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(Chest. 2001;120:1984-1988.)
© 2001 American College of Chest Physicians

Predictive Value of Microalbuminuria in Medical ICU Patients*

Results of a Pilot Study

Omar Abid, MD; Qinghua Sun, MD; Kenji Sugimoto, MD; Dany Mercan, MD and Jean-Louis Vincent, MD, PhD, FCCP

* From the Departments of Intensive Care (Drs. Abid, Sun, Sugimoto, Vincent) and Biochemistry (Dr. Mercan), Erasme University Hospital, Free University of Brussels, Belgium.

Correspondence to: Jean-Louis Vincent, MD. PhD, FCCP, Department of Intensive Care, Erasme University Hospital, Route de Lennik 808, B-1070 Brussels, Belgium; e-mail: jlvincen{at}ulb.ac.be


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Study objectives: To evaluate the predictive value of microalbuminuria in the development of acute respiratory failure (ARF) and multiple organ failure (MOF) in ICU patients.

Design: Prospective, observational study.

Setting: A 31-bed, mixed medicosurgical ICU in a university hospital.

Patients: All adult medical patients admitted to the ICU over a 2-month period, except those receiving nephrotoxic drugs, or those with urologic trauma resulting in frank hematuria or urinary infection, or with existing chronic renal disease (serum creatinine level >= 2.0 mg/dL).

Interventions: None.

Measurements and results: Urinary samples for microalbumin measurement were collected at hospital admission and at 8, 24, 48, 72, 96, and 120 h after hospital admission. The severity of illness was assessed by the APACHE (acute physiology and chronic health evaluation) II score calculated on the first ICU day, and the degree of organ dysfunction was assessed using the sequential organ failure assessment (SOFA) score. Acute respiratory failure (ARF) was defined as a SOFA respiratory score >= 3. Patients were separated into two groups according to the trend in microalbuminuria levels over the first 48 h: patients in group 1 had increasing microalbuminuria levels, and patients in group 2 had decreasing microalbuminuria levels. Group 1 included 14 patients in whom microalbuminuria levels increased from 5.2 ± 2.0 to 19.0 ± 3.0 mg/dL. Group 2 included 26 patients in whom microalbuminuria levels decreased from 16.4 ± 4.0 to 7.8 ± 3.0 mg/dL. The hospital mortality rate was 43% in group 1 and 15% in group 2 (p < 0.05). The APACHE II score and the SOFA score were higher in group 1 than in group 2. The negative predictive value of increasing microalbuminuria was 100% for the development of ARF and 96% for MOF; the positive predictive value of increasing microalbuminuria was 57% for the development of ARF and 50% for MOF.

Conclusions: Accurate identification of patients destined for ARF and MOF development may enable therapeutic strategies to be applied to limit the disease process. Trend analysis of urinary albumin excretion over the first 48 h of an ICU admission may provide a useful means of identifying such patients. Additional studies need to be performed in larger, mixed patient populations to confirm these findings.

Key Words: acute respiratory failure • endothelial permeability • multiple organ failure • outcome • severity of illness


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
As the interface between the circulating blood and vascular smooth-muscle cells, endothelial cells have several key functions: they actively regulate vascular tone and permeability, leukocyte extravasation, the balance between coagulation and fibrinolysis, and the proliferation of vascular smooth-muscle and renal mesangial cells.1 Inflammatory mediators, such as tumor necrosis factor, interleukins, and oxygen free radicals, can dramatically alter the role of the endothelium in acute diseases, and in sepsis particularly.2 3 4 An early feature is increased capillary permeability causing an extravasation of plasma proteins and water, leading to interstitial edema. Small increases in glomerular permeability are amplified by the renal concentrating mechanism to produce large changes in albumin excretion, since the tubular reabsorptive mechanisms for albumin are close to saturation.5 Microalbuminuria is often associated with increased vascular permeability in acute inflammatory conditions.6 7 8 In such conditions, microalbuminuria has a rapid onset and typically lasts for < 48 h unless complications occur. The degree of development of microalbuminuria can be proportional to the severity of the illness. For example, albumin excretion increases within 30 min of surgery and is proportional to the magnitude of the surgical procedure.7 Microalbuminuria is an early feature of sepsis and may predict disease severity and outcome in children admitted to the hospital with bacterial meningitis.9 In postoperative patients with sepsis, the degree of microalbuminuria correlated with the degree of organ dysfunction as measured using the sequential organ failure assessment (SOFA) score. 10 In acute pancreatitis, high levels of microalbuminuria are usually followed by severe complications.11

The aim of this study was to determine the presence of a relationship between microalbuminuria and the risk of developing acute respiratory failure (ARF) and multiple organ failure (MOF).


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
All adult (>= 18 years old) medical patients admitted to the ICU over a 2-month period (June 1, 1998, to July 31, 1998) were eligible to enter the study, except for patients with urologic trauma resulting in frank hematuria, urinary infection, or existing chronic renal disease (serum creatinine level >= 2.0 mg/dL). Patients receiving nephrotoxic drugs, admitted to the hospital following a surgical procedure, or remaining in the ICU for < 48 h were also excluded. The study protocol was approved by the local research and ethics committee, who waved formal informed consent in view of the observational nature of the study.

All patients had a Foley urinary catheter in place. Urinary samples for microalbumin measurement were collected at hospital admission and at 8, 24, 48, 72, 96, and 120 h after hospital admission. Twenty microliters of urine diluted 1:20 in buffer were applied to an absorbent card, followed by a gold-antibody complex to human albumin. After washing, the intensity of the bound antibody conjugate was read using a reflectance meter calibrated in milligrams per liter. The method covered an analytical range from 20 to 200 mg/L, with a coefficient of variation < 10%. To exclude the influence of urinary flow, we also calculated the microalbuminuria/urinary creatinine ratio. The hourly urinary volumes were recorded, together with blood samples, arterial blood gas data (PaO2), and fraction of inspired oxygen (FIO2) for the whole study period. The lowest PaO2/FIO2 ratio during the 24-h study period was recorded. The severity of illness was assessed by the APACHE (acute physiology and chronic health evaluation) II score,12 calculated on the first ICU day. The degrees of organ dysfunction were assessed using the SOFA score (Table 1) ,13 calculated from the time of hospital admission until either the fifth day or the day of ICU discharge, whichever came first.


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  		Table 1.. The SOFA Score

 
ARF was defined as a respiratory SOFA score >= 3. MOF was defined as two or more organ failures assessed by SOFA scores of >= 3.13 Severe sepsis was defined as the presence of fever (temperature > 38.5°C) or hypothermia (temperature < 35.5°C), leukocytosis or leukopenia (WBC count > 10,000 µL or < 4,000/µL), and hypotension (systolic arterial pressure < 90 mm Hg for > 2 h requiring fluid challenge and/or vasoactive agents), in the presence of a source of infection. The patients were classified into two groups: group 1 patients had increasing microalbuminuria levels over the first 48 h, and group 2 patients had decreasing or stable microalbuminuria levels over the first 48 h. The hospital mortality rate was used as the end point for survival.

Statistical analysis of the data included univariate analysis of variance for repeated measures. Linear regression analysis was used to compare change in microalbuminuria levels with the lowest PaO2/FIO2 ratio. The differences between groups were analyzed by the Student’s t test for unpaired data. Differences were considered significant at p < 0.05. Data are expressed as mean ± SD.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Forty patients were included in the study. The hospital admission diagnoses and demographics of the patients are presented in Tables 2 and 3 . Thirteen patients (32%) had severe sepsis. In group 1 patients (n = 14), microalbuminuria levels increased continuously from 5.2 ± 2.0 to 19.0 ± 3.0 mg/dL (microalbuminuria/urinary creatinine ratio from 0.3 ± 0.1 to 0.95 ± 0.15) over the ICU stay. In group 2 patients (n = 26), microalbuminuria decreased from 16.4 ± 4.0 to 7.8 ± 3.0 mg/dL (microalbuminuria/urinary creatinine ratio from 0.82 ± 0.2 to 0.39 ± 0.15) over the ICU stay. The hospital mortality rate was 43% in group 1 and 15% in group 2 (p < 0.05 between groups).


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  		Table 2.. Hospital Admission Diagnoses in the 40 Patients

 
The severity of illness, as measured by the APACHE II score, was higher in group 1 than in group 2 (16 ± 5 vs 10 ± 4, p < 0.05), and the total SOFA score in the course of the ICU stay was higher in group 1 than in group 2 (8 ± 3 vs 5 ± 2; p < 0.05; Table 3 ). All complications occurred between 48 h and 96 h after hospital admission. In group 1 patients, acute respiratory failure (ARF) developed in eight patients and MOF developed seven patients; in group 2 patients, MOF developed in one patient and ARF developed in no patients (p < 0.05 between groups; Table 3 ). All patients with ARF showed an inverse relationship between the degree of change in microalbuminuria level and the lowest PaO2/FIO2 ratio during the first 48 h (Fig 1 ). The negative predictive value of increasing microalbuminuria was 100% for ARF and 96% for MOF; the positive predictive value of increasing microalbuminuria was 57% for the development of ARF and 50% for MOF (Table 4 ).


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  		Table 3.. Demographics of Study Population*

 


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  		Figure 1.. Relation between changes (Delta) in microalbuminuria during the first 48 h and the lowest PaO2/FIO2 ratio during that period in patients with ARF. Linear regression analysis of change in microalbuminuria compared with the lowest PaO2/FIO2 ratio showed a positive correlation (r = 0.72, p < 0.05) with slope of - 0.00073 mg/dL/mm Hg

 

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  		Table 4.. Diagnostic Sensitivity, Specificity, and Predictive Value of Microalbuminuria for ARF and MOF

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
Microalbuminuria is thought to be a marker of widespread vascular damage, which may underlie the propensity of microalbuminuric patients to develop severe extrarenal vascular disease.14 It is now well established that microalbuminuria is an important predictor for the subsequent development of overt diabetic nephropathy, characterized by proteinuria, high BP, and a fall in glomerular filtration rate.15 16 17 18 Studies have shown that many acute inflammatory conditions are associated with microalbuminuria. The rapid increase in renal permeability to plasma proteins after trauma,8 surgery,6 7 or ischemia,19 20 21 which is proportional to the severity of the insult, led to the suggestion that increased renal and vascular permeability occur simultaneously, and may share common pathways during the early stages of the acute disease process.

All patients in the present study had a urinary catheter in situ, but previous studies have shown that nontraumatic bladder catheterization does not induce microalbuminuria.7 Some patients may have chronic microalbuminuria due to diabetic or hypertensive nephropathy, so that it is important to evaluate the trend rather than assess a single value. Also, patients with decreasing microalbuminuria had an initially higher microalbumin level and yet a more favorable course.

We found that increasing microalbuminuria during the first 48 h in the ICU was associated with more complications during the ICU stay. Increasing microalbuminuria had a good sensitivity and specificity to predict the development of ARF and MOF. In addition, a high APACHE II score was significantly associated with increasing microalbuminuria levels.

The present study focused on medical patients admitted to the ICU, as surgical patients commonly develop transient microalbuminuria, and it was therefore decided to exclude them from this pilot study. Other researchers have reported similar findings in various groups of patients. De Gaudio et al10 recently reported that in 55 postoperative patients with sepsis, an increasing microalbuminuria/creatinine ratio correlated with an increasing SOFA score. In a study of 40 trauma patients, the same authors22 reported that the degree of increase in microalbuminuria over the first 24 h following trauma was related to the severity of the trauma. In a study of the albumin excretion rate in the early posttrauma period, Gosling et al8 showed that not only was the hospital admission albumin excretion rate inversely associated with the PaO2/FIO2 ratio, but in patients with normal lung function, lung injury was associated with significantly higher degrees of microalbuminuria. These results are in agreement with our finding that patients with ARF showed an inverse relationship between the degree of change in microalbuminuria and the lowest PaO2/FIO2 ratio.

Understanding of the pathogenesis of ARF and MOF are essential for the development of appropriate and effective interventions.23 The success of such interventions may, however, depend on the early identification of patients at risk. Laboratory investigations and standard physiologic monitoring are poor predictors of ARF in individual patients24 ; while several markers have been proposed, including BAL fluid interleukin-8 levels,25 blood concentrations of plasma elastase,26 or von Willebrand factor,27 28 none are sufficiently sensitive or specific. In animal studies of ARDS and MOF initiated by complement activation and hypoxia, not only are the characteristic changes of hydrostatic pulmonary edema and inflammatory infiltration produced in the lungs, but similar effects are seen in the vascular beds of others organ with signs of microvascular failure.29 Assessment of alterations in endothelial permeability, such as the presence of microalbuminuria, may thus be a useful, early, and simple indicator of patients at risk for development of ARF and MOF.


   Conclusion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
Accurate identification of patients destined to develop ARF and MOF may enable therapeutic strategies to be applied to limit the disease process. The present study was limited by the small number of patients and the restriction to medical patients, but trend analysis of urinary albumin excretion during the first 48 h of ICU admission may represent a useful marker of critical illness. The technique is simple and routinely available, requiring inexpensive equipment accessible to all institutions. Additional studies should be performed in larger populations of mixed ICU patients before this technique can become an accepted part of clinical practice.


   Footnotes
 
Abbreviations: APACHE = acute physiology and chronic health evaluation; ARF = acute respiratory failure; FIO2 = fraction of inspired oxygen; MOF = multiple organ failure; SOFA = sequential organ failure assessment

Received for publication January 24, 2000. Accepted for publication May 25, 2001.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

  1. Henrich, WL (1991) The endothelium: a key regulator of vascular tone. Am J Med Sci 302,319-328[CrossRef][ISI][Medline]
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  15. Jarrett, RJ, Viberti, GC, Argyropoulos, A, et al (1984) Microalbuminuria predicts mortality in non-insulin-dependent diabetics. Diabet Med 1,17-19[Medline]
  16. Mathiesen, ER, Oxenboll, B, Johansen, K, et al (1984) Incipient nephropathy in type 1 (insulin-dependent) diabetes. Diabetologia 26,406-410[ISI][Medline]
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  18. Mogensen, CE (1984) Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med 310,356-360[Abstract]
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