Accepted Manuscript. Epidemiology of Cardiac Surgery Associated Acute Kidney Injury. Eric AJ. Hoste, Wim Vandenberghe

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1 Accepted Manuscript Epidemiology of Cardiac Surgery Associated Acute Kidney Injury Eric AJ. Hoste, Wim Vandenberghe PII: S (17) DOI: /j.bpa Reference: YBEAN 968 To appear in: Best Practice & Research Clinical Anaesthesiology Received Date: 31 October 2017 Accepted Date: 2 November 2017 Please cite this article as: Hoste EA, Vandenberghe W, Epidemiology of Cardiac Surgery Associated Acute Kidney Injury, Best Practice & Research Clinical Anaesthesiology (2017), doi: / j.bpa This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 Epidemiology of Cardiac Surgery Associated Acute Kidney Injury Eric AJ Hoste 1, 2 Wim Vandenberghe 1 1 Department of Intensive Care Medicine, Ghent University Hospital, Ghent University, Gent, Belgium. 2 Research Foundation-Flanders, Brussels, Belgium. Correspondence: Eric AJ Hoste Department of Intensive Care Medicine Ghent University Hospital, Ghent University De Pintelaan Gent. Phone: Eric.Hoste@UGent.be 1

3 Abstract Acute kidney injury (AKI) is defined by the KDIGO definition into 3 stages on basis of an increase of serum creatinine or a period of oliguria. AKI is defined as rapid reversal when the episode is 48 hours or less. When AKI persists for 7 days or longer, the term acute kidney disease (AKD) is used. Subclinical AKI is defined by increased concentration of an AKI biomarker, without meeting the KDIGO definition for AKI. In contrast to this, functional AKI is defined by the KDIGO definition, while the AKI biomarker concentration is not increased. AKI is multifactorial and heterogeneous and occurs in half of ICU patients as defined by the current KDIGO definition for AKI. In this review, we specifically describe the epidemiology of cardiac surgery associated AKI (CSA-AKI), and describe the role of scoring systems and specific AKI biomarkers. Keywords: Acute Kidney Injury Epidemiology Cardiac Surgery 2

4 Introduction Acute kidney injury (AKI) is a frequent occurring complication in ICU patients (1). The pathophysiology of AKI in this specific setting is often multifactorial and dependent on the baseline characteristics of the patients and specific procedures during or after surgery. Here we will describe the epidemiology of AKI occurring after cardiac surgery as a typical example of postoperative AKI. The Acute Disease Quality Initiative (ADQI) proposed the terminology cardiac surgery associated AKI (CSA-AKI) for this (2). Since, cardiac dysfunction is considered the main contributing cause of decline in kidney function, CSA-AKI is classified as acute cardiorenal syndrome type I (CRS type 1) (3). Definition of AKI CSA-AKI has been defined by at least 35 different definitions in medical literature (2). Previously, this condition was often referred to with the non-uniform definition worsening renal function (WRF). Since 2012, the consensus definition of AKI is the modified version of the RIFLE and AKIN classifications as proposed by the Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Working Group (4). KDIGO defines and stages occurrence of AKI on an acute increase of serum creatinine or a period of oliguria (table 1). More recently, ADQI defined rapid reversal of AKI by an episode of AKI which lasts 48 hours or less, and Acute Kidney Disease (AKD) by a duration of AKI of 7 days or more (table 2)(5). CSA-AKI typically occurs after cardiac surgery, but may already begin before this procedure, i.e. in patients who present with cardiogenic shock or after contrast administration. Early CSA-AKI occurs within 7 d after cardiac surgery, and is more likely induced by cardiac surgery, while late AKI occurs between 7 and 30 days after cardiac surgery and has only an association with the preceding cardiac surgery (2). 3

5 Prediction of AKI: scoring systems Several scores have been developed to predict CSA-AKI. Examples of these are the Cleveland clinic score (6), Mehta score (7), Ng score (8), the Murphy score (9), and the CRATE score (10). The first two scores were developed in US populations, with the latter three in Australian, UK and Spanish populations respectively. Older scores often predict nonconsensus definitions of AKI or use of renal replacement therapy (RRT), while more recent scores use the KDIGO consensus or its variants (RIFLE or AKIN) as an endpoint. The discrimination of these scores is reasonably good, with area under the receiver operating characteristic curve values generally in the range of , when compared between discovery and validation cohorts or when applied in different cohorts or settings (11, 12). Functional AKI and Damage: the role of new kidney biomarkers The KDIGO definition of AKI is based on a decline of glomerular filtration rate (GFR) with resultant increase of serum creatinine or a period of oliguria. As such, this definition only captures a decline in GFR, and not true damage to the kidneys. In a normal scenario, this functional decline of kidney function is preceded by stress or damage to the kidneys (figure 1) which can be demonstrated by increased concentration of specific kidney biomarkers (13). Subclinical AKI occurs when a patient has a positive biomarker reading without meeting the KDIGO criteria for AKI. Similar to AKI defined by KDIGO, this condition is also reported with worse clinical outcomes (14, 15). At present over a dozen of AKI biomarkers have been evaluated in in-vitro and clinical studies. Of these, neutrophil gelatinase associated lipocalin (NGAL) (16, 17) and the combination biomarker test tissue inhibitor of metalloproteinases-2 4

6 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7)(NephroCheck ) are available for clinical use (18 22). Increased concentrations of biomarkers indicate more damage, which led to the CSA-NGAL score as a tool to monitor damage to the tubules and guide therapeutic and preventive actions (23). NGAL has been studied most in this setting, and its diagnostic ability for CSA-AKI is generally good (17), however, there is considerable variation and some studies showed low predictive value for this biomarker (24). Clinical experience showed good discriminative ability for the NephroCheck to diagnose CSA-AKI. However, the number of patients studied in this specific setting is still limited. Biomarkers can also be used for risk stratification. Recently, a pilot study demonstrated that application of a bundle of AKI measures in a cohort of cardiac surgery patients at increased risk for AKI, as defined by the NephroCheck, resulted in less AKI (25). Functional AKI is often referred to when patients meet the KDIGO criteria for AKI but without increased concentration of kidney damage biomarkers (24). Epidemiology and outcomes of AKI Two recent meta-analyses found that the incidence of CSA-AKI defined by RIFLE, AKIN and KDIGO definitions was 22% (26, 27). The majority of CSA-AKI patients will only have mild AKI with maximum severity stage 1 (14-18% of patients or 61-81% of AKI patients); stage 2 occurs in 17-20% of patients ( % of AKI patients), and 12-16% will have stage 3 ( of AKI patients). RRT is used in 2.3% to 3.1% of patients (10-14% of AKI patients). CSA-AKI is associated with increased costs and use of resources as indicated by a longer length of hospital stay in CSA-AKI patients compared to no AKI patients (15 d vs d). Increasing severity of AKI is associated with increased duration of hospital stay (stage 1: 14 d, stage 2: 18 d, and stage 3: 26.3 d). 5

7 CSA-AKI patients experience a short-term mortality of 10% compared to 1.7% of patients without AKI (OR = 8.52, 95%CI = 8.00 to 9.07), with a stepwise increase in short-term mortality with increasing AKI stage (stage 1: 5.7%, stage 2: 16.2%, and stage 3: 36.7%). Longterm mortality is also increased in CSA-AKI patients compared to CS patients without AKI (30% vs. 11.9%). After adjustment for other covariates that may explain mortality, there is a proportional increased risk for mortality to severity stages of AKI (28, 29). While some found this association between CSA-AKI and mortality persist for over a 10-y follow up period, a large study in Uruguay found that after 5-y follow up this association disappeared (29). 6

8 Practice Points AKI is defined by the KDIGO definition into 3 severity stages, and based on an increase of serum creatinine or an episode of oliguria Rapid reversal is defined by an AKI period of 48 h or less Acute Kidney Disease is defined by an episode of 7 days or longer AKI occurs in half of ICU patients, and 1 in 5 of cardiac surgery patients RRT is used in % of cardiac surgery patients (CSA-)AKI is associated with mortality after adjustment for covariates Research Agenda To better characterize risk factors and biomarkers for development of AKI To better characterize risk factors and biomarkers for long-term outcomes after AKI More studies are warranted on the use of biomarkers for risk stratification in therapy for AKI prevention. 7

9 Tables Table 1: The Kidney Disease: Improving Global Outcomes (KDIGO), diagnosis and grading system for Acute Kidney Injury (4). a) AKI is defined by either an increase of serum creatinine or an episode of oliguria: Increase of serum creatinine 0.3 mg/dl (26.5 µmol/l) within 48-hours, or Increase of serum creatinine by 1.5-fold above baseline, know or assumed to have occurred within 7 days, or Urine volume < 0.5 ml/kg/h for 6 hours. b) AKI severity is staged by the worst of either serum creatinine changes or oliguria Stage Serum creatinine Urine output to 1.9 times baseline <0.5 ml/kg/h for 6-12 h OR > 0.3 mg/dl (26.5 µmol/l) increase to 2.9 times baseline <0.5 ml/kg/h for 12 h times baseline OR Increase of serum creatinine to 4.0 mg/dl (353.6 µmol/l) OR RRT <0.3 ml/kg/h for 24 h OR Anuria for 12 h OR In patients <18y, decrease of egfr to <35 ml/min per 1.73m2 8

10 Table 2: Nomenclature used in Acute Kidney Injury (4, 5) Rapid reversal Acute Kidney Injury Acute Kidney Injury Duration of 48h Duration of 7 days Acute Kidney Disease Duration of > 7 days and < 90 days Functional Acute Kidney Injury KDIGO positive Biomarker negative Subclinical Acute Kidney Injury KDIGO negative Biomarker positive 9

11 Figures Figure 1: Transition of normal kidney function to acute kidney injury (after (13)) Normal Subclinical AKI Increased susceptibility Very early injury KDIGO 1, 2, 3 Stress Damage Decreased GFR Biomarker positive KDIGO 3 with RRT KDIGO positive Failure Legend: GFR = glomerular filtration rate, KDIGO = kidney disease: improving global outcomes criteria and stages for acute kidney injury, RRT = renal replacement therapy Death AKI 10

12 Conflicts of interest EH: Speakers fee from Alexion, and Astute Medical. Study grant from Bellco. Travel grant from AM Pharma. Ghent University Research grant for AKI biomarker research. WV: nill 11

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