmonary Bypass: Principles and Practice, edited by Gravlee GP, Davis RF, Kurusz M, Utley JR, Philadelphia, Lippincott Williams & Wilkins, 2000, pp 186–196
144. Rigden SP, Dillon MJ, Kind PR, de Leval M, Stark J, Barratt TM: The beneficial effect of mannitol on postoperative renal function in children undergoing cardiopulmonary bypass surgery. Clin Nephrol 21: 148–151, 1984
145. Fisher AR, Jones P, Barlow P, Kennington S, Saville S, Farrimond J, Yacoub M: The influence of mannitol on renal function during and after open-heart surgery. Perfusion 13: 181–186, 1998
146. Ip-Yam PC, Murphy S, Baines M, Fox MA, Desmond MJ, Innes PA: Renal function and proteinuria after cardiopulmonary bypass: The effects of temperature and mannitol. Anesth Analg 78: 842–847, 1994
147. Carcoana OV, Mathew JP, Davis E, Byrne DW, Hayslett JP, Hines RL, Garwood S: Mannitol and dopamine in patients undergoing cardiopulmonary bypass: A randomized clinical trial. Anesth Analg 97: 1222–1229, 2003
148. Sirivella S, Gielchinsky I, Parsonnet V: Mannitol, furosemide, and dopamine infusion in postoperative renal failure complicating cardiac surgery. Ann Thorac Surg 69: 501–506, 2000
149. Sullivan GW, Carper HT, Novick WJ Jr, Mandell GL: Inhibition of the inflammatory action of interleukin-1 and tumor necrosis factor (alpha) on neutrophil function by pentoxifylline. Infect Immun 56: 1722–1729, 1988
150. Cagli K, Ulas MM, Ozisik K, Kale A, Bakuy V, Emir M, Balci M, Topbas M, Sener E, Tasdemir O: The intraoperative effect of pentoxifylline on the inflammatory process and leukocytes in cardiac surgery patients undergoing cardiopulmonary bypass. Perfusion 20: 45–51, 2005
151. Zhang M, Xu YJ, Saini HK, Turan B, Liu PP, Dhalla NS: Pentoxifylline attenuates cardiac dysfunction and reduces TNF-alpha level in the ischemic-reperfused heart. Am J Physiol Heart Circ Physiol. 289: H832–H839, 2005
152. Boldt J, Brosch C, Piper SN, Suttner S, Lehmann A, Werling C: Influence of prophylactic use of pentoxifylline on postoperative organ function in elderly cardiac surgery patients. Crit Care Med 29: 952–958, 2001
153. Loef BG, Henning RH, Epema AH, Rietman GW, van Oeveren W, Navis GJ, Ebels T: Effect of dexamethasone on perioperative renal function impairment during cardiac surgery with cardiopulmonary bypass. Br J Anaesth 93: 793–798, 2004
154. Shernan SK, Fitch JC, Nussmeier NA, Chen JC, Rollins SA, Mojcik CF, Malloy KJ, Todaro TG, Filloon T, Boyce SW, Gangahar DM, Goldberg M, Saidman LJ, Mangano DT; Pexelizumab Study Investigators: Impact of pexelizumab, an anti-C5 complement antibody, on total mortality and adverse cardiovascular outcomes in cardiac surgical patients undergoing cardiopulmonary bypass. Ann Thorac Surg 77: 942–949, 2004
155. Sucu N, Cinel I, Unlu A, Aytacoglu B, Tamer L, Kocak Z, Karaca K, Gul A, Dikmengil M, Atik U, Oral U: N-acetylcysteine for preventing pump-induced oxidoinflammatory response during cardiopulmonary bypass. Surg Today 34: 237–242, 2004
156. Tossios P, Bloch W, Huebner A, Raji MR, Dodos F, Klass O, Suedkamp M, Kasper SM, Hellmich M, Mehlhorn U: N-acetylcysteine prevents reactive oxygen species-mediated myocardial stress in patients undergoing cardiac surgery: Results of a randomized, double-blind, placebo-controlled clinical trial. Thorac Cardiovasc Surg 126: 1513–1520, 2003
157. Kshirsagar AV, Poole C, Mottl A, Shoham D, Franceschini N, Tudor G, Agrawal M, Denu-Ciocca C, Magnus Ohman E, Finn WF: N-acetylcysteine for the prevention of radiocontrast induced nephropathy: A meta-analysis of prospective controlled trials. J Am Soc Nephrol 15: 761–769, 2004
158. Myles PS, Hunt JO, Holdgaard HO, McRae R, Buckland MR, Moloney J, Hall J, Bujor MA, Esmore DS, Davis BB, Morgan DJ: Clonidine and cardiac surgery: Haemodynamic and metabolic effects, myocardial ischaemia and recovery. Anaesth Intensive Care 27: 137–147, 1999
159. Kulka PJ, Tryba M, Zenz M: Preoperative alpha2-adrenergic receptor agonists prevent the deterioration of renal function after cardiac surgery: Results of a randomized, controlled trial. Crit Care Med 24: 947–952, 1996
160. Fansa I, Gol M, Nisanoglu V, Yavas S, Iscan Z, Tasdemir O: Does diltiazem inhibit the inflammatory response in cardiopulmonary bypass? Med Sci Monit 9: PI30–PI36, 2003
161. Chanda J, Canver CC: Reversal of preexisting vasospasm in coronary artery conduits. Ann Thorac Surg 72: 476–480, 2001
162. Bergman AS, Odar-Cederlof I, Westman L, Bjellerup P, Hoglund P, Ohqvist G: Diltiazem infusion for renal protection in cardiac surgical patients with preexisting renal dysfunction. J Cardiothorac Vasc Anesth 16: 294–299, 2002
163. Piper SN, Kumle B, Maleck WH, Kiessling AH, Lehmann A, Rohm KD, Suttner SW, Boldt J: Diltiazem may preserve renal tubular integrity after cardiac surgery. Can J Anaesth 50: 285–292, 2003
164. Young EW, Diab A, Kirsh MM: Intravenous diltiazem and acute renal failure after cardiac operations. Ann Thorac Surg 65: 1316–1319, 1998
165. Amar D, Fleisher M: Diltiazem treatment does not alter renal function after thoracic surgery. Chest 119: 1476–1479, 2001
166. Durmaz I, Yagdi T, Calkavur T, Mahmudov R, Apaydin AZ, Posacioglu H, Atay Y, Engin C: Prophylactic dialysis in patients with renal dysfunction undergoing on-pump coronary artery bypass surgery. Ann Thorac Surg 75: 859–864, 2003