Perioperative Acute Kidney Injury

Abstract

Perioperative organ injury is among the leading causes of morbidity and mortality of surgical patients. Among different types of perioperative organ injury, acute kidney injury occurs particularly frequently and has an exceptionally detrimental effect on surgical outcomes. Currently, acute kidney injury is most commonly diagnosed by assessing increases in serum creatinine concentration or decreased urine output. Recently, novel biomarkers have become a focus of translational research for improving timely detection and prognosis for acute kidney injury. However, specificity and timing of biomarker release continue to present challenges to their integration into existing diagnostic regimens. Despite many clinical trials using various pharmacologic or non-pharmacologic interventions, reliable means to prevent or reverse acute kidney injury are still lacking. Nevertheless, several recent randomized multi-center trials provide new insights into renal replacement strategies, composition of intravenous fluid replacement, goal-directed fluid therapy, or remote ischemic preconditioning in their impact on perioperative acute kidney injury. In this review, we provide an update on the latest progress toward the understanding of disease mechanism, diagnosis, and managing perioperative acute kidney injury, as well as highlight areas of ongoing research efforts for preventing and treating acute kidney injury in surgical patients.

Introduction

Over the past century, considerable progress has been made in anesthesia safety. Advancements in specialty training, improved monitoring modalities, and safer airway management have all contributed to better patient outcomes. However, surgical morbidity and mortality has essentially remained unchanged and continues to be a leading health burden in Western countries.¹ Among different types of organ injury, specifically with regard to organ dysfunction in the postoperative period, acute kidney injury remains particularly prominent, occurring in 20 to 40 % of high-risk patients.² Moreover, patients with a diagnosis of sepsis and acute kidney injury have an associated mortality rate of 70 %.³ Current experimental outcomes suggest acute kidney injury may precipitate a decline in other organ systems, thus impacting rates of multi-organ failure, sepsis, and death.⁴ Even subclinical acute kidney injury is correlated to an increased likelihood of mortality.⁵ Preventing and treating acute kidney injury represents multiple obstacles toward improving outcomes among surgical patients.

Historically, treatment modalities toward prevention of acute kidney injury have been limited. For example, prophylactic use of low-dose dopamine (“renal dopamine”) or treatment with high doses of furosemide to block ATP consumption by renal tubular epithelial cells, have proven detrimental instead of protective in perioperative clinical trials.⁶ In order to make a definitive diagnosis early in the injury process and effectively treat perioperative acute kidney injury, the obstacle of finding reliable identification tools must be overcome. Approaches based on alterations of serum creatinine may delay identification and intervention because of its relatively late diagnostic presentation. Therefore, the search for novel and specific biomarkers toward early identification of acute kidney injury has challenged this field of research.

Based on these unresolved questions, mechanistic insight into acute kidney injury, novel biomarkers, and therapeutic modalities to prevent or treat are intense areas of research. Many ongoing translational studies and clinical trials are aiming to provide a more acute understanding of the disease process, to establish diagnostic, preventive, or therapeutic options for acute kidney injury in perioperative patients. Through this review, we put these recent and ongoing studies into the context of established findings of perioperative acute kidney injury. We hope that these efforts will soon be successful and lead to an improvement in our diagnostic, preventive, or therapeutic options for surgical patients experiencing acute kidney injury.

Acute Kidney Injury Definition

Acute kidney injury is one of a number of acute kidney diseases, occurring in the presence or absence of other acute or chronic renal disease processes.⁷ A condition which affects kidney structure and function is categorized as acute or chronic, based upon interval of time. An inclusive nomenclature to enhance understanding and communication has been proposed to systematically classify functional and structural criteria for acute kidney injury, acute kidney disease, chronic kidney disease, and no known kidney disease (Supplementary Table 1).⁷

The publication of Risk, Injury, Failure, Loss, End-stage renal disease criteria (RIFLE) in 2004 created a standard, widely used definition for acute kidney injury.⁸ The establishment of these standards ended a plethora of no fewer than 60 definitions for acute kidney injury in acute renal failure literature.⁹ These standardized criteria established a uniform manner to define acute kidney injury, improving accuracy in reporting incidence and outcomes, and allowing comparability of studies regarding the diagnosis of acute kidney injury. This allowed our understanding to evolve from a “simple loss of function” to a more mature reality where acute kidney injury is a multifaceted, heterogeneous disease process.^10,11 However, a significant limitation of the Risk, Injury, Failure, Loss, End-stage renal disease standards is that it underestimated the effect of small acute creatinine changes on mortality as part of the criterion.¹² In response to this shortcoming, the Acute Kidney Injury Network (AKIN) modified the Risk, Injury, Failure, Loss, End-stage criteria, taking into account small increases in creatinine (≥0.3 mg/dL) over time (≥48 hours) (Table 1).¹³ In 2012, the Kidney Disease Improving Global Outcomes (KDIGO) taskforce offered a cohesive interpretation of the Risk, Injury, Failure, Loss, End-stage renal disease criteria, Acute Kidney Injury Network (AKIN), and pediatric Risk, Injury, Failure, Loss, End-stage renal disease criteria (pRIFLE) as “a single definition for practice, research, and public health.”¹⁴ The Kidney Disease Improving Global Outcomes classification stages the presence of acute kidney injury from an acute increase in serum creatinine or a period of oliguria.¹⁵ As it relates to time, the Acute Dialysis Quality Initiative Group recently clarified that “acute kidney injury” occurs within 48 hours or less and “acute kidney disease” when acute kidney injury persists for seven days or longer.¹⁵

Table 1:

AKI Classification Systems

RIFLE (7 Days)	AKIN (48 Hours)	KDIGO
Risk	Stage 1	Stage 1
Increased sCr × 1.5 or GFR decrease >25% OR urine output <0.5 ml kg–1 h–1 for 6 h	Increased sCr × 1.5–2 or sCr increase ≥0.3 mg dl–1 OR urine output <0.5 ml kg–1 h–1 for >6 h	Increased sCr × 1.5–1.9 within seven days OR sCr increase ≥0.3 mg dl–1 within 48 h OR urine output <0.5 ml kg–1 h–1 for 6-12 h
Injury	Stage 2	Stage 2
Increased sCr × 2 or GFR decrease >50% OR urine output <0.5 ml kg–1 h–1 for 12 h	Increased sCr × 2–3 OR urine output <0.5 ml kg–1 h–1 for >12h	Increased sCr × 2–2.9 OR urine output <0.5 ml kg–1 h–1 for ≥12h
Failure	Stage 3	Stage 3
Increased sCr × 3 or GFR decrease by 75% or sCr ≥ 4 mg dl–1 with an acute rise in sCr (≥0.5 mg dl–1) OR urine output <0.3 ml kg–1 h–1 for 24 h or anuria for 12 h	Increased sCr × 3 or more or sCr ≥ 4 mg dl–1 with an acute rise in sCr (≥0.5 mg dl–1) OR urine output <0.3 ml kg–1 h–1 for >24 h or anuria for 12 h	Increased sCr × 3 or more or sCr ≥ 4 mg dl–1 or initiation of RRT or GFR decrease to <35 ml min–1 (1.73 m) –2 in patients <18 yr old OR urine output <0.3 ml kg–1 h–1 for ≥24 h or anuria for ≥12 h
Loss
Persistent acute renal failure=complete loss of kidney function >4 weeks
End-stage Kidney Disease
ESRD >3 months

Comparison of the three most notable and historic classification systems used to diagnose AKI. The initial system was the RIFLE (Risk, Injury, Failure, Loss of kidney function, End-stage renal failure), which was developed by an international consensus in 2004. It defined 5 stages of renal injury: risk-end stage disease. A short time later the Acute Kidney Injury Network (AKIN) developed their own diagnostic criteria that uses a smaller creatinine change to define AKI. This was based on studies showing that even small changes in serum creatinine resulted in adverse outcomes.^2–6 In 2012, the KDIGO (Kidney Disease: Improving Global Outcomes) classification system was produced and has been the main system in use since.⁹ The KDIGO system was created by combining the two prior systems and utilizing studies showing which patients were missed by the two prior classification system.

Acute kidney injury has two subgroups, “subclinical acute kidney injury” and “functional acute kidney injury,” and has recently been described with the introduction of biomarkers as a diagnostic tool.¹⁶ Elevated concentrations of an acute kidney injury biomarker, without meeting Kidney Disease Improving Global Outcomes classifications, is defined as subclinical acute kidney injury. Whereas, functional acute kidney injury meets the Kidney Disease Improving Global Outcomes definition, but fails to demonstrate an increase in biomarker concentration.¹⁷ While it is tempting to assume that subclinical acute kidney injury is an innocuous phenomenon with surgical patients, current evidence suggests that even minor increases of perioperative creatinine levels—not meeting Kidney Disease Improving Global Outcomes definition for acute kidney injury—are related to a doubling of perioperative mortality and longer hospital length-of-stay.⁵ Haase et al. determined even without diagnostic fluctuations in serum creatinine, subclinical AKI is associated with adverse outcomes.¹⁸

Epidemiology of Perioperative Acute Kidney Injury

The effect of acute kidney injury on individual outcomes and healthcare systems is remarkable. Acute kidney injury in industrialized countries costs an estimated $1 billion, claims 300,000 lives, and contributes to the development of 300,000 advanced chronic kidney disease cases annually.^19,20 Acute kidney injury correlates with elevated mortality rates, longer hospital stays, and increased treatment expenses, with the seriousness of acute kidney injury directly linked to patient-centered outcomes. While multiple studies have since substantiated the impact of acute kidney injury, the prevalence of acute kidney injury is dependent upon the definition, criteria, and study population.

Kork et al. retrospectively examined 37,000 non-cardiac patients in a single-center study utilizing the Kidney Disease Improving Global Outcomes criteria.⁵ Acute kidney injury occurred in 6% of the study population. After adjusting for multiple variables including age, hospital length of stay, sex, pre-operative creatinine and hemoglobin, the authors determined that minor changes in creatinine levels (25 to 49% above baseline), increased the risk of death by two-fold and increased the length of hospitalization by three days.⁵ In 2017, O’Connor et al. investigated the association between postoperative acute kidney injury using the Kidney Disease Improving Global Outcomes standards for a retrospective cohort study and found that 6.8% of investigated patients sustained acute kidney injury resulting in a 13.3% in-hospital mortality rate compared with 0.9% without acute kidney injury (P < 0.001). At one year, 26.6% of patients with acute kidney injury died compared to 6.1% of patients without acute kidney injury (P < 0.001) resulting in an adjusted hazard ratio for death of 2.96 (95% C.I. 1.86 to 4.71; P < 0.001) for acute kidney injury.²¹ Both studies concluded that in non-cardiac surgery patients, the presence of even mild forms of acute kidney injury posed a significant risk of death and increased the length of hospital stay.^5,21 The frequency, risk factors, and outcomes following non-cardiac surgery have not been well identified and could offer a multitude of possibilities for further analysis in postoperative acute kidney injury research.

Cardiac surgery-associated acute kidney injury is a frequent source of perioperative acute kidney injury. Recent meta-analysis found the incidence of acute kidney injury in cardiac surgery patients to be as significant as 25 to 30%.^22,23 In 2016, Hu et al. analyzed the pooled incidence rates of acute kidney injury in 300,000 post-cardiac surgery patients and determined the incidence of to be 22.3% (95% CI, 19.8-25.1). Utilizing Kidney Disease Improving Global Outcomes criteria, pooled rates for the development were 13.6%, 3.8%, and 2.7% for Stage 1, Stage 2, and Stage 3 respectively, with 2.3% requiring renal replacement therapy.²² The development of acute kidney injury increased monetary cost and length of hospitalization.²² The connection between acute kidney injury and post-cardiac surgery has pronounced short- and long-term morbidity outcomes. In a cohort study looking at over 1,000 patients undertaking elective cardiac surgery, acute kidney injury patients had a 26% 5-year cumulative risk of death, more than double the cumulative risk in patients without acute kidney injury.²⁴ Although the role of acute kidney injury is well established in patients receiving cardiac surgery, less information is available regarding non-cardiac surgery.

To determine if the type of surgery influenced whether a patient develops acute kidney injury, Grams and colleagues performed a retrospective study of 161,185 Veterans Health Administration patients in 2016.²⁵ Cardiac surgery presented the greatest risk for postoperative acute kidney injury (RR, 1.22; 95% CI, 1.17-1.27), proceeded by general thoracic (RR, 0.92; 95% CI, 0.87-0.98), orthopedic (RR, 0.70; 95% CI, 0.67-0.73), vascular (RR, 0.68; 95% CI, 0.64-0.71), urologic (RR, 0.65; 95% CI, 0.61-0.69), and ear, nose, and throat (RR, 0.32; 95% CI, 0.28-0.37).²⁵ Although cardiac surgery posed the greatest postoperative risk, similar risk factors including advanced age, African American race, hypertension, diabetes mellitus, and a lower estimated glomerular filtration rate was observed across surgical types.²⁵ Further, acute kidney injury post-operative patients had longer hospitalization, higher rates of 30-day readmission, heightened risk for developing end-stage renal disease, and higher mortality rates (19% vs 8%). These findings corroborated research from Kork et al. and O’Connor et al. which examined the occurrence of morbidity acute kidney injury among the non-cardiac perioperative population. Taken together, these data indicate the acute kidney injury occurs more frequently than previously anticipated. Even smaller changes in kidney function are associated with higher degrees of morbidity and mortality. Therefore, clinicians should carefully consider clinical and laboratory signs of mild kidney injury in order to be prepared to manage potential clinical complications, such as organ injury, multi-organ failure, or sepsis.

Pathophysiology of Perioperative Acute Kidney Injury

Historically, acute kidney injury was categorized into pre-renal, renal, and post-renal causes. Pre-renal acute kidney injury is a functional response to renal hypoperfusion, where intrinsic renal tubular function remains intact. Pre-renal acute kidney injury results from a hypovolemic or low circulating volume or low cardiac output state. Post-renal acute kidney injury is caused by the blockage of urinary flow downstream in the urinary tract inducing a backup into the kidney and consequent hydronephrosis. Like pre-renal acute kidney injury, there is no inherent renal disease present, if urinary flow is re-established before permanent structural damage develops. In contrast, intrinsic acute kidney injury results from a disease process of the renal vascular, glomeruli, tubules, or interstitium.²⁶ This traditional classification provides a convenient but somewhat simplistic framework as acute kidney injury often crosses these boundaries. For example, prolonged pre-renal acute kidney injury can lead to secondary intrinsic acute tubular necrosis.²⁷

Perioperative acute kidney injury and the ways in which it develops is multifaceted and complex. Hypoperfusion, inflammation, and neuroendocrine response to surgery are the frequent mechanisms affecting renal perfusion.^28,29 Reduction of blood pressure and renal hypoperfusion are frequent consequences of perioperative hypovolemia, as well as the vasodilatory and cardio-depressant effects of anesthesia. In a low perfusion state, the kidneys can exhibit remarkable autoregulation, maintaining constant renal blood flow, and consequently glomerular filtration rate despite fluctuating mean arterial pressure and volume status. Prostaglandin signaling decreases afferent arteriolar resistance, which increases blood flow to the glomeruli and sustains the glomerular capillary pressure in low perfusion state. The activation of the renin-angiotensin-aldosterone systems and release of angiotensin II raises efferent arteriolar resistance, sustaining the glomerular capillary pressure.²⁶ If renal hypoperfusion persists or drops below the autoregulatory range, endogenous vasoconstrictors released from the renal sympathetic system result in afferent arteriolar vasoconstriction. This effectively reduces renal blood flow leading to renal tubular ischemia and reduced glomerular filtration rate.^26,30–32 The diminishing of oxygen balance induces renal tissue hypoxia and ATP starvation that stimulates extracellular matrix production, collagen deposition, and fibrosis.³³ As a metabolic product of ATP,³⁴ adenosine binds to kidney cell surface receptors to match blood flow with energy consumption.^2,35 The interstitial concentration of adenosine rises when neighboring cells are in a negative energy balance.³⁵ To recover from a negative energy balance and high oxygen demand, it is unnecessary to increase blood flow, but rather, to lower the glomerular filtration fraction. This phenomenon has been termed “acute renal success.”^36,37 By reducing the filtration rate, the number of sodium ions that must be transported per oxygen delivered is reduced, conserving energy and improving the energy balance.³⁵ Renal perfusion is capitalized to a rate that is adequate to promote healing while maintaining excretory function without the risk of inhibiting volume conservation.³⁶

Renal autoregulation can also be disrupted by using non-steroidal anti-inflammatory drugs (NSAIDs) during the perioperative period. These inhibit the enzyme cyclooxygenase and prohibit the production of renal prostaglandins. This leads to the unopposed constriction of both the afferent and efferent arterioles by angiotensin II in a state of persistent renal hypoperfusion, decreasing renal perfusion flow and glomerular filtration rate (Figure 1).

Figure 1. Glomerular Filtration as a Function of Glomerular Blood Flow.

Panel A shows normal glomerular blood flow with normal glomerular filtration rate. Panel B shows reduced renal perfusion pressure within the autoregulatory range, caused by intraoperative conditions such as anesthesia and medication induced hypotension or hypovolemia. Normal glomerular filtration rate is maintained with prostaglandin-mediated afferent arteriolar vasodilation and Angiotensin II-mediated efferent arteriolar vasoconstriction. Panel C shows persistent reduction in renal perfusion pressure below the autoregulatory range. This can be seen intraoperatively with protracted systemic hypotension or severe hypovolemia due to hemorrhage and blood loss. In this state, endogenous vasoconstrictors released from the renal sympathetic nerves increase the afferent arteriolar resistance, which results in a rapid decline in glomerular filtration rate and decrease in renal blood flow. This eventually leads to tubular cell damage and cell death. Panel D shows reduced glomerular filtration rate with nonsteroidal anti-inflammatory drug use due to loss of vasodilatory prostaglandin. Panel E shows the effect of angiotensin-converting-enzyme inhibitor or angiotensin-receptor blocker. Loss of angiotensin II decreases both the afferent and efferent arteriolar resistance, relaxing the efferent arteriole significantly more. The net clinical effect is unchanged or slightly decreased glomerular filtration rate. Panel F shows the effect of chronic hypertension on the preglomerular arterial vessels, primarily the afferent arterioles. Chronic hypertension eventually leads to thickening of arteriole walls and narrowing of lumen, a process known as arteriolosclerosis. This results in inadequate blood flow through the glomeruli and may produce glomerular and tubulointerstitial ischemia. Conditions displayed in Panel D-F can contribute to the development of “normotensive” perioperative acute kidney injury.

In addition to hypoperfusion-induced injury, systemic inflammation and cytokine release caused by trauma and surgical stress directly induce tubular injury and subsequent systemic inflammation.^2,34,38 The etiology of this inflammation-induced acute kidney injury is multifactorial, including renin-angiotensin-aldosterone system activation, renal microcirculatory dysfunction, increased oxidative stress, cytokine-induced injury, endothelial cell injury, and activation of pro-apoptotic pathways.^{27–29,39,40} All these factors predispose the surgical patient to develop acute kidney injury during the perioperative period. In recent years, evidence in both basic science and clinical research has led to a new understanding that acute kidney injury is not a mere singular organ injury. Acute kidney injury is now perceived as a multifaceted systemic disease process that engenders distant organ dysfunctions, including pulmonary,⁴¹ cardiac,⁴² neurologic, immunologic, hepatic, and gastrointestinal dysfunctions (Figure 2).^43–45 Recent studies highlight that acute kidney injury can cause remote organ injury, for example, to the intestine. Dr. Lee et al. provides mechanistic insight of the inflammatory activation of Paneth cells that are contained at the bottom of crypts located at the intestinal mucosa.⁶ Activation of Paneth cells leads to massive release of inflammatory mediators (such as IL-17A), causing a disruption of the intestinal barrier function, translocation of bacteria from the intestinal lumen into the blood stream, promoting sepsis and multi-organ failure (Figure 3).⁶ These studies highlight in an elegant way a functional role of acute kidney injury beyond its filter function, suggesting that kidney injury and acute kidney injury trigger inflammation and morbidity in distal organ systems.⁴

Figure 2. Consequences of acute kidney injury on remote organ functions.

There is increasing evidence that acute kidney injury directly contributes to remote injury in the heart, lung, brain, liver, immunologic, and other organ systems. 1) In the hepatic system, acute kidney injury causes intestinal barrier breakdown and greater gut translocation and delivery of endotoxins and microorganisms to the portal system. This results in hepatic inflammation and apoptosis along with hepatic overproduction and systemic release of pro-inflammatory cytokines. 2) Acute kidney injury is also associated with cerebral dysfunction, including uremic encephalopathy. Activation of neuro-inflammatory cascade results in increase in vascular permeability and breakdown of blood-brain barrier. 3) In the cardiac system, acute kidney injury is associated with cardiorenal syndrome, which is a state of concomitant heart and kidney failure. Suggested mechanisms of acute kidney injury-induced cardiac dysfunction include fluid overload and uremia-induced decrease in myocardial contractility. 4) In the pulmonary system, the remote effect of acute kidney injury is due to activation of inflammatory cascade leading to an increase in pulmonary vascular permeability and lung neutrophil infiltration. This leads to accumulation of fluid within the lung tissue, causing pulmonary edema. 5) In the immunologic system, acute kidney injury has a profound impact on humoral and cellular immunity and overall immunocompetence. This is due to a combination of increase in oxidative stress, impaired clearance of the reticuloendothelial system, and decreased clearance of circulating cytokines, leading to higher rate of infections in patients with acute kidney injury.

Figure 3. Paneth Cell-Mediated Multiorgan Systemic Inflammation after Acute Kidney Injury.

Recent experimental studies indicate that acute loss of kidney function causes small intestinal Paneth cells in the intestinal crypts to generate and degranulate proinflammatory IL-17-A into the intestinal lumen, which directly causes intestinal cellular injury and intestinal barrier breakdown. This allows for bacterial translocation and portal delivery of IL-17-A-containing macrophages, which causes hepatic injury and hepatic release of IL-6 and TNF-alpha into the circulation, leading to further hepatic and systemic inflammation. These studies highlight that acute kidney injury is not merely a bystander but can initiate a downward spiral triggering multi-organ failure and death.⁶

Many questions regarding organ “cross-talk” during acute kidney injury still remain unclear, for example how communication between the kidneys and distal organs—such as the gut, lungs, heart or the brain—are communicated. Similarly, many mechanistic aspects of acute kidney injury continue to be the focus of basic and translational research. Experimental data suggest that during acute kidney injury, a combination pro-inflammatory cytokine and chemokine release, leukocyte extravasation, induction of remote oxidative stress, and ion channels dysregulation can occur.^46,39,47 Similarly, a number of anti-inflammatory pathways that can be targeted for acute kidney injury prevention or treatment have been identified, such as purinergic,^48–50 or hypoxia-elicited anti-inflammatory signaling pathways,⁵¹ or inflammatory end-points that are under the control of microRNAs.^41,52–54

Patient-associated Risk Factors for Acute Kidney Injury

Several elements are correlated with a heightened risk for perioperative acute kidney injury in patients. Pre-existing perioperative elevation of creatinine (>1.2mg/dl or higher) is a significant predictor for post-operative acute kidney injury among both cardiac and non-cardiac surgery populations.^31,30,40 Furthermore, independent risk factors for perioperative acute kidney injury include advanced age, African American race, pre-existing hypertension, active congestive heart failure, chronic kidney disease, pulmonary disease, insulin-dependent diabetes mellitus, peripheral vascular disease, presence of ascites and high body mass index.^{25,29,30,55–58} For example, acute kidney injury prevalence among bariatric surgery cases is 5 to 10%.^55,58 In addition to being a general risk factor, a high body mass index may increase the risk of perioperative acute kidney injury. It is hypothesized that an increase in oxidative stress, pro-inflammatory cytokines, and endothelial dysfunction associated with obesity could influence whether a patient develops acute kidney injury.^29,59–62 Conflicting data exist regarding the influence of gender on acute kidney injury occurrence. Within cardiac surgery literature, the evidence is inconclusive with conflicting results that female gender may pose an increased perioperative risk for developing acute kidney injury.^54,55 However, among general surgery patients, the American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) 2005 - 2006 national data collection showed that male sex, rather than female, doubles the acute kidney injury threat after general surgery.^55,58 From a clinical perspective, many of these factors are not modifiable. Identifying these patient-associated comorbidities may help with individual preoperative risk-stratification and prevention. Such clinical risk factors may include male sex, particularly in general surgery patients, obesity, advanced age, African American race, pre-existing hypertension, active congestive heart failure, chronic kidney disease, pulmonary disease, insulin-dependent diabetes mellitus, and peripheral vascular disease.

Surgery-associated risk factors for perioperative acute kidney injury

Acute Kidney Injury is a dangerous complication in both cardiac and non-cardiac surgeries, and independently associated with emergency surgery.⁵⁸ One-third of acute kidney injury cases which occurred among patients who are critically ill have previous history of major surgery.⁶³

Acute Kidney Injury in Cardiac and Vascular Surgery.

In vascular and cardiac surgeries, acute kidney injury is a well-established obstacle. Within these surgical settings, acute kidney injury is correlated with prolonged aortic cross-clamp and ischemia time, the creation of micro- and macro-emboli, low cardiac output state, prolonged hypotension, and the use of vasopressors and inotropes. In addition to low mean arterial pressure (MAP) during CPB, there are reports of contact-activated systemic inflammation, triggered by blood flow across the artificial surface of the bypass circuit. These damaging elements of CPB compromise renal blood flow and lead to renin-angiotensin-aldosterone system activation, decline of renal perfusion pressure, and worsening renal insult.⁶⁴ Furthermore, components of CPB (pump, oxygenator, suction, filters) impose mechanical damage to the circulating erythrocytes, leading to intraoperative hemolysis and release of free hemoglobin. Free hemoglobin can cause direct injury to the renal epithelium via generation of free-radical species and obstructive cast formation.⁶⁵ Strategies to minimize renal injury with CPB have been explored and include a goal-directed oxygen delivery threshold for adjusting arterial pump flow according to the hematocrit value and when necessary by blood transfusion when thresholds cannot be maintained with increased pump flow.⁶⁶ Similar to a goal-directed oxygen delivery strategy, maintenance of a mixed venous oxygen saturation (SvO2) target above 75% during CPB is hypothesized to optimize system perfusion and may be linked with a lower risk of postoperative acute kidney injury.⁶⁷ Further investigations are still needed to understand the optimal strategies necessary to reduce acute kidney injury risk during CPB among high-risk cases.

With the apparent renal implications of CPB, it may appear intuitive that off-pump coronary artery bypass (CAB) would exhibit renal sparing effect compared to the traditional on-pump coronary artery bypass graft (CABG) surgery. But to date, clear consensus has not been reached. The CABG Off or On Pump Revascularization Study (CORONARY) randomized 4,752 patients from 2006 through 2011 at 79 centers in 19 countries to on-pump or off-pump technique. The study found no significant difference in new renal failure requiring dialysis at 30 days, but a substantial decrease in the incidence of acute kidney injury was observed (28.0% vs. 32.1%; RR, 0.87; 95% CI, 0.80 to 0.96; P=0.01) in the off-pump group.⁶⁸ In contrast, the German Off Pump Coronary Artery Bypass Grafting in Elderly Patients (GOPCABE) trial randomized 1,593 elderly patients to either on or off technique from 2008 through 2011 and found that off-pump CABG surgery was not correlated with a decreased incidence or reduced severity of acute kidney injury (P=0.174).⁶⁹ Current evidence does not demonstrate a consistent reduction in the relative risk of acute kidney injury or dialysis with an off-pump revascularization technique. Given the lack of supporting evidence, off-pump CABG surgery should not routinely be recommended for all CABG patients at risk of perioperative acute kidney injury, especially in light of associated lower off-pump CABG revascularization success rates.^68,70

Acute Kidney Injury in Non-Cardiac Surgery.

Occurrence of acute kidney injury among non-cardiac and non-vascular surgeries has been studied less extensively than during cardiac surgery, probably due to its overall lower incidence. According to the American College of Surgeons-National Surgical Quality Improvement Program national data collection, complications due to acute kidney injury occur in approximately 1% of general surgery cases, resulting in an eight-fold increase in all-cause 30-day mortality.⁵⁸ Within the general surgery category, intraperitoneal surgery is an established risk for developing perioperative acute kidney injury.⁵⁸ Procedure-related factors in abdominal surgery include intraoperative blood transfusions, episodes of intraoperative hemodynamic instability, and the use of vasopressors and diuretics.^28,71 Increase in intra-abdominal pressure, often due to an excessive fluid administration or rapid fluid shift, is predictive of postoperative renal impairment.^72,73 The reduction in perfusion pressure is attributed to mechanical compression of renal vasculature, causing a decreasing renal perfusion pressure and inducing renal ischemia.^73,72 Of note, laparoscopic surgery with transient elevations in intra-abdominal pressure due to pneumo-peritoneum may result in a clinical decline in urine output, without causing an increase in postoperative acute kidney injury rates.^29,71

Diagnosis of Perioperative Acute Kidney Injury

Diagnostic Criteria Utilizing Creatinine and Urine Output.

Multiple definitions and measurements to diagnose acute kidney injury have been explored and studied over the past thirty years. Measurements of serum creatinine and urine output remain the foundation of acute kidney injury diagnosis because they are both easily measurable and distinct to the kidney. The Risk, Injury, Failure, Loss, End-stage renal disease and Acute Kidney Injury Network criteria were each developed with the goal of creating a standardized definition of acute kidney injury that would also allow early and accurate diagnosis and treatment.^{48, 54, 12,74} In 2012, the Kidney Disease Improving Global Outcomes classification system emerged and remains the primary classification system for acute kidney injury⁵⁶ (Supplemental Table 2).

Diagnostic Difficulties in the Perioperative Period.

Despite the development of a uniform standard to define acute kidney injury, the Kidney Disease Improving Global Outcomes classification system still has recognized limitations, particularly in the perioperative period. Urine output is a sensitive detection tool for identifying acute kidney injury and is appropriately included in all acute kidney injury definitions. However, the perioperative period has shown to be a unique environment with its own diagnostic challenges. Studies have shown that urine output frequently is decreased in the intraoperative and postoperative period due to the release of aldosterone and vasopressin from stress, hypovolemia, or even anesthesia.^75,76 A 2010 study noted during surgery, only 5 to 15% of a crystalloid volume load is excreted in the urine, as opposed to 40 to 75% in a non-anesthetized patient.⁵⁹ This decrease in urine output was unchanged whether the anesthesia was performed using isoflurane or a propofol infusion. Several studies have examined the relationship between fluid administration and intraoperative urine output and its correlation with postoperative acute kidney injury. One such randomized prospective study examined 107 patients undergoing bariatric surgery who received either high- or low-volume amounts of Ringer’s Lactate. The authors failed to find a correlation between low urine output in the intraoperative period and postoperative acute kidney injury. In conclusion, urine output is a less useful criterion for diagnosing perioperative acute kidney injury, necessitating a need for other diagnostic methodologies.

Serum creatinine is also a flawed diagnostic tool and can be an inaccurate marker for glomerular filtration rate. As a primary diagnostic criterion for acute kidney injury, serum creatinine is problematic because of the temporal delay from injury to the necessary diagnostic rise in creatinine. Creatinine will begin to rise after the glomerular filtration rate is decreased by 50%.⁷⁷ An initial creatinine rise may occur on postoperative day one, however, the clear majority of patients fail to meet criteria for acute kidney injury until postoperative day two. Due to this “creatinine blind window of acute kidney injury,” perioperative acute kidney injury is frequently recognized late in the kidney injury process. Serum creatinine can also be altered by a variety of other factors than kidney junction, many of which are common in the perioperative period, including muscle injury, volume overload, nutrition, and steroids.⁷⁷ In summary, the clinical practice of predominantly basing the clinical diagnosis of AKI on measurements of serum creatinine has many limitations, such as a delay in diagnosing early stages of AKI. Research into the efficacy of novel biologic markers is ongoing to improve the identification and treatment of acute kidney injury.

Novel Acute Kidney Injury Biomarkers.

The utility of biomarkers as reliable measurement tools for detecting minor but significant renal injury has been a focus of translational and bench research. As shown in Supplementary Table 2, there are numerous ongoing clinical trials to further sharpen our view and clinical approaches for novel acute kidney injury biomarkers (Supplementary Table 2). A highly precise biomarker would be ideal for renal injury and sensitive from insult to resolution (e.g., accounting for the “creatinine blind” window). Currently, biomarkers showing the most promise all have differing levels of sensitivity and specificity for acute kidney injury, with vastly differing time courses. They are described in more detail below (Figure 4).⁷⁸

Figure 4. Biomarkers Over Time After Acute Kidney Injury.

Schematic representation of the levels of several biomarkers over time. The baseline (time 0) is immediately following cardiac bypass (CBP). The lines are a schematic of the predicted rise and fall of the biomarkers following CBP as a function of time and when levels become significant enough to cross the threshold for diagnosing acute kidney injury. These patterns and specifically the timeline for diagnosing acute kidney injury, represent ideal circumstances (the shortest possible time interval shown in a clinical study), and not necessarily what will prove to be clinically verifiable.

neutrophil gelatinase-associated lipocalin = urinary neutrophil-associated lipocalin; kidney injury molecule-1= urinary kidney injury molecule; cystatin C= serum cystatin C; [tissue inhibitor of metalloproteinases-2]*[IGFBP7]= tissue inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein-7 (IGFBP7); serum Cr= serum creatinine.⁷⁸

Modified from Figure 1, from McIlroy DR, Wagener G, Lee HT: Biomarkers of Acute Kidney Injury: An Evolving Domain. Anesthesiology 2010;112(4):998-1004

The neutrophil gelatinase-associated lipocalin (NGAL) molecule is absent in urine and plasma of healthy individuals. The molecule was initially discovered in a screening study that was designed to identify genes that are differentially expressed in the early periods following renal ischemia. By clamping the renal artery in mice for 45 minutes, cDNA microarrays were used to define changes in renal gene expression. The authors identified seven upregulated genes, including neutrophil gelatinase-associated lipocalin, an easily measurable stable polypeptide found in the urine during the kidney injury process.^79,80 However, point-of-care testing is unable to detect the renal isoform of neutrophil gelatinase associated lipocalin. Initial studies showed promise as a predictive indicator of acute kidney injury within cardiac surgery cases, where urine neutrophil gelatinase-associated lipocalin levels are diagnostic of acute kidney injury at two hours post-cardiac bypass. In a pediatric trial, similar findings in cardiopulmonary bypass patients were observed with neutrophil gelatinase-associated lipocalin levels elevated in acute kidney injury patients within two hours, compared to 1 to 3 days for diagnostic creatinine levels.⁸¹ Criticism of these early neutrophil gelatinase-associated lipocalin trials was the homogenous study population and comorbidity exclusion criteria.^81,82,83 Subsequent studies with heterogeneous surgical populations found no association between neutrophil gelatinase-associated lipocalin and acute kidney injury.^84,85 An examination of non-cardiac surgery cases, showed higher levels of urine and serum neutrophil gelatinase-associated lipocalin among those who have diabetes, an infection, and chronic kidney disease, but failed to correlate an association between neutrophil gelatinase-associated lipocalin levels and acute kidney injury.⁶⁵ Specificity of neutrophil gelatinase-associated lipocalin has been estimated to range between 70 to 80%, however sensitivity is unpredictable, varying from 40 to 90%.⁷⁸ The reason for such discrepancy is uncertain. However, neutrophil gelatinase-associated lipocalin levels may be affected by a wide range of factors, such as infections, certain tumors, cardiovascular disease, pre-existing renal disease, age, and diabetes. The influence of confounding variables has raised concerns regarding its diagnostic performance.^86,87 Research is still ongoing for neutrophil gelatinase-associated lipocalin with several studies evaluating opportunities in contrast-induced nephropathy and utilizing neutrophil gelatinase-associated lipocalin to project whether there will be a need for renal replacement therapy.^88,89 Better defining which patient populations will benefit from neutrophil gelatinase-associated lipocalin as a diagnostic tool and its role in combination with other biomarkers is the next step in the research of this important protein.

Another promising biomarker is the kidney injury molecule-1 (KIM-1). Kidney injury molecule-1 is a type-1 membrane glycoprotein that is upregulated after an ischemic or nephrotoxic injury to the proximal tubule epithelial cells.⁹⁰ Studies show kidney injury molecule-1 functions as a cell adhesion molecule in the reconstruction of injured proximal tubules.⁷⁸ A trial examining the occurrence of acute kidney injury during cardiac surgery in pediatric cases, found kidney injury molecule-1 to be an excellent diagnostic molecule with elevated urine levels within 6 hours after cardiac bypass.⁷¹ However, another study in adult cardiac surgery patients showed good specificity, but only a sensitivity of 50% when using urinary kidney injury molecule-1 to diagnose acute kidney injury.⁹¹ This study, along with others, showed that kidney injury molecule-1 is potentially more useful when used as part of a panel combining several biomarkers.^91,92 However, there is currently no point-of-care device in the marketplace for immediate assessment of kidney injury molecule-1.

Cystatin C is unique in that it is a very small, charged molecule completely filtered at the glomerulus where it undergoes catabolism by proximal tubule cells. Because of this, there is virtually zero measurable cystatin C found in the urine of healthy kidneys.⁷⁰ The above characteristics and a short half-life in the serum (two hours), have made several investigators propose that serum cystatin C is an ideal surrogate for glomerular filtration rate and tubular cell integrity.^70,93,94,95 Two studies examining the use of serum cystatin C have had mixed results, with one showing its ability to diagnose acute kidney injury occurring within six hours following surgery, whereas the other found it to be no better than creatinine.^92,96 However, this study did show that urine cystatin C levels rose within 6 hours after bypass in those with acute kidney injury, necessitating further study to clarify its role. Currently, the number of patients studied utilizing cystatin C is small, making the results and future of this molecule as a novel acute kidney injury biomarker still to be seen.

Tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor binding protein-7 (IGFBP-7) get released during cell cycle arrest and could potentially present sensitive and precise biomarker molecules for diagnosing acute kidney injury. During normal cell proliferation, a cell must go through each stage of the cell cycle (G₁-M). However, when cells are damaged, they utilize cell cycle arrest as a protective mechanism to circumvent replication of damaged DNA. When renal cells enter cell cycle arrest, this adaptive response is mediated by surrounding cells through the release of tissue inhibitor of metalloproteinases-2 and insulin-like growth factor binding protein-7. Their presence in the urine is hypothesized to be one of the earliest signs of cellular kidney damage.^75,97 Tissue inhibitor of metalloproteinases-2 and insulin-like growth factor binding protein-7 biomarkers were identified and consequently confirmed in the second phase of the SAPHIRE trial which examined samples from over 700 patients across 35 centers.^75,97 Univariate analysis showed that tissue inhibitor of metalloproteinases-2 and insulin-like growth factor binding protein-7 >2.0 was correlated to an elevated risk of all-cause mortality or renal replacement therapy (hazard ratio, 2.11; 95%, CI 95% CI, 1.37 to 3.23; P<0.001). In a multivariate analysis adjusted for the clinical model, tissue inhibitor of metalloproteinases-2, and insulin-like growth factor binding protein-7 levels >0.3 was associated with death or renal replacement therapy among subjects who developed acute kidney injury. The SAPHIRE trial also determined that the combination of the two biomarkers proved to be of greater prognostic value for acute kidney injury than either in isolation. Tissue inhibitor of metalloproteinases-2 and insulin-like growth factor binding protein-7 was appreciably more predictive to previously described markers of acute kidney injury (P < 0.002), such as neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, in a heterogeneous population.⁹⁸ A recent meta-analysis found they accurately predicted the probability to develop acute kidney injury and subsequent necessity for renal replacement therapy with a sensitivity and specificity of 0.69 and 0.81, respectively.⁹⁹ These numbers are promising, and will be the focus of several upcoming translational studies to determine its clinical application.

Although several studies were able to demonstrate a statistical association between biomarker level and acute kidney injury, it has been more difficult to prove that biomarker measurements alter clinical outcomes. A recent study comparing the use of a furosemide stress test (which involves giving an IV dose of furosemide followed by two hours of close urine output monitoring), was equally or more effective at predicting acute kidney injury and necessity of renal replacement therapy than several biomarkers, including neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and tissue inhibitor of metalloproteinases-2 and insulin-like growth factor binding protein-7.¹⁰⁰ This shows that we should not necessarily forget about previously used methods of acute kidney injury diagnosis, such as urine output and creatinine, but potentially find other modalities to complement and enhance their diagnostic capability. This is especially true in the perioperative period where urine output cannot be relied on as an accurate indicator of acute kidney injury.

The future of biomarkers remains an active and dynamic area of intense research, with translational studies merging biomarker “panels” with existing diagnostic criteria to improve detection and intervention. A promising recent study examined several renal biomarkers, including kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, and cystatin C, and failed to show that any of them alone were better at predicting the necessity of renal replacement therapy or hospital mortality than changes in creatinine.¹⁰¹ However, when the biomarkers were combined, along with a measure of change in creatinine, they could predict adverse events with excellent sensitivity and specificity. NephroCheck (Astute Medical, San Diego, CA, USA), was authorized by the US Food and Drug Administration in 2014 as a point-of-care urinary biomarker assay, to evaluate acute kidney injury development.¹⁰² This in vitro urine assessment quantitatively measures tissue inhibitor of metalloproteinases-2 and insulin-like growth factor binding protein-7 with reference intervals established in healthy adults and stable chronic morbid conditions without preexisting acute kidney injury.¹⁰³ Daubin et al. evaluated the NephroCheck in critically ill patients and determined acute kidney injury patients have a significantly higher score than patients without acute kidney injury (0.43 [0.07-2.06] versus 0.15 [0.07-0.35]; P = 0.027). However, the authors noted the NephroCheck was unable to distinguish between temporary and persistent acute kidney injury.¹⁰⁴

The future of point-of-care testing is bright, but significant confounding hurdles must be accounted for to validate the integration of point-of-care testing with biomarker panels. As more biomarkers become commercially available, translational research is necessary to evaluate the efficacy of biomarker panels and point-of-care testing to allow for early intervention, risk assessment, and diagnosis of acute kidney injury.

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.^{106,107,108,109} This continues to be an area of intense research with numerous ongoing translational and clinical trials (Supplementary Table 3). 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 non-vascular, 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 Table 4). 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 anti-inflammatory, anti-apoptotic, and anti-oxidative interventions to prevent and treat acute kidney injury.

N-acetylcysteine is a precursor of intracellular glutathione which 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. 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).¹¹² The anti-oxidative 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.^{111,113,114,115}

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 anti-inflammatory, 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 (RR 1.17, 95% CI: 0.98-1.39; P=0.076). Statin administration both pre- and post-surgery actually increased acute kidney injury risk when compared to preoperative statin therapy alone (p=0.040).¹¹⁸ A meta-analysis by Zhao et al. suggests 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 ICU or hospital, and in-hospital death.¹¹⁷ 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 anti-inflammatory, anti-apoptotic, and anti-oxidative properties across organ systems.^{119,120,121,122} Several studies have also demonstrated inhibition of inflammatory mediators including IL-1, IL-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.^{125,126,127,128} 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 (RR 0.44, 95% CI 0.26-0.76; P= 0.003) and cohort studies (RR 0.74, 95% CI 0.63-0.86; 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, multi-center trials will have to confirm these findings in order to establish the basis for its routine clinical use to prevent perioperative AKI.²⁹

Beyond pharmacologic intervention, opportunities for non-pharmacologic 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 where short, non-lethal 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 placed around the upper arm is expanded to 200 to 300 mm Hg pressure for a 5-minute duration, and then the pressure is released, followed by several repeat cycles. Remote ischemic preconditioning is thought to activate several pathways including systemic anti-inflammatory, 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.^132,133,134

Clinically, some controversy exists to 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. 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% versus 52.5%) with sham (absolute risk reduction 15%; 95% CI, 2.56-27.44; P= 0.02).¹³⁴ 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. and Theilmann et al.^136,137 Despite these exciting findings, the discussion of remote ischemic preconditioning and kidney protection remains inconclusive with other post-cardiac surgery outcomes trials unable to establish a protective effect.^138,139,140 The differences in these outcomes could be related to study design (e.g. the selection of primary endpoints), different patient populations (high risk versus 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 Due to the very non-invasive 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 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 (CRRT) and sustained low efficiency dialysis (SLED).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 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.^145,146,147 The ELAIN 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 AKIKI trial, which failed to show a reduction in mortality as a function of renal replacement therapy timing.^145,146,147 Most recently, the 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 12h) or delayed initiation (delay of 48h) 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 to the delayed initiation of renal replacement. Importantly, there was overall less use of renal-replacement therapy in the delayed-strategy group, as 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 amongst perioperative physicians for many decades. Historically, conventional regimens were characterized by the liberal administration of large intravenous-fluid volumes (e.g. more than 7 liters 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), time to recovery, and length of hospital stay.^{152,153,154–156} 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 RELIEF trial was an international, randomized, assessor-blinded trial which 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 liters versus 6.1 liters 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 versus 5.0% liberal fluid group (P <0.001).¹⁵¹ Brandstrup, in the editorial response to the Myles et al. RELIEF trial, eloquently surmised “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.^{107,158,159,160,161} Utilizing 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 in order to analyze the virtues of using goal-directed therapy to prevent acute kidney injury in non-cardiac surgical populations.

The OPTIMISE 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 ≥1.5 mg dl-1); 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 RR 0.84, 95% CI, 0.71-1.0; and an ARR, 6.8%, 95% CI, −0.3% to 13.9%; P = 0.07.¹⁶⁶ There was no difference in the secondary outcomes of seven-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 attribute the inconsistent benefits to an infused fluid volume that serves only to increase the unstressed capacity while the stressed volume and hemodynamics remain largely unchanged.¹⁶⁷ 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.^{168,169,170–172,173} 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.

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%; AOR 0.82; 95% CI, 0.70 - 0.95; P=0.01).¹⁷⁴ In this trial of non-critically ill adult patients, balanced crystalloids 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 OR 0.91; 95% CI, 0.84-0.99; conditional OR 0.90; 95% CI, 0.82-0.99; 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 to 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, as 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 Trial (6S) were landmark trials that compared the effects of resuscitation with hydroxyethyl starch and crystalloid solutions.^159,176 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 US 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. 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.”¹⁷⁸ Currently two prospective, randomized, controlled, double-blind trials are underway, the PHOENICS trial (NCT03278548) and TETHYS trial (NCT03338218). Currently, hydroxyethyl starch should be administered with caution in critically ill patients until new evidence from 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 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. While albumin appears safe, it is 2 to 5 times more expensive than crystalloid, and offers no significant difference in patient outcomes.¹⁵⁹ Another colloid alternative to crystalloid extensively utilized worldwide is gelatin, a degradation product of collagen.¹⁸¹ Gelatin-based solutions are similarly costly (>10 times crystalloid) with evidence of safety and efficacy from large prospective randomized controlled trials surprisingly limited.¹⁸² Moeller et al. found risk ratios after gelatin administration were 1.15 (95% CI, 0.96-1.38) for mortality, 1.10 (0.86-1.41) for requiring allogeneic blood transfusion, 1.35 (0.58-3.14) for acute kidney injury, and 3.01 (1.27-7.14) for anaphylaxis.¹⁸³ 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.¹⁸³ 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 12g/dl for female and less than 13 g/dl for male patients, is linked with perioperative acute kidney injury in both cardiac and non-cardiac surgery patients.^184,185,186 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 pro-inflammatory state.^28,76,186,92 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. performed a prospective analysis of implementing an Electronic Health Record screening and decision matrix at Cincinnati Children’s Hospital.¹⁸⁷ 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. retrospectively reviewed records of neonates who underwent congenital heart surgery at Arnold Palmer Hospital for Children.¹⁸⁹ 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; OR, 4.48 (95% CI, 1.02-19.63).¹⁸⁹ Further, a difference in peak lactate (P = 0.002), inotropic score (P = 0.02), and duration of mechanical ventilation (P = .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.¹¹⁰ 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 (OR 1.14, 95% CI, 1.02 to 1.28; P=0.02), without reducing the prevalence of acute kidney injury. Based on the NICE-SUGAR 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 of (110-149 mg/dl) or the statement from the European Renal Best Practice based on guidelines from the Kidney Disease Improving Global Outcomes of (140-180 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, the PrevAKI trial was conducted to analyze the value of implementing a “Kidney Disease Improving Global Outcomes bundle” in cardiac-associated acute kidney injury.¹⁹² In the PrevAKI Trial, Meersch et al. 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.¹⁹² 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%; ARR 16.6%, 95% CI 5.5-27.9%; P = 0.004). A Kidney Disease Improving Global Outcomes bundle enhanced hemodynamic parameters (P < 0.05), reduced hyperglycemia (P < 0.001) as well as 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. Göcze et al. 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.¹⁹³ This rapid urinary biomarker assessment panel significantly improved risk stratification (p<0.001). Further, in combination with clinical parameters, Göcze et al. successfully allowed for early initiation of renal protective measures (i.e. hemodynamic optimization) and escalation of care prior to the development of acute kidney injury.¹⁹³ 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.

Conclusions

The development of acute kidney injury has important implications for recovery and outcomes of surgical patients. Decreased urine output and an increase in serum creatinine concentrations are classically used to diagnose acute kidney injury. The search for earlier and more specific biomarkers is an area of intense research. We believe that their introduction into routine clinical praxis is eminent. A uniform classification of acute kidney injury by the Kidney Disease Improving Global Outcomes workgroup has allowed for advances in medical practice, research, and public health. Promising therapeutic advances to prevent or treat perioperative acute kidney injury continue to be a challenge. Although previous clinical trials have been disappointing, new preclinical and clinical interventions are targeting novel pathophysiology aspects of acute kidney injury inflammatory and oxidative stress response, endothelial dysfunction, microRNA modulators, as well as renal-specific vasodilators. Clinical research continues to explore our evolving understanding of fluid balance and type of fluid used in the resuscitation of the perioperative patient, renal replacement therapy, and alternative therapeutic approaches, such as remote ischemic preconditioning.

Advancements in risk stratification systems, with the use of instantaneous analytics, has the potential to emerge as an effective means of acute kidney injury risk assessment in the perioperative setting.¹⁹⁴ This combination of clinical parameters, biomarkers, and electronic medical record risk stratification will allow timely identification of subclinical acute kidney injury and initiation of renal protective measures. Once identified, a phased approach to more complex and costly evaluations can be integrated into existing low-cost and low-risk therapies.¹⁹⁴ The importance of rapid diagnosis cannot be overstated. It extends the opportunity for intervention, preventing the progression and development of subclinical injury to acute kidney injury. Further multicenter trials and translational research are needed to further define or establish appropriate therapeutic and diagnostic opportunities in acute kidney injury. The historic premise of “do no harm” continues to be a cornerstone in acute kidney injury management, including hemodynamic monitoring approaches, fluid replacement therapy, and avoidance of nephrotoxic agents.

Appendix 1:

Inclusion Criteria to Accompany Supplementary Table 3

NCT	Inclusion criteria
NCT02698930	patients with infective endocarditis patients who are scheduled to undergo open heart surgery
NCT02607163	the patients undergoing ascending, arch and/or proximal descending aorta surgery with cardiopulmonary bypass 20 - 100 yrs. old
NCT02875873	Need for plasma expansion, and the clinician considers that Plasma-Lyte® or 0.9% saline are equally appropriate for patients, with no specific indications or contraindications for any of the fluids or for rapid or slow infusion. Patients not expected to be discharged on the day after their admission. At least one of the following risk factors for acute renal injury: Age ≥ 65 years Hypotension (mean arterial pressure [MAP] < 65 mmHg or systolic blood pressure [SBP] < 90 mmHg) or use of vasopressors Sepsis Use of invasive mechanical ventilation or of continuous noninvasive mechanical ventilation (including high-flow nasal cannula) > 12 hours Oliguria (< 0.5 mL/kg/hour for ≥ 3 hours) Serum creatinine ≥ 1.2 mg/dL for women or ≥ 1.4 mg/dL for men Liver cirrhosis or acute liver failure
NCT03277677	Age ≥ 18 years old Who need fluid resuscitation in the Emergency Room (ER) Who have fulfilled the criteria for sepsis/septic shock within the previous 24 hours according to sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection Patients with infection and resulted from a hosťs systemic inflammatory response syndrome (SIRS) to infection are defined as sepsis if meet the criteria 2 or more of Temperature >38°C or <36°C Heart rate >90/min Respiratory rate >20/min or PaCo2 <32 mm Hg (4.3 kPa) White blood cell count >12000/mm3 or <4000/mm3 or >10% immature bands. Patient who have Septic shock is a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality. Patients with septic shock can be identified with a clinical construct of sepsis with persisting hypotension requiring vasopressors to maintain MAP ≥65 mm Hg and having a serum lactate level >2 mmol/L (18 mg/dL) despite adequate volume resuscitation. AND where informed consent is obtainable either from the patient or by proxy (first degree relative, spouse) if patients arenť in fully conscious status (e.g. comatose, drowsiness, irritable).
NCT03188614	Shock patients
NCT02980003	Consecutive patients scheduled for coronary angiography and/or angioplasty; eGFR <60 mL/min/1.73 m2, but >15 mL/min/1.73 m2 (MDRD formula).
NCT02799368	Individuals aged 18 years or older with eGFR < 45 mL/min/1.73m2 or eGFR < 60 mL/min/1.73m2 who have at least one condition Diabetes mellitus Age > 60 year Able and willing to provide informed consent
NCT02793661	Age > 18 years old 15 ml/min/m2 ≤ eGFR ≤ 40 ml/min/m2 High volume contrast-requiring cardiovascular procedures (estimated contrast volume > 3 times eGFR value) Patient has agreed to all FU testing
NCT02974946	Patients undergoing surgery (elective or in-house urgent) Patient 18 years old and over Patient able to give written consent Patient at risk of developing AKI after cardiac surgery (at least one factor) Diabetics (IDDM or NIDDM) with normal kidney function pre-op Patients with eGFR 20-60 Patients undergoing combined cardiac procedures when the CPB time is likely to exceed 120 minutes Patients with Hb of 12.5 g/dl or below Logistic Euroscore of 5 and above Patient not involved with another study
NCT01866800	Subject is 65 years old who is able and willing to give an informed consent. Patients undergoing planned trans-femoral TAVI. Calculated eGFR below 60ml/min/1.73m2 (MDRD)
NCT03509935	Age equal or superior to 18 years. Major surgeries requiring ICU admission associated with one of the following criteria: Use of vasoactive drugs Use of inotropic drugs Mean blood pressure less than 65 mmHg or SBP <90 mmHg. Hyperlactatemia> 2 mmol / L Heart rate> 90 bpm. Invasive mechanical ventilation required for at least 6 hours at the time of inclusion. Hypoxia: satO2 <92% in ambient air. Length of surgery greater than 4 hours. Request for transfusion of blood products in a surgical block Oliguria during procedure, defined as diuresis <0.5 ml/kg/h.
NCT02481518	Age > 18 years Eastern Cooperative Oncology Group score 0-2 First Diagnosed Head and neck cancer and plan for treatment with cisplatin Serum creatinine ≤1.5 mg/dl or eGFR≥60(ml/min/1.73 m2)
NCT03056248	A male or female greater than 18 years Stable renal function with creatinine change <0.3mg/dl in the preceding 1 month prior to scheduled surgery Procedure such as aortic valve surgery, mitral valve surgery, coronary artery bypass grafting, or combination of the above mentioned procedures Have estimated glomerular filtration rate greater than or equal to 15ml/min/ 1.73m2 as calculated by chronic kidney disease Epidemiology Collaboration (CKD-EPI) formula
NCT03331146	Patients CCFS score ≥ 6 Patients admitted to UAB cardiac intensive care unit (CICU) following elective cardiac surgery with cardiopulmonary bypass under general endotracheal anesthesia 19 years old Estimated glomerular filtration rate (eGFR) ≥ 30 ml/min/1.73 m2
NCT03476460	Patients >65 years, Both sexes, With at least one of the following criteria: diabetes or stable heart failure or chronic kidney disease (estimated glomerular filtration rate between 30 and 60 ml/min), Undergoing CT scan with contrast Written informed consent.
NCT03396770	On-pump cardiac surgery; Informed and written consent of the patient or inclusion according to the emergency procedure; Affiliated patient or beneficiary of a social protection
NCT02531412	Patients admitted to the ICU in the immediate postoperative period (first 24 hours) of major surgery, defined as involving general anesthesia, ventilation, opening of large cavities (cranial, thoracic, abdominal). Patients with informed consent signed by them or their responsible relative. Patients who are likely to survive at least 48 hours after admission to the ICU. Patients who have measured "baseline" creatinine before UCI admission, in the last three months.
NCT03206658	Patients older than 18 years of age Patients critically ill requiring invasive mechanical ventilation with some organic failure in addition to respiratory failure. Organic scale failure will be categorized according to the (Sequential Organ Failure Assessment) scale and will be considered present when there is a score ≥2 in some organ / system, except renal. Patients with normal renal function or chronic kidney disease KDOQI 1-3 Patients without acute renal injury according to the (acute kidney injury network) AKIN criteria. Normal serum K levels (less than or equal to 5 mEq / L). Women with (a) negative pregnancy test, (b) surgical sterilization, or (c) completed menopause. Systolic blood pressure> 90 mmHg and mean arterial pressure> 70 mmHg. Diuresis in the first 6 hrs. from admission to intensive therapy> 0.5 ml / kg / hr. The patient will give written and signed informed consent prior to any specific study procedure. However, if a patient cannot do so before, his or her legal representative the Institute may give written informed consent.
NCT03329443	patients admitted to angiography unit over 18 informed consent
NCT01275729	18 yrs. or older increase in serum creatinine of 0.3 mg/dl within 48 hours or an increase of greater than or equal to 150% from baseline or sustained oliguria (UOP < 0.5 cc/kg/hr. for 6 hours with the last 48hours) written informed consent patients with an indwelling bladder catheter
NCT02983422	Patients with acute injury (AKI) with no lack of circulating volume (central venous pressure >8cmH2O)
NCT02771509	Patient is either male or female ≥ 18 years. Patient has provided written informed consent, and is willing and able to comply with the requirements of the study protocol, including screening procedures. Patient must be scheduled for and undergo a non-emergent cardiac surgical procedure involving CPB. Eligible procedures include: Coronary artery bypass graft (CABG) alone Aortic valve replacement or repair alone, with or without aortic root repair Mitral, tricuspid, or pulmonic valve replacement or repair alone Combined replacement of several cardiac valves CABG with aortic, mitral, tricuspid, or pulmonic valve replacement or repair CABG with combined cardiac valve replacement or repair. Patient must have the following risk factor(s) for AKI prior to surgery: Estimated glomerular filtration rate (eGFR) of ≥ 20 and < 30 ml/min/1.73m2, or eGFR ≥ 30 and < 60 mL/min/1.73m2 and ONE of the following Additional Risk Factors (other than age ≥ 75 years), or eGFR ≥ 60 ml/min/1.73m2 and TWO of the following Additional Risk Factors eGFR will be calculated using the abbreviated MDRD equation (MDRD-4, often referred to as the Levey equation): eGFR = 186.3 x sCr-1.154 x Age-0.203 x [0.742 if Female] x [1.212 if Black] Additional Risk Factors: Combined valve and coronary surgery Previous cardiac surgery with sternotomy Left ventricular ejection fraction (LVEF) < 35% by invasive or noninvasive diagnostic cardiac imaging within 90 days prior to surgery Diabetes mellitus requiring insulin treatment Non-insulin-requiring diabetes with documented presence of at least moderate (+2) proteinuria on urine analysis (medical history or dipstick) Documented NYHA Class III or IV within 1 year prior to index surgery Age ≥ 75 years can be considered an Additional Risk Factor only for patients with eGFR ≥ 60 ml/min/1.73m2. Patient must have presented for surgery without prior evidence of active renal injury defined as no acute rise in sCr > 0.3 mg/dL or no 50% increase in sCr between the time of Screening and pre-surgery. Patienťs body mass index (BMI) < 35 at Screening. Female patients of childbearing potential (including perimenopausal women who have had a menstrual period within 1 year): Must have a negative serum pregnancy test prior to surgery. Must agree (1) to use 2 forms of effective birth control regimen (at least one-barrier method) during the 90-day study period or (2) to maintain total abstinence throughout the 90-day study period. Male patients must agree to use condoms or other suitable means of pregnancy prevention such as abstinence during the 90-day study period.
NCT02474667	All patients must provide written informed consent using an Institutional Review Board/Independent Ethics Committee (IRB/IEC) approved consent form, and must understand and be willing and able to comply with the requirements of the study, including screening procedures and all required study visits. Males and females ≥ 18 years of age. Oligoanuric renal failure (less than 200 mL of UO per day) requiring hemodialysis or peritoneal dialysis initiated at least 3 months prior to transplantation. Patient is to be the recipient of a first kidney transplant from a deceased donor. Study drug can be administered starting within 30 hours after restoration of blood flow to the engrafted kidney. Body mass index < 35 based on dry weight. Dry weight and height parameters obtained within 7 days prior to study entry may be used. Estimated donor organ cold ischemia time less than 30 hours (for PMP kidneys less than 40 hours). Females of childbearing potential (including perimenopausal women who have had a menstrual period within 1 year): Must have a negative serum pregnancy test prior to transplantation. Must agree to use 2 forms of effective birth control regimen (at least one-barrier method) during the initial 30-day study period OR agree to maintain total abstinence throughout the initial 30-day study period. Male patients must agree to use condoms or other suitable means of pregnancy prevention such as abstinence during the initial 30-day study period. Patient has poor renal function in the first 24 hours post-transplantation based on an average UO of less than 50 mL per hour over any 8 consecutive hours, to maximize the likelihood that the patient requires dialysis within the first 7 days post-transplant, irrespective of pre-transplant donor and recipient risk factors. Reason for low UO is not due to structural or vascular abnormalities which, when indicated should be confirmed with a renal ultrasound with Doppler study and/or vascular or urinary tract contrast studies.
NCT02808351	Planned diagnostic coronary or peripheral artery angiography Type 2 diabetes mellitus CKD stages ≥2 Statin naive, or not on statin treatment for at least 14 days Withdrawal metformin or aminophylline for 48h before angiography Total iodixanol volume
NCT02869347	Estimated glomerular filtration rate (eGFR) of <50 ml/min/1.73m2 At least one of the following risk factors: diabetes mellitus, age at least 75 years, anemia (baseline hematocrit value less or equal 39% for men and less or equal 36% for women), congestive heart failure class III or IV by New York Heart Association classification, history of pulmonary edema.
NCT02962102	Age ≥ 18 Admitted to the ICU within 48h prior to enrollment Likely to remain in the ICU (alive) for ≥72h Naso/orogastric tube or ability to swallow High risk of severe AKI
NCT03401710	All adult patients > 18 years old hospitalized with acute kidney injury and anemia
NCT03007537	Preoperative hemoglobin＜130g/L; Surgery: valve, coronary artery bypass graft or surgery for congenital heart diseases; Volunteers with informed consent.
NCT02665377	De novo Htx. Preoperative GFR > 30ml/min/1,73m2. >18 years old. Written consent.
NCT02836899	Provide written informed consent Age ≥ 18 years of age Elective cardiac or aortic surgery with CPB>90 minutes Stable pre-operative renal function without evidence of plasma creatinine level increase of ≥ 0.3 mg/dL over the prior 3 months and without renal replacement therapy (RRT). Clinical evidence of endothelial dysfunction assessed by a specifically designed questionnaire.
NCT02664753	The emergency inclusion procedure was correctly applied according to French law (signature of consent form by a patient-designated trusted person or a family member, or a medical decision to proceed with patient inclusion if the latter two persons are unavailable) ---- OR ---- signature of the consent form by the patient The patient must be insured or beneficiary of a health insurance plan The patient is at least 18 years old The patient has been admitted to a participating ICU for severe sepsis or septic shock within the last 72 hours The patient has sepsis or septic shock according to international criteria SEPSIS 3 (Singer et al, The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3); JAMA 2016). The patient has acute renal insufficiency with an KDIGO score of 3 The patient has started continuous renal replacement therapy (CRRT) or intermittent renal replacement therapy (IRRT) within the past 24 hours, or will start RRT (CRRT or IRRT) within the next 24 hours
NCT02531724	Patients in the cardiothoracic intensive care after cardiac surgery with cardiopulmonary bypass Acute kidney injury, defined as increase in S-creatinine 50% or 27 mol/L Normal S-creatinine before surgery
NCT01720030	Clinically diagnosed adult patients with AKI
NCT03510897	Male or female, age ≥ 18 years old At risk for AKI following cardiac surgery on the basis of at least one of the following pre-operatively assessed risk factors: Reduced renal function Diabetes with ongoing insulin treatment Albuminuria Undergoes non-emergent open chest cavity cardiovascular surgeries, with use of cardiopulmonary bypass (CPB), with or without hypothermic circulatory arrest
NCT03403751	Has either suspected or documented diagnosis of abdominal sepsis requiring treatment with parenteral antibiotics and planned or completed surgical (laparotomy or laparoscopy) or interventional radiologic procedures within 24 hours of evaluation by medical personnel. Recommended surgical or interventional radiologic procedures be performed with 12 hours of evaluation by medical personnel. Initial diagnosis of AKI Stage 2 or 3 according to KDIGO AKI criteria established either upon presentation to medical care in those patients with suspected abdominal sepsis or in those patients in whom the initial diagnosis of AKI is established during the 48-hour period from the suspected diagnosis of abdominal sepsis. Study medication must be administered within 6 hours of confirmation of onset of Stage 2 or 3 AKI as established at the study site, under the following criteria: After the decision is made by the attending surgeon at the study site for a surgical or interventional radiology procedure for the abdominal infection OR After confirmed diagnosis of abdominal infection has been established by a surgical or interventional radiology procedure
NCT03526367	Age 18-80 years old The STEMI patients within 12 h of onset (or within 12-24 h of onset with chest pain and persistent ST-segment elevation or the presence of a new LBBB); The patients planned primary PCI; At least one of the following:
NCT03273751	Adult patients scheduled to undergo open, laparoscopic, or robot-assisted laparoscopic partial nephrectomy Normal contralateral renal function was defined as split renal function of >40% as determined by preoperative Tc-99m DiethyleneTriamine Pentaacetic Acid (DTPA) kidney scan Written informed consent
NCT03236441	Patient with non-ST elevation myocardial infarction or unstable angina Referral for cardiac catheterization and percutaneous coronary intervention Contrast-induced acute kidney injury risk score of ≥11
NCT02997748	Patients who are scheduled to undergo cardiac surgery with cardiopulmonary bypass Cleveland Clinic Score >=6
NCT02518087	Patients with more than 18 years old. Non emergent cardiac surgery patients requiring expected CPB time > 60 minutes: double valve replacement or valve replacement plus coronary arterial bypass graft (CABG). Written informed consent from patient or legal surrogates.
NCT03384875	Scheduled for non-emergent cardiac surgery requiring CPB for i) heart valve replacement with any other procedure, without hypothermic circulatory arrest (HCA), or ii) aortic reconstruction with or without another procedure, with HCA
NCT02250131	Patients undergoing cardiac operations with CPB. Expected CPB duration > 90 minutes.
NCT03373318	Adult patients (> 18 years) scheduled for cardiopulmonary bypass surgery with Glomerular Filtration Rate (GFR) greater than or equal to 60 and left ventricular ejection fraction greater than or equal to 40%
NCT02568722	Age ≥ 18 years Admission to an intensive care unit (ICU) Evidence of kidney dysfunction [serum creatinine ≥100 µmol/L (women) and ≥ 130 µmol/L (men)] Evidence of severe AKI defined by at least 1 of the following 3 criteria: i) ≥ 2-fold increase in serum creatinine from a known pre-morbid baseline or during the current hospitalization; OR ii) Achievement of a serum creatinine ≥ 354 µmol/L with evidence of a minimum increase of 27 µmol/L from pre-morbid baseline or during the current hospitalization; OR iii) Urine output < 6.0 mL/kg over the preceding 12 hours
NCT02937935	Patients with cirrhosis (diagnosed based on clinical, biochemical, radiological or histological diagnosis) with stage 3 Acute Kidney Injury defined as an increase of serum creatinine to more than 300 fold and more than 4 mg/dl.
NCT03343340	- Patients with ACLF defined based on APASL criteria with septic shock associated AKI
NCT03396757	All of the following criteria must be fulfilled to be included in the observational study (first stage): Adults (>18 years) Hospitalized in a study ICU. Evidence of acute kidney injury compatible with the diagnosis of acute tubular necrosis in a context of ischemic or toxic aggression and who receive (or received for the same episode) invasive mechanical ventilation and/or catecholamine infusion. Acute kidney injury stage 3 of KDIGO classification defined by at least one of the following criteria: serum creatinine concentration of more than 4 mg/dl (354 µmol/liter) or greater than 3 times the baseline creatinine level, anuria (urine output of 100 ml/day or less) for more than 12 hours, oliguria (urine output below 0.3 ml/kg/h or below 500 ml/day) for more than 24 hours. To be randomized (randomization stage), supplemental criteria must be fulfilled. These criteria can appear either immediately after inclusion in the observational stage, or during the follow-up of the patient in the observational stage, in the absence of any non-inclusion criteria (listed below) at the time of randomization: Oliguria/anuria (urine output <0.3 ml/kg/h or <500 ml/day) for more than 72 hours or serum urea concentration comprised between 40 and 50 mmol/l. Affiliation to a social security regime
NCT02937961	Patients with Cirrhosis with septic shock associated AKI (Acute Kidney Injury) stage 3 AKIN/KDIGO stage 2.
NCT03175328	patients will eligible if they are adults (18 years of age or older) who were admitted to the ICU with SAKI at KDIGO stage 2.
NCT01062984	Age 18 or older and able to sign consent (or surrogate). Must have been referred to the inpatient Nephrology consult service for evaluation of AKI. Expected survival of at least 48 hours.
NCT02669589	Critically ill patients with clinical indication for CRRT (clinical decision to use continuous RRT due to hemodynamic instability) Or Severe acute kidney injury (KDIGO 3-classification) despite optimal resuscitation At least one of the following conditions Sepsis or septic shock Use of catecholamines (norepinephrine or epinephrine ≥ 0.1 µg/kg/min or norepinephrine ≥ 0.05 µg/kg/min + dobutamine (any dose) or norepinephrine ≥ 0.05 µg/kg/min + vasopressin (any dose) or epinephrine ≥ 0.05 µg/kg/min + norepinephrine ≥ 0.05 µg/kg/min) Refractory fluid overload: worsening pulmonary edema: PaO2/FiO2 < 300 mmHg and/or fluid balance > 10% of body weight) 18-90 years old Intention to provide full intensive care treatment for at least 3 days Written informed consent of the patient or the legal representatives or the authorized representative or the inclusion due to an emergency situation
NCT02384525	body temperature < 36 °C or > 38 °C heart rate > 90 BPM respiratory rate > 20 or aPaCO2 < 32 mmHg on ABG White blood cell count < 4,000 cells/mm3 or > 12,000 cells/mm3 or band forms (immature white blood cells) ≥10% Evidence of infection WBCs in normally sterile fluid Perforated viscus radiologically proven infection more than Injury stage in AKI according to RIFLE criteria septic AKI which is not explained by other cause patients signed a written informed consent.
NCT03329313	Age > 18 years old Acute kidney injury requiring renal replacement therapy Dialysis type: on line sustained low efficiency dialysis -filtration SOFA score > 5 Sodium serum level between 135 and 145mmol/l
NCT03438877	Age older than 18 years; Be diagnosed as AKI according to KDIGO recommendation; Having indications for renal replacement therapy.
NCT02786277	Phase 1 of the trial will enroll all inpatients at study hospitals who meet Kidney Disease: Improving Global Outcomes Stage 1 Creatinine criteria for AKI Phase 2 and phase 3 of the trial will use a machine-learning based algorithm to target enrollment to those patients expected to derive benefit from alerting, based upon our experience in the prior trial period.
NCT02753751	Adult ≥ 18 years admitted to a participating study hospital Acute Kidney Injury as defined by KDIGO consensus creatinine criteria (0.3mg/dl increase in serum creatinine over 48 hours or 50% relative increase over 7 days).
NCT02793167	adult patients with an Alert for AKI (based on KDIGO guidelines)
NCT02771977	Acute Kidney Injury based upon the Kidney Disease: Improving Global Outcomes creatinine criteria (a 0.3mg/dl increase over 48 hours or 50% increase over 7 days) and exposure within the past 24 hours to one of the following classes of medications: Non-steroidal anti-inflammatory drug Renin Angiotensin Aldosterone System Antagonists Proton Pump Inhibitors
NCT01621152	All patients who are admitted in adult ICUs in Mayo Clinic Rochester Foley catheter for hourly UOP measurement
NCT03219398	Subjects aged 18-60 years old undergoing laparoscopic surgery, with American Society of Anesthesiologist (ASA) 1, body mass index 18-25. Patients who agreed to participate in this study and sign informed consent.
NCT03534141	Liver transplantation from a donor after neurologic determination of death
NCT02928887	age greater than or equal to 18 years undergoing cardiopulmonary bypass surgery
NCT02643745	age >18 years patients undergoing scheduled cardiac surgery Informed consent
NCT03590028	Age >18 years old Initial ESTOP AKI score ≥0.12 within the last 8 hours.
NCT02643745	age >18 years patients undergoing scheduled cardiac surgery Informed consent
NCT03244514	Adult patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) Urinary [TIMP-2] * [IGFBP7] >= 0.3 4h after CPB Written informed consent
NCT03178435	All adult patients (≥18 year old) admitted to the intensive care unit and do not fulfill the criteria for the diagnosis of AKI by Kidney Disease Improving Global Outcome (KDIGO) definition
NCT03236103	Adult patients with VAD in place who are admitted to the hospital for acute medical illness during the study period. For those with multiple admissions during the study period only the first admission will be studied. Patients who are able to give consent. In case of patients that are mentally impaired we will obtain consent from power of attorney and when patients regain intact mental capacity, we will reobtain consent from the patient.
NCT03564314	Adult patients (18 years of age and older) who develop hospital-acquired acute kidney injury on identified general and vascular surgery units in Alberta
NCT02726620	60 years and older Inpatients Scheduled for a non-cardiac surgical procedure under general or central neuraxial anesthesia
NCT02915575	Age ≥ 18 yrs. At least a doubling of serum creatinine during hospitalization (including need for dialysis) Have a primary care physician (PCP) No nephrologist follow up arranged after hospital discharge
NCT02483039	Age ≥ 18 yrs. Kidney Disease Improving Global Outcomes (KDIGO) stage 2 AKI and above (including need for dialysis)
NCT03165552	All patients aged over 18 registered with the practice
NCT03015623	AKI, as determined by the Investigator based on his/her clinical judgment Able to tolerate indwelling intravascular access Has tolerated Continuous Renal Replacement Therapy for at least 12 hours prior to IP treatment Likely to require Continuous Renal Replacement Therapy for at least an additional 48 hours Ability to give informed consent
NCT02933892	Patients scheduled to undergo non-emergent cardiac catheterization at University Medical Center Hospital, Lubbock, TX from January 2016 to January 2018. Emergent cardiac catheterizations will be defined as a catheterization scheduled < 24 hours from a cardiac event. Patients willing to be randomized to TFA or TRA procedure. Patients signed and dated the informed consent agreeing to participate in the study. Patients with chronic kidney disease, defined as eGFR = 15-59mL/min defined by the MDRD formula. (eGFR is a standard of care measurement for all patients undergoing coronary intervention.). Patients ages 18-88 years old.