Melanie Meersch

Effect of Early vs Delayed Initiation of Renal Replacement Therapy on Mortality in Critically Ill Patients With Acute Kidney Injury: The ELAIN Randomized Clinical Trial

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 (≥2 times baseline or urinary output <0.5 mL/kg/h for ≥12 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, -∞ 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. TRIAL REGISTRATION German Clinical Trial Registry Identifier: DRKS00004367.

Urinary TIMP-2 and IGFBP7 as early biomarkers of acute kidney injury and renal recovery following cardiac surgery.

Background Difficulties in prediction and early identification of (acute kidney injury) AKI have hindered the ability to develop preventive and therapeutic measures for this syndrome. We tested the hypothesis that a urine test measuring insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in acute kidney injury (AKI), could predict AKI in cardiac surgery patients. Methods We studied 50 patients at high risk for AKI undergoing cardiac surgery with cardiopulmonary bypass (CPB). Serial urine samples were analyzed for [TIMP-2]*[IGFBP7] concentrations. The primary outcome measure was AKI as defined by international consensus criteria following surgery. Furthermore, we investigated whether urine [TIMP-2]*[IGFBP7] could predict renal recovery from AKI prior to hospital discharge. Results 26 patients (52%) developed AKI. Diagnosis based on serum creatinine and/or oliguria did not occur until 1–3 days after CPB. In contrast, urine concentration of [TIMP-2]*[IGFBP7] rose from a mean of 0.49 (SE 0.24) at baseline to 1.51 (SE 0.57) 4 h after CPB in patients who developed AKI. The maximum urinary [TIMP-2]*[IGFBP7] concentration achieved in the first 24 hours following surgery (composite time point) demonstrated an area under the receiver-operating characteristic curve of 0.84. Sensitivity was 0.92, and specificity was 0.81 for a cutoff value of 0.50. The decline in urinary [TIMP-2]*[IGFBP7] values was the strongest predictor for renal recovery. Conclusions Urinary [TIMP-2]*[IGFBP7] serves as a sensitive and specific biomarker to predict AKI early after cardiac surgery and to predict renal recovery. Clinical Trial Registration Information: www.germanctr.de/, DRKS-ID: DRKS00005062

Effect of Remote Ischemic Preconditioning on Kidney Injury Among High-Risk Patients Undergoing Cardiac Surgery: A Randomized Clinical Trial

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 PARTICIPANTS In 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 MEASURES The 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/mL2/1000; 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.

FGF23 signaling impairs neutrophil recruitment and host defense during CKD

Chronic kidney disease (CKD) has been associated with impaired host response and increased susceptibility to infections. Leukocyte recruitment during inflammation must be tightly regulated to protect the host against pathogens. FGF23 levels are increased in blood during CKD, and levels of this hormone have been associated with a variety of adverse effects in CKD patients. Here, we have shown that CKD impairs leukocyte recruitment into inflamed tissue and host defense in mice and humans. FGF23 neutralization during CKD in murine models restored leukocyte recruitment and host defense. Intravital microscopy of animals with chronic kidney failure showed that FGF23 inhibits chemokine-activated leukocyte arrest on the endothelium, and downregulation of FGF receptor 2 (FGFR2) on PMNs rescued host defense in these mice. In vitro, FGF23 inhibited PMN adhesion, arrest under flow, and transendothelial migration. Mechanistically, FGF23 binding to FGFR2 counteracted selectin- and chemokine-triggered β2 integrin activation on PMNs by activating protein kinase A (PKA) and inhibiting activation of the small GTPase Rap1. Moreover, knockdown of PKA abolished the inhibitory effect of FGF23 on integrin activation. Together, our data reveal that FGF23 acts directly on PMNs and dampens host defense by direct interference with chemokine signaling and integrin activation.

Validation of Cell-Cycle Arrest Biomarkers for Acute Kidney Injury after Pediatric Cardiac Surgery

Background The lack of early biomarkers for acute kidney injury (AKI) seriously inhibits the initiation of preventive and therapeutic measures for this syndrome in a timely manner. We tested the hypothesis that insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, function as early biomarkers for AKI after congenital heart surgery with cardiopulmonary bypass (CPB). Methods We prospectively studied 51 children undergoing cardiac surgery with CPB. Serial urine samples were analyzed for [TIMP-2]•[IGFBP7]. The primary outcome measure was AKI defined by the pRIFLE criteria within 72 hours after surgery. Results 12 children (24%) developed AKI within 1.67 (SE 0.3) days after surgery. Children who developed AKI after cardiac surgery had a significant higher urinary [TIMP-2]•[IGFBP7] as early as 4 h after the procedure, compared to children who did not develop AKI (mean of 1.93 ((ng/ml)2/1000) (SE 0.4) vs 0.47 ((ng/ml)2/1000) (SE 0.1), respectively; p<0.05). Urinary [TIMP-2]•[IGFBP7] 4 hours following surgery demonstrated an area under the receiver-operating characteristic curve of 0.85. Sensitivity was 0.83, and specificity was 0.77 for a cutoff value of 0.70 ((ng/ml)2/1000). Conclusions Urinary [TIMP-2]•[IGFBP7] represent sensitive, specific, and highly predictive early biomarkers for AKI after surgery for congenital heart disease. Trial Registration www.germanctr.de/, DRKS00005062

Long-term Effects of Remote Ischemic Preconditioning on Kidney Function in High-risk Cardiac Surgery Patients: Follow-up Results from the Renalrip Trial

Background: In a multicenter, randomized trial, the authors enrolled patients at high-risk for acute kidney injury as identified by a Cleveland Clinic Foundation score of 6 or more. The authors enrolled 240 patients at four hospitals and randomized them to remote ischemic preconditioning or control. The authors found that remote ischemic preconditioning reduced acute kidney injury in high-risk patients undergoing cardiac surgery. The authors now report on the effects of remote ischemic preconditioning on 90-day outcomes. Methods: In this follow-up study of the RenalRIP trial, the authors examined the effect of remote ischemic preconditioning on the composite endpoint major adverse kidney events consisting of mortality, need for renal replacement therapy, and persistent renal dysfunction at 90 days. Secondary outcomes were persistent renal dysfunction and dialysis dependence in patients with acute kidney injury. Results: Remote ischemic preconditioning significantly reduced the occurrence of major adverse kidney events at 90 days (17 of 120 [14.2%]) versus control (30 of 120 [25.0%]; absolute risk reduction, 10.8%; 95% CI, 0.9 to 20.8%; P = 0.034). In those patients who developed acute kidney injury after cardiac surgery, 2 of 38 subjects in the remote ischemic preconditioning group (5.3%) and 13 of 56 subjects in the control group (23.2%) failed to recover renal function at 90 days (absolute risk reduction, 17.9%; 95% CI, 4.8 to 31.1%; P = 0.020). Acute kidney injury biomarkers were also increased in patients reaching the major adverse kidney event endpoint compared to patients who did not. Conclusions: Remote ischemic preconditioning significantly reduced the 3-month incidence of a composite endpoint major adverse kidney events consisting of mortality, need for renal replacement therapy, and persistent renal dysfunction in high-risk patients undergoing cardiac surgery. Furthermore, remote ischemic preconditioning enhanced renal recovery in patients with acute kidney injury.

Patient with chronic renal failure undergoing surgery.

Purpose of review Chronic kidney disease (CKD) is an increasing health problem worldwide and is associated with a number of clinical challenges. In this paper, we review recent studies that deal with strategies for the management of patients with CKD undergoing surgery. Recent findings Effective strategies for nephroprotection are crucial for the handling of patients with CKD in the perioperative setting to prevent complications and to avoid the progression of CKD. Due to the lack of perioperative studies with CKD patients there are only level 2 recommendations. First of all, this requires the identification of CKD patients through risk assessment and preoperative laboratory tests. In this regard, biomarkers, such as cystatin C may facilitate the detection of chronically impaired renal function. Secondly, particular attention should be paid to the maintenance of hemodynamic stability, including an adequate blood pressure and cardiac index and the preservation of intravascular volume. There is clear evidence that an unimpaired renal perfusion, guaranteed through hemodynamic stability, and an undisturbed fluid balance both reduce the incidence of acute kidney injury (AKI) and consequently the further deterioration of renal function. Thirdly, several studies demonstrate that tight glycemic control is associated with less renal impairment and better survival for patients with CKD. Lastly, the highest priority for the patient with CKD should be assigned to the prevention of AKI, which is an action of proven efficacy. Summary Identification and risk stratification is crucial for the perioperative management of patients with CKD. To improve clinical outcomes, nonemergent procedures should be postponed, renal function optimized, nephrotoxic drugs avoided, and AKI prevented.

Perioperative Acute Kidney Injury: An Under-recognized Problem

The incidence of perioperative acute kidney injury (AKI) is more common than previously recognized, especially in high-risk patients undergoing higher risk procedures. The growing number of patients who develop perioperative AKI is related, in part, to the aging population and increase in the number of individuals with chronic comorbidities, particularly those with premorbid chronic kidney disease. Despite the acceptance of standardization in the definition of AKI, clinicians routinely underdiagnose it and fail to appreciate that it is associated with considerable morbidity and mortality. Unfortunately, few, if any, preemptive therapies have proven effective in preventing AKI. Timely diagnostic methods using evolving biomarkers raises the prospect of detection of kidney damage before the onset of irreversible loss of function, but remain under investigation. Clear evidence supporting any therapeutic intervention except renal replacement therapy remains elusive. Renal replacement therapy is indicated for select patients with progressive AKI; however, the ideal timing, method, and application of it remain under debate. It is fundamental to identify patients at risk for AKI. The Kidney Disease: Improving Global Outcomes guidelines suggest preventive strategies that include avoidance of nephrotoxic agents and hyperglycemia, optimization of hemodynamics, restoration of the circulating volume, and institution of functional hemodynamic monitoring. Clear evidence in support of this approach, however, is lacking. Recently, the perioperative administration of dexmedetomidine and the provision of remote ischemic preconditioning have been studied to potentially limit the development of perioperative AKI. This review discusses accepted standard definitions of AKI, highlights associated risk factors for its development, and provides an overview of its epidemiology and pathology. It emphasizes potential preventive strategies, the possible role of emerging biomarkers in defining its presence more expeditiously before irreversible injury, and current recommended guidelines and therapeutic approaches. The ultimate goal of this article is to bring to the attention of clinicians the seriousness of this potentially preventable or modifiable perioperative complication.The incidence of perioperative acute kidney injury (AKI) is more common than previously recognized, especially in high-risk patients undergoing higher risk procedures. The growing number of patients who develop perioperative AKI is related, in part, to the aging population and increase in the number of individuals with chronic comorbidities, particularly those with premorbid chronic kidney disease. Despite the acceptance of standardization in the definition of AKI, clinicians routinely underdiagnose it and fail to appreciate that it is associated with considerable morbidity and mortality. Unfortunately, few, if any, preemptive therapies have proven effective in preventing AKI. Timely diagnostic methods using evolving biomarkers raises the prospect of detection of kidney damage before the onset of irreversible loss of function, but remain under investigation. Clear evidence supporting any therapeutic intervention except renal replacement therapy remains elusive. Renal replacement therapy is indicated for select patients with progressive AKI; however, the ideal timing, method, and application of it remain under debate. It is fundamental to identify patients at risk for AKI. The Kidney Disease: Improving Global Outcomes guidelines suggest preventive strategies that include avoidance of nephrotoxic agents and hyperglycemia, optimization of hemodynamics, restoration of the circulating volume, and institution of functional hemodynamic monitoring. Clear evidence in support of this approach, however, is lacking. Recently, the perioperative administration of dexmedetomidine and the provision of remote ischemic preconditioning have been studied to potentially limit the development of perioperative AKI. This review discusses accepted standard definitions of AKI, highlights associated risk factors for its development, and provides an overview of its epidemiology and pathology. It emphasizes potential preventive strategies, the possible role of emerging biomarkers in defining its presence more expeditiously before irreversible injury, and current recommended guidelines and therapeutic approaches. The ultimate goal of this article is to bring to the attention of clinicians the seriousness of this potentially preventable or modifiable perioperative complication.

Early versus late initiation of renal replacement therapy in critically ill patients with acute kidney injury (The ELAIN-Trial): study protocol for a randomized controlled trial

BackgroundAcute kidney injury remains a common complication in critically ill patients and despite multiple trials and observational studies, the optimal timing for initiation of renal replacement therapy is still unclear. The early versus late initiation of renal replacement therapy in critically ill patients with acute kidney injury (ELAIN) study is a randomized, single-center, prospective, two-arm, parallel group trial to reduce mortality in patients with severe acute kidney injury. We describe the study design and discuss aspects of the need for a trial in this patient cohort.Methods/designOur plan is to randomize critically ill patients with acute kidney injury to ‘early’ or ‘late’ initiation of renal replacement therapy according to stage 2 and 3 of the KDIGO classification using a specific trial protocol. We plan to guide data collection and analysis using pre-existing definitions and testing. The primary endpoint is overall survival in a 90-day follow-up period. Secondary endpoints include 28-day, 60-day, 90-day and 1-year all-cause mortality, recovery of renal function, ICU and hospital length-of-stay. The primary analysis will be an intention-to-treat analysis; secondary analyses include treated analyses. We will also specify rules for handling data and determining outcome.DiscussionSeveral challenges for study design and execution can be seen in our trial, and it should generate results that will inform and influence the practice of renal replacement therapy in critically ill patients with acute kidney injury.Trial registrationGerman Clinical Trials Register: DRKS00004367 (www.germanctr.de); 28 May 2013.

Urinary hyaluronic acid as an early predictor of acute kidney injury after cardiac surgery.

Cardiac surgery–associated acute kidney injury (CSA-AKI) is a frequent, complex clinical problem in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). CSA-AKI is an important predictor of morbidity and mortality after cardiac surgery [(1)][1]. Changes in serum creatinine level