Perioperative Acute Kidney Injury

Sam D. Gumbert, M.D.; Felix Kork, M.D., M.Sc.; Maisie L. Jackson, M.D.; Naveen Vanga, M.D.; Semhar J. Ghebremichael, M.D.; Christy Y. Wang, M.D.; Holger K. Eltzschig, M.D., Ph.D.

Disclosures

Anesthesiology. 2019;132(1):180-204. 

In This Article

Therapeutic Approaches for Perioperative Acute Kidney Injury

Developing successful therapies to treat acute kidney injury has been an elusive endeavor. Despite significant advancements in diagnosis, surgical techniques, anesthetic methods, and critical care management, the frequency of perioperative acute kidney injury has remained essentially unchanged.[105] Although numerous agents have shown promise, a single strategy toward improving treatment options for acute kidney injury has failed to demonstrate utility in clinical care.[106–109] This continues to be an area of intense research with numerous ongoing translational and clinical trials (Supplementary Digital Content 3, http://links.lww.com/ALN/C57). Moreover, many exciting recent studies have found important concepts that are critical for patient management in acute kidney injury prevention.

Pharmacologic Interventions

Pharmacologic interventions to effectively treat and prevent acute kidney injury have been evaluated extensively across perioperative environments including major nonvascular, cardiovascular, contrast-induced acute kidney injury, and intensive care units. In addition, there is a substantial number of ongoing clinical trials to define and evaluate pharmacologic interventions in the perioperative setting (Supplementary Digital Content 4, http://links.lww.com/ALN/C58). Historically, evidence for pharmacological intervention decreasing rates of acute kidney injury has largely been unsupported by quality data. More recent pharmacologic research has investigated the potential benefit of antiinflammatory, antiapoptotic, and antioxidative interventions to prevent and treat acute kidney injury.

N-Acetylcysteine is a precursor of intracellular glutathione that reduces the oxidative burst response of neutrophils by improving oxygen free radical scavenging.[110] In prospective randomized controlled trials, intravenous N-acetylcysteine failed to prevent postoperative renal dysfunction or reduce mortality rates in high-risk CPB surgery patients.[111] Similarly, a double-blinded randomized controlled trial by Song et al.[112] failed to establish a protective benefit of N-acetylcysteine in off-pump CPB surgery, with similar rates of acute kidney injury observed between treatment and control groups (35% N-acetylcysteine vs. 32% control; P = 0.695). The antioxidative benefit of allopurinol and supplements such as selenium, zinc, and vitamins C, E, and B1 have also failed to show benefit in clinical trials.[113,114] Current evidence does not support the role of N-acetylcysteine or supplements such as selenium, zinc, and vitamins C, E, and B1 to prevent acute kidney injury.[111,113–115]

The lipid-lowering 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or statins are a drug class with increasing research interest because of their potential antiinflammatory, antioxidative, and endothelial protective properties.[29,116,117] A 2018 study involving eight randomized controlled trials investigated the effect of cardiac surgery-associated acute kidney injury and perioperative statin therapy but did not find a correlation between statin administration and acute kidney injury reduction (relative risk 1.17; 95% CI, 0.98 to 1.39; P = 0.076). Statin administration both pre- and postsurgery actually increased acute kidney injury risk when compared with preoperative statin therapy alone (P = 0.040).[118] A meta-analysis by Zhao et al.[117] suggests that sufficient evidence has accrued to reject the hypothesis that perioperative statin therapy decreases the prevalence of acute kidney injury and secondary postoperative consequences such as renal replacement therapy, mechanical ventilation, length of stay in the intensive care unit (ICU) or hospital, and in-hospital death. In summary, the present evidence does not substantiate using statin therapy in the treatment or prevention of acute kidney injury.

Dexmedetomidine, a selective α2-adrenergic receptor agonist, was another candidate agent for perioperative kidney protection through increasing renal blood flow and also decreasing oxidative insult to the kidney. In animal models, dexmedetomidine has demonstrated antiinflammatory, antiapoptotic, and antioxidative properties across organ systems.[119–122] Several studies have also demonstrated inhibition of inflammatory mediators including interleukin-1, interleukin-6, and TNF-α.[123,124] The clinical application of dexmedetomidine's renoprotective properties has successfully reduced the incidence of cardiac surgery-associated acute kidney injury in valvular heart surgery populations.[125–128] The presumed beneficial effect includes a reduction in norepinephrine release, enhanced hemodynamic stability, and myocardial oxygen supply/demand balance.[29] In a recent meta-analysis involving 19,266 patients, dexmedetomidine was found to lower rates of cardiac surgery-associated acute kidney injury in both randomized controlled trials (relative risk, 0.44; 95% CI, 0.26 to 0.76; P = 0.003) and cohort studies (relative risk, 0.74; 95% CI, 0.63 to 0.86; P = 0.0001).[129] However, dexmedetomidine failed to decrease postoperative mortality, duration of mechanical ventilator, and length of stay in the ICU or hospital.[129] Based on these studies, dexmedetomidine may have the capacity to attenuate acute kidney injury in surgical patients. However, additional high-quality, multicenter trials will have to confirm these findings to establish the basis for its routine clinical use to prevent perioperative acute kidney injury.[29] Beyond pharmacologic intervention, opportunities for nonpharmacologic therapy such as remote ischemic preconditioning and renal replacement therapy have been researched extensively to treat and prevent acute kidney injury.

Remote Ischemic Preconditioning

Ischemic preconditioning is an experimental strategy in which short, nonlethal episodes of ischemia are applied to provide protection from a subsequent, more lethal ischemic insult.[42,130,131] As a more recently discovered form of ischemic preconditioning, remote ischemic preconditioning is achieved through application of brief periods of ischemia and reperfusion of remote tissues or organs, resulting in the protective adaptive response of distant organ systems. Usually, a blood pressure cuff is placed around the upper arm is inflated to 200 to 300 mm Hg pressure for a 5-min duration, and then the pressure is released, followed by several repeat cycles. Remote ischemic preconditioning is thought to activate several pathways including systemic antiinflammatory, neuronal, and humoral signaling pathways.[132] In this regard, remote ischemic preconditioning offers a novel, noninvasive, and inexpensive strategy to decrease the occurrence of acute kidney injury.[132–134]

Clinically, some controversy exists regarding the effectiveness of remote ischemic preconditioning on acute kidney injury. The outcomes of remote ischemic preconditioning on the kidney has been investigated extensively within the framework of adult vascular and cardiac surgery. In a large multicenter, randomized double-blind clinical trial, Zarbock et al.[134] recently found that remote ischemic preconditioning before cardiac surgery in high-risk patients was effective for decreasing the rate of acute kidney injury (37.5% vs. 52.5%) compared to sham (absolute risk reduction, 15%; 95% CI, 2.56 to 27.44; P = 0.02). In addition, a subsequent long-term follow up by the same authors revealed remote ischemic preconditioning lowered the 3-month prevalence of a composite endpoint of major adverse kidney events consisting of death, necessity of renal replacement therapy, and chronic renal dysfunction.[135] These findings are supported by similar randomized controlled trials in the cardiac and vascular literature conducted by Ali et al.[136] and Thielmann et al.[137] Despite these exciting findings, the discussion of remote ischemic preconditioning and kidney protection remains inconclusive with other postcardiac surgery outcomes trials unable to establish a protective effect.[138–140] The differences in these outcomes could be related to study design (e.g., the selection of primary endpoints), different patient populations (high risk vs. lower risk of acute kidney injury), or the specific protocol used for remote ischemic preconditioning. Additionally, anesthetic type may alter the effect of remote ischemic preconditioning, with reports of propofol blunting the observed beneficial effects relative to volatile anesthetics.[141,142] Because of the very noninvasive nature, unknown side effects, and promising initial findings, the threshold to introduce remote ischemic preconditioning into routine clinical practice is relatively low. Nevertheless, further multicenter trials are needed to fully establish the clinical benefits, dose, and ideal patient population for remote ischemic preconditioning therapy to prevent acute kidney injury in surgical patients.

Renal Replacement Therapy

Renal replacement therapy is the only therapy for acute kidney injury to date. The Kidney Disease Improving Global Outcomes criteria advocate initiating renal replacement therapy when fluid accumulation becomes life-threatening or major imbalances (e.g., acidosis, electrolyte abnormalities, and uremia) occur.[29,143] The ideal mode of renal replacement therapy, the correct timing of when to begin therapy, and the duration are still under debate.[29] A recent meta-analysis evaluating renal replacement therapy modalities on clinical outcomes failed to find statistical differences for the pooled mortality results (ICU, in-hospital, or 30-day) and dialysis dependence between continuous renal replacement therapy and sustained low efficiency dialysis.[144] Clinical studies to address the exact timing of when to initiate renal replacement therapy show conflicting data as well. Two large prospective randomized controlled trials, the Artificial Kidney Initiation in Kidney Injury (AKIKI) trial and the Early versus Late Initiation of Renal Replacement Therapy in Critically Ill Patients with Acute Kidney Injury (ELAIN) trial, evaluated the influence of renal replacement therapy timing in ICU patients with acute kidney injury.[145–147] The Early versus Late Initiation of Renal Replacement Therapy in Critically Ill Patients with Acute Kidney Injury trial reported that early initiation of renal replacement therapy in patients suffering from acute kidney injury resulted in a significant reduction in 90-day mortality. This is in contrast to the Artificial Kidney Initiation in Kidney Injury trial, which failed to show a reduction in mortality as a function of renal replacement therapy timing.[145–147] Most recently, the Initiation of Dialysis Early versus Delayed in the Intensive Care Unit (IDEAL-ICU) trial examined a relatively homogenous population of patients with early-stage septic shock who had severe acute kidney injury.[148] In this multicenter randomized trial, patients with early sepsis were randomized to early (within 12 h) or delayed initiation (delay of 48 h) of renal replacement therapy. The trial was stopped early after an interim analysis. In this group of patients, early initiation of renal replacement therapy failed to demonstrate a lowering of mortality at 90 days, compared with the delayed initiation of renal replacement. Importantly, there was overall less use of renal replacement therapy in the delayed-strategy group, because 75% of patients in the delayed group recovered their kidney function spontaneously. However, it is important to keep in mind that starting treatments late in the chain of acute kidney injury (e.g., at the stage of severe acute kidney injury) does not improve patient outcomes. Therefore, it is important that we detect patients who suffer from a progressive form of acute kidney injury early. In addition, the Acute Disease Quality Initiative (ADQI) workgroup suggested a more personalized approach should be considered for initiation of renal replacement therapy, based on the dynamic assessment of different clinical parameters that reflect the mismatch of demand and capacity.[149] Based on the conflicting results from these trials, there continues to be a need for additional research to reduce the variability of timing in the initiation of renal replacement therapy.[149]

Fluid Replacement Approaches

The administration of fluids is a mainstay of therapy to prevent hypovolemia and improve renal perfusion. However, the debate of restrictive versus liberal fluid therapy has been an ongoing argument among perioperative physicians for many decades. Historically, conventional regimens were characterized by the liberal administration of large intravenous fluid volumes (e.g., more than 7 l for open abdominal surgery) to account for fluid deficits, vasodilation, hemorrhage, and fluid accumulation in extravascular spaces.[150,151] However, with the introduction of Enhanced Recovery After Surgery (ERAS) protocols, a more restrictive pattern of fluid administration has been proposed with the benefit of fewer complications (i.e., pulmonary, acute kidney injury, sepsis, and wound healing), shorter time to recovery, and shorter length of hospital stay.[152–156] To investigate the outcome of liberal versus restrictive fluid administration in the perioperative patient, the Restrictive versus Liberal Fluid Therapy in Major Abdominal Surgery (RELIEF) trial was conducted in 2018.

The Restrictive versus Liberal Fluid Therapy in Major Abdominal Surgery trial was an international, randomized, assessor-blinded trial that compared a restrictive intravenous fluid regimen to a liberal regimen in 3,000 patients undergoing major abdominal surgery.[151] The median intravenous fluid intake for the group with restricted fluid was 3.7 l versus 6.1 l in the liberal fluid group.[151] They found that a regimen consisting of restricted fluid intake had no correlation with higher rates of disability-free survival than a regimen of liberal fluid intake. However, the study did find that a restricted fluid regimen was correlated to higher rates of acute kidney injury (8.6% restrictive vs. 5.0% liberal fluid group [P < 0.001]).[151] Brandstrup,[157] in the editorial response to the Myles et al.[151] Restrictive versus Liberal Fluid Therapy in Major Abdominal Surgery trial, eloquently surmised that "a modestly liberal administration of balanced salt solutions does not create substantial fluid retention, and it appears to be safe to administer a fluid volume that slightly exceeds zero fluid balance, although patients for whom an ERAS protocol is used might not need it. In addition, we learn that physiologic principles remain valid: both hypovolemia and oliguria must be recognized and treated with fluid."[157] Based on these findings, a reasonably liberal fluid intake regimen is potentially safer than a highly restricted fluid intake regimen for fluid resuscitation of the perioperative patient.[157]

Goal-directed Hemodynamic Therapy

Maintaining volume status and perfusion pressure are central tenants of the Kidney Disease Improving Global Outcomes recommendations. Early goal-directed hemodynamic therapy was proposed to optimize fluid resuscitation and cardiac output to improve microvascular perfusion pressure and cellular oxygenation while minimizing the harmful effects of fluid overload.[107,158–161] Goal-directed hemodynamic therapy, predefined algorithms of fluid loading, and inotropic support are utilized to account for variables such as myocardial performance,[162,163] vascular tone, regional blood flow distribution,[164] venous reservoir capacity, and capillary permeability.[165] A recent randomized controlled trial, the Optimization of Cardiovascular Management to Improve Surgical Outcome trial (OPTIMISE), was conducted to analyze the virtues of using goal-directed therapy to prevent acute kidney injury in noncardiac surgical populations.

The Optimization of Cardiovascular Management to Improve Surgical Outcome trial was a pragmatic, multicenter, randomized, observer-blinded trial of 734 high-risk patients. Patients were over the age of 65 undergoing major gastrointestinal surgery with the presence of cardiac or respiratory disease, renal impairment (serum creatinine levels of at least 1.5 mg dl−1), or diabetes mellitus or undergoing emergency surgery.[166] Patients were randomized to standard of care or a cardiac output–guided hemodynamic therapy algorithm for intravenous fluid and inotrope support during and after surgery.[166] Patients receiving intervention had a relative risk of 0.84 (95% CI, 0.71 to 1.0) and an absolute risk reduction of 6.8% (95% CI, −0.3% to 13.9%; P = 0.07).[166] There was no difference in the secondary outcomes of 7-day morbidity, critical care days, all-cause mortality at 30 and 180 days, or acute hospital length of stay.[166] The question of whether goal-directed therapy improves postoperative outcome is still under debate. Gelman and Bigatello[167] attribute the inconsistent benefits to an infused fluid volume that serves only to increase the unstressed capacity, whereas the stressed volume and hemodynamics remain largely unchanged. Further, variability is influenced by type of hemodynamic monitor, fluid administered algorithms, as well as the type and duration of hemodynamic intervention. Multicenter randomized controlled trials are needed to understand the role of goal-directed therapy in acute kidney injury outcomes. Based on these studies, the value of using goal-directed hemodynamic monitoring approaches to guide specific algorithms for fluid replacement remains questionable. Even in today's world, perioperative physicians may still be faced with the challenge of utilizing best clinical judgment in a complex clinical environment to make decisions about hemodynamic optimization of surgical patients.

Impact of Intravenous Fluid Composition

In line with the previous discussion of hemodynamic optimization, an ongoing argument in the field focuses on the type of fluid used in resuscitation. Isotonic crystalloid remains the standard for first-line resuscitation fluid therapy in the perioperative and ICU environments. Globally, the most frequently employed isotonic crystalloid is 0.9% sodium chloride. However, accumulating evidence suggests patients are at risk of adverse effects to acid–base homeostasis, renal vasoconstriction, reduced glomerular filtration rate, increased risk of acute kidney injury, and death.[168–173] Based on this research, a supraphysiologic chloride concentration of saline could be a potential contributor to kidney injury.[174] Two large-scale studies investigated the effect of balanced crystalloids and saline in critical and noncritical populations: the Isotonic Solutions and Major Adverse Renal Events Trial (SMART), examined using balanced crystalloids versus saline in patients in medical (SMART–MED) and nonmedical (SMART–SURG) ICUs; and the Saline against Lactated Ringer's or Plasma-Lyte in the Emergency Department (SALT–ED) trial.[174,175]

The SALT-ED trial was a single-center, pragmatic, multiple-crossover study comparing balanced crystalloids with saline in 13,347 adults treated with intravenous crystalloids during hospitalization outside of the ICU environment.[174] There was not a significant difference between the two groups in the number of hospital-free days. However, there was a lower prevalence of major adverse kidney events in the balanced crystalloids group (4.7% vs. 5.6%; adjusted odds ratio, 0.82; 95% CI, 0.70 to 0.95; P = 0.01).[174] In this trial of noncritically ill adult patients, balanced crystalloid treatment did not result in reduced time to hospital discharge, but it did find there was a lower prevalence of composite death, new renal replacement therapy, and chronic renal dysfunction.[174]

The SMART trial was a pragmatic, cluster-randomized, multiple-crossover design study of 15,802 ICU adult patients who received either 0.9% sodium chloride or balanced crystalloid solutions.[175] Similar to the SALT-ED trial, the main outcomes were major adverse kidney events within 30 days, new renal replacement therapy, or chronic renal dysfunction.[175] A major adverse kidney event occurred in 14.3% of the study population who received balanced-crystalloid solutions, and in the cohort who received 0.9% sodium chloride solution, 15.4% suffered from a major adverse kidney event (marginal odds ratio 0.91; 95% CI, 0.84 to 0.99; conditional odds ratio, 0.90; 95% CI, 0.82 to 0.99; P = 0.04).[175] Among critically ill adults, using balanced crystalloids lowered death rates from any cause, new renal replacement therapy, or chronic renal dysfunction.[175] Based on these recent, high-quality clinical trials, a balanced crystalloid solution with electrolyte compositions comparable with plasma is preferred for volume resuscitation to minimize adverse kidney events and death.[29]

In a classical view of microvascular fluid dynamics, colloids were hypothesized to be more effective than crystalloids in reestablishing circulating plasma volume, because their volume of distribution was thought to be comparatively maximized within the intravascular compartment, reducing time to hemodynamic stability with a comparatively smaller volume, with an effective longer duration. Through the investigation of crystalloid resuscitation alternatives, various controlled studies have scrutinized the efficacy of albumin, hydroxyethyl starch, and gelatin-based colloids.

The Crystalloid Versus Hydroxyethyl Starch Trial (CHEST) and Scandinavian Starch for Severe Sepsis/Septic Shock (6S) trial were landmark trials that compared the effects of resuscitation with hydroxyethyl starch and crystalloid solutions.[176,177] Findings from these trials demonstrate an association of acute kidney injury risk, increased rate of renal replacement therapy, and death with hydroxyethyl starch among ICU and septic patient populations.[176,177] These findings led drug regulators in Europe and the United States to issue black box safety warnings in 2013 against the use of hydroxyethyl starch. However, the use of hydroxyethyl starch-containing solutions remains controversial. As Weiss et al.[178] recently highlighted, "every drug can be used safely and effectively when it is used appropriately, according to its indication and in the right patient population." Currently, two prospective, randomized, controlled, double-blind trials are underway, the Safety and Efficacy of 6% Hydroxyethyl Starch (HES) Solution versus an Electrolyte Solution in Patients Undergoing Elective Abdominal Surgery (PHOENICS) trial (NCT03278548) and the Safety and Efficacy of a 6% Hydroxyethyl Starch (HES) Solution versus an Electrolyte Solution in Trauma Patients (TETHYS) trial (NCT03338218). Hydroxyethyl starch should be administered with caution in critically ill patients until new evidence from these ongoing trials is made available.

After concerns were raised about the safety profile of hydroxyethyl starch, a renewed interest in the safety and efficacy of gelatin and albumin colloid alternatives occurred in the marketplace. The use of albumin, a natural colloid, is an effective plasma volume expander and has been shown to improve microcirculation.[179,180] In the Saline versus Albumin Fluid Evaluation (SAFE) trial, a double-blinded randomized controlled trial, there was no observed difference in urine output, organ failure, and duration of renal replacement therapy between saline and 4% albumin solutions. Although albumin appears safe, it is two to five times more expensive than crystalloid and offers no significant difference in patient outcomes.[181] Another colloid alternative to crystalloid extensively utilized worldwide is gelatin, a degradation product of collagen. Gelatin-based solutions are similarly costly (more than 10 times more costly than crystalloid) with evidence of safety and efficacy from large prospective randomized controlled trials surprisingly limited.[182] Moeller et al.[183] found risk ratios after gelatin administration were 1.15 (95% CI, 0.96 to 1.38) for mortality, 1.10 (0.86 to 1.41) for requiring allogeneic blood transfusion, 1.35 (0.58 to 3.14) for acute kidney injury, and 3.01 (1.27 to 7.14) for anaphylaxis. Like hydroxyethyl starch, the authors concluded an increased risk of mortality, renal failure, anaphylaxis, and coagulation impairment with gelatin administration.[183] A novel prospective, double-blind randomized controlled trial (NCT02715466) is investigating the therapeutic value and safety of gelatin in patients with early severe sepsis or septic shock. Considering cheaper and safer crystalloid alternatives, the administration of gelatins should be undertaken with caution until further evidence from a well designed trial supporting its use is made available.

Impact of Anemia and Transfusion on Perioperative Acute Kidney Injury

Preoperative anemia, defined by the World Health Organization as less than 12 g/dl for female patients and less than 13 g/dl for male patients, is linked with perioperative acute kidney injury in both cardiac and noncardiac surgery patients.[184–186] Early postoperative decrements in hemoglobin level have also been linked with acute kidney injury.[184] Anemia leads to a state of decreased oxygen-carrying capacity, putting the vulnerable renal medulla at an increased risk of hypoxic injury. An anemic state also imposes greater oxidative stress on the renal tubules, in part because of the inherent protective function of red blood cells.[186] In addition to preoperative anemic state, perioperative blood transfusion has also been recognized as an independent risk factor for perioperative acute kidney injury. The deleterious effect of allogeneic transfusion has been attributed to the preservation and storage effect of red blood cells, promoting oxidative stress and a proinflammatory state.[186] It is important to note that both anemia and transfusion are associated with acute kidney injury. Measures to optimize a patient's overall preoperative status while minimizing surgical bleeding should be employed to reduce hematologic related acute kidney injury risk.

Avoidance of Nephrotoxic Drugs

Nephrotoxin-induced acute kidney injury is a considerable risk to patients in the perioperative period. Avoidance and minimizing the duration of exposure of these agents reduces the risk of acute kidney injury development.[29] Goldstein et al.[187] performed a prospective analysis of implementing an electronic health record screening and decision matrix at Cincinnati Children's Hospital, Cincinnati, Ohio. In 1,749 patients, implementation of a surveillance system reduced the exposure rate and acute kidney injury rate by 38% and 64%, respectively.[187] As highlighted in these studies, scrutinizing for nephrotoxic exposure has the potential to reduce avoidable harm and can help to prevent perioperative acute kidney injury.

Glycemic Control and Nutritional Support

Like nephrotoxic exposure, glycemic control and nutritional support are modifiable, independent predictors of outcome that should be optimized in the perioperative patient. In epidemiological studies, protein-calorie malnutrition is a significant risk factor for in-hospital death among patients suffering from acute kidney injury.[188] Such patients frequently have accelerated protein breakdown and increased caloric needs, especially if they are critically ill or undergoing renal replacement therapy.[26] Piggot et al.[189] retrospectively reviewed records of neonates who underwent congenital heart surgery at Arnold Palmer Hospital for Children in Orlando, Florida. In a multivariable analysis, an inability to reach caloric goal preoperatively was independently associated with stage 2 or 3 acute kidney injury (P = 0.04; odds ratio, 4.48; 95% CI, 1.02 to 19.63).[189] Further, a difference in peak lactate (P = 0.002), inotropic score (P = 0.02), and duration of mechanical ventilation (P = 0.013) was also observed.[189] Nutrition is fundamental for cellular and organ function, with malnutrition potentially worsening the severity of illness and contributory to acute kidney injury. Similarly, hyperglycemia is considered one of the best independent predictors of mortality and worse outcomes.[190] The Kidney Disease Improving Global Outcomes criteria recommend maintaining blood glucose concentrations between 110 and 149 mg/dl in critically ill patients to minimize perioperative hyperglycemia associated with increased mortality, surgical complications, and acute kidney injury risk.[188] The Normoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation (NICE–SUGAR) trial investigated restrictive blood glucose targets.[191] This parallel-group randomized controlled trial demonstrated a higher mortality in ICU patients with restrictive targets (odds ratio, 1.14; 95% CI, 1.02 to 1.28; P = 0.02) without reducing the prevalence of acute kidney injury. Based on the Normoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation trial and subsequent meta-analysis, it seems practical to adopt higher glycemic values, avoiding the inherent risks of hypoglycemia associated with tight glycemic benchmarks. Practical targets should be in accordance with the 2012 guidelines set forth by the Kidney Disease Improving Global Outcomes (110 to 149 mg/dl) or the statement from the European Renal Best Practice based on guidelines from the Kidney Disease Improving Global Outcomes (140 to 180 mg/dl).[143,188]

Preventative Acute Kidney Injury Bundle Protocols

The effectiveness of implementing preventative measures such as nutritional support and glycemic control, minimizing nephrotoxic medication exposure, and hemodynamic optimization have largely been studied independently. In 2017, a randomized controlled trial was conducted to analyze the value of implementing a "Kidney Disease Improving Global Outcomes bundle" in cardiac-associated acute kidney injury. In the trial, Meersch et al.[192] implemented a Kidney Disease Improving Global Outcomes protocol to optimize intravascular volume and hemodynamics, minimize nephrotoxic exposure, and prevent hyperglycemia in 882 high-risk cardiac surgery patients. The prevalence of acute kidney injury, identified by tissue inhibitor of metalloproteinases-2 and insulin-like growth factor binding protein-7 biomarkers, was reduced with the Kidney Disease Improving Global Outcomes bundle (55.1 vs. 71.7%; absolute risk reduction, 16.6%; 95% CI, 5.5 to 27.9%; P = 0.004). A Kidney Disease Improving Global Outcomes bundle enhanced hemodynamic parameters (P < 0.05), reduced hyperglycemia (P < 0.001), and ephrotoxic agent utilization of (P < 0.001).[192] However, the PrevAKI trial was not sufficiently powered to demonstrate a change in secondary outcomes of rate of dialysis, length of stay, and adverse kidney events with bundle implementation.[192] Current therapy has focused on minimizing the progression and optimizing the clinical response of the specific perioperative environment to improve acute kidney injury with limited success in secondary endpoints. Gocze et al.[193] examined urinary cell cycle arrest biomarkers, insulin-like growth factor-binding protein-7, and tissue inhibitor of metalloproteinase-2 in 107 high-risk surgical patients to predict early identification of acute kidney injury and allow for preventive measures. This rapid urinary biomarker assessment panel significantly improved risk stratification (P < 0.001). Further, in combination with clinical parameters, Gocze et al.[193] successfully allowed for early initiation of renal protective measures (i.e., hemodynamic optimization) and escalation of care before the development of acute kidney injury. Based on these studies, combinations of biomarker panels for early detection of perioperative acute kidney injury in conjunction with accelerated intervention protocols have great promise to become a cornerstone of acute kidney injury prevention in surgical patients.

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