Osteopontin and acute kidney injury

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

531
44. Dharan KS, John GT, Antonisamy B et al. Prediction of mortality in
acute renal failure in the tropics. Ren Fail 2005; 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 Transplant 2008; 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

Johan M. Lorenzen1,*, Carsten Hafer1,*, Robert Faulhaber-Walter1, Philipp Kmpers1, Jan T. Kielstein1,
Hermann Haller1 and Danilo Fliser2
1

Department 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: J.M.Lorenzen@gmail.com
*

These authors contributed equally to the study.

Abstract
Background. The cytokine osteopontin is involved in the
pathophysiology of experimental acute kidney injury. We
have tested the hypothesis that osteopontin levels might
serve as a biomarker predicting outcome in critically ill
patients requiring renal replacement therapy after acute
kidney injury.
Methods. We measured circulating plasma osteopontin
levels in 109 critically ill patients with acute kidney injury at inception of renal replacement therapy and 4 weeks
thereafter. Critically ill patients without acute kidney injury served as controls. Osteopontin was measured with
ELISA.
Results. Baseline osteopontin levels in patients with acute
kidney injury were significantly higher compared with
controls (P < 0.0001). Baseline osteopontin levels in patients recovering from acute kidney injury were significantly elevated compared with patients with permanent
loss of kidney function after acute kidney injury (P =
0.01). In addition, in patients recovering from acute kidney
injury without further need for renal replacement therapy,
osteopontin levels were significantly lower 4 weeks after
initiation of renal replacement therapy (P = 0.0005). Moreover, multivariate Cox analysis revealed osteopontin levels
at renal replacement therapy inception as an independent
and powerful predictor of mortality (P < 0.0001). In the
ROC-curve analysis, an osteopontin cut-off value of
577 ng/mL separated survivors from non-survivors with

a sensitivity of 100% and a specificity of 61% (AUC

0.82; 95% confidence interval: 0.740.89; P < 0.0001).
Conclusions. Osteopontin may serve as a novel biomarker
for both, overall survival and renal outcome in critically ill
patients with acute kidney injury, that require renal replacement therapy.
Keywords: acute kidney injury; mortality; osteopontin;
renal replacement therapy

Introduction
Acute kidney injury (AKI) in critically ill patients has been
identified as an independent risk factor for increased mortality [1]. Survival of patients with AKI in the intensive
care unit (ICU) is still unacceptably low despite significant
advances in supportive care [2]. A recent multinational,
multi-centre study of 29 000 critically ill patients including
1700 with AKI revealed that the in-hospital mortality is
high, exceeding 60% [3]. Thus, detection of patients at
particular risk for both death and prolonged kidney failure
after AKI in the setting of intensive care medicine and
renal replacement therapy (RRT) remains an area of utmost
interest.
Osteopontin (OPN) is a cytokine that is broadly expressed and upregulated during inflammation and various

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Osteopontin predicts survival in critically ill patients with acute

kidney injury

532

J.M. Lorenzen et al.

Table 1. Demographic, clinical and laboratory characteristics of patients

Total
109
64 (59)
45 (41)

69
40
29

Non-survivors
40
25
15

P-value
0.64
0.39

46
27
36
52
25
93
71
8
6
13
2
1
4
4
2
2
10
15
84
34
113
75.5
100
616

(42)
(25)
(33)
(4063)
(2228)

27
16
26
52
25.4

(1015)
(1.53)
(02)
(0.54)
(34)
(13)
(02)

59
46
4
2
14
2
2
4
4
2
2

(1115.5)
(12.5)
(02)
(24)
(34)
(13)
(03)

34
25
4
4
13
2
1
3
4
2
2

9
9
51
33
82
77
99
451

(13)
(13)
(74)
(2636)
(46191)
(7093)
(84109)
(408625)

1
6
33
35
145.5
74
100
631

(9)
(14)
(77)
(2736)
(56197)
(6790)
(85110)
(432638)

(39)
(23)
(38)
(4463)
(2228)

19
11
10
51
24.7

(48)
(28)
(24)
(3763)
(2228)

(1015)
(23)
(02)
(04)
(34)
(23)
(02)
(3)
(15)
(82)
(2939.8)
(67211.5)
(6486)
(89111)
(619649)

0.77
0.62
0.94
0.77
0.42
0.12
0.68
0.02*
0.62
0.23
0.94
0.83
0.39
0.13
0.07
0.8
0.3
0.58
0.16
0.27
0.27
<0.0001*

*
P < 0.05.
ICU, intensive care unit; BMI, body mass index; RRT, renal replacement therapy; eGFR, estimated glomerular filtration rate; SOFA, Sequential Organ
Failure Assessment; APACHE II, Acute Physiology and Chronic Health Evaluation II; MAP, mean arterial blood pressure; CRP, C-reactive protein.

other conditions [46]. OPN has an arginineglycine

aspartic acid cell binding sequence, and via this sequence, it interacts with a variety of cell surface receptors
[79]. Secreted OPN binds to the v3 integrin-receptor
and subsequently induces phosphoinositide-3-kinase/Aktdependent NF-kB activation [46]. It is involved in the recruitment and retention of macrophages and T cells to sites
of inflammation. Classical mediators of acute inflammation
such as tumour necrosis factor and interleukin-1 strongly
induce OPN expression [1012], while other mediators that
can induce OPN are angiotensin II, transforming growth
factor , and hypoxia [1318]. Circulating OPN has therefore been proposed to be a mediator in the pathogenesis of
systemic inflammatory response syndrome (SIRS) and
sepsis [19]. Moreover, recent experimental studies have
highlighted a role for OPN in various models of AKI
[2028].
In the present study, we tested the hypothesis that OPN
might serve as a biomarker predicting survival and renal outcome in critically ill patients with AKI requiring RRT. In the
initial 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 blood
samples 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 of

Helsinki and German Federal Guidelines. Patients in seven ICUs of the
tertiary care centre at the Hannover Medical School suffering from AKI
were evaluated for inclusion. Patients with non-obstructive, RRTdependent AKI were included. The inclusion criteria were loss of kidney
function of >30% calculated estimated glomerular filtration rate (eGFR)
with either the MDRD or CockroftGault equation and/or cystatin C-GFR
within 48 h prior to inclusion and oliguria/anuria (<30 mL/h >6 h prior to
inclusion) or hyperkalaemia (>6.5 mmol/L) or severe metabolic acidosis
(pH <7.15 and bicarbonate <12). Exclusion criteria were pre-existing
chronic kidney disease as defined by eGFR <60 mL/min or a serum creatinine concentration >1.7 mg/dL more than 10 days prior to initiation of
the first RRT. Further exclusion criteria were participation in another study,
consent denial or withdrawal, and need for extracorporeal membrane oxygenation therapy. The enrolment was performed by attending nephrologists
after obtaining written informed consent from a patient or his/her legal
representatives. If the patient was recovering and able to communicate,
he/she was informed of the study purpose, and consent was required to
further maintain his/her status as a study participant.
After inclusion, the specific medical condition leading to RRT initiation
was documented out of a list of four possible causes requiring immediate
RRT. All patients received a nutritional intake of at least 2530 kcal/kg/day,
preferentially delivered as enteral nutrition. The prescribed protein intake
was >1.2 g/kg/day. RRT in all patients was performed in a slow extended
dialysis (SLED) mode using the GENIUSTM dialysis system (Fresenius
Medical Care, Bad Homburg, Germany) as described in detail elsewhere
[20]. The dose of the RRT was tailored according to the patient individual
need, starting with at least one treatment daily. RRT was discontinued in
patients meeting the following criteria for renal recovery: urine output
>1000 mL/day and/or increased solute clearance, i.e. decline in pretreatment serum creatinine concentration with eGFR >15 mL/min (by
MDRD, CockroftGault equation and/or cystatin C-GFR). Serum cystatin
C, serum creatinine and serum C reactive protein (CRP) levels were determined by routine laboratory methods.

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Number of patients
Male (n; %)
Female (n; %)
Discipline of ICU admission
Medicine (n; %)
General surgery (n; %)
Cardiac surgery (n; %)
Age (years)
BMI (kg/m2)
Indication for RRT
eGFR loss >30%
Oliguria/anuria
Metabolic acidosis
Hyperkalaemia
SOFA score
Renal
Coagulation
Cardiovascular
Nervous system
Respiratory system
Liver
RIFLE class
Risk (n; %)
Injury (n; %)
Failure (n; %)
APACHE II score
CRP (mg/L)
MAP (mmHg)
Heart rate (bpm)
Osteopontin (ng/mL)

Survivors

Osteopontin and acute kidney injury

533
ation coefficient. Parameters independently associated with survival
were identified by univariate and multivariate Cox proportional hazards
models. Variables found to be statistically significant at a 10% level in the
univariate analysis were included in the multivariate model using backward elimination. Two-sided P-values <0.05 were considered statistically
significant for all statistical procedures used. The distribution of the timeto-event variables was estimated using the KaplanMeier method with
log-rank testing. Receiver operator characteristics (ROC) procedures were
used to identify optimal cut-off values. All statistical analyses were performed with the SPSS package (SPSS Inc., Chicago, IL, USA) and
GraphPad Prism software (GraphPad Prism Software Inc., San Diego,
CA, USA).

p<0.0001

plasma OPN (ng/mL)

750

500

250

Results

0
non-survivors

survivors

Patient characteristics and OPN levels at baseline

p=0.01

500

250

0
renal recovery

no recovery

Fig. 1. Box and whisker plots of baseline circulating osteopontin (OPN)

levels of survivors vs. non-survivors at 4 weeks after initiation of RRT in
critically ill patients with acute kidney injury (AKI) (A). OPN levels in
patients recovering from AKI are elevated to patients without renal
recovery (B).
Failure Assessment (SOFA) score [31] and Acute Physiology and
Chronic Health Evaluation II (APACHE II) score [32] were obtained
for each patient immediately before initiation of RRT. The presence of
sepsis was defined according to the SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions [33]. AKI was classified post hoc by means of
the RIFLE criteria at initiation of RRT [34].
Sampling and quantification of OPN
Samples for quantification of OPN were obtained for each patient immediately before initiation of RRT and 4 weeks thereafter in survivors. Aliquots were stored at 80C for further analysis. OPN levels were measured
in plasma and in collected spent dialysate (n = 8) using a commercially
available ELISA (R&D Systems, Minneapolis, MN, USA). The detection
limit was 0.011 ng/mL, and the intra- and inter-assay coefficients of variance were 2.6% and 5.4%, respectively. All measurements were performed
in duplicate by investigators blinded to patients characteristics and outcome. Age-matched critically ill patients without AKI, patients with essential hypertension and micro-inflammation, and healthy subjects served as
controls.

Patients were grouped as survivors and non-survivors at

4 weeks after initiation of RRT. Patient groups were comparable with respect to baseline demographics, indications
for RRT and the proportion of RIFLE categories (Table 1).
Differences in the renal SOFA subscore and OPN levels in
survivors vs. non-survivors at baseline were highly significant (P = 0.02 and P < 0.0001, respectively). Baseline
OPN levels in critically ill patients with AKI [n = 109;
616 (432638) ng/mL] were elevated 2-fold compared
with critically ill non-AKI patients [n = 15; 226 (179
344)ng/mL; P < 0.0001]. Patients with sepsis had higher
SOFA and Apache II scores that resulted from more severe
cardiovascular and respiratory impairment compared with
patients with either non-SIRS/Sepsis or SIRS, respectively
(data not shown). Consistently, septic patients had poorer
28-day survival [53% vs. 76% (non-SIRS/Sepsis) and 70%
(SIRS)]. Differences in OPN levels in patients with nonSIRS/Sepsis, SIRS or Sepsis did not reach statistical significance (P = 0.09).
Circulating OPN levels in critically ill patients
We did not find an association between OPN and APACHE
II or SOFA score. However, OPN levels correlated significantly with the renal SOFA subscore (r = 0.219, P = 0.022),
while there was no association with any other subgroup.
Furthermore, OPN levels in patients in the RIFLE failure
group were significantly elevated compared with the
RIFLE risk group (P < 0.01). We found no significant differences in OPN levels in patients with or without sepsis
(P = 0.07), diabetes (P = 0.78), surgery (P = 0.27) or shock
(P = 0.21). Similarly, OPN levels did not differ between
patients on a medical, general surgical or cardiac surgical
ICU as assessed by ANOVA (P = 0.75). Baseline OPN
levels did not correlate with serum cystatin C levels (P =
0.64) or serum creatinine levels (P = 0.4).

Study outcomes and statistical analysis

The main objective of the study was to analyse the predictive value of OPN
concerning mortality and renal recovery of critically ill patients with AKI
receiving RRT. The study end point was defined as survival 4 weeks after
initiation of RRT and renal recovery (no RRT requirement) in survivors
4 weeks after initiation of RRT.
Continuous variables are expressed as medians with corresponding
25th and 75th percentiles (IQR) and were compared by using the
MannWhitney rank-sum test or the KruskalWallis one-way analysis
of variance. Categorical variables were compared using the test. Correlations between variables were assessed by the Spearman rank correl-

Circulating OPN levels in patients with AKI and

renal recovery
Twenty-four of 69 surviving patients (35%) were still
dependent upon RRT at 4 weeks after initiation of therapy.
OPN levels at initiation of RRT predicted renal recovery
since baseline OPN levels in patients recovering from
AKI were significantly higher compared with patients still
dependent upon RRT at 4 weeks after start of therapy

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plasma OPN (ng/mL)

750

534

J.M. Lorenzen et al.

Table 2. Univariate and multivariate Cox regression analysis for survival

Univariate

Multivariate

Variables

HR

95% CI

P-value

HR

95% CI

P-value

OPN (ng/mL)
Age
Gender (M/F)
Body mass index
Sepsis (yes/no)
Diabetes (yes/no)
Surgery (yes/no)
Shock (yes/no)
S-creatinine
RIFLE criteria
SOFA score
APACHE II score
CRP
Heart rate

3.891
0.991
0.839
0.996
2.222
1.137
0.635
2.618
0.998
1.578
1.061
1.038
1.001
1.003

2.3266.509
0.9711.012
0.4421.592
0.9351.061
1.1944.134
0.4452.903
0.3371.195
0.9287.382
0.9871.010
0.8552.912
0.9601.172
0.9941.084
0.9981.003
0.9891.016

0.0001*
0.386
0.591
0.896
0.012*
0.788
0.159
0.069
0.801
0.145
0.244
0.088
0.516
0.699

4.241

2.4537.332

0.0001*

0.901

0.5941.367

0.625

2.124

0.7416.089

0.161

1.049

1.0001.100

0.049*

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

(Figure 1). In patients recovering from AKI after initiation
of RRT, plasma OPN levels decreased significantly (P =
0.0005), while in patients still requiring dialysis 4 weeks
after initiation of treatment, OPN levels did not change
(P = 0.19). Importantly, we did not detect OPN in spent
dialysate (n = 8), indicating that it is not removed by the
treatment procedure. Moreover, OPN levels were not associated with urinary output, indicating that increased OPN
levels are not a matter of impaired urinary excretion (r =
0.04, P = 0.7). Dependence upon RRT was significantly
associated with baseline OPN levels (HR 0.995, 95% confidence 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 in
non-survivors were significantly elevated compared with
survivors [631 (619649) vs. 451 (408625)ng/mL, P <
0.0001] (Figure 1). To determine the relationship between

OPN levels at initiation of RRT and mortality, we initially

performed univariate Cox proportional hazards analyses.
In our cohort of 109 critically ill patients with AKI, age,
gender, body weight, height or body mass index were not
significantly associated with survival (Table 2). The same
was true for heart rate, the presence of diabetes, major
surgery, serum C-reactive protein and serum creatinine levels prior admission to the ICU. RIFLE criteria were also
not of prognostic value. Among the variables tested OPN
levels, APACHE II and SOFA scores, sepsis, and the presence of non-septic shock displayed prognostic significance
at a 10% level and were subsequently subjected to multivariate Cox regression analysis (Table 2). Only OPN levels
(P < 0.0001) and Apache II score (P = 0.049) remained
independent predictors of survival. In fact, OPN levels
were identified as the strongest independent prognostic
factor for survival in our cohort, with an area under the
ROC curve (AUC) value of 0.82 (standard error of the
mean: 0.04; 95% confidence interval: 0.740.89; P <
0.0001) (Figure 2). For comparison, the SOFA score
yielded an AUC value of 0.57 (standard error of the mean:

100
100

Percent survival

Sensitivity %

80
60
40

AUC 0.82
p < 0.0001

20

80
60
40

OPN below 577 ng/ml

OPN above 577 ng/ml

20

p < 0.0001

20

40

60

80

100

100% - Specificity%
Fig. 2. Receiver-operating curve (ROC) analysis of circulating osteopontin
(OPN) levels for the prediction of survival 4 weeks after initiation of renal
replacement therapy [area under the curve: 0.82; standard error of the
mean (SEM): 0.04; 95% confidence interval: 0.740.89; P < 0.0001].

0
0

10

20

days
Fig. 3. KaplanMeier curves of survival stratified to circulating osteopontin
(OPN) above and below a cut-point of 577 ng/mL. Log-rank test confirmed
statistical significance for OPN (P < 0.0001).

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*
P < 0.05.
OPN, osteopontin; SOFA, Sequential Organ Failure Assessment; APACHE II, Acute Physiology and Chronic Health Evaluation II; CRP, C-reactive
protein; CI, confidence interval; HR, hazard ratio.

Osteopontin and acute kidney injury

Discussion
Our study is the first clinical evaluation of circulating
OPN levels in critically ill patients with AKI requiring
RRT. The results are as follows: (i) baseline OPN levels
in patients with AKI are significantly elevated compared
with control subjects. (ii) OPN levels in patients in the RIFLE failure group were significantly higher compared
with the RIFLE risk group, (iii) OPN levels in patients recovering from AKI were significantly elevated compared
with patients with complete and permanent loss of kidney
function and (iv) OPN levels decrease in patients recovering from AKI, while they remain high in patients still
dependent upon RRT 4 weeks after initiation of RRT.
(v) OPN levels in non-survivors are significantly higher
than in survivors, (vi) OPN levels were identified as the
strongest independent prognostic factor for 28-day survival in the multivariate Cox proportional hazards regression analysis, and (vii) an OPN cut-off value of 577 ng/mL
separates survivors from non-survivors with a sensitivity of
100%. (viii) Baseline OPN levels were not predictive concerning long-term survival.
In experimental studies using gene profiling, OPN
mRNA was found to be enhanced in kidneys of male SpragueDawley rats recovering from experimental AKI as a
result of ischaemia/reperfusion injury [21]. Such upregulation may represent a beneficial adaptive response because
the disruption of the OPN gene in OPN knockout mice results in more severe injury after experimental AKI [22].
OPN expression correlates with macrophage infiltration
in various animal models of acute and chronic kidney injury such as glomerulonephritis, hypertensive glomerulosclerosis and cyclosporine nephropathy [2325]. OPN
gene and protein expression is induced in both proximal
and distal tubular cells following toxin-induced AKI
[26]. Hypoxia is also associated with increased tubular expression of OPN in vitro and in vivo [27,28]. Here, OPN
acts as a survival factor and protects cells from entering

apoptosis. Despite diminished macrophage infiltration

and interstitial fibrosis, the obstructed kidneys of OPN
knockout mice exhibit increased levels of tubular cell
apoptosis compared with wild-type mice, suggesting that
OPN is capable of providing survival signals to tubular
epithelial cells in vivo [29]. These experimental findings
might explain the differences in OPN values observed in
our cohort. We hypothesize that the differences in OPN levels with regard to renal recovery and overall mortality are
due to the complex function of OPN in injury and disease.
In response to tubular injury, the local expression of OPN
might be upregulated. Similar to experimental studies on
the role of OPN in AKI [2129], it is conceivable that
OPN also serves as a survival factor within the kidney protecting tubular epithelial cells from entering apoptosis in
humans. Once tubular epithelial cells recover from the insult, the tubular expression of OPN decreases since its
anti-apoptotic signals are no longer required resulting in
lower circulating levels of OPN. There are several factors
that indicate that the differences in circulating levels of
OPN in patients recovering from AKI as opposed to patients still dependent upon RRT at 4 weeks after initiation
of therapy can be attributed to its role as a survival factor
within the tubular epithelium rather than removal by treatment procedure or altered urokinetics/urodynamics in patients with incipient diuresis as compared with anuric
patients. These include the lack of an association between
OPN and markers of renal function (i.e. cystatin C and
serum creatinine) as well as urinary output and the lack
of a detection of OPN in spent dialysate. The results of
our study permit the conclusion that the level of circulating
OPN at the time of renal injury predicts the probability of
renal recovery.
OPN levels also predicted overall 28-day survival in critically ill patients with AKI. This finding is well in line with
other studies pertaining to the prognostic significance of
OPN for mortality. OPN was identified as a strong independent predictor of mortality in patients with chronic heart failure, non-small cell lung cancer and breast cancer [3537].
Osteopontin has been shown to be a mediator of severe
inflammation in patients with systemic inflammatory response syndrome and sepsis, possibly by altering the release of IL-6 [19]. We speculate that the level of critical
illness and inflammation is reflected by circulating levels
of OPN. OPN might serve as a marker and mediator of
multi-organ dysfunction through the retention of inflammatory cells and the release of IL-6. Death ensues as a
consequence of severe inflammation. These patients present
with the highest levels of circulating OPN.
There are certain limitations to our study. Our study represents results from a relatively small, single-centre cohort
of adult patients without pre-existing renal impairment. In
addition, the overwhelming majority of our patients presented with severe AKI (RIFLE category failure). Thus,
our results need validation in larger trials, including patients with pre-existing chronic kidney disease (CKD)
and a larger number of patients with less severe AKI.
The fact that the vast majority of patients in our cohort presented with severe AKI underlines the prognostic significance of OPN as a predictor of mortality, since more

Downloaded from http://ndt.oxfordjournals.org/ by guest on August 24, 2015

0.06; 95% confidence interval: 0.460.68; P = 0.227), and

the APACHE II score yielded an AUC value of 0.603
(standard error of the mean: 0.06; 95% confidence interval: 0.490.72; P = 0.073). An OPN cut-off value of
577 ng/mL separated survivors from non-survivors with
a sensitivity of 100% (95% confidence interval: 92.4
100) and a specificity of 61% (95% confidence interval:
56.561). The positive and negative predictive values were
59.7% (95% confidence interval: 55.259.7) and 100%
(95% confidence interval: 92.8100), respectively. Figure 3
illustrates the KaplanMeier curve of survival 4 weeks
after initiation of RRT stratified to OPN above and below
a cut-point of 577 ng/mL. Log-rank test confirmed statistical significance for OPN (P < 0.0001). We also analysed
the patients survival status 3.5 years after inclusion into
the Handout trial concerning the association with baseline
OPN levels. In the group of survivors, 36 patients were
lost to follow-up, 6 patients died during the follow-up
period and 27 patients were still alive. Baseline OPN levels
were not predictive concerning long-term survival (P = 0.6).

535

536

Conflict of interest statement. None declared.

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severe AKI is also associated with higher mortality rates

[1,3]. Differences in the SOFA renal subscore and OPN levels that reached statistical significance in survivors vs.
non-survivors in our cohort further corroborate the significance of the kidney and osteopontin levels for the prediction of mortality. Moreover, chronic kidney disease, as the
term implies, is associated with chronic intra-renal changes
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and serum creatinine levels. Moreover, OPN shows a close
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our hypothesis that OPN in the setting of acute kidney injury is upregulated to counteract an acute insult. It does not
seem to have predictive value once the kidney has entered a
regenerative process. Its significance in this setting lies in
the acute phase. Since many patients were lost to follow-up,
this finding has to be verified in future studies.
In conclusion, we identified OPN as a strong and independent predictor of survival in critically ill patients with
AKI. Moreover, OPN levels at the time of kidney injury
predict the probability of recovery of kidney function, with
a significant decrease of OPN plasma levels in patients recovering from AKI who require RRT.

J.M. Lorenzen et al.

Outcomes of cancer and non-cancer patients with AKI

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10471055

Received for publication: 26.2.10; Accepted in revised form: 21.7.10

Nephrol Dial Transplant (2011) 26: 537543

doi: 10.1093/ndt/gfq441
Advance Access publication 28 July 2010

Elizabeth Maccariello1,2,3, Carla Valente1,2, Lina Nogueira1,2, Helio Bonomo Jr.1,2, Marcia Ismael1,2,
Jose Eduardo Machado1,2, Fernanda Baldotto1,2, Marise Godinho1,2, Eduardo Rocha1,2,4
and Marcio Soares1,5
1

NepHro Consultoria em Doenas Renais, Rio de Janeiro, Brazil, 2Rede DOr de Hospitais, Rio de Janeiro, Brazil, 3Department of
Nephrology, Hospital Universitrio Antnio Pedro, Universidade Federal Fluminense, Rio de Janeiro, Brazil, 4Department of
Nephrology, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil and 5Intensive Care Unit, Instituto
Nacional de Cncer, Rio de Janeiro, Brazil
Correspondence and offprint requests to: Elizabeth Maccariello; E-mail: emaccariello@yahoo.com.br

Abstract
Background. Studies on cancer patients with acute kidney
injury (AKI) are restricted to specialized intensive care
units (ICUs). The aim of this study was to compare the
characteristics and outcomes of cancer and non-cancer patients requiring renal replacement therapy (RRT) for AKI
in general ICUs.
Methods. A prospective cohort study was conducted in 14
ICUs from three tertiary care hospitals. A total of 773
(non-cancer 85%; cancer 15%) consecutive patients were
included over a 44-month period. Logistic regression was
used to identify factors associated with hospital mortality.
Results. Continuous RRT was used in 79% patients. The
main contributing factors for AKI were sepsis (72%) and
ischaemia/shock (66%); AKI was multifactorial in 87% of
cancer and in 71% non-cancer patients. Hospital mortality
rates were higher in cancer (78%) than in non-cancer

patients (68%) (P = 0.042). However, in multivariate analyses, older age, medical admission, poor chronic health status, comorbidities, ICU days until the RRT start and number
of associated organ dysfunctions were associated with hospital mortality. The diagnosis of cancer was not independently associated with mortality [odds ratio = 1.54 (95%
confidence interval, 0.882.62), P = 0.115]. Mortality in
cancer patients was mostly dependent on the number of associated organ dysfunctions. Of note, 85% cancer patients
recovered renal function at hospital discharge.
Conclusions. In general ICUs, one in six patients requiring RRT has cancer. Despite a relatively higher mortality,
the presence of cancer was not independently associated
with mortality in the present cohort.
Keywords: acute kidney injury; cancer; intensive care unit; outcome;
renal replacement therapy

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Outcomes of cancer and non-cancer patients with acute kidney injury

and need of renal replacement therapy admitted to general intensive
care units