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Featured Articles: Narrative Review Article

Perioperative Renoprotection: General Mechanisms and Treatment Approaches

Molinari, Luca MD*,†; Sakhuja, Ankit MD*,‡; Kellum, John A. MD*

Author Information
doi: 10.1213/ANE.0000000000005107


See Article, p 1663

Acute kidney injury (AKI) is a clinical syndrome characterized by a sudden decrease in renal function thought to be caused by damage to the kidneys. The clinical diagnosis of AKI is based on the Kidney Disease: Improving Global Outcomes (KDIGO) criteria that utilize both increase in serum creatinine and decrease in urine output (Table 1).1 Renal function, that is, glomerular filtration rate (GFR), is inversely proportional to serum creatinine. This effect is more significant at lower values of creatinine. For a patient with baseline creatinine 0.8 mg/dL, a 0.3 mg/dL change reflects a 37.5% change in GFR. Therefore, minimal changes in serum creatinine can be reflective of much larger changes in renal function and consequently be of clinical relevance. This was shown among patients undergoing cardiothoracic surgery2 and in both surgical and nonsurgical hospitalized patients.3

Table 1. - KDIGO Criteria and Stage for AKI
AKI sCr Criteria UO Criteria
Stage 1 sCr 1.5–1.9 times baseline or increase of ≥0.3 mg/dL within any 48 h period UO <0.5 mL/kg for 6–12 h
Stage 2 sCr 2.0–2.9 times baseline UO <0.5 mL/kg for ≥12 h
Stage 3 sCr ≥3.0 times baseline or increase to ≥4.0 mg/dL or decrease in eGFR to <35 mL/min per 1.73 m2 (in patients <18 y) UO <0.3 mL/kg for ≥24 h or anuria for ≥12 h or Initiation of RRT (/acute dialysis)
Abbreviations: AKI, acute kidney injury; eGFR, estimated glomerular filtration rate; KDIGO, Kidney Disease Improving Global Outcomes; RRT, renal replacement therapy; sCr, serum creatinine; UO, urinary output.

Creatinine, however, is an imperfect marker of renal function, as it is affected by muscle mass, diet, volume overload,4 and sepsis.5 It is also the biochemical end result of renal injury, so it will be delayed relative to the start of damage. In addition, it is not a direct marker of renal parenchymal damage and is neither sensitive nor specific.

As significant damage must occur before appreciable change in renal function, there is a great interest in biomarkers that can provide direct information about parenchymal damage in a timely fashion.6 Neutrophil gelatinase-associated lipocalin has been shown to predict AKI after cardiac surgery and kidney surgery.6,7 Urinary liver-type fatty acid–binding protein and kidney injury molecule-1 were similarly found to be useful in predicting AKI after cardiac surgery.8

In addition to the damage biomarkers, markers of kidney stress have garnered considerable interest in recent years, especially to aid in risk stratification for perioperative AKI (Figure 1). These markers are tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor–binding protein 7 (IGFBP7). They are released in urine in response to renal epithelial cell stress and are mediators of cell cycle arrest. Together, the product of urinary ([TIMP-2]•[IGFBP7]) has an area under the curve (AUC) of 0.80 to predict moderate-to-severe AKI within next 12 hours.9 As they can allow for intraoperative detection of the risk for development of moderate to severe AKI in patients undergoing cardiac surgery,10 they can be very helpful in risk stratification of these patients.

Figure 1.:
The potential shift in the diagnostic approach to AKI. Currently, the diagnosis of AKI is based only on serum creatinine and urinary output, but this has several pitfalls and limitations. In the last years, more researchers are suggesting the implementation of biomarkers of kidney stress and damage as a tool to allow an early identification of AKI (“subclinical AKI”) and also a better risk stratification of patients who already have developed AKI. Subclinical AKI is a condition in which serum creatinine and urinary output criteria for AKI are still not fulfilled, but the kidney may have already suffered from a reversible/irreversible stress or even damage. During this condition, biomarkers may have already been released and be detectable. AKI indicates acute kidney injury; IGFBP7, insulin-like growth factor–binding protein 7; KIM-1, kidney injury molecule-1; L-FABP, liver-type fatty acid–binding protein; NGAL, neutrophil gelatinase-associated lipocalin; TIMP-2, tissue inhibitor of metalloproteinases-2.

With this article, we aim to provide a review of the epidemiology, major risk factors, and mechanisms of perioperative AKI, and discuss potential renoprotective strategies.


AKI is very common among hospitalized patients, affecting approximately 12% of overall hospital admissions.11 It is even more common in those critically ill, with estimates varying from 35%12 to 57%13 and is associated with mortality rates over 50% when severe enough to require extracorporeal kidney support (EKS).12 There is a stepwise increase in mortality with increasing severity of AKI (from 6.0% for mild AKI to 65.5% for severe AKI).14,15

AKI is more common after major surgeries, affecting up to 11.8% of patients.16 Highest rates of postoperative AKI are seen in cardiac surgery, where it can affect over a third of patients.17,18 In comparison, AKI is seen in 13.1% after general, 12.1% after thoracic, 6.7%–10.8%19 after orthopedic, 9.3% after vascular surgery, and 8.6% after urologic surgeries.16 The risk of AKI is much higher in patients requiring admission to an intensive care unit (ICU) after surgeries, with rates of AKI approximately 52% after elective surgery and 56% after emergency surgery.13

The development of postoperative AKI affects not only short-term but also long-term outcomes. It is associated with an increase in ICU and hospital length of stay (LOS), postdischarge readmission rates, in-hospital mortality (8%–13%),16,17,20 1-year mortality (19%–30%),16,17,20 development of chronic kidney disease (CKD), and end-stage renal disease (ESRD; 0.94%).16,21 Importantly, even relatively mild AKI, such as in the setting of transient oliguria without an increase in serum creatinine, is associated with a significant increased risk of death, dialysis, and persistent renal dysfunction at 6 months after cardiac surgery.22


Most surgery-related AKI occurs within 48 hours of surgery. AKI occurring within the first 48 hours is typically associated with underlying health, whereas

AKI occurring after 48 hours is related to postoperative complications or drugs.23

Preoperative Risk Factors

As detailed in Table 2, there are several preoperative risk factors that are associated with development of AKI.23,24 With a 20% increase in risk for AKI with every 10 mL/min reduction in estimated GFR below 60 mL/min,16 preexisting CKD is the strongest risk factor for development of postoperative AKI.25–27

Table 2. - Perioperative Risk Factors for Postoperative AKI
Preoperative Factors Intraoperative Factors Postoperative Factors
Preoperative hospital stay >5 d Emergent surgery (versus elective) Sepsis
Preoperative sepsis Laparotomy (versus laparoscopy) Hemodynamic instability
Race (African American) Abdominal surgery Low cardiac output
Sex (male)  IAH Hypotension
Age  Longer duration of surgery Hypovolemia
High ASA physical status  IV contrast
High RCRI score  Hemodynamic instability
 Use of diuretics
 Transfusion of PRBC
 Highly invasive procedures
Comorbidities Cardiac surgery Respiratory failure
Mechanical ventilation
 CKD  Prolonged aortic cross-clamping
 Diabetes mellitus  Need to return to CPB
 Chronic pulmonary disease  CPB nonpulsatile
 Current smoking  Low-flow and low-pressure perfusion
 Congestive heart failure  Low cardiac output
 Arterial hypertension  Prolonged hypotension
 Peripheral vascular disease  Hypovolemia
 Coronary artery disease  Venous congestion
 Previous myocardial infarction  Vasopressors and inotropes
 Arterial fibrillation  Low hematocrit during CPB
 Previous stroke  Embolism
 Liver disease  Hemolysis and hemoglobinuria
 Cancer  Length of CPB >100–120 min
 Bleeding disorders  No use off-pump techniques
 Concomitant endocarditis
Medications Vascular surgery Leak of surgical anastomosis
 Diuretics  No use of cold renal perfusion
 NSAIDs  Open surgery (versus endovascular)
 Nephrotoxic antibiotics  Operative time
 Steroids (chronic therapy)  Anatomic complexity
 Contrast agents  Bleeding >1000 mL
 ACEi/ARBs  Hemoglobin <10 g/dL
 Time of HCA
Thrombocytopenia Transplant surgery Positive fluid balance within 48 h
eGFR reduction  Cirrhosis Transfusion of PRBC
Anemia  CKD Use of diuretics
Hypoalbuminemia  Immunosuppressive drugs Use of vasopressor
High C-reactive protein Use of NSAIDs
Bicarbonate <23 mEq/L Resume ACEi 15 d postsurgery
Abbreviations: ACEi, angiotensin-converting enzyme inhibitors; AKI, acute kidney injury; ARBs, angiotensin receptor blockers; ASA, American Society of Anesthesiologists; CKD, chronic kidney disease; CPB, cardiopulmonary bypass; eGFR, estimated glomerular filtration rate; HCA, hypothermic circulatory arrest; IAH, intra-abdominal hypertension; IV, intravenous; NSAIDs, nonsteroidal anti-inflammatory drugs; PRBC, packed red blood cells; RCRI, Revised Cardiac Risk Index.

Another important category of preoperative risk factor is being on a certain class of medications, such as renin-angiotensin-aldosterone system (RAAS) inhibitors (angiotensin-converting enzyme inhibitors [ACEi] and angiotensin receptor blockers [ARBs]),16,28 diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), nephrotoxic antibiotics (eg, aminoglycoside, vancomycin, piperacillin/tazobactam), and chronic therapy with steroids.16,24,26 Other preoperative risk factors are summarized in Table 2.

Intraoperative Risk Factors

Many intraoperative factors are associated with the development of AKI and are specific to each surgery. Cardiac surgery has one of the highest rates of postoperative AKI. As detailed in Table 2, AKI associated with cardiac surgery is multifactorial, but one of the biggest risk factors is generation of various injurious molecules (eg, free hemoglobin, myoglobin, inflammatory mediators, complement) due to the entire circulation being produced by the cardiopulmonary bypass circuit. In fact, off-pump techniques have shown a reduction in AKI29; however, they were not associated with a decrease in need for dialysis or mortality.30 Other causes of AKI in cardiac surgery are nonpulsatile flow, hemodynamic instability, cardiac dysfunction, and reperfusion injury. Reperfusion after surgery leads to the production of reactive oxidative species, further enhancing inflammation and AKI.31,32 Similarly, hemolysis from the bypass pump leads to the release of catalytic iron and production of reactive oxygen species leading to oxidative stress and tubular cell injury.31–33

Among those undergoing abdominal surgery, the need for an emergent surgery25,26 or laparotomy26 is associated with a higher risk of AKI. The presence of intra-abdominal hypertension (IAH), defined as intra-abdominal pressure (IAP) >12 mm Hg on 2 consecutive measures, is also associated with increased risk for perioperative AKI for both abdominal34,35 and cardiac surgeries.36

Transplant surgery is one of the more complex surgeries and is associated with a higher risk of AKI. The peak incidence of AKI has been reported as 78% for liver transplants and 87% for double-lung transplants.37 AKI in these patients is usually multifactorial, with risk factors including long surgical ischemia time, underlying comorbidities (eg, cirrhosis, CKD), and the use of immunosuppressive drugs, some of which can themselves be nephrotoxic (eg, calcineurin inhibitors). Moreover, these patients can have muscle wasting, generalized edema, and high bilirubin concentration—all of which can falsely alter serum creatinine concentration and thus reduce our ability to detect AKI.37 Other intraoperative risk factors for AKI after abdominal, cardiac, vascular, and transplant surgery are reported in Table 2.

Postoperative Risk Factors

Postoperative period is a critical time for development of AKI. Hypotension and sepsis in the postoperative period are the major risk factors for AKI.23,31,38,39 Use of nephrotoxic medications in the postoperative period, such as NSAIDs or certain antibiotics (vancomycin, piperacillin/tazobactam, etc), could also contribute to the overall risk of AKI in this time period. We have detailed other postoperative risk factors in Table 2.


Figure 2.:
The principal mechanisms underlying the development of perioperative AKI. Each box represents a different mechanism and the possible causes leading to the above general mechanism. Hypoperfusion can be caused by reduced preload (eg, hypovolemia, bleeding, positive pressure ventilation), systemic vasodilatation (eg, anesthetic drugs, sepsis), increased peripheral resistances, low cardiac output, intra-abdominal hypertension, loss of RAAS compensation (eg, use of ACEi/ARBs, CKD). Venous congestion can be caused by right heart failure (eg, cardioplegia) and intra-abdominal hypertension. Inflammation can be caused by surgery, ischemia, trauma, and sepsis, and it leads to the production of DAMPs, PAMPs, and cytokines, which are ultimately responsible for endothelial damage, microcirculation alteration, microthrombi formation, and oxidative stress. Urinary tract obstruction can be caused by different intrarenal (eg, casts formed following hemolysis, hemoglobinuria, myoglobinuria, dehydration, hypovolemia, tubular cells injury) and extrarenal conditions (eg, abdominal and pelvic cancer, prostate hypertrophy, retroperitoneal fibrosis, surgery complications, nephrolithiasis, Foley catheter misplacement or malfunction). Nephrotoxic drugs and agents have different ways to lead to perioperative AKI and the most involved in the perioperative setting are NSAIDs, ACEi/ARBs, antibiotics (eg, aminoglycosides, vancomycin, piperacillin/tazobactam, ciprofloxacin), antiviral (eg, acyclovir), and contrast agents. ACEi indicates angiotensin-converting enzyme inhibitors; AKI, acute kidney injury; ARBs, angiotensin receptor blockers; CKD, chronic kidney disease; DAMPS, damage-associated molecular patterns; NSAIDs, nonsteroidal anti-inflammatory drugs; PAMPs, pathogen-associated molecular patterns; RAAS, renin-angiotensin-aldosterone system.

The development of perioperative AKI is frequently multifactorial, with multiple pathophysiological mechanisms at play simultaneously. The most common mechanisms include development of renal hypoperfusion, venous congestion, IAH, inflammation, urinary tract obstruction, and/or the use of nephrotoxic agents (Figure 2).

Renal Hypoperfusion

Renal hypoperfusion in perioperative settings can be caused by many factors, including hypovolemia, systemic vasodilatation (due to anesthesia or inflammation), positive pressure ventilation, and/or low cardiac output. These factors are relatively common during the perioperative period but are also closely monitored and easily addressed in most patients. While renal hypoperfusion is still an important mechanism of perioperative AKI, it is relatively rare in modern surgical ICUs. The kidneys have important compensatory mechanisms (autoregulation, RAAS, and sympathetic nervous system)40 to keep renal blood flow and GFR relatively constant during these conditions. However, when these mechanisms are either impaired or if hypoperfusion is sustained, the kidneys face an initial reduction in GFR without parenchymal damage, which can later progress to parenchymal damage.40 Patients on RAAS inhibitors are especially susceptible to these compensatory mechanisms being overwhelmed.

Renal Venous Congestion and IAH

Conditions that affect cardiac output and, in particular, the right heart function may lead to an elevation in central venous pressure and renal venous congestion. Renal venous congestion may compress the tubules and alter the gradient pressure in the glomerulus, ultimately affecting GFR.33 This situation may be the result of cardioplegia provoked during cardiac surgery, high pleural pressure during thoracic surgery, or IAH occurred during major abdominal surgery.41

High IAP can be seen after abdominal surgeries due to reduced abdominal compliance, fluid overload, or capillary leak.42 When IAP remains elevated (>12 mm Hg) for a prolonged time, it can progress to IAH, which is characterized by decreased renal arterial inflow and venous outflow leading to AKI.40,42


Systemic inflammation can be triggered by many factors, both intraoperative and postoperative. Sepsis, ischemic injury, trauma, and surgery itself can all lead to inflammation. These triggers cause a release of proinflammatory cytokines and damage-associated molecular patterns that exert pleiotropic effects leading to alteration of RAAS, microcirculation, and endothelial cell integrity. They also cause oxidative stress, initiation of apoptosis cascade, and alteration of coagulation pathways with the formation of microvascular thrombi. All these effects lead to organ stress and, ultimately, to organ injury.27,33,41 All of these factors may be present in sepsis43,44 and in major surgery. In cardiac surgery, nonpulsatile flow, hemodynamic instability, reperfusion injury, and hemolysis may also cause inflammation, as well as reperfusion after surgery and hemolysis from the bypass as specific causes of oxidative stress further increasing the risk of AKI.31–33 In major abdominal surgery, the stimuli to inflammation can also result from ischemia-reperfusion injury and from the release of bacterial products (eg, endotoxin) with altered visceral perfusion.38

Urinary Tract Obstruction

Urinary tract obstruction as a direct/indirect consequence of colorectal, urological, and gynecological surgery41 can lead to an increase in tubular pressure leading to tubular cells damage, impaired renal blood flow, inflammation, and AKI.40 A misplaced or malfunctioning Foley catheter can also cause urinary obstruction in the perioperative period.41

Nephrotoxic Drugs and Agents

Many drugs taken during the perioperative setting can cause drug-induced AKI. NSAIDs used for perioperative pain management can affect renal blood flow autoregulation through the inhibition of cyclooxygenase and reduction of prostaglandin, with the ultimate result of reduced afferent renal arteriolar vasodilatation leading to reduced glomerular perfusion and GFR.27 ACEi/ARBs are commonly used in patients undergoing cardiac surgery or patients with hypertension or heart failure. These drugs also affect the compensatory mechanisms of renal vasculature leading to greater effect of hypoperfusion on renal injury.45

Similarly, use of iodinated contrast media during the perioperative period can lead to contrast-associated AKI (CA-AKI). CA-AKI is likely multifactorial and includes tubular damage (higher viscosity of tubular fluid and alteration of tubular cells polarity) and alterations in renal circulation (arteriolar vasoconstriction and microvascular thrombosis due to increased blood viscosity and osmolality) by the contrast media used. The former finally leads to tubular obstruction and injury while the latter lead to renal ischemia in oxygen-sensible area like the outer medulla.33,46

Many antibiotics used in the perioperative period, either for postsurgical prophylaxis or management of sepsis, are independently associated with development of AKI. Tubular injury by the drugs seems to be a mechanism common to many of these medications.47 For example, aminoglycosides cause AKI by damaging proximal tubular cells after apical transportation of the drug. Development of obstructive tubular casts as a cause for AKI has also been recently hypothesized as one of the etiologies for AKI from vancomycin.48


In this section, we aim to provide a description of the different treatments, strategies, and procedures that may provide a perioperative renoprotective effect.

Fluid Management

Intravenous fluids are an important part of the management of perioperative hypovolemia, but literature has evolved with time over best type and amount of fluids. The general consensus has evolved over the years in favor of using crystalloids over colloids. Multiple studies have established superiority of crystalloids over hydroxyethyl starch (HES) in terms of mortality, bleeding risk, and need for dialysis especially in patients with sepsis.49–51 Outcomes are comparable when using albumin compared to crystalloids.52,53 With the significantly higher costs of colloids, crystalloids have been considered the fluid of choice for resuscitation. However, colloids continue to play a role in perioperative care at both ends of the fluid management spectrum—as part of low-volume fluid management in some surgeries and for high-volume resuscitation as a “second” line agent.

In recent years, there has been increasing recognition of the association of hyperchloremia with development of AKI and increased mortality in critically ill patients54–56 and after noncardiac surgery.57 This has led to strong interest in preferential utilization of intravenous fluids with more physiologic chloride content, also known as balanced crystalloids for resuscitation. Zhou et al58 compared balanced crystalloids and saline in a rat model for sepsis and found that those that received balanced crystalloids had lower levels of proinflammatory interleukin-6, higher incidence of AKI (76% vs 100%; P < .05) and higher 24-hour survival (76.6% vs 53.3%; P = .01) in comparison to rats that received normal saline for fluid resuscitation. A retrospective study looking into 31,920 adults undergoing elective or emergency open general surgery found that those receiving Plasma-Lyte (a form of balanced crystalloid) had lower rates of AKI needing dialysis (1.0% vs 8.3%; P < .001) and mortality (2.9% vs 5.6%; P < .001).59 A prospective, open-label, sequential period study of 1533 critically ill patients by Yunos et al60 found that the use of balanced crystalloids was associated with a significant decrease in the risk of AKI and need for dialysis. The 0.9% Saline vs Plasma-Lyte 148 for Intensive Care Fluid Therapy (SPLIT) trial61 was one of the first randomized controlled trials (RCT) investigating the role of balanced crystalloids for resuscitation in critically ill patients and did not find any difference in AKI, need for dialysis, or mortality but was limited by low severity and insufficient sample size. Furthermore, about two thirds of patients in each group already received about a liter of balanced crystalloid 24 hours before enrollment and received only about 1.2 L of fluid in the balanced crystalloid group and 1.4 L in normal saline group on the day of enrollment. In comparison, the Saline against Lactated Ringer’s or Plasma-Lyte in the Emergency Department (SALT-ED) trial,62 which was a single-center, multiple crossover trial of noncritically ill patients in emergency room, found that balanced crystalloids led to a decrease in major adverse kidney events at 30 days (MAKE30) outcome of patients receiving balanced crystalloids (4.7% vs 5.6%; P = .01). MAKE30 was defined as a composite of death, new dialysis for AKI, or persistent renal dysfunction at 30 days. The Isotonic Solutions and Major Adverse Renal Events Trial (SMART) trial63 investigated similar questions among patients admitted to ICUs and it also found MAKE30 outcomes to be in favor of balanced crystalloids (14.3% vs 15.4%; P = .04). Pfortmueller et al64 also investigated the role of balanced crystalloids in the form of a RCT among patients undergoing major abdominal surgery and found less metabolic acidosis and decreased need for vasopressor support in patients who received perioperative fluid therapy with balanced crystalloids. In light of these studies, we support the growing consensus about using balanced crystalloids in a perioperative setting.24,27,33,41,65

The second question that has generated considerable debate over the years has been determining the amount of fluid to be used for resuscitation, especially in the perioperative setting. In the past, liberal fluid regimen was quite commonly used in the intraoperative setting, frequently leading to positive fluid balance, which is associated with higher mortality, need for EKS, and may also lead to fluid overload with longer hospital stay.66,67 Enhanced Recovery After Surgery protocols have therefore suggested a more restrictive perioperative fluid regimen to reduce complications.68 It is however important to consider the complexities involved in this decision-making, as is evident from the study of Myles et al69 that showed higher rate of AKI (8.6% vs 5.0%; P < .001) among patients undergoing major abdominal surgery who received restrictive fluid strategy. The ideal approach is to avoid both too restrictive and too liberal fluid regimens and rather personalize fluids for a particular patient using various techniques such as point of care ultrasound (eg, evaluation of stroke volume and inferior vena cava diameter) and/or more invasive monitoring parameters (eg, pulse pressure variation, stroke volume variation, and cardiac index).

Hemodynamic Management and Goal-Directed Therapy

Perioperative hypotension can lead to renal hypoperfusion and consequently postoperative AKI. Increasing duration and degree of hypotension is associated with increasing risk for AKI. Sun et al70 found an odds ratio (OR) for AKI of 2.34 for mean arterial pressure (MAP) <55 mm Hg for 11–20 minutes and 3.53 when hypotension persisted for more than 20 minutes. Similar findings have been confirmed by other studies.71,72

To avoid perioperative hypotension, low cardiac output state, as well as detrimental fluid overload, many researchers have investigated the use of “goal-directed therapy” (GDT) to implement perioperative hemodynamic monitoring and optimization. A recent meta-analysis by Chong et al73 of 11,659 adult surgical patients found that GDT that targeted cardiac output and other hemodynamic parameters reduced both development of AKI (OR = 0.69, 95% CI, 0.58–0.92) and mortality (OR = 0.66, 95% CI, 0.50–0.87). Similar findings were reported by a meta-analysis74 that showed a renoprotective effect of GDT (OR for AKI is 0.64, 95% CI, 0.62–0.87), which was more prominent in trials that enrolled high-risk patients.

Vasopressors and Blood Pressure Management

Although individualized, a MAP goal of ≥65 mm Hg is usually considered optimal for management of postoperative patients.1,75 Vasopressors are frequently used to maintain systemic pressure and consequently renal perfusion, especially in postoperative settings. Norepinephrine is usually the primary vasopressor of choice, especially in patients with vasodilatory shock (eg, sepsis).76 Recent findings in liver transplant population suggest that norepinephrine may need to be titrated to reach a MAP of 75 mm Hg to guarantee optimal renal perfusion and function.77 These patients, however, also have a high risk of underlying renal disease, and a personalized approach is needed. Low-dose dopamine, once thought to augment renal blood flow, has been clearly disproven for treatment or prevention of AKI.1,37,75,78,79 A similar story exists for fenoldopam, a selective D1 receptor agonist. Although some studies have suggested possible benefit (as well as side effects such as hypotension),80–82 currently this agent is not recommended for treatment or prevention of perioperative AKI.32

Vasopressin, a second-line vasopressor, has been extensively investigated. Experimental evidence regarding a renoprotective effect of vasopressin in shock has not been confirmed in RCTs.83–85 One of the most recent additions to the armamentarium of vasopressors is exogenous angiotensin II. It has been approved by the Food and Drug Administration (FDA) for vasodilatory shock and it has been associated with improved survival at 28 days in patients with vasodilatory shock who develop AKI requiring EKS.86


Inotropes are used to increase myocardial contractility and can be used alone or in combination with vasopressors. Dobutamine is a common inotrope used widely in clinical practice.87–89 It is also used for management of right heart failure, the latter being associated with a high risk of AKI. It is interesting to note that trial on Prevention of cardiac surgery-associated AKI by implementing the KDIGO guidelines in high risk patients identified by biomarkers (PrevAKI), which implemented KDIGO bundles in high-risk patients undergoing cardiac surgery, had a higher utilization of dobutamine in the intervention arm, which may be reflective of undiagnosed right heart failure and low cardiac output states in these high-risk patients.90 Epinephrine is another potent inotrope and vasopressor that is used frequently in patients with refractory shock.


Diuretics, in particular furosemide, are used during perioperative settings to prevent fluid overload and to promote diuresis. Although diuretic use can increase the risk of AKI,37,91,92 loop diuretics are essential tools in the management fluid overload (both in patients with and without AKI) and with careful use, benefits can outweigh risks.1,93 However, diuretics are not effective in preventing AKI, preventing the need for EKS, or for weaning anuric patients from EKS.93–95

Mannitol use is no longer supported to prevent AKI.79 This was confirmed in a neurosurgical population where the intraoperative use of mannitol resulted in an increased risk of postoperative AKI.96 Recent studies have also shown a lack of renoprotective effect of mannitol during partial nephrectomy.97,98 Natriuretic peptides have been widely studied in the past few decades for their ability to cause afferent renal vasodilatation, natriuresis, and increase in GFR.79 They have been shown to have some potential renoprotective effects in cardiac surgery,99 although these results have not been confirmed in other high-risk populations, such as those with heart failure.79,100

Sodium Bicarbonate

Sodium bicarbonate has been used for its potential renoprotective effect in various clinical settings. A multicenter RCT investigating the role of urinary alkalinization to prevent AKI following cardiac surgery, however, was stopped early due to inefficacy and increased mortality in the intervention group.101 Two separate meta-analyses also reported showing no reduction in perioperative AKI with the use of sodium bicarbonate.102,103 The role of sodium bicarbonate has also been explored in the context of CA-AKI; however, the recent Prevention of Serious Adverse Events Following Angiography (PRESERVE) trial that enrolled over 5000 patients at high risk for renal dysfunction who were undergoing angiography did not show any renoprotective effect of sodium bicarbonate.104 Thus, the current role of bicarbonate therapy is restricted to patients who have already developed moderate-to-severe AKI and have simultaneous severe metabolic acidosis. However, evidence for benefit is quite limited—a subgroup analysis from a small study in this setting.105

Sedation and Analgesia

Fluorinated anesthetics, like sevoflurane, are frequently used during surgery and seem to have a safe renal profile, even in patients with CKD.106 Propofol, an intravenous sedative, has some possible renoprotective effects, as it can reduce oxidative stress, inflammation, and also ischemic-reperfusion injury.107 Moreover, when compared to sevoflurane among patients undergoing cardiac surgery, propofol is associated with lower incidence and severity of AKI.33,108 However, propofol also abolishes the potential protective effects of remote ischemic preconditioning (RIPC; see below).

Dexmedetomidine, a selective α2-adrenergic receptor agonist, when used as an intravenous sedative, has shown promising renoprotective effect, probably through a similar ability to reduce oxidative stress and inflammation, as well as increasing renal blood flow.27 RCTs in cardiac surgery confirmed the perioperative renoprotective effect of dexmedetomidine infusion both in adult109,110 and pediatric patients.111 However, these studies have been quite small, and meta-analyses have shown high variability of results and classification of AKI.82,99,112 Further research is required to further evaluate a potential renoprotective role for dexmedetomidine.

Glycemia and Anemia Management

Glycemic control is crucial in both critical care and perioperative settings. Both hypoglycemia and hyperglycemia are associated with increased mortality and AKI.113 The glucose targets have, however, evolved over time. The first was a very strict target of glucose range of 80–110 mg/dL.114 A recent meta-analysis showed that, in comparison to perioperative liberal control (an upper target of <180 mg/dL), tight glucose control (TGC with an upper target <150 mg/dL) was associated with lower risk of AKI, sepsis, and other surgical complications. The TGC, however, was associated with a higher risk of hypoglycemia (even severe).115 Consequently, KIDGO guidelines recommend a glucose target of 110–149 mg/dL in patients with or at risk of AKI; however, European Renal Best Practice recommends a more liberal target of 110–180 mg/dL.1,116

Anemia and transfusion of packed red blood cells (PRBC) are important risk factors for perioperative AKI. Hemoglobin level <8 g/dL is generally considered a preoperative risk factor,33 but depending on the surgery, an even higher value can still be concerning (eg, <10 g/dL).117 For that reason, it is usually better to try to optimize hemoglobin before undergoing surgery and reducing blood loss during surgery itself to reduce to minimum the number of PRBC transfused.37 The literature of the renoprotective effects of erythropoietin is also evolving.82,118–121

Statins and Antioxidant Supplementations

Statins have very pleiotropic effects in reducing inflammation and oxidative and endothelial stress.27 The role as renoprotective agents in perioperative settings, however, has not been confirmed.82,122–125 Similarly, there is currently no evidence to support the use of antioxidant supplementations (eg, vitamin C, N-acetylcysteine, polyunsaturated fatty acid, allopurinol, zinc, selenium, vitamin E and B1) to prevent AKI.27,126–128

Avoiding Nephrotoxic Drugs

As discussed above, many drugs are associated with an increased risk of perioperative AKI. For these reasons, reducing exposure to these drugs in the perioperative time, when possible, is recommended. NSAIDs, though great analgesics, are greatly associated with a higher risk of AKI and thus should be minimized in patients at a high risk of postoperative AKI. Aminoglycosides also are associated with significant AKI risk and thus should be minimized or used with careful monitoring in these patients. Vancomycin is commonly used in perioperative settings but needs close drug monitoring to avoid AKI. Piperacillin/tazobactam, a commonly used antibiotic in critically ill patients, especially among those septic in the postoperative period is also associated with higher risk of AKI.129 Therefore, careful monitoring and alternative medications (eg, cefepime) should be considered when possible.

Goldstein et al130 through series of studies have consistently shown successful reduction in the incidence of nephrotoxic AKI. Most recently, in the multicenter Nephrotoxic Injury Negated by Just-in time Action (NINJA) study, they were able to reduce the incidence of nephrotoxic AKI by 23.8% by integrating screening for nephrotoxic exposure with careful monitoring of renal function and substituting for alternative medications when possible.130 Thus, careful monitoring of renal function when using these medications, along with therapeutic drug monitoring and substitution to nonnephrotoxic medications when feasible, can effectively decrease the incidence of nephrotoxic AKI.


The KDIGO workgroup has proposed a set of clinical actions, “KDIGO AKI bundle,” to both prevent and improve the management of patients with AKI (Table 3).1 As urinary [TIMP-2]•[IGFBP7] can be used to identify patients at a high risk for developing moderate-to-severe AKI, its role as a trigger to implement a “KDIGO AKI bundle” has been explored in different clinical settings. The Biomarker Guided Intervention for Prevention of Acute Kidney Injury (BigpAK) study131 found such utilization of “KDIGO AKI bundle” among patients after a major abdominal surgery was associated with lower rates of moderate-to-severe AKI, ICU, and hospital LOS, suggesting the role of this approach in perioperative period.

The PrevAKI study90 found similar results among high-risk patients undergoing cardiac surgery. Using a urinary [TIMP-2]•[IGFBP7] cutoff of >0.3 to identify those at a high risk to develop postcardiac surgery AKI, they randomized patients to standard care or to a “KDIGO AKI bundle” group (see Table 3 for bundle details). Using the bundle intervention resulted in significantly reduced incidence of AKI in the intervention group (55.1% vs 71.7%; P = .004). It also led to improvements in hemodynamic parameters, hyperglycemia, and use of ACEi/ARBs.

Table 3. - Biomarkers-Guided Strategy and Interventions
PrevAKI trial (Meersch et al90)
• Avoid nephrotoxic agents.
• Discontinue ACEi/ARBs for the first 48 h after surgery.
• Close monitoring of sCr and urinary output.
• Avoid hyperglycemia for the first 72 h.
• Evaluate alternatives to contrast agents.
• Close hemodynamic monitoring using PICCO catheter to optimize the volume status and hemodynamic parameters using a predefined algorithm.
BigpAK study (Göcze et al131)
• Increased continuous intravenous fluid administration for 6 h guided by central venous pressure and fluid responsiveness test.
• Nephrology consultation to adjust medications and management of acid-base, electrolyte, and albumin status.
AKRT study (Engelman et al132)
[TIMP-2]•[IGFBP7] <0.3 (“fast track recovery”)
• Remove Foley catheter, arterial line, central line.
• May use ACEi/ARBs.
• Consider holding diuretic if Toradol used.
• Transfusion threshold Hb <7.0 g/dL.
• Check sCr daily.
[TIMP-2]•[IGFBP7] ≥0.3 and ≤2.0
• Keep Foley and monitor UO hourly.
• Transfer to telemetry.
• Avoid nephrotoxic agents (ACEi/ARBs, NSAIDs, vancomycin, gentamycin).
• Transfusion threshold Hb <7.0 g/dL, unless oliguric.
• If oliguria (UO <0.5 mL/kg/h per 3 h), activate AKRT/nephrology consult.
• Use lactated Ringer’s solution for bolus.
• Hold diuretics unless presence of pulmonary edema.
• Repeat [TIMP-2]•[IGFBP7] in 24 h.
[TIMP-2]•[IGFBP7] >2.0
• Activate AKRT.
• Keep Foley and monitor UO hourly.
• Maintain hemodynamic monitoring.
• Avoid nephrotoxic agents (ACEi/ARBs, NSAIDs, vancomycin, gentamycin).
• Adjust medication for renal function.
• Goal-directed therapy.
• Reassess transfusion threshold.
• Nephrology consult.
• Hold diuretics unless presence of pulmonary edema.
• Repeat [TIMP-2]•[IGFBP7] in 24 h.
Abbreviations: ACEi, angiotensin-converting enzyme inhibitors; AKRT, acute kidney response team; ARBs, angiotensin receptor blockers; BigpAK, Biomarker Guided Intervention for Prevention of Acute Kidney Injury; Hb, hemoglobin; IGFBP7, insulin-like growth factor–binding protein 7; NSAIDs, nonsteroidal anti-inflammatory drugs; PICCO, Pulse index Contour Cardiac Output; PrevAKI, Prevention of cardiac surgery-associated AKI by implementing the KDIGO guidelines in high risk patients identified by biomarkers; sCr, serum creatinine; TIMP-2, tissue inhibitor of metalloproteinases-2; UO, urinary output.

Engelman et al132 also investigated the role of biomarker-guided application of “KDIGO AKI bundle” in patients undergoing cardiac surgery. Their approach differed in that they performed [TIMP-2]•[IGFBP7] measurement the first morning after cardiac surgery and activated a multidisciplinary acute kidney response team (AKRT) if the value was ≥0.3. The AKRT then implemented treatment algorithm based on KDIGO guidelines (Table 3). Using this approach, they were able to reduce moderate-to-severe AKI within 7 days by 89% (P = .01) in the intervention period. Thus, there is an evolving role of biomarkers-guided therapy in prevention and management of perioperative AKI.


RIPC is a phenomenon that consists of inducing brief episodes of transient ischemia of 1 tissue (eg, skeletal muscle) to protect against ischemia-reperfusion injury in a remotely situated organ (eg, kidneys). Since the stimulus is not prolonged or lethal to cells, it leads to an adaptive response that provides protection against future more-injurious stimuli.133

RenalRIPC, a multicenter, RCT of patients at high risk for AKI after cardiac surgery showed the renoprotective role of RIPC when performed after induction of anesthesia but before skin incision (rates of postoperative AKI were 52.5% in controls versus 37.5% in RIPC group; P = .02). Similar findings have been reported by other RCTs.134,135 A meta-analysis in cardiac surgery patients reported reduction in AKI136; however, the literature has not been consistent. A meta-analysis of RCTs by Pierce et al137 showed that reduction in AKI was restricted to patients in whom propofol was not used as an anesthetic. RIPC has shown mixed results in patients undergoing cardiac angiography.138–140 Similarly, its role in preventing AKI among patients undergoing elective major vascular surgical procedures has not been established.141 Finally, a Cochrane Library systematic review of 28 RCTs including all surgery types showed that, when taken together, there was no benefit of RIPC on development of postoperative AKI.142 Thus, the renoprotective effect of RIPC still needs further investigation.


AKI leads to development of hyperkalemia, metabolic acidosis, and hypervolemia, all of which are associated with worse outcomes. Emergent treatment of these abnormalities is important and includes medical therapies like potassium-lowering medications, sodium bicarbonate infusions, and diuresis, but initiation of EKS in the form of dialysis/hemofiltration (continuous or intermittent) is sometimes a necessary life-saving measure. Approximately 0.2% patients after major surgery need EKS.16 Rates of EKS may be as high as 24% among patients with KDIGO AKI stage 3. Need for EKS is associated with a higher risk for mortality (54% at 1 year) and development of ESRD (12% at 1 year). Appropriate timing of EKS has been a matter of debate in recent years, with studies showing both improved mortality and lack of benefit with early initiation.143–145 Importantly, studies in surgical patients provide stronger support for early initiation. We recommend individualization of care for each patient in collaboration with experts in nephrology.


AKI is common in the perioperative time period and is associated with higher morbidity, mortality, and increased health care costs. It has diverse mechanisms but is usually multifactorial. As there are no directed therapies for AKI, a better understanding and management of the mechanisms that underlie are important to both prevent the development of AKI and appropriately manage patients who develop it, despite our best efforts. There are available renoprotective strategies such as appropriate volume resuscitation, close hemodynamic monitoring, and avoidance of nephrotoxic agents in perioperative period, all of which can improve outcomes. There will likely be a greater role of biomarkers in improving the detection and outcomes of perioperative AKI in future.


The authors thank Ms Karen Nieri for her editorial assistance in preparing this article.


Name: Luca Molinari, MD.

Contribution: This author helped conduct the literature review, prepare the manuscript, and prepare tables and figures.

Conflicts of Interest: None.

Name: Ankit Sakhuja, MD.

Contribution: This author helped conduct the literature review, prepare the manuscript, and prepare tables and figures.

Conflicts of Interest: None.

Name: John A. Kellum, MD.

Contribution: This author helped conduct the literature review, prepare the manuscript, and prepare tables and figures.

Conflicts of Interest: J. A. Kellum discloses consulting fees and/or grant support from Astute Medical/BioMerieux, Baxter, and NxStage.

This manuscript was handled by: Alexander Zarbock, MD.


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