Prevention of cardiac surgery-associated AKI by implementing the KDIGO guidelines in high risk patients identified by biomarkers: the PrevAKI randomized controlled trial

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Abstract

Purpose

Care 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.

Methods

In 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.

Results

AKI 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.

Conclusion

An 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 material

The online version of this article (doi:10.1007/s00134-016-4670-3) contains supplementary material, which is available to authorized users.

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Most cited references 26

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Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury

Kianoush B Kashani, Ali Al-Khafaji, Thomas Ardiles … (2013)

Introduction Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI. Methods We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection. Results Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine 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 AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P 0.72. Furthermore, [TIMP-2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method. Conclusions Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI. Trial registration ClinicalTrials.gov number NCT01209169.

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Classifying AKI by Urine Output versus Serum Creatinine Level.

John A. Kellum, Florentina E Sileanu, Raghavan Murugan … (2015)

Severity of AKI is determined by the magnitude of increase in serum creatinine level or decrease in urine output. However, patients manifesting both oliguria and azotemia and those in which these impairments are persistent are more likely to have worse disease. Thus, we investigated the relationship of AKI severity and duration across creatinine and urine output domains with the risk for RRT and likelihood of renal recovery and survival using a large, academic medical center database of critically ill patients. We analyzed electronic records from 32,045 patients treated between 2000 and 2008, of which 23,866 (74.5%) developed AKI. We classified patients by levels of serum creatinine and/or urine output according to Kidney Disease Improving Global Outcomes staging criteria for AKI. In-hospital mortality and RRT rates increased from 4.3% and 0%, respectively, for no AKI to 51.1% and 55.3%, respectively, when serum creatinine level and urine output both indicated stage 3 AKI. Both short- and long-term outcomes were worse when patients had any stage of AKI defined by both criteria. Duration of AKI was also a significant predictor of long-term outcomes irrespective of severity. We conclude that short- and long-term risk of death or RRT is greatest when patients meet both the serum creatinine level and urine output criteria for AKI and when these abnormalities persist.

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Urinary TIMP-2 and IGFBP7 as Early Biomarkers of Acute Kidney Injury and Renal Recovery following Cardiac Surgery

Melanie Meersch, Christoph Schmidt, Hugo Van Aken … (2014)

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

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Author and article information

Contributors

Alexander Zarbock:

ORCID: http://orcid.org/0000-0002-2124-1714

+49 251 83-47282 , zarbock@uni-muenster.de

Journal

Journal ID (nlm-ta): Intensive Care Med

Journal ID (iso-abbrev): Intensive Care Med

Title: Intensive Care Medicine

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0342-4642

ISSN (Electronic): 1432-1238

Publication date (Electronic): 21 January 2017

Publication date PMC-release: 21 January 2017

Publication date (Print): 2017

Volume: 43

Issue: 11

Pages: 1551-1561

Affiliations

[1 ]ISNI 0000 0004 0551 4246, GRID grid.16149.3b, Department of Anesthesiology, , Intensive Care and Pain Medicine University, Hospital Münster, ; Albert-Schweitzer-Campus 1, Building A1, 48149 Münster, Germany

[2 ]ISNI 0000 0001 2172 9288, GRID grid.5949.1, Department of Cardiac Surgery, , University of Münster, ; Münster, Germany

[3 ]ISNI 0000 0001 2172 9288, GRID grid.5949.1, Institute of Biostatistics and Clinical Research, , University of Münster, ; Münster, Germany

Author information

Alexander Zarbock http://orcid.org/0000-0002-2124-1714

Article

Publisher ID: 4670

DOI: 10.1007/s00134-016-4670-3

PMC ID: 5633630

PubMed ID: 28110412

SO-VID: 2c6594c0-243e-4547-9046-ade4c093bcda

License:

Open AccessThe article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, a link is provided to the Creative Commons license and any changes made are indicated.

History

Date received : 15 October 2016

Date accepted : 28 December 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;

Award ID: 428/6-1

Award Recipient : Alexander Zarbock

Funded by: Innovative Medizinische Forschung Münster

Funded by: FundRef http://dx.doi.org/10.13039/100009777, Astute Medical;

Funded by: European Society of Intensive Care Medicine

Custom metadata

ScienceOpen disciplines: Emergency medicine & Trauma

Keywords: acute kidney injury,kdigo guidelines,biomarkers,[timp-2]·[igfbp7],cardiac surgery,major adverse kidney events

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ScienceOpen disciplines: Emergency medicine & Trauma

Keywords: acute kidney injury, kdigo guidelines, biomarkers, [timp-2]·[igfbp7], cardiac surgery, major adverse kidney events

Prevention of cardiac surgery-associated AKI by implementing the KDIGO guidelines in high risk patients identified by biomarkers: the PrevAKI randomized controlled trial

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Karger: Nephrology

Most cited references 26

Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury

Classifying AKI by Urine Output versus Serum Creatinine Level.

Urinary TIMP-2 and IGFBP7 as Early Biomarkers of Acute Kidney Injury and Renal Recovery following Cardiac Surgery

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