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Uchino S, Kellum JA, Bellomo R, et al. Acute Renal Failure in Critically Ill PatientsA Multinational, Multicenter Study. JAMA. 2005;294(7):813–818. doi:10.1001/jama.294.7.813
Context Although acute renal failure (ARF) is believed to be common in the setting
of critical illness and is associated with a high risk of death, little is
known about its epidemiology and outcome or how these vary in different regions
of the world.
Objectives To determine the period prevalence of ARF in intensive care unit (ICU)
patients in multiple countries; to characterize differences in etiology, illness
severity, and clinical practice; and to determine the impact of these differences
on patient outcomes.
Design, Setting, and Patients Prospective observational study of ICU patients who either were treated
with renal replacement therapy (RRT) or fulfilled at least 1 of the predefined
criteria for ARF from September 2000 to December 2001 at 54 hospitals in 23
Main Outcome Measures Occurrence of ARF, factors contributing to etiology, illness severity,
treatment, need for renal support after hospital discharge, and hospital mortality.
Results Of 29 269 critically ill patients admitted during the study period,
1738 (5.7%; 95% confidence interval [CI], 5.5%-6.0%) had ARF during their
ICU stay, including 1260 who were treated with RRT. The most common contributing
factor to ARF was septic shock (47.5%; 95% CI, 45.2%-49.5%). Approximately
30% of patients had preadmission renal dysfunction. Overall hospital mortality
was 60.3% (95% CI, 58.0%-62.6%). Dialysis dependence at hospital discharge
was 13.8% (95% CI, 11.2%-16.3%) for survivors. Independent risk factors for
hospital mortality included use of vasopressors (odds ratio [OR], 1.95; 95%
CI, 1.50-2.55; P<.001), mechanical ventilation
(OR, 2.11; 95% CI, 1.58-2.82; P<.001), septic
shock (OR, 1.36; 95% CI, 1.03-1.79; P = .03),
cardiogenic shock (OR, 1.41; 95% CI, 1.05-1.90; P = .02),
and hepatorenal syndrome (OR, 1.87; 95% CI, 1.07-3.28; P = .03).
Conclusion In this multinational study, the period prevalence of ARF requiring
RRT in the ICU was between 5% and 6% and was associated with a high hospital
The epidemiology and outcome of acute renal failure (ARF) in critically
ill patients in different regions of the world are not well understood. Although
there have been several epidemiological studies of ARF,1-16 most
are either single center1-3,6-8,12 or
if multicenter are confined to a single country.4,5,9-11,13,15,16 The
period prevalence and hospital mortality reported in these studies have varied
widely (single-center studies: 1%-25%; multicenter studies: 39%-71%) and most
studies are not comparable because they used different inclusion criteria.
In 1 multinational study14 that collected data
for a general severity scoring system and provided further but limited and
indirect information about the epidemiology of ARF, more than 90% of participating
centers were in Europe or North America. All studies of ARF have been conducted
in Australia, Europe, or North America.
We conducted a multinational, multicenter, prospective, epidemiological
survey of ARF in intensive care unit (ICU) patients. The objectives of this
study were to determine the period prevalence of ARF in ICU patients in multiple
countries; to characterize differences in etiology, illness severity, and
clinical practice; and to determine the association of these differences with
This study was conducted at 54 centers in 23 countries from September
2000 to December 2001 (participating centers are listed at the end of the
article). The study protocol was reviewed by the ethics committees or investigational
review boards at each participating site. Because of the anonymous and noninterventional
fashion of this study, the ethical committees of most study centers waived
the need for informed consent. At centers in which the ethics committees or
investigational review boards required informed consent, formal written consent
was obtained from patients or surrogates.
All patients who were older than 12 years (several ICUs treated adolescents)
and who were admitted to 1 of the participating ICUs during the observational
period were considered for study inclusion. From this population, only patients
who were treated with renal replacement therapy (RRT) other than for drug
poisoning or who had at least 1 of the predefined criteria for ARF were included
in the study.
The criteria for ARF were oliguria defined as urine output of less than
200 mL in 12 hours and/or marked azotemia defined as a blood urea nitrogen
level higher than 84 mg/dL (>30 mmol/L). These criteria were chosen because
they are simple, objective, numerically identifiable, and likely to be considered
triggers for the initiation of RRT in the ICU. While other definitions for
ARF exist and recent consensus criteria for acute renal dysfunction include
less severe forms,17,18 our intent
was to study severe ARF that likely would be treated with RRT. Patients with
any dialysis treatment before admission to the ICU or patients with end-stage
renal failure and receiving dialysis were excluded.
The following information was prospectively obtained at study inclusion
and was recorded on a standardized case report form developed for this study:
sex, date of birth, body weight (measured or estimated at ICU admission),
date of hospital admission, premorbid renal function (any evidence of abnormal
serum level of creatinine or creatinine clearance prior to hospital admission),
premorbid creatinine level, date of ICU admission, the Simplified Acute Physiology
Score19 (SAPS II) on the day of ICU admission,
creatinine and blood urea nitrogen levels at ICU admission, and primary diagnosis.
The contributing factors to ARF were identified from a list of 7 possible
choices (septic shock, cardiogenic shock, hypovolemia, drug-induced, obstructive
uropathy, major surgery, and other) according to the judgment of the treating
clinician. More than 1 contributing factor could be selected in each case.
When a patient was treated with RRT, the initial mode of RRT was recorded.
Renal replacement therapy was defined as either peritoneal dialysis or any
technique of renal support requiring an extracorporeal circuit and an artificial
membrane. Need for mechanical ventilation and inotropes/vasopressors at inclusion
into the study, date of ICU discharge, date of hospital discharge, survival
at ICU and hospital discharge, and need for RRT at hospital discharge were
Data were collected by means of an electronically prepared Excel-based
data collection tool (Microsoft Corp, Seattle, Wash), which was made available
to participating centers with instructions. All centers were asked to complete
data entry and e-mail the data to the central office, where the data were
screened in detail by a dedicated intensive care specialist for any missing
information, logical errors, insufficient detail, or addition of queries.
Any queries generated an immediate e-mail inquiry and were to be resolved
within 48 hours.
Data are presented as median and interquartile range (IQR; 25th to 75th
percentiles) or percentages (95% confidence intervals [CIs]). Multivariable
logistic regression analysis was conducted to investigate risk factors for
hospital mortality (proc LOGIST version 6.12, SAS Institute Inc, Cary, NC).
The following variables were investigated as independent risk factors using
a backward elimination approach: type and size of hospital, type and size
of ICU, age, sex, body weight, premorbid renal function, hospital stay prior
to ARF, SAPS II score, serum creatinine and urea nitrogen levels at ICU admission,
use of mechanical ventilation, use of vasopressors or inotropes, reason for
ICU admission, and factors contributing to ARF. Variables were allowed to
remain in the models if the multivariable analysis yielded a P<.05. Mode of RRT was not used as a variable because patients not
receiving RRT were included. The contribution of dummy variables, such as
ICU admission diagnosis and study center, to the model was assessed using
a likelihood ratio χ2. All other variables were assessed based
on the Wald χ2; P<.05 was considered
From September 2000 to December 2001, 29 269 critically ill patients
were admitted to the ICUs at 54 study centers (Table 1) in 23 countries (2 centers did not provide the number of
ICU admissions). The median screening period at each study center was 183
days (IQR, 131-215 days). Among these patients, 1738 patients (5.7%; 95% CI,
5.5%-6.0%) had ARF sometime during their ICU stay as defined by the study
criteria (57 patients from the 2 centers that did not provide the number of
ICU admissions were excluded from this calculation). The period prevalence
ranged from 1.4% to 25.9% across all study centers. Of the patients with ARF
documented by study criteria, 1260 patients (4.2%; 95% CI, 4.0%-4.4%) were
treated with RRT and 478 (1.6%; 95% CI, 1.4%-1.7%) had ARF but were not treated
Patient demographics are shown in Table
1. The median age of patients with ARF was 67 years (IQR, 53-75
years). The median SAPS II score was 48 (IQR, 38-61). The median body weight
was 74 kg (IQR, 63-85 kg). Approximately 30% of patients had chronic renal
dysfunction but were not receiving dialysis treatment. Estimated creatinine
clearance at ICU admission was 35 mL/min (IQR, 20-59 mL/min) (0.58 mL/s; IQR,
0.33-0.99 mL/s). Among the patients who were treated with RRT, continuous
RRT was the most common initial modality used (80.0%), followed by intermittent
RRT (16.9%), and peritoneal dialysis and slow continuous ultrafiltration (3.2%).
The major reason for ICU admission was medical in 58.9% of patients
and surgical in the remaining 41.1%. Cardiovascular surgery was the most common
diagnostic grouping, followed by medical respiratory, medical cardiovascular,
gastrointestinal tract surgery, medical gastrointestinal tract, and sepsis.
In 47.5% of patients, ARF was associated with septic shock. Thirty-four percent
of ARF was associated with major surgery, 27% was related to cardiogenic shock,
26% was related to hypovolemia, and 19% of ARF was potentially drug-related.
Medical and surgical ICU admissions by diagnostic groups and the distribution
of other possible contributing factors to ARF appear in Table 2.
Fifty-two percent of all ARF patients died in the ICU and another 8%
died in the hospital after discharge from the ICU, resulting in the overall
hospital mortality of 60.3% (95% CI, 58.0%-62.6%); whereas SAPS II predicted
mortality was 45.6% (P<.001) (Table 3). Of patients who survived to hospital discharge, 13.8%
(95% CI, 11.2%-16.3%) required RRT at the time of discharge. The median length
of ICU stay was 10 days (IQR, 5-22 days) and the median length of hospital
stay was 22 days (IQR, 11-44 days). The period prevalence and mortality (observed
and predicted) by country appear in Table 3.
However, these data are shown for illustrative purposes and comparisons across
countries are not possible because sampling was not representative in any
The following variables were entered in the backward elimination model
building process of multivariate regression analysis and were not found to
be significant independent predictors of outcome, so did not contribute to
the final model: sex, premorbid renal impairment, estimated creatinine clearance,
some of the contributing factors to ARF (major surgery, hypovolemia, drug-induced,
and obstructive uropathy), type of hospital (academic or nonacademic), and
number of hospital beds. In the final model, important risk factors for outcome
included vasopressors, mechanical ventilation, sepsis/septic shock, cardiogenic
shock, hepatorenal syndrome diagnostic grouping, type of ICU, and number of
beds in each ICU. The complete results of multivariate regression analysis
appear in Table 4. As a separate analysis,
we repeated the multivariate regression using ICU mortality as the dependent
variable and the results were essentially the same (data not shown).
This study is, to our knowledge, the first large international investigation
of the epidemiology and outcome of ARF in critically ill patients. We screened
nearly 30 000 patients and found that the period prevalence of ARF associated
with critical illness using our simple inclusion criteria was 5.7%. This is
the largest and most globally representative study of the period prevalence
of ARF in the ICU. The period prevalence of ARF had been reported from 1.5%
to 24%, depending on populations studied and criteria used.2,5,6,13,14 In
our study, period prevalence of ARF varied among study centers to a nearly
identical extent (1.4%-25.9%) despite our use of a single set of criteria.
We recognize that even though we studied only 54 centers and 23 countries,
we speculate that the worldwide period prevalence of ARF (according to our
definition) in critically ill patients is approximately 6%. Based on our research,
the worldwide period prevalence of acute RRT in the ICU is approximately 4%
(or two thirds of those with ARF).
Septic shock was the most common contributing factor to ARF. The frequency
in which it was a contributing factor to the development of ARF was around
50% in all centers. Logistic regression showed that study center, older age,
time between hospital and study inclusion, SAPS II score, use of mechanical
ventilation, and vasopressors were all independent significant risk factors
for mortality. These findings are consistent with previous findings.2-5,13,16 The
effects of time between hospital admission and study inclusion (development
of ARF) suggests that the delayed development of ARF while in the hospital
selects a particular group of patients with a poor prognosis.
We found that observed mortality was significantly higher than SAPS
II predicted mortality (60.3% vs 45.6%; P<.001).
The developmental cohort for the SAPS II score excluded burn, coronary care,
and cardiac surgery patients.19 In our study,
there were approximately 300 cardiac surgery patients and 10 burn patients.
Six study centers included some patients from their coronary care units, although
such patients contributed to a small population. Therefore, we recalculated
observed and predicted mortality after excluding cardiac surgery patients
and found that the difference in observed vs predicted mortality still remained
significant (61.3% vs 46.1%; P<.001). Several
epidemiological studies of SAPS II11-13,15 for
ARF have previously reported various relationships between observed and predicted
mortality (from overestimation to underestimation). Considering that our study
is multinational and thus fairly representative of a variety of populations,
it is likely that SAPS II generally underestimates mortality in ARF patients.
We found that most survivors of ARF (86%) were dialysis-independent
at hospital discharge. Although these results are consistent with recent clinical
trials of ARF,20-22 they
are better than estimates from large epidemiological studies in the United
States in which roughly 65% of surviving patients are thought to be free of
dialysis at hospital discharge.3,23 These
findings could significantly impact the way in which interventional trials
are designed in the future.
Our study has several limitations. First, centers chose to participate
in this study and are most likely not representative of any single country.
Therefore, it is likely that there was a self-selection bias toward centers
with a particular interest in ARF and its management. These centers might
have managed more ARF patients, treated them more aggressively, used continuous
RRT more frequently, and produced different outcomes compared with other institutions.
However, the period prevalence of ARF, the demographic features of the patients,
and overall mortality were similar to previous studies.
Second, this is an observational study not a randomized controlled trial.
However, the sample size is the largest in the literature and the data were
collected in 23 countries around the world. As such, this study provides the
first available estimates of global treatment and outcomes for ARF. We did
not include some potentially important variables in the multivariate analysis,
such as mode and intensity of RRT, timing of the beginning of treatment, and
hospital admission diagnosis. We did not include mode or intensity of RRT
as variables in the logistic regression analysis because approximately one
third of patients were not treated with RRT. Mode and intensity of RRT might
affect outcome of ARF patients but available data are inconsistent.20-22,24-26
Third, we only considered baseline clinical variables and data obtained
at study inclusion in our analysis. This component of the study focuses on
the epidemiological aspects of ARF, and this choice likely affected our findings.
Had we collected information at hospital or ICU admission, we might have found
that other variables influenced final outcome. However, the focus of our investigation
related to the onset of ARF in the ICU and the understanding of what factors
detectable at that time might have influenced subsequent outcome.
Fourth, our definition of ARF was probably skewed toward a high level
of severity. On the other hand, no accepted or validated definitions of ARF
exist. We did not provide clinicians with a standardized definition of chronic
renal failure. No consensus definition exists in this setting and the diagnosis
is complex and involves data obtained from history, biochemical analysis,
body size, sex, hematological information, and imaging. We consider it unlikely
that this would have influenced our major findings because the period prevalence
was essentially the same as that found in previous studies.2,5,6,13,14 Unlike
some of these studies, we did not find that patients with chronic renal failure
had a better outcome once we corrected for other variables. This difference
may reflect the effect of study centers outside of developed countries, the
greater numbers of variables available for analysis, and differences in the
impact of premorbid care and comorbidites once patients from developing countries
Fifth, although we did not have the resources to conduct an onsite data
audit, all data inconsistencies were immediately resolved by electronic communication
and data completeness was more than 99% at the time of statistical analysis.
Nonetheless, the lack of independent data validation is a significant limitation
of our database.
Finally, our database did not include long-term follow-up and thus the
outcomes for patients following hospital discharge are unknown. For this reason,
we chose not to analyze data using survival rates (eg, Cox proportional hazards)
because we would have had to assume that survival postdischarge resembled
in-hospital survival rates and this seems unlikely. Furthermore, our intent
was to examine all-cause hospital mortality truncated at 28 days rather than
survival rates because hospital mortality has been the most common end point
for clinical trials of ARF. There is controversy as to whether prolonging
in-hospital survival represents a benefit if hospital mortality is the same.
However, the absence of postdischarge information is a significant limitation
of our study.
In summary, we have conducted a multinational, multicenter, prospective,
epidemiological study of ARF that includes the largest and most representative
sample of ICUs and ARF patients so far. We found a period prevalence of ARF
in the ICU of approximately 6%, with close to two thirds of such patients
receiving RRT. In this study, premorbid renal dysfunction was common, sepsis
was the dominant cause of ARF in the ICU, SAPS II scores underestimated mortality,
and most survivors were dialysis-independent at hospital discharge. This information
may be helpful in the design of future international interventional trials,
which would apply to worldwide practice, in regard to the statistical power
and choice of appropriate outcome measures.
Corresponding Author: John A. Kellum, MD,
CRISMA Laboratory, Department of Critical Care Medicine, University of Pittsburgh,
3550 Terrace St, Pittsburgh, PA 15261 (firstname.lastname@example.org).
Author Contributions: Dr Uchino had full access
to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Uchino, Kellum, Bellomo,
Acquisition of data: Uchino, Kellum, Bellomo,
Morimatsu, Morgera, Schetz, Tan, Bouman, Macedo, Gibney, Tolwani.
Analysis and interpretation of data: Uchino,
Kellum, Bellomo, Doig, Tan, Tolwani, Ronco.
Drafting of the manuscript: Uchino, Kellum,
Bellomo, Tan, Gibney, Ronco.
Critical revision of the manuscript for important
intellectual content: Uchino, Kellum, Bellomo, Doig, Morimatsu, Morgera,
Schetz, Tan, Bouman, Macedo, Tolwani, Ronco.
Statistical analysis: Uchino, Kellum, Bellomo,
Obtained funding: Kellum, Bellomo.
Administrative, technical, or material support:
Kellum, Bellomo, Tan, Gibney.
Study supervision: Kellum, Bellomo, Macedo,
Financial Disclosures: None reported.
Funding/Support: This study was supported by
an unrestricted educational grant from the Austin Hospital Anaesthesia and
Intensive Care Trust Fund.
Role of the Sponsor: The Austin Hospital Anaesthesia
and Intensive Care Trust Fund had no role in the design and conduct of the
study; collection, management, analysis, or interpretation of the data; nor
any role in preparation, review, or approval of the manuscript.
Participating Centers and InvestigatorsAustralia: Intensive Care Unit, Austin and Repatriation
Medical Center (Hiroshi Morimatsu, Rinaldo Bellomo); Department of Intensive
Care, Western Hospital (Craig French); Intensive Care Unit, Epworth Foundation
(John Mulder); Department of Intensive Care, Sir Charles Gairdner Hospital
(Mary Pinder, Brigit Roberts); Intensive Care, Frankston Hospital (John Botha,
Pradeen Mudholkar); Critical Care Unit, Flinders Medical Centre (Andrew Holt,
Tamara Hunt). Belgium: Service de Soins Intensifs,
Clinique Saint-Pierre (Patrick Maurice Honoré, Gaetan Clerbaux); Dienst
Intensieve Geneeskunde, Universitair Ziekenhuis Gasthuisberg (Miet Schetz,
Alexander Wilmer). Brazil: Nephrology Division, University
of São Paulo School of Medicine (Luis Yu, Ettiene V. Macedo); Nephrology
Division, do Hospital Servidor Público Estadual de São Paulo
(Sandra Maria Rodriques Laranja, Cassio José Rodrigues); Nephrology
Unit, Casa de Saúde São José/CDR Serviços Hospitalares
(José Hermógenes Rocco Suassuna, Frederico Ruzany); Lutheran
University of Brazil (Bruno Campos, Jayme Burmeister). Canada: Intensive Care, Maisonneuve-Rosemont Hospital (Martine Leblanc,
Lynne Senécal); Division of Critical Care Medicine, University of Alberta,
Edmonton (R. T. Noel Gibney, Curtis Johnston, Peter Brindley). China: Intensive Care Unit, Department of Anaesthesia, Pamela Youde
Nethersole Eastern Hospital (Ian K. S. Tan); Surgical Intensive Care Unit,
Beijing Chao Yang Hospital (Hui De Chen, Li Wan). Czech
Republic: Intensive Care Unit, Department of Internal Medicine, Charles
University Hospital Plzen (Richard Rokyta, Ales Krouzecky). Germany: Department of Nephrology, University Hospital Charité,
CCM (Stanislao Morgera, Hans-Hellmut Neumayer); Klinik für Anaesthesiologie,
Universitätsklinikum Duesseldorf (Kindgen-Milles Detlef, Eckhard Mueller). Greece: Intensive Care Unit, General Regional Hospital,
“G. Papanikolau” (Vicky Tsiora, Kostas Sombolos). Indonesia: Intensive Care Unit, National Cardiovascular Center and
Mitra Keluarga Hospital (Iqbal Mustafa, Iwayan Suranadi). Israel: Intermediate Intensive Care Unit, Rambam Medical Center (Yaron
Bar-Lavie, Farid Nakhoul). Italy: Anesthesia and
Intensive Care Unit, Cliniche Humanitas-Gavazzeni (Roberto Ceriani, Franco
Bortone); Nephrology-Intensive Care, St Bortolo Hospital (Claudio Ronco, Nereo
Zamperetti); Istituto di Anestesia e Rianimazione Servizio di Anestesia e
Rianimazione per la Cardiochirurgia, Ospedale San Raffaele IRCCS Università
Vita e Salute (Federico Pappalardo, Giovanni Marino); Unità Operativa
di Rianimazione, Ospedale Vittorio Emanuele (Prospero Calabrese, Francesco
Monaco); Anestesia e Rianimazione, City Hospital of Sesto San Giovanni (Chiara
Liverani, Stefano Clementi); Intensive Care Unit, Surgical and Medical Emergencies
Institute (Rosanna Coltrinari, Benedetto Marini). Japan: Intensive Care Center, Teikyo University School of Medicine Ichihara
Hospital (Nobuo Fuke, Masaaki Miyazawa); Intensive Care Unit, Okayama University
Hospital (Hiroshi Katayama, Toshiaki Kurasako); Department of Emergency and
Critical Care Medicine, Graduate School of Medicine, Chiba University (Hiroyuki
Hirasawa, Shigeto Oda); Emergency and Critical Care Medicine, Fukuoka University
Hospital (Koichi Tanigawa, Keiichi Tanaka). the Netherlands: Intensive Care Unit, Onze Lieve Vrouwe Gasthuis (Helena Maria Oudemans-Van
Straaten); Adult Intensive Care Unit, Academic Medical Center (Catherine S.
C. Bouman, Anne-Cornelie J. M. de Pont). Norway: Department
of Anaesthesia, Rikshospitalet (Jan Frederik Bugge, Fridtjov Riddervold);
Department of Anaestesiology, University and Regional Hospital, Tromsø
(Paul Åge Nilsen, Joar Julsrud). Portugal: Unidade
de Cuidados Intensivos (ICU), Hospital de Curry Cabral (Fernando Teixeira
e Costa, Paulo Marcelino); Unidade de Cuidados Intensivos Polivalente, Hospital
Fernando Fonseca (Isabel Maria Serra). Russia: Unit
for Extracorporeal Blood Purification, Bakoulev Scientific Center for Cardiovascular
Surgery (Mike Yaroustovsky, Rachik Grigoriyanc). Singapore: Medicine Department, National University of Singapore (Kang Hoe Lee);
Surgical Intensive Care Unit, Tan Tock Seng Hospital (Shi Loo, Kulgit Singh). Spain: Anaesthesiology and Critical Care Department, Hospital
Comarcal De Vinaros (Ferran Barrachina, Julio Llorens); Department of Intensive
Care Medicine, Section of Severe Trauma, Hospital Universitario “12
de Octubre” (Jose Angel Sanchez-Izquierdo-Riera, Darío Toral-Vazquez). Sweden: Department of Anesthesia and Intensive Care, Sunderby
Hospital (Ivar Wizelius, Dan Hermansson). Switzerland: Department
of Surgery, Surgery Intensive Care Unit and Department of Medicine, Medical
Intensive Care Unit, University Hospital Zürich (Tomislav Gaspert, Marco
Maggiorini). United Kingdom: Center for Nephrology,
Royal Free Hospital (Andrew Davenport). United States: Department
of Critical Care Medicine, University of Pittsburgh Medical Center (Ramesh
Venkataraman, John A. Kellum); Department of Medicine, Section of Nephrology,
University of Chicago (Patrick Murray, Sharon Trevino); Surgical Intensive
Care Unit, Mount Sinai Medical Center (Ernest Benjamin, Jerry Hufanda); Nephrology
and Hypertension-M82, Cleveland Clinic Foundation (Emil Paganini); Department
of Medicine, Division of Nephrology, University of Alabama, Birmingham (Ashita
Tolwani, David Warnock); Internal Medicine/Nephrology, University of Nebraska
Medical Center (Nabil Guirguis). Uruguay: Department
of Critical Care Medicine, Impasa (Raúl Lombardi, Teresita Llopart).