IMPORTANCE Optimal timing of initiation of renal replacement therapy (RRT) for severe acute kidney injury (AKI) but without life-threatening indications is still unknown. OBJECTIVE To determine whether early initiation of RRT in patients who are critically ill with AKI reduces 90-day all-cause mortality. DESIGN, SETTING, AND PARTICIPANTS Single-center randomized clinical trial of 231 critically ill patients with AKI Kidney Disease: Improving Global Outcomes (KDIGO) stage 2 (Ն2 times baseline or urinary output <0.5 mL/kg/h for Ն12 hours) and plasma neutrophil gelatinase-associated lipocalin level higher than 150 ng/mL enrolled between August 2013 and June 2015 from a university hospital in Germany. INTERVENTIONS Early (within 8 hours of diagnosis of KDIGO stage 2; n = 112) or delayed (within 12 hours of stage 3 AKI or no initiation; n = 119) initiation of RRT. MAIN OUTCOMES AND MEASURES The primary end point was mortality at 90 days after randomization. Secondary end points included 28-and 60-day mortality, clinical evidence of organ dysfunction, recovery of renal function, requirement of RRT after day 90, duration of renal support, and intensive care unit (ICU) and hospital length of stay. RESULTS Among 231 patients (mean age, 67 years; men, 146 [63.2%]), all patients in the early group (n = 112) and 108 of 119 patients (90.8%) in the delayed group received RRT. All patients completed follow-up at 90 days. Median time (Q1, Q3) from meeting full eligibility criteria to RRT initiation was significantly shorter in the early group (6.0 hours [Q1, Q3: 4.0, 7.0]) than in the delayed group (25.5 h [Q1, Q3: 18.8, 40.3]; difference, −21.0 [95% CI, −24.0 to −18.0]; P < .001). Early initiation of RRT significantly reduced 90-day mortality (44 of 112 patients [39.3%]) compared with delayed initiation of RRT (65 of 119 patients [54.7%]; hazard ratio [HR], 0.66 [95% CI, 0.45 to 0.97]; difference, −15.4% [95% CI, −28.1% to −2.6%]; P = .03). More patients in the early group recovered renal function by day 90 (60 of 112 patients [53.6%] in the early group vs 46 of 119 patients [38.7%] in the delayed group; odds ratio [OR], 0.55 [95% CI, 0.32 to 0. 93]; difference, 14.9% [95% CI, 2.2% to 27.6%]; P = .02). Duration of RRT and length of hospital stay were significantly shorter in the early group than in the delayed group (RRT: 9 days [Q1, Q3: 4, 44] in the early group vs 25 days [Q1, Q3: 7, >90] in the delayed group; P = .04; HR, 0.69 [95% CI, 0.48 to 1.00]; difference, −18 days [95% CI, −41 to 4]; hospital stay: 51 days [Q1, Q3: 31, 74] in the early group vs 82 days [Q1, Q3: 67, >90] in the delayed group; P < .001; HR, 0.34 [95% CI, 0.22 to 0.52]; difference, −37 days [95% CI, −ϱ to −19.5]), but there was no significant effect on requirement of RRT after day 90, organ dysfunction, and length of ICU stay. CONCLUSIONS AND RELEVANCE Among critically ill patients with AKI, early RRT compared with delayed initiation of RRT reduced mortality over the first 90 days. Further multicenter trials of this intervention are warranted.

PurposeCare bundles are recommended in patients at high risk for acute kidney injury (AKI), although they have not been proven to improve outcomes. We sought to establish the efficacy of an implementation of the Kidney Disease Improving Global Outcomes (KDIGO) guidelines to prevent cardiac surgery-associated AKI in high risk patients defined by renal biomarkers.MethodsIn this single-center trial, we examined the effect of a “KDIGO bundle” consisting of optimization of volume status and hemodynamics, avoidance of nephrotoxic drugs, and preventing hyperglycemia in high risk patients defined as urinary [TIMP-2]·[IGFBP7] > 0.3 undergoing cardiac surgery. The primary endpoint was the rate of AKI defined by KDIGO criteria within the first 72 h after surgery. Secondary endpoints included AKI severity, need for dialysis, length of stay, and major adverse kidney events (MAKE) at days 30, 60, and 90.ResultsAKI was significantly reduced with the intervention compared to controls [55.1 vs. 71.7%; ARR 16.6% (95 CI 5.5–27.9%); p = 0.004]. The implementation of the bundle resulted in significantly improved hemodynamic parameters at different time points (p < 0.05), less hyperglycemia (p < 0.001) and use of ACEi/ARBs (p < 0.001) compared to controls. Rates of moderate to severe AKI were also significantly reduced by the intervention compared to controls. There were no significant effects on other secondary outcomes.ConclusionAn implementation of the KDIGO guidelines compared with standard care reduced the frequency and severity of AKI after cardiac surgery in high risk patients. Adequately powered multicenter trials are warranted to examine mortality and long-term renal outcomes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00134-016-4670-3) contains supplementary material, which is available to authorized users.

IMPORTANCEAlthough current guidelines suggest the use of regional citrate anticoagulation (which involves the addition of a citrate solution to the blood before the filter of the extracorporeal dialysis circuit) as first-line treatment for continuous kidney replacement therapy in critically ill patients, the evidence for this recommendation is based on few clinical trials and meta-analyses.OBJECTIVE To determine the effect of regional citrate anticoagulation, compared with systemic heparin anticoagulation, on filter life span and mortality. DESIGN, SETTING, AND PARTICIPANTSA parallel-group, randomized multicenter clinical trial in 26 centers across Germany was conducted between March 2016 and December 2018 (final date of follow-up, January 21, 2020). The trial was terminated early after 596 critically ill patients with severe acute kidney injury or clinical indications for initiation of kidney replacement therapy had been enrolled. INTERVENTIONSPatients were randomized to receive either regional citrate anticoagulation (n = 300), which consisted of a target ionized calcium level of 1.0 to 1.40 mg/dL, or systemic heparin anticoagulation (n = 296), which consisted of a target activated partial thromboplastin time of 45 to 60 seconds, for continuous kidney replacement therapy. MAIN OUTCOMES AND MEASURESCoprimary outcomes were filter life span and 90-day mortality. Secondary end points included bleeding complications and new infections. RESULTS Among 638 patients randomized, 596 (93.4%) (mean age, 67.5 years; 183 [30.7%] women) completed the trial. In the regional citrate group vs systemic heparin group, median filter life span was 47 hours (interquartile range [IQR], 19-70 hours) vs 26 hours (IQR, 12-51 hours) (difference, 15 hours [95% CI, 11 to 20 hours]; P < .001). Ninety-day all-cause mortality occurred in 150 of 300 patients vs 156 of 296 patients (Kaplan-Meier estimator percentages, 51.2% vs 53.6%; unadjusted difference, -2.4% [95% CI, -10.5% to 5.8%]; unadjusted hazard ratio, 0.91 [95% CI, 0.72 to 1.13]; unadjusted P = .38; adjusted difference, -6.1% [95% CI, -12.6% to 0.4%]; primary adjusted hazard ratio, 0.79 [95% CI, 0.63 to 1.004]; primary adjusted P = .054). Of 38 prespecified secondary end points, 34 showed no significant difference. Compared with the systemic heparin group, the regional citrate group had significantly fewer bleeding complications (15/300 [5.1%] vs 49/296 [16.9%]; difference, -11.8% [95% CI, -16.8% to -6.8%]; P < .001) and significantly more new infections (204/300 [68.0%] vs 164/296 [55.4%]; difference, 12.6% [95% CI, 4.9% to 20.3%]; P = .002).CONCLUSIONS AND RELEVANCE Among critically ill patients with acute kidney injury receiving continuous kidney replacement therapy, anticoagulation with regional citrate, compared with systemic heparin anticoagulation, resulted in significantly longer filter life span. The trial was terminated early and was therefore underpowered to reach conclusions about the effect of anticoagulation strategy on mortality.

IMPORTANCE No interventions have yet been identified to reduce the risk of acute kidney injury in the setting of cardiac surgery.OBJECTIVE To determine whether remote ischemic preconditioning reduces the rate and severity of acute kidney injury in patients undergoing cardiac surgery. DESIGN, SETTING, AND PARTICIPANTSIn this multicenter trial, we enrolled 240 patients at high risk for acute kidney injury, as identified by a Cleveland Clinic Foundation score of 6 or higher, between August 2013 and June 2014 at 4 hospitals in Germany. We randomized them to receive remote ischemic preconditioning or sham remote ischemic preconditioning (control). All patients completed follow-up 30 days after surgery and were analyzed according to the intention-to-treat principle.INTERVENTIONS Patients received either remote ischemic preconditioning (3 cycles of 5-minute ischemia and 5-minute reperfusion in one upper arm after induction of anesthesia) or sham remote ischemic preconditioning (control), both via blood pressure cuff inflation. MAIN OUTCOMES AND MEASURESThe primary end point was the rate of acute kidney injury defined by Kidney Disease: Improving Global Outcomes criteria within the first 72 hours after cardiac surgery. Secondary end points included use of renal replacement therapy, duration of intensive care unit stay, occurrence of myocardial infarction and stroke, in-hospital and 30-day mortality, and change in acute kidney injury biomarkers.RESULTS Acute kidney injury was significantly reduced with remote ischemic preconditioning (45 of 120 patients [37.5%]) compared with control (63 of 120 patients [52.5%]; absolute risk reduction, 15%; 95% CI, 2.56%-27.44%; P = .02). Fewer patients receiving remote ischemic preconditioning received renal replacement therapy (7 [5.8%] vs 19 [15.8%]; absolute risk reduction, 10%; 95% CI, 2.25%-17.75%; P = .01), and remote ischemic preconditioning reduced intensive care unit stay (3 days [interquartile range, 2-5]) vs 4 days (interquartile range, 2-7) (P = .04). There was no significant effect of remote ischemic preconditioning on myocardial infarction, stroke, or mortality. Remote ischemic preconditioning significantly attenuated the release of urinary insulinlike growth factor-binding protein 7 and tissue inhibitor of metalloproteinases 2 after surgery (remote ischemic preconditioning, 0.36 vs control, 0.97 ng/mL 2 /1000; difference, 0.61; 95% CI, 0.27-0.86; P < .001). No adverse events were reported with remote ischemic preconditioning.CONCLUSIONS AND RELEVANCE Among high-risk patients undergoing cardiac surgery, remote ischemic preconditioning compared with no ischemic preconditioning significantly reduced the rate of acute kidney injury and use of renal replacement therapy. The observed reduction in the rate of acute kidney injury and the need for renal replacement warrants further investigation.TRIAL REGISTRATION German Clinical Trials Register Identifier: DRKS00005333

BACKGROUND: Prospective, single-center trials have shown that the implementation of the Kidney Disease: Improving Global Outcomes (KDIGO) recommendations in high-risk patients significantly reduced the development of acute kidney injury (AKI) after surgery. We sought to evaluate the feasibility of implementing a bundle of supportive measures based on the KDIGO guideline in high-risk patients undergoing cardiac surgery in a multicenter setting in preparation for a large definitive trial. METHODS: In this multicenter, multinational, randomized controlled trial, we examined the adherence to the KDIGO bundle consisting of optimization of volume status and hemodynamics, functional hemodynamic monitoring, avoidance of nephrotoxic drugs, and prevention of hyperglycemia in high-risk patients identified by the urinary biomarkers tissue inhibitor of metalloproteinases-2 [TIMP-2] and insulin growth factor-binding protein 7 [IGFBP7] after cardiac surgery. The primary end point was the adherence to the bundle protocol and was evaluated by the percentage of compliant patients with a 95% confidence interval (CI) according to Clopper-Pearson. Secondary end points included the development and severity of AKI. RESULTS: In total, 278 patients were included in the final analysis. In the intervention group, 65.4% of patients received the complete bundle as compared to 4.2% in the control group (absolute risk reduction [ARR] 61.2 [95% CI, 52.6-69.9]; P < .001). AKI rates were statistically not different in both groups (46.3% intervention versus 41.5% control group; ARR −4.8% [95% CI, −16.4 to 6.9]; P = .423). However, the occurrence of moderate and severe AKI was significantly lower in the intervention group as compared to the control group (14.0% vs 23.9%; ARR 10.0% [95% CI, 0.9-19.1]; P = .034). There were no significant effects on other specified secondary outcomes. CONCLUSIONS: Implementation of a KDIGO-derived treatment bundle is feasible in a multinational setting. Furthermore, moderate to severe AKI was significantly reduced in the intervention group. (Anesth Analg XXX;XXX:00-00) KEY POINTS• Question: Is it feasible to implement a bundle of supportive measures in high-risk patients undergoing cardiac surgery in a multinational setting? • Findings: In this multicenter randomized clinical trial, we found that the implementation of the Kidney Disease: Improving Global Outcomes (KDIGO) bundle is feasible in a multinational setting and that these supportive measures significantly reduced the occurrence of moderate and severe acute kidney injury (AKI). • Meaning: The findings underpin the need for a definitive trial to evaluate whether the KDIGO bundle reduces the occurrence of AKI in high-risk patients after cardiac surgery.