Journal of Postgraduate Medicine: Microalbuminuria: A biomarker of ... http://www.jpgmonline.com/printarticle.asp?issn=0022-3859;year=201...

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ORIGINAL ARTICLE
Year : 2014 | Volume : 60 | Issue : 2 | Page : 145-150

Microalbuminuria: A biomarker of sepsis and efficacy of treatment in patients admitted to a medical

intensive care unit of a tertiary referral center
RR Bhadade1, R deSouza1, MJ Harde2, B Sridhar1,
1 Department of Medicine, Topiwala National Medical College and B.Y.L. Nair Ch. Hospital, Mumbai Central, Mumbai, Maharashtra, India
2 Department of Anaesthesiology, Topiwala National Medical College and B.Y.L. Nair Ch. Hospital, Mumbai Central, Mumbai, Maharashtra, India

Correspondence Address:
R R Bhadade
Department of Medicine, Topiwala National Medical College and B.Y.L. Nair Ch. Hospital, Mumbai Central, Mumbai, Maharashtra
India

Abstract
Background: The outcome of sepsis is significantly affected by early institution of goal-directed therapies and hence, the search for an
early marker of sepsis continues. Aims and Objectives: To observe microalbuminuria levels between patients with sepsis and those
without sepsis s admitted to the medical intensive care unit (MICU) of a tertiary referral centre (primary) as also to assess the change in
microalbuminuria levels in the first 24 hours as a predictor of mortality and morbidity relative to the APACHE II and SOFA scores.
Materials and Methods: This was a prospective observational study where 125 patients with sepsis and 38 without were assessed.
Trend of microalbuminuria was assessed from the change of ACR value within 6 hours of admission (ACR1) to the ACR value at 24 hours
(ACR2) in both groups of patients. Results and Conclusion: Significantly higher levels of microalbuminuria were found among patients
with sepsis as compared to those without sepsis. The levels decreased in survivors with sepsis after 24 hours, whereas they continued to
remain almost at the same levels among those without sepsis. The change in microalbuminuria levels over 24 hours can be used to
measure the effectiveness of therapy. Persistence of high levels or increasing trend of microalbuminuria levels over 24 hours was found to
be a predictor of a poor outcome. A high level of microalbuminuria at 24 hours and increasing trend of microalbuminuria also predicted
mortality better than APACHE II and SOFA scores.

How to cite this article:

Bhadade R R, deSouza R, Harde M J, Sridhar B. Microalbuminuria: A biomarker of sepsis and efficacy of treatment in patients admitted to a medical
intensive care unit of a tertiary referral center.J Postgrad Med 2014;60:145-150

How to cite this URL:

Bhadade R R, deSouza R, Harde M J, Sridhar B. Microalbuminuria: A biomarker of sepsis and efficacy of treatment in patients admitted to a medical
intensive care unit of a tertiary referral center. J Postgrad Med [serial online] 2014 [cited 2017 Oct 4 ];60:145-150
Available from: http://www.jpgmonline.com/text.asp?2014/60/2/145/132320

Full Text

Introduction

Diagnosing sepsis early is vital for patient management and outcome, as early institution of appropriate therapy can be life-saving for the
patient. The gold standard for diagnosis of sepsis is the isolation of causative organism in the culture of appropriate body fluids or tissue,
which usually takes more than 24 hours causing delay in the initiation of targeted therapy which in turn impacts outcome. [1] For this
reason, the search for early marker of sepsis continues.

The host defense in sepsis involves potent inflammatory cascades which release a plethora of pro-inflammatory molecules into the
circulation. The endothelium becomes dysfunctional due to the sustained onslaught of these molecules and the simultaneous oxidative
stress. An early event is the loss of barrier integrity leading to systemic capillary leak. The glomerular manifestation of this enhanced
capillary permeability is increased excretion of albumin in the urine. The severity of the changes in systemic vascular permeability may be
indirectly reflected in the levels of microalbuminuria. Assay of the amount of albumin excreted in a random urine sample, expressed as
ACR (albumin/creatinine ratio), is proven to be a simple, validated, and reliable test. [2]

The present study was thus carried out with the primary objective of assessing whether there exists any significant difference between
microalbuminuria levels between patients with sepsis and those without admitted to the medical intensive care unit (MICU). In addition,
we also attempted to assess whether the change in microalbuminuria levels in the first 24 hours could help to predict the mortality and
morbidity by comparing the microalbuminuria levels with APACHE II (Acute physiology and chronic health evaluation) and SOFA
(Sequential Organ Failure Assessment) scores.

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Materials and Methods

This was a prospective observational study carried out in the MICU of a tertiary care, teaching, public hospital between September 2011
and November 2012. The study was approved by the institutional review board and written informed consent from patients or legal
guardians (where applicable) was taken. Assent was taken if the age of the patient was below 18 years. Consecutive patients (>15 years
old) admitted to MICU in a tertiary care hospital were recruited. Patients with anuria, macroscopic hematuria [confirmed with dipstick],
history of preexisting chronic kidney disease (patients on long-term renal replacement therapy, and/or sonologic features of chronic
damage and/or history of glomerular filtration rate of <30 ml/min), female patients with menstruation or pregnancy, patients with
significant proteinuria [more than 1+ protein on dipstick] due to renal and post renal causes, for example urinary tract infection, new
infection after 48 hours of ICU admission, i.e., nosocomial infection were exclusions. The following data were collected for each patient:
Age, gender, date, and time of admission; complete physical and general examination; provisional diagnosis; whether co-morbid
conditions such as diabetes mellitus (DM), hypertension were present and clinical and laboratory parameters. Information on cultures sent
and antibiotics administered were noted. APACHE II scores and SOFA scores were calculated from data collected during the first 24 hours
following ICU admission. We also noted need for oxygen supplementation, duration of mechanical ventilation, length of stay in the ICU,
and mortality. Patients were divided into two groups: Patients without sepsis and patients with sepsis. Spot urine samples were collected
within 6 hours of admission and again at 24 hours, for quantification of albumin: Creatinine ratio (ACR), which were referred to as ACR1
and ACR2, respectively. All samples were stored at -20°C pending analysis. Urinary microalbumin was measured by the
immunoturbidimetric method and urinary creatinine by modified kinetic Jaffe reaction. [3] To compensate for variations in urine
concentration in spot-check samples, the amount of albumin is compared against its concentration of creatinine and this is termed as the
albumin/creatinine ratio (ACR).

Case definition: Microalbuminuria was defined by ACR values between 30 and 299 mg/g, ACR of >300 mg/g was considered as clinical
proteinuria, and <30 mg/g was considered normal. [2],[4] Trend of microalbuminuria was assessed from the change of ACR value within
6 hours of admission (ACR1) to the ACR value at 24 hours (ACR2) in both groups of patients. The difference of ACR2 from ACR1 (D ACR =
ACR1-ACR2) was calculated. As patients with DM and hypertension could n have pre-existing microalbuminuria, that value was noted
while among the survivors if pre-existing level of microalbuminuria was not known, the levels of microalbuminuria were measured one
month after discharge and compared with ACR1 and ACR2.

Statistical analysis

The outcome of each patient was classified as either death or discharge. The chi-square test was used to compare categorical outcomes.
Mortality prediction scores were compared with microalbuminuria, based on Receiver Operating Characteristics (ROC) curve analysis with
the area under curve (AUC) being the determining factor.

Using the formula for comparison of two proportions of Machin D et al., and based upon results of a pilot study done by us (t, showing
96% microalbuminuria of >30 mg/gm in cases with sepsis, and 69% in those without sepsis) and a mortality of of 25% in sepsis, a total
sample size of 72 was obtained with a beta error of ten percent at 5% significance. [5] All analyses were done at 5% significance using
SPSS 18.

Results

We eventually enrolled 125 patients of which 87 belonged to sepsis group while 38 belonged to non-sepsis group. Eighty-four (67.2%)
patients were male and 41 (32.8%) were female. Sepsis group had 63 males (72.4%) and 24 females (27.6%). Non-sepsis group had 21
males (55.3%) and 17 females (44.7). The median age group for the whole study population was 33 years, while the median age of
sepsis and non-sepsis groups were 35 and 30 years, respectively. The median APACHE II and SOFA scores in current study population
were 9 and 6, respectively. The sepsis group had median APACHE II and SOFA scores of 12 and 7, respectively, while non-sepsis group
had 4.5 and 2, respectively. Co-morbid illnesses were present in 15 patients of the sepsis group with 2 patients of DM, 4 patients of DM
with hypertension, and 1 patient of hypertension with obstructive airway disease and 8 patients of non-sepsis group with 1 patient of DM,
3 patients of hypertension with/without ischaemic heart disease, and 1 of DM with hypertension. Thirty-four patients had severe sepsis,
28 had multiorgan dysfunction syndrome (MODS), 22 had sepsis, and 3 had septic shock. In sepsis group, 31 patients died; whereas, 8
died in non-sepsis group. Results of changes in ACR1, ACR2, and D ACR are given in [Figure 1], [Figure 2], [Figure 3] and [Figure 4] and
[Table 1].{Figure 1}{Figure 2}{Figure 3}{Figure 4}{Table 1}

Discussion

Diagnosing sepsis early is vital for patient management and outcome as early institution of appropriate therapy can be life-saving for the
patient. Of the many sepsis markers available, procalcitonin (PCT) is considered specific and sensitive in identifying systemic bacterial
infections, it has certain limitations such as increases in several non-infectious inflammatory conditions and absence of increase in
localized infections. [6],[7] Another alternative is C-reactive protein (CRP) which has the limitations of low specificity for the diagnosis of
sepsis, slow induction time and lack of correlation with severity of disease, even though it is cheaper. [6],[7],[8],[9],[10] The levels of
microalbuminuria start increasing within hours of an inflammatory insult as against delayed increases in levels of PCT and CRP. [11] The
American College of Chest Physicians/ Society of Critical Care Medicine Consensus Conference definitions were used to delineate patients
with sepsis, severe sepsis, septic shock and MODS. [12],[13] On the basis of the above, patients were divided into two groups: Patients
without sepsis and patients with sepsis. In both groups, patients were comparable with respect to demographic parameters. There was no

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significant difference in the distribution of patients with co-morbid illnesses between the two groups and also the proportion of patients
with confounding factors such as DM and hypertension was much less.

In the current study, of 125 patients, 37 died. The higher mortality in our study could be the result of a greater number of patients with
severe sepsis and MODS. As age is a factor in calculating APACHE II score, comparatively lower scores in our study population could be
the result of a younger study population. However, Basu et al. did find higher scores. [14],[15],[16]

In the current study, the median levels for ACR1 were 152.70 mg/g {IQR (interquartile range) 108.71 to 194.92} and 44.48 mg/g (IQR
26.80 to 108.41) for the sepsis and non-sepsis groups, respectively. The levels of microalbuminuria were significantly high among the
patients with sepsis at admission as compared to those without sepsis. These levels continued to remain significantly high among the
non-survivors, whereas they had dropped among those who survived. The effect of the inflammatory cascade that occurs in response to
sepsis damages the endothelium of the capillaries with damage to the glycocalyx layer of endothelium which normally acts as a barrier
against passage of albumin across the capillary wall. Damage to the glycocalyx results in increased permeability of the capillaries with
resultant loss of albumin into urine. [15]

In our study, the microalbuminuria levels after 24 hours and median DACR levels were found to decrease significantly among the patients
with sepsis as compared to the patients without sepsis [Figure 4]. The decrease in levels after 24 hours of ICU admission could be the
result of the decrease in the inflammatory processes occurring as a result of treatment. The initiation of early treatment might help to
protect the glycocalyx layer and prevent further rise in capillary permeability. On the basis of these observations, it could be said that
microalbuminuria has a discriminatory role in the diagnosis of sepsis and to check the effect of treatment. Microalbuminuria was used as a
tool to document the effect of treatment of high doses of N-acetyl cysteine, an antioxidant, and low-dose hydrocortisone, respectively, in
severe clinical sepsis by Singh A et al. [17],[18]

In the current study, the area under curve (AUC) of Receiver Operating Characteristics (ROC) curve for differentiating sepsis and non-
sepsis was highest for ACR1 (0.817) followed by ACR2 (0.722) and DACR (0.631) [Figure 5] and [Table 2]. ACR1 was found to have a
differentiating value between sepsis and non-sepsis. In this current study, based on the area under ROC curve, the ability to distinguish
between sepsis and non-sepsis was highest for ACR1 at a cutoff of >62.62 mg/g with a sensitivity of 93.1% and specificity of 71.05%.
The higher sensitivity and specificity found in our study could be due to the comparatively lower value of cutoff in our study. In our study,
the survivors (88) had a median ACR1 of 105.135 mg/g which decreased to a value of 68.48 mg/g after 24 hours with a median ACR
1value of -13.88 mg/g. On the other hand, those who expired (37) had a median ACR1 of 172.98 mg/g which increased to 246.22 mg/g
after 24 hours with a median ACR 1 value of 60.13 mg/g. Similar findings were echoed in both studies done by Basu et al. [14],[15]
{Figure 5}{Table 2}

Our study has demonstrated using the area under the ROC curves for prediction of mortality was highest for ACR2 (0.943) and DACR
(0.943) followed by APACHE II (0.835), SOFA and ACR1 (0.725) [Figure 6], [Table 3] and [Table 4]. Basu et al. had found that ACR2 was
as good as APACHE II for mortality prediction. [14],[15] Gosling et al. had found ACR1 as good a predictor of mortality as APACHE II
among surgical patients but not medical patients. [19] Thus in our study, ACR2 has the highest value among ACR1, ACR2, and DACR for
predicting mortality. However, in our study, ACR2 has performed significantly better than APACHE II as the area under curve was
significantly higher for ACR2. The finding of ACR2 as better predictor of mortality could be explained on the presence of ongoing
inflammatory processes among those who expired and hence the higher levels of ACR2 among them. On the other hand, a lower level of
ACR2 might indicate decrease in the inflammatory activity and explain the improved survival. A similar logic explains the better ability of
DACR in prediction of mortality where an increasing trend predicts a poorer outcome, whereas a decreasing trend predicts a better
outcome. Abid et al. had also found a higher mortality among patients with increasing microalbuminuria levels. [20] In the past, studies
done by Gosling, Thorevska, Gopal, found microalbuminuria as a good marker in the prediction of mortality. [19],[20],[21],[22]
Microalbuminuria is a noninvasive, inexpensive, and ready-to-use bedside screening test to identify the patients who have sepsis (Positive
predictive value [PPV 88%]). Furthermore, the findings of 93% sensitivity and 71% specificity of 6 hours ACR appears comparable to the
reported mean percentage sensitivity of 85% and specificity of 83% of PCT, and 69%, and 61%, respectively, of CRP, in differentiating
infected individuals from uninfected controls. [17] The ACR test results can be made available as early as 30 minutes. The ACR can also
be estimated by the ICU nurses as well as a point-of-care test, within 15 minutes, as shown in Gosling et al.'s study. [21]{Figure 6}{Table
3}{Table 4}

Our study had a few limitations. Many conditions such as age (>40 years), smoking, alcohol, BMI (Body mass index), diabetes mellitus,
and hypertension are independent causes of microalbuminuria in the general population, these patients were included, since their
exclusion would have made the study population less representative of the real life scenario. [23],[24] During the course of treatment,
certain nephrotoxic antibiotics were used within creatinine clearance range, thereby limiting kidney injury and ACR levels. The presence of
DM or hypertension did not act as a confounding factor in the comparative analysis of patients; as such patients were similarly distributed
in the two groups. Among the patients with diabetes and hypertension, only 4 patients survived and although microalbuminuria levels in
those patients after one month were measured, it was difficult to compare the values during the illness and after the illness due to the
small number of patients. Further studies among larger population with pre-existing diabetes/hypertension will be required to know the
effect of illness on levels of pre-existing microalbuminuria. Critically ill patients with urinary tract infections and chronic renal insufficiency
were excluded from the study, which may be a limitation to the universal applicability of microalbuminuria as a diagnostic tool.

Several potential applications of microalbuminuria measurement in the critically ill are suggested by this study. Urine ACR is significantly
higher in the sepsis group in comparison to non-sepsis group. Serial monitoring of bedside urine albumin-creatinine measurement might
help in the early identification of patients with sepsis that requires early targeted therapy. Another potential application may be in
excluding patients at risk at 24 hours of admission. The 24-hour ACR assessment predicts ICU survival and may have the potential to
monitor the efficacy of therapeutic interventions delivered, such as fluid resuscitation, appropriate antibiotics, vasopressors, and inotropes
that affect the endothelium. There are very few studies being done in this regard, future large-scale studies of microalbuminuria in larger
populations may be attempted to evaluate the usefulness of this biomarker. [14],[15],[25] The use of serial levels of microalbuminuria for
more than 24 hours and together with other biomarkers may be attempted for better prediction of sepsis and mortality.

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