osteopontin predicts survival in critically ill patients with acute kidney injury

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42. Lins RL, Elseviers MM, Daelemans R et al. Re-evaluation and

modification of the Stuivenberg Hospital Acute Renal Failure

(SHARF) scoring system for the prognosis of acute renal failure: an

independent multicentre, prospective study. Nephrol Dial Transplant

2004; 19: 22822288

43. Mehta RL, Pascual MT, Gruta CG et al. Refining predictive models

in critically ill patients with acute renal failure. J Am Soc Nephrol

2002; 13: 13501357

44. Dharan KS, John GT, Antonisamy Bet al. Prediction of mortality in

acute renal failure in the tropics. Ren Fail2005; 27: 289296

45. Bagshaw SM, George C, Bellomo R. A comparison of the RIFLE

and AKIN criteria for acute kidney injury in critically ill patients.

Nephrol Dial Transplant2008; 23: 15691574

Received for publication: 5.10.09; Accepted in revised form: 12.7.10

Nephrol Dial Transplant (2011) 26: 531537

doi: 10.1093/ndt/gfq498

Advance Access publication 23 August 2010

Osteopontin predicts survival in critically ill patients with acute

kidney injury

Johan M. Lorenzen1,*, Carsten Hafer1,*, Robert Faulhaber-Walter1, Philipp Kmpers1, Jan T. Kielstein1,Hermann Haller1 and Danilo Fliser2

1Department of Medicine, Division of Nephrology and Hypertension, Hanover Medical School, Hannover, Germany and 2Saarland

University Medical Centre, Homburg/Saar, Germany

Correspondence and offprint requests to: Johan M. Lorenzen; E-mail: [email protected]*These authors contributed equally to the study.

Abstract

Background.The cytokine osteopontin is involved in thepathophysiology of experimental acute kidney injury. Wehave tested the hypothesis that osteopontin levels mightserve as a biomarker predicting outcome in critically illpatients requiring renal replacement therapy after acutekidney injury.Methods. We measured circulating plasma osteopontinlevels in 109 critically ill patients with acute kidney in-jury at inception of renal replacement therapy and 4 weeksthereafter. Critically ill patients without acute kidney in-jury served as controls. Osteopontin was measured withELISA.Results.Baseline osteopontin levels in patients with acutekidney injury were significantly higher compared withcontrols (P < 0.0001). Baseline osteopontin levels in pa-tients recovering from acute kidney injury were signifi-cantly elevated compared with patients with permanentloss of kidney function after acute kidney injury (P =0.01). In addition, in patients recovering from acute kidneyinjury without further need for renal replacement therapy,osteopontin levels were significantly lower 4 weeks afterinitiation of renal replacement therapy (P = 0.0005). More-over, multivariate Cox analysis revealed osteopontin levelsat renal replacement therapy inception as an independentand powerful predictor of mortality (P < 0.0001). In theROC-curve analysis, an osteopontin cut-off value of577 ng/mL separated survivors from non-survivors with

a sensitivity of 100% and a specificity of 61% (AUC0.82; 95% confidence interval: 0.740.89; P < 0.0001).Conclusions.Osteopontin may serve as a novel biomarkerfor both, overall survival and renal outcome in critically ill

patients with acute kidney injury, that require renal re-placement therapy.

Keywords:acute kidney injury; mortality; osteopontin;renal replacement therapy

Introduction

Acute kidney injury (AKI) in critically ill patients has beenidentified as an independent risk factor for increased mor-tality [1]. Survival of patients with AKI in the intensive

care unit (ICU) is still unacceptably low despite significantadvances in supportive care [2]. A recent multinational,multi-centre study of 29 000 critically ill patients including1700 with AKI revealed that the in-hospital mortality ishigh, exceeding 60% [3]. Thus, detection of patients atparticular risk for both death and prolonged kidney failureafter AKI in the setting of intensive care medicine andrenal replacement therapy (RRT) remains an area of utmostinterest.

Osteopontin (OPN) is a cytokine that is broadly ex-pressed and upregulated during inflammation and various

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other conditions [46]. OPN has an arginineglycineaspartic acid cell binding sequence, and via this se-quence, it interacts with a variety of cell surface receptors[79]. Secreted OPN binds to the v3 integrin-receptor

and subsequently induces phosphoinositide-3-kinase/Akt-dependent NF-kB activation [46]. It is involved in the re-cruitment and retention of macrophages and T cells to sitesof inflammation. Classical mediators of acute inflammationsuch as tumour necrosis factorand interleukin-1 stronglyinduce OPN expression [1012], while other mediators thatcan induce OPN are angiotensin II, transforming growthfactor, and hypoxia [1318]. Circulating OPN has there-fore been proposed to be a mediator in the pathogenesis ofsystemic inflammatory response syndrome (SIRS) andsepsis [19]. Moreover, recent experimental studies havehighlighted a role for OPN in various models of AKI[2028].

In the present study, we tested the hypothesis that OPNmight serve as a biomarker predicting survival and renal out-come in critically ill patients with AKI requiring RRT. In theinitial stage, OPN might reflect the level of renal injury.

Materials and methods

Patients and methods

This study is a post hoc measurement of prospectively collected bloodsamples from the HANDOUT trial [30]. The study protocol was approved

by the Hannover Medical School Ethics Committee (project/approval

no. 2905) and was conducted in accordance with the Declaration ofHelsinki and German Federal Guidelines. Patients in seven ICUs of thetertiary care centre at the Hannover Medical School suffering from AKIwere evaluated for inclusion. Patients with non-obstructive, RRT-

dependent AKI were included. The inclusion criteria were loss of kidneyfunction of >30% calculated estimated glomerular filtration rate (eGFR)with either the MDRD or CockroftGault equation and/or cystatin C-GFRwithin 48 h prior to inclusion and oliguria/anuria (6 h prior toinclusion) or hyperkalaemia (>6.5 mmol/L) or severe metabolic acidosis(pH 1000 mL/day and/or increased solute clearance, i.e. decline in pre-treatment serum creatinine concentration with eGFR >15 mL/min (byMDRD, CockroftGault equation and/or cystatin C-GFR). Serum cystatinC, serum creatinine and serum C reactive protein (CRP) levels were deter-mined by routine laboratory methods.

Table 1. Demographic, clinical and laboratory characteristics of patients

Total Survivors Non-survivors P-value

Number of patients 109 69 40 0.64Male (n; %) 64 (59) 40 25Female (n; %) 45 (41) 29 15

Discipline of ICU admission 0.39Medicine (n; %) 46 (42) 27 (39) 19 (48)General surgery (n; %) 27 (25) 16 (23) 11 (28)

Cardiac surgery (n; %) 36 (33) 26 (38) 10 (24)Age (years) 52 (4063) 52 (4463) 51 (3763) 0.77BMI (kg/m

2) 25 (2228) 25.4 (2228) 24.7 (2228) 0.62

Indication for RRTeGFR loss >30% 93 59 34 0.94Oliguria/anuria 71 46 25 0.77Metabolic acidosis 8 4 4 0.42Hyperkalaemia 6 2 4 0.12

SOFA score 13 (1015) 14 (1115.5) 13 (1015) 0.68Renal 2 (1.53) 2 (12.5) 2 (23) 0.02*

Coagulation 1 (02) 2 (02) 1 (02) 0.62Cardiovascular 4 (0.54) 4 (24) 3 (04) 0.23

Nervous system 4 (34) 4 (34) 4 (34) 0.94Respiratory system 2 (13) 2 (13) 2 (23) 0.83Liver 2 (02) 2 (03) 2 (02) 0.39

RIFLE class 0.13Risk (n; %) 10 (9) 9 (13) 1 (3) 0.07

Injury (n; %) 15 (14) 9 (13) 6 (15) 0.8Failure (n; %) 84 (77) 51 (74) 33 (82) 0.3

APACHE II score 34 (2736) 33 (2636) 35 (2939.8) 0.58CRP (mg/L) 113 (56197) 82 (46191) 145.5 (67211.5) 0.16MAP (mmHg) 75.5 (6790) 77 (7093) 74 (6486) 0.27Heart rate (bpm) 100 (85110) 99 (84109) 100 (89111) 0.27Osteopontin (ng/mL) 616 (432638) 451 (408625) 631 (619649)


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Failure Assessment (SOFA) score [31] and Acute Physiology andChronic Health Evaluation II (APACHE II) score [32] were obtainedfor each patient immediately before initiation of RRT. The presence of

sepsis was defined according to the SCCM/ESICM/ACCP/ATS/SIS Inter-national Sepsis Definitions [33]. AKI was classified post hoc by means ofthe RIFLE criteria at initiation of RRT [34].

Sampling and quantification of OPN

Samples for quantification of OPN were obtained for each patient imme-diately before initiation of RRT and 4 weeks thereafter in survivors. Ali-quots were stored at80C for further analysis. OPN levels were measuredin plasma and in collected spent dialysate (n = 8) using a commerciallyavailable ELISA (R&D Systems, Minneapolis, MN, USA). The detectionlimit was 0.011 ng/mL, and the intra- and inter-assay coefficients of vari-ance were 2.6% and 5.4%, respectively. All measurements were performedin duplicate by investigators blinded to patients characteristics and out-come. Age-matched critically ill patients without AKI, patients with essen-tial hypertension and micro-inflammation, and healthy subjects served ascontrols.

Study outcomes and statistical analysis

The main objective of the study was to analyse the predictive value of OPNconcerning mortality and renal recovery of critically ill patients with AKIreceiving RRT. The study end point was defined as survival 4 weeks afterinitiation of RRT and renal recovery (no RRT requirement) in survivors4 weeks after initiation of RRT.

Continuous variables are expressed as medians with corresponding25th and 75th percentiles (IQR) and were compared by using theMannWhitney rank-sum test or the KruskalWallis one-way analysisof variance. Categorical variables were compared using the test. Cor-relations between variables were assessed by the Spearman rank correl-

ation coefficient. Parameters independently associated with survivalwere identified by univariate and multivariate Cox proportional hazardsmodels. Variables found to be statistically significant at a 10% level in theunivariate analysis were included in the multivariate model using back-ward elimination. Two-sided P-values


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[579.7 (414633.9) vs. 427 (395452)ng/mL; P = 0.01]

(Figure 1). In patients recovering from AKI after initiationof RRT, plasma OPN levels decreased significantly (P =0.0005), while in patients still requiring dialysis 4 weeksafter initiation of treatment, OPN levels did not change(P = 0.19). Importantly, we did not detect OPN in spentdialysate (n = 8), indicating that it is not removed by thetreatment procedure. Moreover, OPN levels were not asso-ciated with urinary output, indicating that increased OPNlevels are not a matter of impaired urinary excretion (r=0.04, P = 0.7). Dependence upon RRT was significantlyassociated with baseline OPN levels (HR 0.995, 95% con-fidence interval 0.9900.999, P = 0.024).

Circulating OPN predicts 28-day mortality in the ICU

in critically ill patients with AKI

A total of 40 patients died in our cohort. OPN levels innon-survivors were significantly elevated compared withsurvivors [631 (619649) vs. 451 (408625)ng/mL, P

osteopontin predicts survival in critically ill patients with acute kidney injury

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