INTRODUCTION Acute kidney injury (AKI) is a syndrome characterized by the rapid decline of renal function which leads to homeostatic imba lance. In the past, the common term of this syndrome was acute renal failure, and since 2004 it has been replaced by acute k idney injury, and accompanied with some new diagnostic criter ia such as KDIGO, RIFLE and AKIN. AKI can occur in many different kinds of patients , such as infection, trauma , toxicit y, surgery… w ith the inc idence ranging from 1 to 80% according to the subjects and definit ions applied. Especially, in cardiac surgery, the AKI rate can be as high as 40% with t he mortalit y up t o 60% in pat ients requir ing rena l replacement therapy (RRT), compared with 2-8% in general cardiac surgery. Therefore, early predict ing and d iagnosing is e ssentia l for effe ctive prevention of AKI. To accomplish it , we need first t o identif y the r isk factors, and then, use predict ion scores to calculate the poss ibilit y of AKI occurrence after surgery. Beside that, us ing so me new b iological markers such as cystatin C, NGAL…which have been init ially reported of having ability to early diagnose AKI is a lso reasonable approach. In Vietnam, there are only a few research on these issues. Therefore, we carried out this study for 2 a ims : 1. To evaluate the role of KDIGO, RIFLE, AKIN criteria, serum cystatin C in diagnosing of AKI in the early period af ter open-heart surgery 2. To determine the risk f actors and the value of Cleveland Clinic, AKICS and ACEF scores to predict AKI in the early period af ter openheart surgery
Trang 1108 INS TITUTE OF CLIN ICAL MED ICAL AND
PHARMACEUTICAL S CIENC ES
NGO DINH TRUNG
STUDY ON THE DIAGNOSTIC VALUE OF KDIGO, RIFLE, AKIN CRITERIA, SERUM CYSTATIN C AND RISK FACTORS FOR CARDIAC SURGERY- ASSOCIATED ACUTE KIDNEY INJURY
Specialty: Anesthes ia and Critical Care
Code: 62720122
SUMMARY OF MEDICAL DOCTORAL THESIS
Hanoi – 2020
Trang 2108 INSTITUT E OF CLINICAL MEDICAL AND
The thesis can be found at:
1 National library
2 Library of the Clinical Medicine Research Institute 108
Trang 31 to 80% according to the subjects and definitions applied Especially,
in cardiac surgery, the AKI rate can be as high as 40% with the mortality up to 60% in patients requiring renal replacement therapy (RRT), compared with 2-8% in general cardiac surgery
Therefore, early predicting and diagnosing is essential for effective prevention of AKI To accomplish it, we need first to identify the risk factors, and then, use prediction scores to calculate the possibility of AKI occurrence after surgery Beside that, using some new biological markers such as cystatin C, NGAL…which have been initially reported
of having ability to early diagnose AKI is also reasonable approach In Vietnam, there are only a few research on these issues Therefore, we carried out this study for 2 aims:
1 To evaluate the role of KDIGO, RIFLE, AKIN criteria, serum cystatin C in diagnosing of AKI in the early period after open-heart surgery
2 To determine the risk factors and the value of Cleveland Clinic, AKICS and ACEF scores to predict AKI in the early period after open- heart surgery
Trang 4Practical significance and ne w contributions
In Vietnam and also in the world, cardiac surgery using cardiopulmonary bypass is very popular The advances in skills, techniques and equipments have helped to improve the overall outcomes However, there have still been some complications, one of them is AKI, which could lead to higher morbidity and mortality of these patients Therefore, early detect and prevent this complication is very important
New contributions of the thesis:
1 Applying new criteria, including KDIGO, RIFLE, AKIN, in diagnosing AKI after cardiac surgery, and giving comparisons and
recommendations for using these criteria in clinica l practice
2 Determining the value of serum cystatin C in diagnosing cardiac surgery-associated acute kidney injury, and the possibility of
application in clinical practice
3 Determining the risk factors and the value of some risk scores (Cleveland Clinic, AKICS and ACEF) in predicting AKI after cardiac surgery, which could help to early predict, diagnose and so prevent
this complication
Structure of the thesis
The dissertation has 122 pages, including 2 pages of Introduction,
35 pages of Overview, 21 pages of Subjects and Methods, 31 pages of Results, 32 pages of Discussion, 2 pages of Conclusion, and 1 page of Recommendation There are 34 tables, 16 figures, 4 pictures with 155 references, including 6 in Vietnamese and 149 in English The published works related to the thesis, studying protocol and list of participating subjects are also included
Trang 5Chapter 1 OVERVIEW 1.1 Anatomical and functional fe atures of kidne y
The structural and functional unit of kidney is nephron, which is composed of a renal corpuscle and a renal tubule The main function
of nephron is to filter out wastes and toxins from the blood, and return needed molecules The renal function is represented by Glomerular filtration rate (GFR) In clinica l practice, creatinine clearance rate (Ccr) is commonly used to evaluate the GFR
1.2 Diagnostic crite ria for acute kidne y injury
For many years, acute renal failure used to be the term indicating
the rapid decline in renal function; however, there was no consensus
definition for this condition Therefore, since 2004, the term acute kidney injury has been proposed to replace “acute renal failure”,
accompanied with s ome newly developed definitions f or AKI such as RIFLE (2004), AKIN (2007) and KDIGO (2012)
According to the RIFLE criteria, AKI is defined as an increase of serum creatinine (Scr) with 50%, corresponding to a decrease in GFR, relative to baseline, of >25% or a urine output (UO) of <0.5 ml/kg per
h for >6h The RIFLE classification considers three severity classes
of AKI (Risk, Injury and Failure), according to the variations in serum creatinine and/or urine output, and two outcome classes (loss of kidney function and end-stage kidney disease)
The AKIN classification is a later version of RIFLE: it only relies on SCr and not on GFR changes; AKI is defined by the sudden decrease (in 48 h) of renal function, defined by an increase in absolute SCr of at least 26.5 μmol/L (0.3 mg/dl) or by a percentage increase in SCr ≥50% (1.5× baseline
Trang 6value), or by a decrease in the UO (documented oliguria <0.5 ml/kg/h for more than 6 h); Stage 1 corresponds to the risk class, but it also considers
an absolute increase in SCr ≥26.5 μmol/L (0.3 mg/dl); Stages 2 and 3 correspond to injury and failure classes, respectively; Stage 3 also considers patients requiring RRT; the two outcome classes were removed from the classification
The KDIGO classification is a combination of RIFLE and AKIN Therefore, AKI has been defined as an increase in SCr ≥0.3 mg/dL (≥26.5 μmol/L) within 48 h; or an increase in SCr to ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 days or a urine volume of <0.5 mL/kg/h for 6 h AKI has been staged in severity according
to the AKIN criteria, with a change is that, patients under 18 with a GFR
<35mL/min and patients with a serum creatinine >4.0mg/dL (absolute value) were added to AKIN stage 3
At present, three criteria above have been still evaluated to reach the consensus in for practice and research
1.3 P athogenesis of acute kidne y injury
The pathogenesis of cardiac surgery associated acute kidney injury (CSA-AKI) is complex and multifactorial It likely involved at least six major injury pathways: 1) exogenous and endogenous toxins; 2) metabolic factors; 3) ischemia and reperfusion; 4) neurohormonal activation; 5) Inflammation; and 6) oxidative stress These mechanisms
of injury are likely to be active at different times (pre, intra, and postoperative) with different intensity and probably act synergistically
Trang 71.4 Risk factors and prediction scores for AKI after cardiac surgery
1.4.1 Risk factos
Preoperative factors: age, heart failure, basal renal function, anemia, diabetes, COPD, emergency, nephrotoxic drugs, contrast agents, genetic…
Intraoperative factors: renal hypoperfusion, type of surgery, cadiopulmonary bypass use (hemodilution, hypothermia, non-pulsatile flow, inflammation, nephrotoxins, embolism)
Postoperative factors: low cardiac output, IABP, vasoactive agents, nephrotoxic drugs, volume depletion, sepsis…
1.4.2 Prediction scores
Based on the risk factors above, some risk scores have been developed to predict AKI after cardiac surgery, such as Cleveland Clinic, STS, AKICS, ACEF… The aim of these models is to early identify the patients who are at high risk of developing into cardiac surgery associated acute kidney injury (CSA-AKI); this may contribute to prevention and management of this complication
These scores consists of different factors, for example, Cleveland Clinic, STS, ACFE are based on preoperative risk factors; meanwhile AKICS uses the factors of pre, intra, and postoperative periods Until now, although some different risk scores have been proposed, there has been no consensus on applying these scores in predicting AKI after cardiac surgery In Vietnam, the research on this kind of model has not been performed yet
1.5 Biomarkers of AKI
Serum creatinin is now still the standard for diagnosing of AKI; however the use of SCr as a marker of AKI has significant limitations
Trang 8SCr is a late marker of disease, and alterations are often not apparent until 48–72 hours post-injury leading to missed early therapeutic opportunities when treatments may be most effective For the last recent years, some new biomarkers have been studied, such as cystatin
C, Neutrophil Gelatinase Associated Lipocalin (NGAL),
interleukin-18, KIM-1, L-FABP… The initial results suggests that some of them may help to early detection of AKI than the conventional one of creatinin
Cystatin C is a 120 amino acid nonglycosylated basic cysteine protease inhibitor widely expressed by all nucleated cells in the body, and is excreted to blood at constant concentration One of significant advantages of cystatin C is that The blood levels of cystatin C are not significantly affected by age, gender, race, overall muscle mass; inflammation or infection Cystatin C is directly and freely filtered by the glomerulus, reabsorbed completely, and is not secreted by the tubule, and is considered an ideal marker for GFR and better than that
of serum creatinin
Chapter 2 SUBJECTS AND METHODS 2.1 Subjects
The subjects were adult patients (over 18 years old) undergoing open heart surgery in 108 Military Central Hospital from January
2015 to December 2017
Exclusion criteria
- Surgery due to heart injury or massive pulmonary embolism
- Preoperative renal failure requiring RRT
- Preoperative Congenital kidney disease, Urinary Tract stone or Kidney Stone Disease, Polycystic Kidney Disease…
Trang 9- Patients who were using medications affecting creatinin excretion (cimetidin, ranintidin, trimethoprim); drugs which interfere with Jaffe's method (cephalotin, cephalozin, acid ascorbic…)
- Patients who died in the during the operation or right after that unable to access the kidney function
- Patients and/or families did not consent to participate in
2.2 Methods
2.2.1 Study design: A descriptive, longitudinal combined with
case-control study
2.2.2 Sample
Sample size: using formula required to estimate a proportion
n = Z21-α/2p(1-p)/d2; in which, Z=1.96 for 95% CI, P is expected true proportion = 36.1% (from the study of Howitt et al (2018); d is
desired precision = 6% Result: n ≥ 247
The study subjects were divided into 2 groups: AKI (case) and non- AKI (control) after surgery
Sampling: all those patients that fulfilled the inclusion criteria
2.2.3 Research variables and conduction
Variables for objective 1
a AKI diagnosing according to KDIGO, RIFLE and AKIN in the early period after surgery
After the operation, serum creatinin (sCr) was measured at the following times: arrival in ICU (T0), 12 hours (T1), 24h (T2), and 48h (T3) after to evaluate the incidence and severity of AKI according to three criteria (KDIGO, RIFLE and AKIN)
Variables included:
- The time point of AKI detection
- The AKI proportion and severity according to KDIGO
Trang 10- Comparison of incidence and severity of AKI among KDIGO, RIFLE and AKIN
- Relation between AKI and ICU and postoperative hospital stay
- Relation between AKI and death
b The diagnostic value of serum cystatin C
- Using KDIGO as the diagnostic criteria for AKI
- The serum level of cystatin C was evaluated postoperatively at 4 time points in coincidence with serum creatinin testing times
- The level of cystatin C was compared between AKI and non-AKI group
- The correlation between serum cystatin C and creatinin level was determined
- The area under the ROC curve ( AUC ) of creatinin and cystatin
C was defined to compare the performance in detecting AKI between two biomarkers
Variables for objective 2
Using KDIGO as the diagnostic criteria for AKI
a Risk factors for AKI
Preoperative:
- Age, gender, body mass index (BMI); body surface area (BSA)
- Comorbidities
- The severity of heart failure based on NYHA classification
- Preoperative renal function (urea, serum creatinin, eGFR)
Trang 11- The amount blood products (packed RBC, fresh frozen plasma, plate let) infused during operation
- Urine output, fluid balance
- Vasoactive agents used in operation
Postoperative:
- Central venous pressure ≥ 12cmH2O
- Duration of vasoactive use >2 hours
- Numbers of vasoactive agents
- Requiring reopening of the chest
- Mechanical ventilation time > 24 hours
- Low cardiac output syndrome
- Some hematology, biochemistry and blood gas parameters
Using univariate analysis to determine the relation between the variables with AKI; and then using multivariate analysis to define independent risk factors to postoperative AKI
b Prediction scores for AKI
- Using 3 scores, including Cleveland Clinic, ACEF and AKICS
- Cleveland Clinic and ACEF were calculated preoperatively, meanwhile AKICS was used after surgery
- Objectives of prediction: total AKI, AKI stage I, II, and III (according to KDIGO criteria)
- AUC of each prediction, cut-off values, sensitivity and specificity were calculated
Data analysis: using SPSS 20.0 software; some main statistical
analysis included uni and multivariate, correlation and area under the ROC curve analysis
Trang 12Chapter 3 RESULTS 3.1 Characte ristics of the subje cts
The study included 247 patients undergoing cardiac surgery using cardiopulmonary bypass
- Mean age: 53.32 ± 12.76 years old Male: 59.9%
- Type of surgery: valve 72.8%, coronary artery bypass grafting (CABG) 9.7%; valve combined with CABG 1.6%
- Severe heart failure (NYHA III-IV) accounted for 19.84%; 2.83% having an ejection fraction less than 40% 40.91% having systolic pulmonary artery pressure over 40mmHg
- Preoperatively, the mean serum creatinin level was 80.47 ± 25.63µmol/L, and mean eGFR was 89.79±24.18ml/min/1.73m2
3.2 Diagnostic value of KDIGO, RIFLE, AKIN and serum cystatin C
3.2.1 Diagnosing AKI based on KDIGO, RIFLE and AKIN
- The postoperative AKI incidence, based on KDIGO criteria, was 48.58%, in which, stage I accounted for 73.33%, stage II 18.33% and stage III 8.33% Among the AKI patients, 6.67% needed renal replacement therapy
Table 3.8 Comparison of AKI incidence among KDIGO, RIFLE
and AKIN
Crite ria KDIGO(1) RIFLE(2) AKIN(3)
AKI n (%) 120(48.58%) 98(39.67%) 116(46.96%)
p p1-2 = 0.04 p2-3=0.10 p1-3=0.71
Trang 13- The AKI incidence, according to KDIGO, was higher than those
of AKIN and RIFLE (48.58% vs 46.96% and 39.67% respectively) Significant difference was seen between KDIGO and RIFLE (p<0,05)
- KDIGO helped to detect 22 AKI cases who were diagnosed by RIFLE; and 4 cases more who not were diagnosed by AKIN
Table 3.12 Relation between AKI and hospitals stays
stay (days) 14,02±7,57 16,86±8,62 20,36±10,37 27,90±12,5 <0,01 Total hospital