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Published in: Critical Care 1/2020

01-12-2020 | Acute Kidney Injury | Research

Urine cell cycle arrest biomarkers distinguish poorly between transient and persistent AKI in early septic shock: a prospective, multicenter study

Authors: Dimitri Titeca-Beauport, Delphine Daubin, Ly Van Vong, Guillaume Belliard, Cédric Bruel, Sami Alaya, Karim Chaoui, Maud Andrieu, Isabelle Rouquette-Vincenti, Frederic Godde, Michel Pascal, Momar Diouf, Christophe Vinsonneau, Kada Klouche, Julien Maizel

Published in: Critical Care | Issue 1/2020

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Abstract

Background

The urine biomarkers tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) have been validated for predicting and stratifying AKI. In this study, we analyzed the utility of these biomarkers for distinguishing between transient and persistent AKI in the early phase of septic shock.

Methods

We performed a prospective, multicenter study in 11 French ICUs. Patients presenting septic shock, with the development of AKI within the first 6 h, were included. Urine [TIMP-2]*[IGFBP7] was determined at inclusion (0 h), 6 h, 12 h, and 24 h. AKI was considered transient if it resolved within 3 days. Discriminative power was evaluated by receiver operating characteristic (ROC) curve analysis.

Results

We included 184 patients, within a median [IQR] time of 1.0 [0.0–3.0] h after norepinephrine (NE) initiation; 100 (54%) patients presented transient and 84 (46%) presented persistent AKI. Median [IQR] baseline urine [TIMP-2]*[IGFBP7] was higher in the persistent AKI group (2.21 [0.81–4.90] (ng/ml)2/1000) than in the transient AKI group (0.75 [0.20–2.12] (ng/ml)2/1000; p < 0.001). Baseline urine [TIMP-2]*[IGFBP7] was poorly discriminant, with an AUROC [95% CI] of 0.67 [0.59–0.73]. The clinical prediction model combining baseline serum creatinine concentration, baseline urine output, baseline NE dose, and baseline extrarenal SOFA performed well for the prediction of persistent AKI, with an AUROC [95% CI] of 0.81 [0.74–0.86]. The addition of urine [TIMP-2]*[IGFBP7] to this model did not improve the predictive performance.

Conclusions

Urine [TIMP-2]*[IGFBP7] measurements in the early phase of septic shock discriminate poorly between transient and persistent AKI and do not improve clinical prediction over that achieved with the usual variables.

Trial registration

Appendix
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Literature
1.
go back to reference Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005;294:813–8.CrossRefPubMed Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005;294:813–8.CrossRefPubMed
2.
go back to reference Bagshaw SM, Uchino S, Bellomo R, Morimatsu H, Morgera S, Schetz M, et al. Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes. Clin J Am Soc Nephrol. 2007;2:431–9.CrossRefPubMed Bagshaw SM, Uchino S, Bellomo R, Morimatsu H, Morgera S, Schetz M, et al. Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes. Clin J Am Soc Nephrol. 2007;2:431–9.CrossRefPubMed
3.
go back to reference Peters E, Antonelli M, Wittebole X, Nanchal R, François B, Sakr Y, et al. A worldwide multicentre evaluation of the influence of deterioration or improvement of acute kidney injury on clinical outcome in critically ill patients with and without sepsis at ICU admission: results from the Intensive Care Over Nations audit. Crit Care. 2018;22:188.PubMedPubMedCentralCrossRef Peters E, Antonelli M, Wittebole X, Nanchal R, François B, Sakr Y, et al. A worldwide multicentre evaluation of the influence of deterioration or improvement of acute kidney injury on clinical outcome in critically ill patients with and without sepsis at ICU admission: results from the Intensive Care Over Nations audit. Crit Care. 2018;22:188.PubMedPubMedCentralCrossRef
4.
go back to reference Bouchard J, Soroko SB, Chertow GM, Himmelfarb J, Ikizler TA, Paganini EP, et al. Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury. Kidney Int. 2009;76:422–7.CrossRefPubMed Bouchard J, Soroko SB, Chertow GM, Himmelfarb J, Ikizler TA, Paganini EP, et al. Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury. Kidney Int. 2009;76:422–7.CrossRefPubMed
5.
go back to reference Legrand M, Dupuis C, Simon C, Gayat E, Mateo J, Lukaszewicz A-C, et al. Association between systemic hemodynamics and septic acute kidney injury in critically ill patients: a retrospective observational study. Crit Care. 2013;17:R278.PubMedPubMedCentralCrossRef Legrand M, Dupuis C, Simon C, Gayat E, Mateo J, Lukaszewicz A-C, et al. Association between systemic hemodynamics and septic acute kidney injury in critically ill patients: a retrospective observational study. Crit Care. 2013;17:R278.PubMedPubMedCentralCrossRef
6.
go back to reference Prowle J, Bagshaw SM, Bellomo R. Renal blood flow, fractional excretion of sodium and acute kidney injury: time for a new paradigm? Curr Opin Crit Care. 2012;18:585–92.CrossRefPubMed Prowle J, Bagshaw SM, Bellomo R. Renal blood flow, fractional excretion of sodium and acute kidney injury: time for a new paradigm? Curr Opin Crit Care. 2012;18:585–92.CrossRefPubMed
7.
go back to reference Calzavacca P, Evans RG, Bailey M, Bellomo R, May CN. Cortical and medullary tissue perfusion and oxygenation in experimental septic acute kidney injury. Crit Care Med. 2015;43:e431–9.CrossRefPubMed Calzavacca P, Evans RG, Bailey M, Bellomo R, May CN. Cortical and medullary tissue perfusion and oxygenation in experimental septic acute kidney injury. Crit Care Med. 2015;43:e431–9.CrossRefPubMed
8.
go back to reference Lankadeva YR, Kosaka J, Evans RG, Bailey SR, Bellomo R, May CN. Intrarenal and urinary oxygenation during norepinephrine resuscitation in ovine septic acute kidney injury. Kidney Int. 2016;90:100–8.CrossRefPubMed Lankadeva YR, Kosaka J, Evans RG, Bailey SR, Bellomo R, May CN. Intrarenal and urinary oxygenation during norepinephrine resuscitation in ovine septic acute kidney injury. Kidney Int. 2016;90:100–8.CrossRefPubMed
9.
go back to reference Darmon M, Vincent F, Dellamonica J, Schortgen F, Gonzalez F, Das V, et al. Diagnostic performance of fractional excretion of urea in the evaluation of critically ill patients with acute kidney injury: a multicenter cohort study. Crit Care. 2011;15:R178.PubMedPubMedCentralCrossRef Darmon M, Vincent F, Dellamonica J, Schortgen F, Gonzalez F, Das V, et al. Diagnostic performance of fractional excretion of urea in the evaluation of critically ill patients with acute kidney injury: a multicenter cohort study. Crit Care. 2011;15:R178.PubMedPubMedCentralCrossRef
10.
go back to reference Dewitte A, Biais M, Petit L, Cochard J-F, Hilbert G, Combe C, et al. Fractional excretion of urea as a diagnostic index in acute kidney injury in intensive care patients. J Crit Care. 2012;27:505–10.CrossRefPubMed Dewitte A, Biais M, Petit L, Cochard J-F, Hilbert G, Combe C, et al. Fractional excretion of urea as a diagnostic index in acute kidney injury in intensive care patients. J Crit Care. 2012;27:505–10.CrossRefPubMed
11.
go back to reference Pons B, Lautrette A, Oziel J, Dellamonica J, Vermesch R, Ezingeard E, et al. Diagnostic accuracy of early urinary index changes in differentiating transient from persistent acute kidney injury in critically ill patients: multicenter cohort study. Crit Care. 2013;17:R56.PubMedPubMedCentralCrossRef Pons B, Lautrette A, Oziel J, Dellamonica J, Vermesch R, Ezingeard E, et al. Diagnostic accuracy of early urinary index changes in differentiating transient from persistent acute kidney injury in critically ill patients: multicenter cohort study. Crit Care. 2013;17:R56.PubMedPubMedCentralCrossRef
12.
go back to reference Bagshaw SM, Bennett M, Devarajan P, Bellomo R. Urine biochemistry in septic and non-septic acute kidney injury: a prospective observational study. J Crit Care. 2013;28:371–8.CrossRefPubMed Bagshaw SM, Bennett M, Devarajan P, Bellomo R. Urine biochemistry in septic and non-septic acute kidney injury: a prospective observational study. J Crit Care. 2013;28:371–8.CrossRefPubMed
13.
go back to reference Vanmassenhove J, Glorieux G, Hoste E, Dhondt A, Vanholder R, Van Biesen W. Urinary output and fractional excretion of sodium and urea as indicators of transient versus intrinsic acute kidney injury during early sepsis. Crit Care. 2013;17:R234.PubMedPubMedCentralCrossRef Vanmassenhove J, Glorieux G, Hoste E, Dhondt A, Vanholder R, Van Biesen W. Urinary output and fractional excretion of sodium and urea as indicators of transient versus intrinsic acute kidney injury during early sepsis. Crit Care. 2013;17:R234.PubMedPubMedCentralCrossRef
14.
go back to reference Wlodzimirow KA, Abu-Hanna A, NM RAA, Spronk PE, Hofstra LS, Kuiper MA, et al. Transient versus persistent acute kidney injury and the diagnostic performance of fractional excretion of urea in critically ill patients. Nephron Clin Pract. 2014;126:8–13.CrossRefPubMed Wlodzimirow KA, Abu-Hanna A, NM RAA, Spronk PE, Hofstra LS, Kuiper MA, et al. Transient versus persistent acute kidney injury and the diagnostic performance of fractional excretion of urea in critically ill patients. Nephron Clin Pract. 2014;126:8–13.CrossRefPubMed
15.
go back to reference Maciel AT, Vitorio D. Urine biochemistry assessment in critically ill patients: controversies and future perspectives. J Clin Monit Comput. 2017;31:539–46.CrossRefPubMed Maciel AT, Vitorio D. Urine biochemistry assessment in critically ill patients: controversies and future perspectives. J Clin Monit Comput. 2017;31:539–46.CrossRefPubMed
16.
go back to reference Honore PM, Nguyen HB, Gong M, Chawla LS, Bagshaw SM, Artigas A, et al. Urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 for risk stratification of acute kidney injury in patients with sepsis. Crit Care Med. 2016;44:1851–60.PubMedPubMedCentralCrossRef Honore PM, Nguyen HB, Gong M, Chawla LS, Bagshaw SM, Artigas A, et al. Urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 for risk stratification of acute kidney injury in patients with sepsis. Crit Care Med. 2016;44:1851–60.PubMedPubMedCentralCrossRef
17.
go back to reference Cuartero M, Ballús J, Sabater J, Pérez X, Nin N, Ordonez-Llanos J, et al. Cell-cycle arrest biomarkers in urine to predict acute kidney injury in septic and non-septic critically ill patients. Ann Intensive Care. 2017;7:92.PubMedPubMedCentralCrossRef Cuartero M, Ballús J, Sabater J, Pérez X, Nin N, Ordonez-Llanos J, et al. Cell-cycle arrest biomarkers in urine to predict acute kidney injury in septic and non-septic critically ill patients. Ann Intensive Care. 2017;7:92.PubMedPubMedCentralCrossRef
18.
go back to reference Maizel J, Daubin D, Vong LV, Titeca-Beauport D, Wetzstein M, Kontar L, et al. Urinary TIMP2 and IGFBP7 identifies high risk patients of short-term progression from mild and moderate to severe acute kidney injury during septic shock: a prospective cohort study. Dis Markers. 2019;2019:3471215.PubMedPubMedCentralCrossRef Maizel J, Daubin D, Vong LV, Titeca-Beauport D, Wetzstein M, Kontar L, et al. Urinary TIMP2 and IGFBP7 identifies high risk patients of short-term progression from mild and moderate to severe acute kidney injury during septic shock: a prospective cohort study. Dis Markers. 2019;2019:3471215.PubMedPubMedCentralCrossRef
19.
go back to reference Dewitte A, Joannès-Boyau O, Sidobre C, Fleureau C, Bats M-L, Derache P, et al. Kinetic eGFR and novel AKI biomarkers to predict renal recovery. Clin J Am Soc Nephrol. 2015;10:1900–10.PubMedPubMedCentralCrossRef Dewitte A, Joannès-Boyau O, Sidobre C, Fleureau C, Bats M-L, Derache P, et al. Kinetic eGFR and novel AKI biomarkers to predict renal recovery. Clin J Am Soc Nephrol. 2015;10:1900–10.PubMedPubMedCentralCrossRef
20.
go back to reference Daubin D, Cristol JP, Dupuy AM, Kuster N, Besnard N, Platon L, et al. Urinary biomarkers IGFBP7 and TIMP-2 for the diagnostic assessment of transient and persistent acute kidney injury in critically ill patients. PLoS One. 2017;12:e0169674.PubMedPubMedCentralCrossRef Daubin D, Cristol JP, Dupuy AM, Kuster N, Besnard N, Platon L, et al. Urinary biomarkers IGFBP7 and TIMP-2 for the diagnostic assessment of transient and persistent acute kidney injury in critically ill patients. PLoS One. 2017;12:e0169674.PubMedPubMedCentralCrossRef
21.
go back to reference Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315:801–10.PubMedPubMedCentralCrossRef Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315:801–10.PubMedPubMedCentralCrossRef
22.
go back to reference Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P, Acute Dialysis Quality Initiative workgroup. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8:R204–12.PubMedPubMedCentralCrossRef Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P, Acute Dialysis Quality Initiative workgroup. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8:R204–12.PubMedPubMedCentralCrossRef
23.
go back to reference Závada J, Hoste E, Cartin-Ceba R, Calzavacca P, Gajic O, Clermont G, et al. A comparison of three methods to estimate baseline creatinine for RIFLE classification. Nephrol Dial Transplant. 2010;25:3911–8.CrossRefPubMed Závada J, Hoste E, Cartin-Ceba R, Calzavacca P, Gajic O, Clermont G, et al. A comparison of three methods to estimate baseline creatinine for RIFLE classification. Nephrol Dial Transplant. 2010;25:3911–8.CrossRefPubMed
24.
go back to reference Chen S. Retooling the creatinine clearance equation to estimate kinetic GFR when the plasma creatinine is changing acutely. J Am Soc Nephrol. 2013;24:877–88.CrossRefPubMed Chen S. Retooling the creatinine clearance equation to estimate kinetic GFR when the plasma creatinine is changing acutely. J Am Soc Nephrol. 2013;24:877–88.CrossRefPubMed
25.
go back to reference Claure-Del Granado R, Mehta RL. Fluid overload in the ICU: evaluation and management. BMC Nephrol. 2016;17(1):109. Claure-Del Granado R, Mehta RL. Fluid overload in the ICU: evaluation and management. BMC Nephrol. 2016;17(1):109.
26.
go back to reference Uchino S, Bellomo R, Bagshaw SM, Goldsmith D. Transient azotaemia is associated with a high risk of death in hospitalized patients. Nephrol Dial Transplant. 2010;25:1833–9.CrossRefPubMed Uchino S, Bellomo R, Bagshaw SM, Goldsmith D. Transient azotaemia is associated with a high risk of death in hospitalized patients. Nephrol Dial Transplant. 2010;25:1833–9.CrossRefPubMed
28.
go back to reference Haase-Fielitz A, Bellomo R, Devarajan P, Story D, Matalanis G, Dragun D, et al. Novel and conventional serum biomarkers predicting acute kidney injury in adult cardiac surgery--a prospective cohort study. Crit Care Med. 2009;37:553–60.CrossRefPubMed Haase-Fielitz A, Bellomo R, Devarajan P, Story D, Matalanis G, Dragun D, et al. Novel and conventional serum biomarkers predicting acute kidney injury in adult cardiac surgery--a prospective cohort study. Crit Care Med. 2009;37:553–60.CrossRefPubMed
29.
go back to reference Kashani K, Al-Khafaji A, Ardiles T, Artigas A, Bagshaw SM, Bell M, et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care. 2013;17:R25.PubMedPubMedCentralCrossRef Kashani K, Al-Khafaji A, Ardiles T, Artigas A, Bagshaw SM, Bell M, et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care. 2013;17:R25.PubMedPubMedCentralCrossRef
30.
go back to reference Bihorac A, Chawla LS, Shaw AD, Al-Khafaji A, Davison DL, Demuth GE, et al. Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication. Am J Respir Crit Care Med. 2014;189:932–9.CrossRefPubMed Bihorac A, Chawla LS, Shaw AD, Al-Khafaji A, Davison DL, Demuth GE, et al. Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication. Am J Respir Crit Care Med. 2014;189:932–9.CrossRefPubMed
31.
go back to reference Langenberg C, Gobe G, Hood S, May CN, Bellomo R. Renal histopathology during experimental septic acute kidney injury and recovery. Crit Care Med. 2014;42:e58–67.CrossRefPubMed Langenberg C, Gobe G, Hood S, May CN, Bellomo R. Renal histopathology during experimental septic acute kidney injury and recovery. Crit Care Med. 2014;42:e58–67.CrossRefPubMed
33.
go back to reference Hoste E, Bihorac A, Al-Khafaji A, Ortega LM, Ostermann M, Haase M, et al. Identification and validation of biomarkers of persistent acute kidney injury: the RUBY study. Intensive Care Med. 2020;46(5):943-53. Hoste E, Bihorac A, Al-Khafaji A, Ortega LM, Ostermann M, Haase M, et al. Identification and validation of biomarkers of persistent acute kidney injury: the RUBY study. Intensive Care Med. 2020;46(5):943-53.
34.
go back to reference Perinel S, Vincent F, Lautrette A, Dellamonica J, Mariat C, Zeni F, et al. Transient and persistent acute kidney injury and the risk of hospital mortality in critically ill patients: results of a multicenter cohort study. Crit Care Med. 2015;43:e269–75.CrossRefPubMed Perinel S, Vincent F, Lautrette A, Dellamonica J, Mariat C, Zeni F, et al. Transient and persistent acute kidney injury and the risk of hospital mortality in critically ill patients: results of a multicenter cohort study. Crit Care Med. 2015;43:e269–75.CrossRefPubMed
35.
go back to reference Sood MM, Shafer LA, Ho J, Reslerova M, Martinka G, Keenan S, et al. Early reversible acute kidney injury is associated with improved survival in septic shock. J Crit Care. 2014;29:711–7.CrossRefPubMed Sood MM, Shafer LA, Ho J, Reslerova M, Martinka G, Keenan S, et al. Early reversible acute kidney injury is associated with improved survival in septic shock. J Crit Care. 2014;29:711–7.CrossRefPubMed
36.
go back to reference Truche AS, Ragey SP, Souweine B, Bailly S, Zafrani L, Bouadma L, et al. ICU survival and need of renal replacement therapy with respect to AKI duration in critically ill patients. Ann Intensive Care. 2018;8:127.PubMedPubMedCentralCrossRef Truche AS, Ragey SP, Souweine B, Bailly S, Zafrani L, Bouadma L, et al. ICU survival and need of renal replacement therapy with respect to AKI duration in critically ill patients. Ann Intensive Care. 2018;8:127.PubMedPubMedCentralCrossRef
37.
go back to reference Jin K, Murugan R, Sileanu FE, Foldes E, Priyanka P, Clermont G, et al. Intensive monitoring of urine output is associated with increased detection of acute kidney injury and improved outcomes. Chest. 2017;152:972–9.CrossRefPubMed Jin K, Murugan R, Sileanu FE, Foldes E, Priyanka P, Clermont G, et al. Intensive monitoring of urine output is associated with increased detection of acute kidney injury and improved outcomes. Chest. 2017;152:972–9.CrossRefPubMed
38.
go back to reference de Jong LAA, Otten-Helmers AG, Spronk PE, van Kan HJM. Bioelectrical impedance measurements for assessment of kidney function in critically ill patients. Crit Care Med. 2019;47:e984–92.CrossRefPubMed de Jong LAA, Otten-Helmers AG, Spronk PE, van Kan HJM. Bioelectrical impedance measurements for assessment of kidney function in critically ill patients. Crit Care Med. 2019;47:e984–92.CrossRefPubMed
39.
go back to reference Siew ED, Matheny ME, Ikizler TA, Lewis JB, Miller RA, Waitman LR, et al. Commonly used surrogates for baseline renal function affect the classification and prognosis of acute kidney injury. Kidney Int. 2010;77:536–42.CrossRefPubMed Siew ED, Matheny ME, Ikizler TA, Lewis JB, Miller RA, Waitman LR, et al. Commonly used surrogates for baseline renal function affect the classification and prognosis of acute kidney injury. Kidney Int. 2010;77:536–42.CrossRefPubMed
40.
go back to reference Siew ED, Matheny ME. Choice of reference serum creatinine in defining acute kidney injury. Nephron. 2015;131:107–12.PubMedCrossRef Siew ED, Matheny ME. Choice of reference serum creatinine in defining acute kidney injury. Nephron. 2015;131:107–12.PubMedCrossRef
Metadata
Title
Urine cell cycle arrest biomarkers distinguish poorly between transient and persistent AKI in early septic shock: a prospective, multicenter study
Authors
Dimitri Titeca-Beauport
Delphine Daubin
Ly Van Vong
Guillaume Belliard
Cédric Bruel
Sami Alaya
Karim Chaoui
Maud Andrieu
Isabelle Rouquette-Vincenti
Frederic Godde
Michel Pascal
Momar Diouf
Christophe Vinsonneau
Kada Klouche
Julien Maizel
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Critical Care / Issue 1/2020
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/s13054-020-02984-6

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