Progress Prediction Of Acute Kidney Injury After Cardiac Surgery, And Studies Comparing The Diagnostic Criteria

Part I. MiR-21and risk of severe AKI and poor outcomes after adult cardiac surgeryAcute kidney injury (AKI) is a common and potentially serious postoperative complication of cardiac surgery. Renal replacement therapy (RRT) is required in approximately2%of cardiac surgical patients, and in those patients, mortality increases to50-60%. The incidence of cardiac surgery-associated AKI (CSA-AKI) is about30%depending on the diagnostic system, the type of cardiac surgery and the mode of detection, and follow an increasingly trend these years. AKI is an independent predictor for death, even a small increase in serum creatinine (0.3mg/dl) is associated with prolonged hospitalization and mortality. With increased severity of AKI, the risks of chronic kidney disease (CKD), end-stage renal disease (ESRD) and death increase accordingly. It has been estimated that the risk of mortality is increased2-to5-fold in patients whose plasma creatinine increases more than2-fold from baseline. Indentifying high-risk patients with kidney function loss, prior to serum creatinine levels demonstrating significant changes is an important clinical objective. The most widely used diagnostic system for CSA-AKI today is based on the patients’level of plasma creatinine. However, because plasma creatinine is not a direct indicator for kidney injury and its change can only be detected after around half of the kidney function is lost, this kind of creatinine-based diagnostic system often causes the delay for diagnose and therapy. However, new biomarkers proposed for early detection for AKI, are of limited use in evaluating the degree of kidney injury and predicting of prognosis. Therefore, there is a need to find other biomarkers that are involved in the etiology of CSA-AKI and have earlier response to severe kidney injury.Objectives:This study evaluated the potential use of miR-21as a risk marker for postoperative AKI progression and other poor outcomes.Methods:The prospectively sample collecting study included120adult patients undergoing cardiac surgery at the ninth ward of Fu Wai Hospital between November2011and June2012. The patients were divided into three groups:40non-AKI controls,39patients with progressive AKI, and41with non-progressive AKI. AKI defined by Acute Kidney Injury Network (AKIN) criteria with a postoperative increase in plasma creatinine≥50%baseline or≥0.3mg/dl. The primary outcome was the progression of postoperative AKI, defined as development to a higher AKIN stage (from stage1to either stage2or3or from stage2to3) after the time of the postoperative sample collection. Secondary outcomes were the need for renal replacement therapy (RRT),30day in-hospital mortality, and length of stay in hospital and ICU after surgery. Urine and plasma levels of miR-21were assessed by quantitative real-time PCR (RT-qPCR). Associations between miR-21levels and AKI progression were determined by estimating areas under receiver operating characteristic curves (AUC).Results:There was no statistically significant difference in sample collecting times between these three groups. One-way ANOVA indicated that Cleveland scores, preoperative eGFR, operation time and CPB time demonstrated statistically significant differences among three groups. Poor clinical outcomes mainly occurred in progressor group. The length of ICU and hospital stay was also higher in patients with AKI progression than in those in the other two groups. The levels of urinary and plasma miR-21expression increased in parallel with progression of AKI. Except for differences in urinary miR-21level between non-AKI patients and non-progressors, all other between-group comparisons were statistically significant. We demonstrated that up-regulated urine and plasma levels of miR-21in patients with AKI were both associated with AKI progression. The AUCs for urine and plasma levels of miR-21associated with established AKI were0.68(95%CI:0.59-0.78) and0.80(95%CI:0.73-0.88), respectively. In multiple logistic regression analysis, a clinical model including Cleveland Scores, preoperative eGFR, operation time, and CPB time was established to adjust for differences in covariables between groups. The AUC-ROC for clinical model alone was0.75(95%CI0.65-0.86). After adjusting for clinical variables, indicated that the prognostic predictive power of urine and plasma miR-21levels for AKI progression were represented by higher AUCs of0.81(95%CI:0.72-0.91) and0.83(95%CI:0.74-0.92), respectively. Urinary and plasma miR-21levels also predicted the need for postoperative renal replacement therapy (RRT), development of Acute Kidney Injury Network (AKIN) stage3AKI,30-day in-hospital mortality and prolonged stay in hospital or ICU. Urine miR-21was a better outcome predictor than plasma miR-21, being associated with higher (1.4-to2.6-fold) unadjusted odds ratio for progression of AKI and other poor outcomes.Conclusions:Urinary and plasma miR-21are associated with severe AKI and other poor postoperative outcomes of cardiac surgery, indicating their potential use as prognostic markers. Part II. Clinical accuracy of RIFLE and AKIN criteria for acute kidney injury in patients undergoing cardiac surgeryThe term’acute kidney injury’(AKI) is currently recognized as the preferred nomenclature for the complex clinical syndrome formerly known as acute renal failure (ARF). AKI has clinical manifestations ranging from a minimal elevation in serum creatinine levels to anuric renal failure. The consensus criteria for AKI developed by the Acute Dialysis Quality Initiative (ADQI) group, first suggested in2004and named with the acronym RIFLE (risk, injury, failure, loss of kidney function, and end-stage renal failure), represent the first concerted effort to overcome the variety of different definitions for AKI. In2007, a modified version was proposed by the Acute Kidney injury Network (AKIN). The two definition systems for AKI differ in three major aspects.(I) In RIFLE the diagnosis is based on changes over a one-week period, while AKIN requires only changes within a designated48-hour period.(Ⅱ) Estimated glomerular filtration rate (eGFR) criteria are not included in AKIN. The percentage change from baseline serum creatinine (sCr) is identical in both definitions, aside from the additional criterion of an absolute sCr increment of≥0.3mg/dL within the AKIN stage1category.(Ⅲ) Renal replacement therapy (RRT) in RIFLE was not assigned to a given severity class, whereas by definition all patients with RRT are placed in stage3by AKIN. The two definition systems are equally accepted in the cardiac surgey setting, but differ in power of diagnosis. Therefore, and it is not clearly determined which has the better clinical accuracy.Objectives:To conduct a comparison of RIFLE and AKIN criteria for their clinical accuracy in a cardiac surgical patient cohort.Methods:We conducted a double-blind, randomized controlled trial in adult cardiac surgical patients. Subjects will be screened either whilst in-patients or at the time of their out-patient appointment prior to planned surgery and their eligibility will be checked according to inclusion/exclusion criteria. Patients were randomized to Rosuvastatin (20mg once daily) or identical placebo capsule. Primary outcome was to establish whether perioperative administration (started not earlier than8days before surgery and continued until the5th post-operative day included; ie, a maximum of14tablets) of Rosuvastatin in patients undergoing elective cardiac surgery leads to a reduction in the incidence of post-operative AKI. Secondary outcomes included requirement for renal replacement therapy and mechanical ventilation, length of stay in intensive care unit, length of stay in hospital and incidence of infection and low cardiac output syndrome. Results:Among529patients, according to AKIN and RIFLE criteria, AKI occurred in43.7%and23.6%, respectively. In addition, the proportion of patients developing AKI according to both criteria classification in stage1/R differed mostly. These200patients were divided into two groups:A+R+group included91patients and A+R-group included109patients. Study groups were well matched. There was no difference with respect to preoperative risk factors between patient groups, except for baseline renal function. There was no statistically significant between group difference in urine output on the first two days after surgery. But patients in A+R+group had higher maximum postoperative plasma creatinine and worse clinical outcomes than those in A+R-group. We demonstrated that RIFLE R stage was an independent predictor for poor clinical outcomes, as being associated with odds ratio(OR) for incidence of low cardiac output syndrome, duration of mechanical ventilation, and length of stay in intensive care unit were2.71(95%CI:1.04-7.04)、1.96(95%CI:1.12-3.45)和1.86(95%CI:1.03-3.36), respectively. Logistic regression analysis identified5predictors of AKI;1was preoperative (left ventricular ejection fraction),1intraoperative (cardiopulmonary bypass duration), and3postoperative (administration of vasoconstrictors, inotropes, and diuretics).Conclusions:(I) AKIN criteria applied in patients undergoing cardiac surgery may lead to over-diagnosis of AKI. Therefore, we suggest application of the RIFLE criteria in patients undergoing cardiac surgery.(Ⅱ) Left ventricular function and cardiopulmonary bypass duration influence AKI development after cardiac surgery and perioperative patient management significantly affects AKI occurrence.(ClinicalTrials.gov NCT01573143).