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Estrogen Protects against Renal Ischemia-Reperfusion Injury by Regulating Th17/Treg Cell Immune Balance
research-article
Author(s):
Yang Zhang
1
,
2
,
3 ,
Yuechen Chang
2 ,
Ziwei Han
2 ,
Ketao Ma
2 ,
Xiansi Zeng
1
,
,
Li Li
1
,
Publication date (Electronic):
6 October 2022
Journal:
Disease Markers
Publisher:
Hindawi
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Abstract
Inflammation is a critical mediator of renal ischemia-reperfusion (I/R) injury (IRI), and T lymphocytes exert a key role in the renal IRI-induced inflammation. Connexin 43 (Cx43) is related to the maintenance of T lymphocyte homeostasis. Various preclinical researches have reported that estrogen is a renoprotective agent based on its anti-inflammatory potential. The present research is aimed at studying the role of T lymphocytes activated by Cx43 in 17 β-estradiol-mediated protection against renal IRI. Female rats were classified into six groups: control rats, I/R rats, ovariectomized rats, ovariectomized I/R rats, and ovariectomized rats treated with 17 β-estradiol or gap27. Levels of serum creatinine (Scr) and blood urea nitrogen (BUN) and Paller scoring were dramatically increased in I/R rats, especially in ovariectomized rats. By contrast, these indicators were markedly decreased by administering estradiol or gap27. Immunofluorescence staining revealed that CD4 + T cells infiltrated kidney tissues in the early stage of IRI. In both peripheral blood and renal tissue, the proportion of CD3 +CD4 + T cells and ratio of CD4 + to CD8 + were high in I/R rats, especially in ovariectomized rats. The proportion of CD3 +CD8 + T cells was low in peripheral blood but high in renal tissues. Administration of estrogen or Gap27 reversed these effects. IL-17 levels in both serum and tissue homogenate were significantly increased in ovariectomized rats subjected to I/R but significantly decreased in estrogen or gap 27 treated rats. The opposite trend was observed for IL-10 levels. Correlation analysis demonstrated that IL-17 was correlated positively with BUN, Scr, and Paller scores, while IL-10 was negatively correlated with these indicators. Western blot showed that Cx43 expression was markedly increased in the peripheral blood T lymphocytes of I/R rats, especially ovariectomized rats. After intervention with estrogen and gap27, Cx43 expression was significantly downregulated. These findings indicate that Cx43 may participate in the regulation of Th17/Treg balance by estrogen against renal IRI.
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Most cited references48
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Immune cells in experimental acute kidney injury.
Hye Jang, Hamid Rabb (2015)
Acute kidney injury (AKI) prolongs hospital stay and increases mortality in various clinical settings. Ischaemia-reperfusion injury (IRI), nephrotoxic agents and infection leading to sepsis are among the major causes of AKI. Inflammatory responses substantially contribute to the overall renal damage in AKI. Both innate and adaptive immune systems are involved in the inflammatory process occurring in post-ischaemic AKI. Proinflammatory damage-associated molecular patterns, hypoxia-inducible factors, adhesion molecules, dysfunction of the renal vascular endothelium, chemokines, cytokines and Toll-like receptors are involved in the activation and recruitment of immune cells into injured kidneys. Immune cells of both the innate and adaptive immune systems, such as neutrophils, dendritic cells, macrophages and lymphocytes contribute to the pathogenesis of renal injury after IRI, and some of their subpopulations also participate in the repair process. These immune cells are also involved in the pathogenesis of nephrotoxic AKI. Experimental studies of immune cells in AKI have resulted in improved understanding of the immune mechanisms underlying AKI and will be the foundation for development of novel diagnostic and therapeutic targets. This Review describes what is currently known about the function of the immune system in the pathogenesis and repair of ischaemic and nephrotoxic AKI.
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Mechanisms and therapeutic targets of ischemic acute kidney injury
Acute kidney injury (AKI) due to renal ischemia reperfusion (IR) is a major clinical problem without effective therapy and is a significant and frequent cause of morbidity and mortality during the perioperative period. Although the pathophysiology of ischemic AKI is not completely understood, several important mechanisms of renal IR-induced AKI have been studied. Renal ischemia and subsequent reperfusion injury initiates signaling cascades mediating renal cell necrosis, apoptosis, and inflammation, leading to AKI. Better understanding of the molecular and cellular pathophysiological mechanisms underlying ischemic AKI will provide more targeted approach to prevent and treat renal IR injury. In this review, we summarize important mechanisms of ischemic AKI, including renal cell death pathways and the contribution of endothelial cells, epithelial cells, and leukocytes to the inflammatory response during ischemic AKI. Additionally, we provide some updated potential therapeutic targets for the prevention or treatment of ischemic AKI, including Toll-like receptors, adenosine receptors, and peptidylarginine deiminase 4. Finally, we propose mechanisms of ischemic AKI-induced liver, intestine, and kidney dysfunction and systemic inflammation mainly mediated by Paneth cell degranulation as a potential explanation for the high mortality observed with AKI.
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Cardiac and Vascular Surgery–Associated Acute Kidney Injury: The 20th International Consensus Conference of the ADQI (Acute Disease Quality Initiative) Group
Mitra Nadim, Lui Forni, Azra Bihorac … (2018)
Introduction Acute kidney injury (AKI) occurs in 7% to 18% of hospitalized patients and complicates the course of 50% to 60% of those admitted to the intensive care unit, carrying both significant mortality and morbidity.1 Even though many cases of AKI are reversible within days to weeks of occurrence, data from multiple large observational and epidemiological studies over the past decade suggest a strong association between AKI and subsequent chronic kidney disease (CKD) and end‐stage renal disease (ESRD).2, 3 Patients with AKI who receive renal replacement therapy (RRT) are >3 times more likely to develop ESRD than those who do not. This rise in the number of patients who receive treatment for ESRD is a global phenomenon associated with considerable patient costs, effects on quality of life, and economic impact on society as a whole. In developing countries, most people with kidney failure have insufficient access to dialysis and/or kidney transplantation. Consequently, the development of effective approaches to the prevention, early recognition, and management of AKI is necessary to reduce the burden of CKD and ESRD.4 Millions of patients undergo cardiac and vascular surgery (CVS) every year in developed countries alone. AKI is a common perioperative complication for patients undergoing both cardiac surgery5, 6, 7, 8, 9 and vascular surgery,9, 10, 11 occurring in 20% to 70% of cases depending on the type of surgery and the definition of AKI used. In addition, more and more of these patients who receive complex CVS are elderly with multiple comorbidities, which predispose to the development of AKI and potentially hasten progression to ESRD. Mortality rates among cardiovascular patients undergoing RRT are between 40% and 70%, and mortality is associated with both the severity of the initial insult and the number of episodes of AKI occurring during the hospital admission.12, 13 In recent years, there have been considerable advances in our understanding of CVS‐associated AKI (CVS‐AKI). Nevertheless, despite the high prevalence, there is little consensus about how best to prevent or treat CVS‐AKI. The aim of this consensus process was to review the current literature on CVS‐AKI; to create the basis for its definition; to develop an initial understanding of its pathophysiology; to explore the potential use of biomarkers for its diagnosis; to critique current literature in the fields of prevention and treatment, so as to make recommendations for clinical practice; and to propose a framework for future research. Methods ADQI (Acute Disease Quality Initiative) is an ongoing process that produces evidence‐based recommendations on the diagnosis, prevention, and management of AKI and on various issues concerning acute dialysis and fluid management (http://www.adqi.org). The conference chairs of the 20th ADQI consensus committee (M.K.N., J.A.K., V.G., C.R., and L.G.F.) convened a panel of experts representing the relevant disciplines—cardiac surgery, vascular surgery, cardiology, nephrology, anesthesiology, and critical care—from North America, Europe, and Asia to discuss the issues related to CVS‐AKI (Data S1). The conference took place June 16 to 19, 2017, and the format of the meeting was a 2.5‐day modified Delphi method to achieve consensus, as described previously (Data S1).14 Results and Discussion Pathophysiology The pathophysiology of CVS‐AKI is complex and poorly understood. Although patients undergoing cardiac and major vascular surgery may experience similar insults to the kidneys, many distinctions exist between these populations. Notable differences are the relative influence of cardiac dysfunction (greater in cardiac surgery) versus warm ischemia–reperfusion injury to the kidneys and increased abdominal pressures (both greater with vascular surgery). Finally, the effect of the cardiopulmonary bypass (CPB) circuit itself in the case of cardiac surgery is notable. Although animal models15, 16 of CPB and cardiac surgery–associated AKI (CS‐AKI) exist, they have not been widely applied to the study of AKI. Furthermore, although clinical studies have been conducted for >40 years, numerous knowledge gaps remain. Observational studies, animal and cell culture work, and mathematical simulations17 are currently available to predict the events likely to occur during cardiac surgery. Hemodynamic disturbances at each level of arterial blood supply dominate the discussion, and inflammatory, immunological, neurohumoral, and mechanical factors are also of significance (Figure 1). Figure 1 Major pathophysiological mechanisms for the development of cardiac and vascular surgery–associated acute kidney injury (CVS‐AKI). Many common factors contribute to the development of CVS‐AKI. Hemodynamic perturbations such as exposure to cardiopulmonary bypass (CPB), cross‐clamping of the aorta, high doses of exogenous vasopressors, and blood‐product transfusion all increase the risk of AKI. Similarly, the mechanical factors outlined may be associated with renal perfusion injury following episodes of ischemia, resulting in increased oxidative stress and associated inflammation as well as embolic disease including cholesterol emboli, all of which increase the pathological burden on the kidney. Other mechanisms such as neurohormonal activation are relevant, as is the generation of free hemoglobin and the liberation of free iron perioperatively, all potentiating AKI. Associated tissue damage is reflected in a systemic inflammatory response, and all these factors contribute to a significant inflammatory response. Immune activation, the generation of reactive oxygen species, and upregulation of proinflammatory transcription factors all play roles. Hemodynamic perturbations Perturbations in the renal blood flow may lead to an imbalance of oxygen supply and demand.18, 19 The inner stripe of the outer medullary portion of the kidney may be susceptible to ischemic damage caused by low resting po 2 (10–20 mm Hg).18 During CPB, cardiac output is preserved, but the target blood pressure under such nonpulsatile conditions is unknown, and inadequate renal perfusion may contribute to AKI. However, using a mathematical model,17 the rewarming phase of CPB appeared to represent the period when the renal medulla may be at most risk because of the combination of high oxygen demand and low oxygen supply occurring at this time. Low cardiac output states during and after cardiac surgery are likely to contribute to the ischemic process, although whether low flow, low blood pressure, or oxygen delivery is the main culprit remains elusive.20 Studies of noncardiac surgery patients suggest that maintenance of sufficient mean arterial pressure is the most important hemodynamic parameter to preserve in the perioperative period21, 22; however, these patients are rarely exposed to hypothermia and hemodilution, so it remains unclear whether this finding also applies to cardiac surgery patients. The period after CPB may be relevant for the development of reperfusion injury,23 and the precise underlying mechanisms need to be fully understood so that preventive and salvage treatments may be developed to mitigate this process. Remote ischemic preconditioning (RIPC) appeared to show great promise in a study of high‐risk patients24 but has been shown to be ineffective (at least with respect to the effect sizes examined) in lower risk patients.25, 26, 27 Some controversy exists regarding the effects of propofol, which has been hypothesized to attenuate the response to RIPC.26 The role of venous congestion in the development of AKI is a potential area of pathophysiological significance.28, 29 The role of high central venous pressure in congestive heart failure is well appreciated.30 The incidence of AKI in this population has led investigators to study it in the context of heart surgery, for which the problem is typically in the right heart, and vascular surgery, for which the problem may be increased abdominal compartment pressures. However, the mechanisms involved are unclear, and although “back pressure” on the glomerular apparatus has been postulated, it is unlikely that this process is the sole cause of this observation. It may be that the renal pelvis is able to compensate for a certain amount of increased venous volume before the pressure–flow relationship inside the poorly compliant renal capsule changes, in keeping with the Monro–Kellie doctrine observed in the brain.31 Whether this truly applies to the kidney is currently a matter of speculation but one that merits further study. Inflammation and immunity The systemic inflammatory response is often observed following major surgery, with considerable variability observed between individuals, although it is recognized that a more severe response is associated with an increased risk of adverse outcomes including AKI.32, 33, 34 Unsurprisingly, CVS is often associated with such a response and may activate the inflammatory cascade through several pathways.35, 36 CVS exposes the patient to a risk profile somewhat different from most other major surgeries. CPB, cross‐clamping of the aorta, high doses of exogenous vasopressors, and high rates of exogenous blood product transfusion, for example, all enhance the risks of AKI, especially when coupled with the risk profile for AKI for most of these patients. Such exposures are associated with perturbations in renal perfusion that induce reperfusion injury following episodes of ischemia, resulting in increased oxidative stress and associated inflammation.37, 38 This process is exacerbated by the significant shunting within the kidney that results in the renal medulla and corticomedullary junction being relatively hypoxic relative to other tissues.18 In cardiac surgery, the entire cardiac output is exposed to an extracorporeal circuit, and this provides a further inflammatory insult through contact activation from the exposure of blood to the CPB circuit; although in the modern CPB circuit biocompatibility has been optimized, measures of immune activation (cytokine and chemokine levels) increase significantly after CPB.36 The generation of reactive oxygen species induces inflammation by upregulation of proinflammatory transcription factors, including NFκ‐B (nuclear factor κ‐B).39, 40 Cytokines and chemokines recruit neutrophils, macrophages, and lymphocytes into the renal parenchyma. Parenchymal infiltration and activation of these immune cells promote AKI and lead to fibrosis. Avoidance of the CPB machine in an attempt to reduce distant organ function has been successful,41 although recently published data suggest that 5‐year survival is lower with off‐pump techniques42; this may be a reflection of improved revascularization of the heart with the on‐pump technique. In the presence of concurrent sepsis, such as with bacterial endocarditis, sepsis and surgery appear to be synergistic in terms of affecting an immune response.43 Iron metabolism and free hemoglobin CVS leads to free hemoglobin liberation with the release of free iron, and this phenomenon has generated much interest regarding CS‐AKI.44, 45, 46, 47 A degree of hemolysis is inevitable whenever red blood cells come into contact with an artificial surface or with air (eg, blood scavenging systems), and this may be coupled with a prolonged period of hypothermia (sometimes as low as 18°C), which creates the perfect environment for hemolysis and liberation of free iron, leading to vasoconstriction through scavenging of nitric oxide by free hemoglobin. Indeed, evidence from a case–control study of patients who developed AKI postoperatively compared with matched controls demonstrated that plasma‐free hemoglobin was less than half that observed in the control group, providing further evidence that hemolysis and free iron may contribute to AKI development.44 Moreover, free hemoglobin and, particularly, free ferrous iron increase production of reactive oxygen species via the Fenton and Haber Weis reactions, especially as free hemoglobin and iron are sequestered within the kidney.48 Plasma‐free hemoglobin also induces HO‐1 (heme oxygenase 1) expression. HO‐1 degrades heme but increases in experimental models of AKI. Plasma HO‐1 is increased in patients who develop AKI, and CPB duration, hemolysis, and inflammation are associated with increased HO‐1 concentrations following cardiac surgery.45 Other mechanisms Oxygen free radical generation and metabolism is an area of active investigation49, 50 (and genetic predisposition to injury is important51, 52), but it is not clear whether this results in increased susceptibility to AKI or to innate impairment of the ability to repair and regenerate healthy renal tissue. The precise nature of the genetic (and epigenetic) variables involved also remains unclear. Furthermore, embolic disease is important for CS‐AKI. Cholesterol emboli53 are at risk for distal migration when a cross‐clamp is applied or released from the aorta, especially in patients with significant atherosclerosis. Moreover, intra‐aortic balloon counterpulsation devices increase the embolic load, and the fact that these devices are typically deployed in patients with severely compromised hemodynamic conditions makes it difficult to discern whether such devices are of overall benefit (by improving cardiac output) or harm (by increasing generation of emboli) to the kidney. In addition, tissue injury releases mitochondrial damage–associated molecular patterns including mitochondrial DNA, which can act as a direct activator of neutrophils, which in turn elicit a systemic inflammatory response syndrome while suppressing polymorphonuclear function. Such molecular patterns have also been seen during CPB and, as such, may participate in the pathogenesis of CVS‐AKI.54 Diagnosis and Risk Assessment Perioperative stratification for AKI Recommendation: We recommend routine implementation of validated clinical risk‐prediction models in the preoperative assessment of all patients undergoing CVS, using estimated glomerular filtration rate (eGFR), cystatin C, and/or albuminuria to improve risk stratification of those at intermediate and high risk of AKI postoperatively (not graded). Rationale: Risk assessment is a dynamic process in which patients with fixed preoperative risk derived from underlying comorbidities are evaluated on the basis of additional and potentially modifiable risks from their clinical status before surgery. The use of currently available risk‐prediction instruments must be guided by the goals of risk assessment in each instance. Preoperative risk assessment may be useful for communicating risks associated with surgery to the patient and in implementing preventive strategies in the intra‐ and postoperative periods, for example, goal‐directed hemodynamic management, individualized blood pressure management,21 and avoidance of the use of NSAIDs for pain management. Postoperative risk assessment is geared toward early identification of AKI that may allow earlier implementation of preventive strategies. Peri‐ and postoperative risk assessment is geared toward early identification of AKI that may allow proactive treatment. An important conceptual point is that kidney injury in the setting of CVS occurs along a continuum and may relate to patient, preoperative, and intraoperative factors and the trajectory of AKI occurrence from baseline conditions; its development over a patient's clinical course should take this aspect into account (Figure 2). Figure 2 Risk assessment for acute kidney injury (AKI) following cardiac and vascular surgery (CVS). This figure provides a framework for the time course of risk assessment for AKI following CVS. Risk assessment should be a continual process that is repeatedly performed in the pre‐, peri‐, and early postoperative time course, and it should incorporate clinical factors and biomarkers if available. Patients deemed to be at high risk of AKI may benefit from the implementation of kidney‐focused care to improve patient outcomes. CHF indicates congestive heart failure; COPD, chronic obstructive pulmonary disease; CPB, cardiopulmonary bypass; EF, ejection fraction; IABP, intra‐aortic balloon pump; IGFBP7, insulin‐like growth factor binding protein 7; KDIGO, Kidney Disease Initiative Global Outcome; NGAL, neutrophil gelatinase–associated lipocalin; PVD, peripheral vascular disease; TIMP2, tissue inhibitor of metalloproteinases 2. Although many risk‐prediction scores for AKI after cardiac surgery have been published, only 8 have been externally validated with C statistics ranging from 0.72 to 0.89 (Table S1).55, 56, 57, 58, 59, 60, 61 In general, these scoring systems have good discrimination in assessing low‐risk groups but relatively poor discrimination in moderate to high‐risk patients.62 There are no externally validated risk‐assessment tools specifically for AKI following vascular surgery; although Kheterpal and colleagues developed and externally validated an AKI risk score for general surgery cases that included but was not limited to vascular surgery.63, 64 The most robust cardiac surgery prediction tools with the best discrimination have used AKI requiring RRT as an outcome. This is problematic because AKI requiring dialysis, although catastrophic in this context, is relatively uncommon, occurring in 1% to 2% of all patients undergoing surgery in most programs. In addition, the decision to initiate RRT varies among clinicians. Less severe forms of AKI are commonly seen after cardiac surgery with reported rates of Kidney Disease Improving Global Outcomes (KDIGO) stage 1 AKI reported between 20% and 70% depending on the patient risk factors and the inclusion of KDIGO serum creatinine (sCr) and/or urine output (UO) criteria for AKI.7, 8, 65, 66, 67, 68 Three of the prediction rules have assessed risk of less severe forms of AKI defined using sCr criteria only.56, 58, 69 Of these, one used the RIFLE criteria of AKI,56 and another used the Acute Kidney Injury Network criteria.69 The risk factors commonly identified in externally validated risk‐prediction models are shown in Figure 2. Preexisting CKD, although variably defined, is the strongest risk factor for AKI in this setting. With 2 exceptions,59, 70 most other prediction tools have used sCr to assess kidney function, which may significantly overestimate kidney function, particularly in malnourished elderly populations. The eGFR, which accounts for age, race, and sex and is subject to similar limitations, is likely a more accurate estimation of kidney function in stable, elective patients. The use of both eGFR and sCr in this context assumes steady‐state kidney function, which is frequently not the case. Newly identified risk factors such as preoperative hemoglobin (anemia/transfusion load) and proteinuria have only been incorporated in recent models, whereas other risk factors have not been rigorously studied for their incremental value when added to existing risk‐prediction models (eg, days from cardiac catheterization to surgery). All risk‐prediction tools have shown only moderate calibration, suggesting significant heterogeneity in the underlying populations.62 Because most risk‐prediction tools have been derived from clinical and administrative databases, they fail to capture acuity of illness, which may account for the calibration discrepancies and the difficulty in discrimination among the moderate‐ to high‐risk groups. Some measure or surrogate for hemodynamic stability is present in all published models whether it is characterized by surgical urgency or the presence of cardiogenic shock. It is likely that risk discrimination would improve if additional objectively defined clinical variables were included. At a minimum, all patients undergoing cardiac and vascular surgical procedures should undergo routine clinical assessment of AKI risk. This involves systematic evaluation of known susceptibilities for development of AKI such as CKD and albuminuria using preoperative sCr and urinalysis in all patients before surgery.71, 72, 73 These results will help frame individualized risk for AKI while perhaps providing insight into patients’ baseline renal function. Whenever possible, efforts should be made to obtain the patient's prior kidney‐function tests to ascertain true baseline function. In summary, the currently available preoperative risk‐assessment tools are beneficial in that they use commonly available data and identify low‐risk patients in the setting of traditional CVS. Nevertheless, they have several limitations: They are predominantly used to predict RRT. Sensitivity and specificity break down at the extremes of the spectrum. They do not account for preoperative eGFR (primarily rely on sCr alone). Intra‐ and postoperative factors play equally important roles in determining the course and severity of AKI; as such, continued risk assessment throughout the peri‐ and postoperative periods is crucial for patients at risk of AKI. Definition and diagnosis of AKI Recommendations: We recommend that AKI should be defined by the KDIGO criteria, including both sCr and UO criteria (not graded). We recommend checking sCr immediately before surgery in all patients and utilizing sCr‐based eGFR to assess renal function in patients with steady state preoperatively so as to ascertain AKI postoperatively (not graded). We recommend repeated clinical reassessment of AKI risk within the first 12 postoperative hours incorporating intra‐ and postoperative variables (not graded). We suggest measuring biomarkers of AKI (eg, TIMP2·IGFBP7 [combination of tissue inhibitor of metalloproteinases 2 and insulin‐like growth factor binding protein 7] or NGAL [neutrophil gelatinase–associated lipocalin]) in patients at high risk of CS‐AKI (grade 2A). Rationale: The current Society of Thoracic Surgeons (STS) database defines AKI by KDIGO sCr‐based stage 3 AKI (sCr ≥3 times baseline or initiation of RRT).74 However, smaller changes in sCr are associated with adverse outcomes following CVS.75, 76, 77, 78 Given the association of stage 1 AKI (sCr 1.5 times baseline or ≥0.3‐mg/dL increase within 48 hours) with adverse outcomes in multiple settings, it is important to recognize stage 1 AKI (based on sCr and/or UO criteria) so that the progression to stage 2 (sCr 2.0 times baseline) or stage 3 AKI and other outcomes can be monitored. In addition, sCr criteria alone may miss ≈30% of patients with AKI, resulting in both misclassification of AKI severity and delay in management. Critically ill patients who meet AKI criteria by both sCr and UO are at higher risk of adverse outcomes including 30‐day mortality and need for RRT in comparison to those who meet a single criterion for AKI.5, 79, 80, 81 The STS database does not distinguish between AKI and acute kidney disease, which is currently defined as the course of the AKI syndrome in those who continue to have renal pathophysiological changes 7 days after the inciting event. Acute kidney disease may last for weeks to months with variable outcomes (full or partial recovery, ESRD).82 Moreover, the timing and trajectory of AKI ( 75 Cardiac … More research needed Intraoperative ultrafiltration Cardiac … More research needed Postoperative KDIGO bundle Cardiac 1Ba … Low tidal volume ventilation strategy Cardiac 1C … Loop diuretics (for prevention of AKI) Cardiac and vascular … 1B Levosimendan Cardiac … 1A Dopamine Cardiac … 1A A‐melanocyte‐stimulating hormone Cardiac … 1B Vasopressin for vasoplegic shock (vs norepinephrine) Cardiac … More research needed Natriuretic peptides Cardiac … More research needed Fenoldopam Cardiac … More research needed Mannitol Cardiac and vascular … More research needed AAA indicates abdominal aortic aneurysm (includes thoracoabdominal); ACEI, angiotensin‐converting enzyme inhibitor; AKI, acute kidney injury; ARB, angiotensin receptor blocker; CPB, cardiopulmonary bypass; CVS, cardiac and vascular surgery; IABP, intra‐aortic balloon pump; KDIGO, Kidney Disease: Improving Global Outcomes; MAP, mean arterial pressure; OPCAB. off‐pump coronary artery bypass. a High‐risk cardiac surgery patients. Rationale: The evidence for most pharmacological and nonpharmacological strategies in the perioperative setting is limited because the majority of studies are single center, are of poor quality with small sample sizes, and/or use variable inclusion criteria. In addition, the timing and dose of pharmacological agents and the definition of AKI vary widely. Pharmacological strategies Perioperative Numerous pharmacological agents including levosimendan,94, 95, 96, 97 statins,98, 99, 100 N‐acetylcysteine,101, 102, 103, 104 sodium bicarbonate,105, 106, 107, 108 and erythropoietin109, 110, 111, 112, 113 have, for the most part, failed to demonstrate benefit for the prevention of CS‐AKI. A possible exception is dexmedetomidine, for which a number of small or low‐quality studies found a reduction in the occurrence of AKI after cardiac surgery.114, 115, 116 Moderate glucose control (127–179 mg/dL) was found in a randomized controlled trial (RCT) to be preferable to tight control (≤126 mg/dL) in patients undergoing coronary artery bypass grafting,117 resulting in lower rates of AKI and mortality, with the most important factor being avoidance of glucose variability throughout the entire perioperative time frame.118, 119 The use of balanced crystalloid solutions guided by measures of fluid responsiveness is supported by the current literature and is consistent with the recommendations for fluid management in critically ill patients with sepsis.97, 120, 121, 122, 123 The administration of hydroxyethyl starch is not indicated for patients at risk of CS‐AKI because of its demonstrated renal toxicity.97, 121 Although albumin may have a role preoperatively in patients with hypoalbuminemia,124 we suggest limiting colloid administration in cardiac surgery patients as much as possible and recommend balanced crystalloid solutions as replacement fluid, in keeping with the literature.120 Preoperative Although evidence is limited, several studies demonstrate that withholding angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers in the preoperative period is associated with reduced incidence of AKI.125, 126, 127 Correction of hypoalbuminemia (level of 2.2 L/min per m2) after cardiac surgery, vasopressin was associated with lower incidence of severe AKI (stages 2 and 3) and RRT use, although, again, study limitations prevent recommendation and further research is needed.154 Nonpharmacological strategies Perioperative Again, results in this area are contradictory. Intravenous contrast before surgery may increase the incidence of AKI and has led to some recommendations for delaying surgery 24 to 72 hours after contrast administration155, 156; however, another study disagrees.157 Preoperative placement of an intra‐aortic balloon pump may prevent AKI and reduce the incidence of RRT in high‐risk patients by improving perfusion and reducing endothelial activation.158, 159 Others, however, have suggested that using an intra‐aortic balloon pump as a surrogate to achieve pulsatile perfusion contributes significantly to lowered aortic pressure in the distal portion of aorta and may impair kidney perfusion.160 Intraoperative The use of CPB is required for the majority of cardiac surgical procedures. During CPB, cardiac output is preserved, but the target blood pressure under such nonpulsatile conditions is unknown. A large RCT demonstrated that maintaining a higher level of mean arterial pressure during normothermic CPB did not reduce the incidence of AKI.161 However, before making any recommendations, further evidence is required. The impact of off‐pump coronary artery bypass (OPCAB) on renal outcomes has been studied extensively and remains another point of controversy. OPCAB exerted a renoprotective effect in patients with normal preoperative sCr but not in patients with preexisting renal disease.162 No impact on the incidence of AKI with the 2 competing strategies was seen in some series,163, 164 whereas others found an association of on‐pump coronary artery bypass with higher incidence of AKI.165 A meta‐analysis of trials (n=17 322 patients) suggests a lower risk for AKI but no difference in the need for RRT in off‐pump surgery patients.166 However, a recently published RCT (n=2932 patients) demonstrated that OPCAB reduced the risk of postoperative AKI in comparison to on‐pump coronary artery bypass grafting, with no discernable difference in kidney function at 1 year.41 Although data suggest a reduction in AKI in OPCAB, a recent RCT42 and several meta‐analyses167, 168 have demonstrated an increase in long‐term, all‐cause mortality in OPCAB compared with on‐pump surgery. Consequently, the greater operative safety and possible prevention of AKI with OPCAB may come at the expense of long‐term survival gains. Catheter manipulation in the thoracic and abdominal aorta may lead to renal artery embolization, with aortic cross‐clamping proximal to the renal arteries associated with ischemia–reperfusion injury, further aggravated by atheroemboli secondary to aortic manipulation.169, 170 Aortic clamping above bilateral renal arteries, adjunctive renal artery procedures, and left renal vein division have been found to increase the incidence of AKI.136 Emboli protection devices may help preserve renal function and prevent procedure‐related atheroembolism during endovascular renal interventions.171 Transradial coronary angiography avoids catheter manipulation in the descending and abdominal aorta, which, compounded by reduced bleeding, leads to less AKI than transfemoral angiography.172 Avoidance of aortic manipulation (the “no touch” technique) in OPCAB has been shown to decrease the risk of postoperative stroke in several studies; however, its effect on AKI incidence remains controversial, with some studies demonstrating lower incidence,173, 174 but others failing to do so.175, 176 Moderate hypothermic circulatory arrest with antegrade cerebral perfusion during complex aortic surgery has been embraced by an increasing number of surgical groups, with data suggesting that this is not associated with an increased AKI risk.177 Conversely, hyperthermic perfusion during CPB, defined as a cumulative time at >37°C, is associated with an increase in AKI incidence.178 In a study achieving clinical equipoise through propensity score matching, duration of hyperthermic perfusion was independently associated with severity of AKI, with a 51% increase in the incidence for every 10 minutes of hyperthermic perfusion.179 Cold renal perfusion has been suggested for pararenal abdominal aorta aneurysm surgery to reduce the incidence of AKI associated with juxtarenal and thoracoabdominal aortic operations.180, 181, 182 Pulsatile perfusion provides surplus mechanical energy transmission to the vascular endothelium. Its impact on clinical outcomes has been extensively studied in a variety of settings; however, the data on renal outcomes are conflicting because of the lack of uniformity in pulsatility delivery.159, 183, 184, 185 A retrospective analysis showed pulsatile CPB conferred a renoprotective effect in higher risk patients undergoing cardiac surgery.186 However, the contemporary use of implantable continuous‐flow left ventricular assist devices challenges this concept.187 The improvement in the hemodynamic environment provided by continuous‐flow left ventricular assist devices leads to better renal function in heart failure patients, implying that the theoretical importance of pulsatility is superseded by increased cardiac output.187, 188 Hemodilution during CPB is an independent risk factor for AKI in adult cardiac surgery,189 with improved outcomes for cases in which significant hemodilution (hematocrit 12 mL/kg) tidal volumes after cardiac surgery.205 Management of CVS‐AKI Workup and monitoring Recommendations: The choice of diagnostic tests and monitoring for patients with CVS‐AKI is determined by the presence and the degree of kidney and/or cardiorespiratory dysfunction (not graded). The diagnostic approach depends on the etiology of organ dysfunction and the expected short‐ and long‐term patient outcomes (not graded). A kidney‐specific and stepwise diagnostic approach for patients with CVS‐AKI and cardiorespiratory dysfunction may be helpful (not graded). Rationale: Effective interventions to reverse the consequences of AKI remain elusive, with efforts focusing on primary prevention. Nevertheless, management of patients who sustain AKI is of vital importance, both to reduce the immediate impact of AKI and to avoid further episodes of AKI and avert the progression of AKI to acute kidney disease or CKD. Organ functional changes are dynamic, and, as such, frequent assessments are required to establish the trajectory that will influence the nature and urgency of interventions. Such assessments should guide preemptive therapies to prevent or manage complications that are anticipated in the setting of AKI. Because the impact of CVS‐AKI on both short‐ and long‐term outcomes of patients is significant, reaching appropriate diagnoses to provide etiology‐specific individualized preventive and/or therapeutic measures is critical. The diagnostic tests and monitoring strategies available are manifold (Table 2) and should be determined by the level of kidney or cardiorespiratory dysfunction present (Figure 4A and 4B). Table 2 Suggested Diagnostic Tests and Monitoring Strategies for CVS‐AKI Category Test Patients Advantage Disadvantage Cardiovascular function Basic hemodynamic monitoring (MAP, cardiac filling pressure, and its trends, Spo 2, HR, RR, temperature) All patients Identification of patients with need for advanced monitoring Ability to evaluate the trends Low resolution Questionable relationship with volume deficiency Advanced hemodynamic monitoring (thermodilution, transpulmonary indicator dilution, arterial‐pressure waveform‐derived, esophageal or suprasternal Doppler, echocardiography, partial CO2 rebreathing, bioimpedance, and bioreactance) Progressive or severe AKI Hemodynamic instability Accuracy High resolution Invasive Limited evidence for effect on outcomes Assist device–related information Patients who need cardiorespiratory support Readily available Informative Requires expertise to interpret Lactate Progressive or severe AKI Hemodynamic instability Indicator of tissue O2 delivery Clearance guides therapy Lacks specificity (eg, epinephrine‐induced increase in lactate) Svo 2 or Scvo 2 Progressive or severe AKI Hemodynamic instability Balance of tissue O2 delivery and consumption Sensitivity can be reduced with shunting and when O2 consumption is low Pulmonary function Blood gas Cardiorespiratory dysfunction Accurate measure of oxygenation and ventilation Limited information concerning cardiac performance Lung US Cardiorespiratory dysfunction Noninvasive Sensitive and specific Interrater variability Lung imaging Cardiorespiratory dysfunction Simple, uniformly available X‐ray exposure; Specificity can be limited Lung compliance Patients on MV Easy to perform May lack specificity Kidney function sCr All patients with CVS‐AKI Available Informative (diagnosis and prediction) Late and insensitive biomarker of kidney dysfunction Urine sediments Kidney dysfunction High specificity Low sensitivity Urine electrolytes Kidney dysfunction Available Confirmatory Limited sensitivity and specificity, Confounded by diuretics Injury/stress biomarkers CVS‐AKI (AKI risk and stage I) Informative (diagnosis, prognosis) Less delayed Limited availability in some areas Kidney US Suspicion of obstruction Highly sensitive and specific Interrater variability Kidney Doppler US Progressive kidney dysfunction Noninvasive Lack of specificity of resistive index Limited images in ICU Urine eosinophils Progressive kidney dysfunction and clinical suspicion of AIN/atheroembolic disease Reasonable specificity Low sensitivity Kidney biopsy Progressive kidney disease with unknown etiology Informative (diagnosis, prognosis) Not done in usual clinical practice Miscellaneous Chemistry panel All patients with CVS‐AKI Available Informative (eg, to assess AKI complications) Glucose monitoring All CVS‐AKI patients Allows appropriate glucose management Myoglobin and sarcoplasmic proteins (eg, creatine kinase, aldolase, LDH, ALT, and AST) Progressive AKI with clinical suspicion Informative (rhabdomyolysis diagnosis) Complement Progressive AKI with clinical suspicion of immunologically mediated renal disease (eg, atheroembolic disease, infection, I/R) Confirmatory Low sensitivity ESR/CRP Progressive AKI with clinical suspicion (eg, Atheroembolic disease, infection, I/R) Confirmatory Peripheral blood smear and hemolysis panel Progressive AKI with clinical suspicion of hemolysis associated AKI (eg, HUS/TTP, DIC) Confirmatory Inflammatory biomarkers Vasodilatory shock Predictor of outcome Limited availability; no standardization AIN indicates acute interstitial nephritits; AKI, acute kidney injury; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C‐reactive protein; CVS, cardiac and vascular surgery; DIC, disseminated intravascular coagulation; ESR, erythrocyte sedimentation rate; HR, heart rate; HUS, hemolytic uremic syndrome; ICU, intensive care unit; I/R, ischemia/reperfusion; LDH, lactate dehydrogenase; MAP, mean arterial pressure; MV, mechanical ventilation; RR, respiratory rate; sCr, serum creatinine; Spo 2, peripheral oxygen saturation; Scvo 2, central venous oxygen saturation; Svo 2, systemic venous oxygen saturation; TTP, thrombotic thrombocytopenic purpura; US, ultrasound. Figure 4 A, Cardiorespiratory‐specific diagnostic approach. This diagnostic approach may be applied to a patient who has a cardiorespiratory cause of acute kidney injury (AKI). The level of intervention is governed by the degree and chronicity of cardiorespiratory dysfunction. Source: ADQI (Acute Disease Quality Initiative) 20th consensus meeting (http://www.adqi.org). Used with permission. B, Kidney‐specific diagnostic approach. This diagnostic approach may be applied to a patient who has a renal‐specific cause of AKI. The level of intervention is governed by the degree and duration of renal dysfunction. This is particularly relevant in the post–intensive care unit phase, in which a patient with persistent AKI (>2 or 3 days) or acute kidney disease should be monitored and followed up. BNP indicates brain natriuretic peptide; CI, cardiac index; CKD, chronic kidney disease; CO, cardiac output; CVP, central venous pressure; CXR, chest x‐ray; EVLW, extravascular lung water; HR, heart rate; MAP, mean arterial pressure; RR, respiratory rate; Scvo 2, central venous oxygen saturation; Spo 2, peripheral oxygen saturation; SVV, stroke volume variation; US, ultrasound. If no evidence shows cardiopulmonary failure, it is essential to try to identify the etiology of the AKI. Following evaluation of cardiorespiratory function and intravascular volume status, urine analysis and medication review are initial steps in assessing such patients. The use of stress or injury biomarkers of AKI may potentially allow more accurate prognostication of AKI because they have been shown to correlate with long‐term outcomes.206, 207 When AKI persists for >48 to 72 hours, nephrology consultation to evaluate other potential causes of AKI and, potentially, disease‐specific management may be helpful. For patients who require RRT, close monitoring of metabolic milieu and hemodynamic/volume status is critical. Once discharged, clinicians should follow patients who recovered from CVS‐AKI for the development of CKD or other post‐AKI complications.2 Pharmacological and nonpharmacological support Recommendations: The management goals for the CVS patient who has sustained AKI include preventing the progression of AKI, promoting renal recovery precluding subsequent episodes of AKI, and treating the acute and chronic consequences of AKI (not graded). We recommend not using natriuretic peptide, fenoldopam, diuretics, dopamine, or mannitol for the treatment of CVS‐AKI (grade 1C). The decision to start RRT should be individualized with consideration of the clinical context and not be based solely on renal function or stage of AKI. Once the decision to initiate RRT has been made, it should be started promptly (not graded). We recommend the use of continuous therapies in patients with hemodynamic instability and in situations in which shifts in fluid balance are poorly tolerated (grade 1B). Rationale: For those patients with CVS‐AKI who present with cardiorespiratory failure, the diagnostic approach needs to focus first on addressing cardiorespiratory dysfunction. Among patients who have significant baseline or acute cardiorespiratory failure or who require substantial support for heart and lung function, the intensity of hemodynamic and intravascular volume status monitoring should be escalated.208 The hemodynamic management of cardiac surgery patients with renal dysfunction should focus on: Improvement of right and left ventricular function Maintenance of MAP and sinus rhythm Optimization of preload Management of right ventricle afterload (pulmonary vascular resistance) Optimization of mechanical ventilation Pharmacological cardiac support A multipharmacological approach is frequently necessary. Catecholamines are often required to improve ventricular function, acting through a direct inotropic effect but also by improving myocardial perfusion and recruitment of unstressed venous preload. Phosphodiesterase type III inhibitors (milrinone and enoximone), calcium sensitizers (levosimendan), and pulmonary vasodilators (inhaled nitric oxide, inhaled prostacyclin, and inhaled milrinone) can improve cardiac performance while reducing afterload on both right and left ventricles. Because the determinant for renal perfusion is the arterial and venous blood pressure, both left ventricle dysfunction and increased central venous pressure are associated with decreased renal perfusion and increased renal afterload contributing to CS‐AKI.209 As noted, increased renal venous pressure also causes an increase in the renal subcapsular pressure, thereby reducing glomerular filtration.210 The use of dynamic measures based on heart–lung interactions to predict fluid responsiveness, such as pulse pressure or stroke volume variation, has been shown to improve outcomes including renal function in both cardiac and noncardiac settings.211 Fluid overload is particularly problematic following cardiac surgery because of the frequent co‐occurrence of low cardiac output and postcardiotomy ventricular impaired relaxation. Following the acute phase, slow and controlled volume unloading, through the use of diuretics and/or continuous RRT, is frequently necessary. Pharmacological kidney support Pharmacological management of CVS‐AKI remains challenging, with no specific approaches available currently. Many drugs including dopamine, loop diuretics, mannitol, and natriuretic peptides have been investigated as primary renal therapy. Although associated with increased UO, none are routinely used because of limited and conflicting data and, in some cases, evidence of harm.140, 145, 212 RCTs with natriuretic peptides have shown inconsistent effects for renal end points. Meta‐analyses demonstrated that atrial natriuretic peptide in high doses was associated with a trend toward increased mortality and more adverse events in patients undergoing cardiac surgery.144 Although there was a reduced need for RRT (with the associated problems using RRT as an end point) with low‐dose atrial natriuretic peptide in patients undergoing CVS, there was no difference in mortality. The majority of studies on atrial natriuretic peptide are underpowered and of low or moderate quality; therefore, atrial natriuretic peptide is not currently recommended for treatment of AKI.213 Although meta‐analyses have suggested a decrease in RRT in patients with CS‐AKI who were treated with fenoldopam, a multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group study of patients with CS‐AKI (n=667) was stopped for futility after an interim analysis. Fenoldopam infusion did not reduce 30‐day mortality or the need for RRT but was associated with an increased rate of hypotension compared with placebo.140 Renal replacement therapy In patients undergoing cardiac surgery, perioperative fluid overload has been associated with worse outcomes and is a primary risk factor for multiorgan failure, including AKI.214, 215, 216 Fluid balance can be achieved with pharmacological agents; however, in some cases, RRT should be considered to correct fluid accumulation, even in nonoliguric patients if the daily fluid balance cannot be maintained or is negative with the use of diuretics, to avoid the negative effects of prolonged fluid overload in critically ill patients (Figure 5).217, 218, 219 Figure 5 Fluid management strategies in critical illness: the place of mechanical fluid removal. Once life‐threatening hypovolemia has been corrected (savage resuscitation), fluid overload (FO) needs to be avoided. Early mechanical fluid removal should be considered if specific indications exist. Note, the existence of an extracorporeal circuit for extracorporeal membrane oxygenation (ECMO) greatly reduces any added risk for renal replacement therapy (RRT), assuming this circuit is used rather than a separate line for RRT. However, some patients will respond well to diuretics, and thus an ECMO circuit in place is only a relative indication for early RRT initiation and only when fluid or solute management dictates. During therapy, hemodynamic and intravascular volume status should be monitored and fluid removal rate and fluid balance targets reassessed regularly, aiming for clinical stability and tolerance of fluid removal. Within this pathway, RRT should be considered at any point if additional solute clearance is necessary. FB indicates fluid balance; UF, ultrafiltration. The optimal timing of RRT initiation remains a topic of much debate. Theoretically, initiation of RRT before the onset of severe AKI could improve survival and promote earlier recovery of kidney function by mitigating injury from acidemia, uremia, fluid overload, and systemic inflammation.220 However, early initiation may put patients at risk associated with RRT when a conservative approach could be used. Meta‐analyses examining the timing of initiation of RRT221, 222, 223, 224 have suggested that earlier initiation of RRT in critically ill patients with AKI may have a beneficial impact on survival. A few small RCTs were included, as well as numerous observational and cohort studies of various qualities with high heterogeneity. Although AKI stage correlates with hospital mortality, many patients with stage 3 AKI will show spontaneous recovery without RRT. In addition, some patients may have urgent indications for RRT (eg, fluid overload not responding to diuretics) without meeting severe AKI criteria. The decision to start RRT should be individualized.219 Recently, 2 large RCTs in critically ill patients compared “early” versus “late” RRT.225, 226 In the ELAIN (Early vs Late Initiation of Renal Replacement Therapy In Critically Ill Patients With Acute Kidney Injury) trial (n=231), patients with AKI stage 2 and serum NGAL >150 ng/mL were randomized to early (RRT within 8 hours of AKI stage 2) or late (RRT within 12 hours of reaching AKI stage 3) RRT.225 Approximately half of the patients were cardiac surgery patients (47%). Patients in the early RRT group had 25% lower mortality compared with those in the late arm. Only 10% of patients in the late group did not receive RRT. In the AKIKI (Artificial Kidney Initiation in Kidney Injury) trial (n=620), patients were randomized to early treatment, defined as RRT within 6 hours of reaching AKI stage 3, or late treatment, defined as RRT initiation when “absolute” indications were fulfilled.226 Mortality (≈50%) was not significantly different between the 2 groups, but approximately half of the patients randomized to late treatment did not receive RRT. Patients in the late treatment group who started RRT had higher mortality (62%) compared with patients in the early RRT group (48.5%). Forty percent of the patients were excluded on the basis of having emergent indications, already receiving RRT, or having indications for initiation of RRT for >5 hours. Clearly, these 2 trials do not definitively identify which patients are likely to benefit most from early initiation of RRT. Studies of dialysis modality (continuous versus intermittent) have failed to demonstrate a consistent benefit of one technique over another.227 However, continuous RRT is recommended for patients with hemodynamic instability that exceeds the ability to manage patients safely with intermittent hemodialysis.213, 219, 228 In addition, fluid removal is generally easier and associated with less hemodynamic instability when using continuous RRT.229, 230 It is possible that the operational characteristics of RRT might influence renal and patient recovery. Several observational studies have suggested that intermittent hemodialysis compared with continuous RRT is associated with less renal recovery and a higher risk of long‐term dialysis dependency.231, 232 Stem cells Use of mesenchymal stem cells, which are nonhematopoietic precursor cells derived from human bone marrow, is currently under investigation (2 trials completed and being analyzed) for the treatment of CS‐AKI.233, 234 The role of mesenchymal stem cells in AKI treatment might depend on the secretion of promitotic, antiapoptotic, anti‐inflammatory, and immunomodulatory factors.235 Knowledge Gaps and Future Research Currently, there is a paucity of data regarding diagnosis, prevention, and treatment, especially in patients undergoing vascular surgery. Consequently, it is imperative to develop research questions to address these issues (Table 3). For many of the pharmacological agents available for the prevention or management of AKI in this setting, larger RCTs will be needed to determine efficacy in different clinical scenarios. It is important to establish the utility of new biomarkers, not only for the early diagnosis and staging of AKI but also for the implementation of preventive measures. Table 3 Knowledge Gaps and Future Research Directions in CVS‐AKI Knowledge Gap Future Research Directions Risk assessment Defining the association of KDIGO stage 1 AKI by urine output and sCr with outcomes in the CVS settings Investigation of acute kidney stress are warranted to better characterize the incidence and outcomes of those with elevations in injury and damage biomarkers before changes in sCr and urine output Development of iterative risk‐prediction models that allow reevaluation of risk in the pre‐, peri‐, and postoperative periods. In this context, we recommend evaluation of the incremental value of real‐time estimated GFR assessment and renal injury/stress biomarkers as part of a risk stratification strategy Feasibility studies to assess renal reserve in the preoperative period for unrecognized renal susceptibility in selected group of patients Risk stratification Development and validation of current and emerging biomarkers of AKI diagnosis, recovery, progression to CKD Research and development of noninvasive, inexpensive, and highly accurate devices for kidney function, hemodynamic, and volume status monitoring (eg, real‐time GFR monitoring devices, kidney perfusion, and intracapsular pressure monitors, etc) Design and investigation of the impact of the biomarker or technology‐guided protocols in the prevention or treatment of CVS‐AKI Prevention of CVS‐AKI Development of biomarker or diagnostic tool‐guided protocols to prevent the progression of CVS‐AKI or facilitate kidney function recovery Investigation and validation of biomarkers and diagnostic tools with more resolution or ability to identify intravascular volume deficiency, microcirculation deficits, and kidney‐related variables and outcomes (eg, severity and location of injury, real‐time kidney function measures, biomarkers of kidney recovery, fibrosis or de novo or progression of CKD or need for RRT) Development of noninvasive, inexpensive, and highly accurate devices for kidney function, hemodynamic, and volume status monitoring (eg, real‐time GFR monitoring devices, kidney perfusion, and intracapsular pressure monitors, etc) Management of CVS‐AKI Development of studies to verify if specific management approaches currently showed as effective in CVS‐AKI primary prevention are also useful for secondary prevention Improvement of definition and monitoring of fluid overload in order to better understand its relationship and management strategies in CVS‐AKI patients Development of large randomized trial on ANP for the prevention and treatment of AKI Evaluation of the role of stem cells in treatment of AKI AKI indicates acute kidney injury; ANP, atrial natriuretic peptide; CKD, chronic kidney disease; CVS, cardiac and vascular surgery; GFR, glomerular filtration rate; KDIGO, Kidney Disease Improving Global Outcome; RRT, renal replacement therapy; sCr, serum creatinine. Sources of Funding This conference was supported by educational grants from OneLegacy Foundation, Baxter, NxStage Medical, Astute Medical, Sphingotec, Fresenius, Ortho Clinical Diagnostics, AM‐Pharma and La Jolla Pharmaceutical. Disclosures Nadim has acted as a consultant for Sphingotec and Baxter. Forni has received speakers fees from Astute medical and as a consultant for Ortho Clinical Diagnostics, Baxter and La Jolla Pharmaceuticals. Bihorac has received speakers honoraria from Astute Medical. Koyner has received research funds from Astute Medical, Bioporto, Satellite Health Care, speakers honoraria from the American Society of Nephrology, expert witness on AKI post cardiac surgery, and consultancy work for Sphingotec and Pfizer. Shaw has received consultancy fees from Edwards, Astute Medical, FAST Biomedical and NxStage. Engelman has received consultancy fees from Astute Medical, Astellas. Liu has received consultancy fees from Potrero Medical, Quark and Theravance. Mehta has received consultancy fees from Baxter, Astute Medical, Sphingotec. Pickkers, Radboud University Medical Center, has received consultancy fees from Baxter, Sphingotec and AM Pharma. Zarbock, has received research fees from Astute Fresenius, Astute Medical, Fresenius, Astellas, Baxter and consultancy fees from Sphingotec and Astellas. Kellum, has received research funding from, Astellas Baxter Bioporto Astute Medical, Grifols Cytosorbents Bard, NxStage, and has received consultancy fees from, Astellas, Baxter, Bioporto, Grifols, Astute Medical, NxStage, Cytosorbents, Sphingotec. Supporting information Table S1. Information Regarding Workgroups and Work Product Data S1. ADQI (Acute Disease Quality Initiative) methodology. Click here for additional data file.
Author and article information
Contributors
Xiansi Zeng:
ORCID: https://orcid.org/0000-0002-1495-701X
Li Li:
ORCID: https://orcid.org/0000-0001-8591-0676
Journal
Journal ID (nlm-ta): Dis Markers
Journal ID (iso-abbrev): Dis Markers
Journal ID (publisher-id): DM
Title:
Disease Markers
Publisher:
Hindawi
ISSN
(Print):
0278-0240
ISSN
(Electronic):
1875-8630
Publication date Collection: 2022
Publication date
(Electronic):
6
October
2022
Volume: 2022
Electronic Location Identifier: 7812099
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Author information
Xiansi Zeng
https://orcid.org/0000-0002-1495-701X
Article
DOI: 10.1155/2022/7812099
PMC ID: 9560860
PubMed ID: 36246554
SO-VID: 9ad87746-86d4-49d0-a147-7f2f7694481b
Copyright © Copyright © 2022 Yang Zhang et al.
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This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
History
Date
received
: 25
May
2022
Date
revision received
: 1
September
2022
Date
accepted
: 23
September
2022
Funding
Funded by: National Natural Science Foundation of China
Award ID: 81260159
Award ID: 81560175
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Subject:
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