AJH
2006; 19:1183–1189
Microalbuminuria, Blood Pressure Load, and Systemic Vascular Permeability in Primary Hypertension Francesca Viazzi, Giovanna Leoncini, Elena Ratto, Valentina Vaccaro, Cinzia Tomolillo, Valeria Falqui, Angelica Parodi, Novella Conti, Giacomo Deferrari, and Roberto Pontremoli Background: Microalbuminuria, a powerful predictor of cardiovascular events, is thought to reflect widespread subclinical vascular abnormalities. To explore the pathogenesis of increased urinary albumin excretion in primary hypertension we evaluated systemic capillary permeability and ambulatory blood pressure (BP) measurement in two groups of matched untreated patients with (n ⫽ 11) and without (n ⫽ 29) microalbuminuria. Methods: Albuminuria was measured as the mean of albumin-to-creatinine ratio (ACR) in three nonconsecutive first morning urine samples. Systemic capillary permeability was evaluated by transcapillary escape rate of albumin (TERalb) (ie, the 1-h decline rate of intravenous 125I-albumin). Twenty-four-hour ambulatory BP, renal hemodynamics, and hormones of the renin-angiotensin-aldosterone system (RAAS) were also assessed.
permeability to albumin (P ⬍ .02) as compared to normoalbuminurics. Renal hemodynamics and RAAS hormones were similar in the two groups. Univariate analysis showed that urinary ACR was related to ambulatory pressure components (P ⬍ .02), TERalb (r ⫽ 0.31, P ⬍ .05), smoking habits (r ⫽ 0.36, P ⫽ .02), and left ventricular mass index (LVMI) (r ⫽ 0.57, P ⬍ .001) among the whole study group. Logistic regression analysis showed that each 1% increment in TERalb or 10 mm Hg increase in systolic BP entailed an almost three times higher risk of having microalbuminuria. Conclusions: Microalbuminuria is associated with greater systemic BP load and increased vascular permeability in patients with primary hypertension. Am J Hypertens 2006;19:1183–1189 © 2006 American Journal of Hypertension, Ltd.
Results: Patients with microalbuminuria showed greater body mass index (BMI) (P ⬍ .04), higher 24-h systolic and diastolic BP levels (P ⫽ .02), and higher capillary
Key Words: Microalbuminuria, vascular permeability, transcapillary escape rate, blood pressure, primary hypertension.
icroalbuminuria has been shown to predict the risk of cardiovascular events or death in patients with primary hypertension.1–3 Increased urinary albumin excretion (UAE) is often a concomitant of several unfavorable metabolic and nonmetabolic risk factors4,5 and indicates the presence of subclinical organ damage at the renal and cardiac level.6,7 Because of its unique ability to reflect many clinically relevant abnormalities, microalbuminuria is currently considered a marker of cardiovascular risk. However, the pathogenetic mechanisms underlying the development of increased UAE are still poorly understood.
M
According to the hypothesis originally proposed by Parving et al,8 both the increase in blood pressure (BP) load and abnormal vascular permeability, possibly due to endothelial dysfunction, seem to concur with the development of microalbuminuria.9 As a matter of fact, although increased systemic vascular permeability has been found in hypertensive patients with atherosclerosis or insulin resistance,10,11 the relationship between capillary permeability and UAE in patients with primary hypertension is still unclear.10,12,13 The present study was therefore initiated in an attempt to clarify the relationship between BP, systemic capillary
Received January 24, 2006. First decision April 14, 2006. Accepted April 24, 2006. From the Department of Internal Medicine and Cardionephrology, Azienda Universitaria Ospedale San Martino, University of Genoa, Genoa, Italy. This work was partly supported by grants from Ministero Università
e Ricerca Scientifica (FIRB2001) and from the Italian Ministero della Salute (ex art.12 D.Lgs 502/92-Esercizio 2003). Address correspondence and reprint requests to Dr. Roberto Pontremoli, Dept. of Internal Medicine and Cardionephrology, Azienda Universitaria Ospedale San Martino, University of Genoa, Viale Benedetto XV, 6 –16132 Genoa, Italy; e-mail:
[email protected]
© 2006 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc.
0895-7061/06/$32.00 doi:10.1016/j.amjhyper.2006.04.012
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permeability, and albuminuria in patients with primary hypertension.
nal resistive index was assessed by ultrasound Doppler of the renal interlobar arteries, as described in Derchi et al.19
Methods
Transcapillary Escape Rate of Albumin
Subjects and Protocols
Patients were given oral iodine during the week preceding the bolus administration to prevent any uptake of 125iodine by the thyroid gland. Free 125I was eluted by passing the injection solution in a Sephadex G-25-M column (Column PD-10; Pharmacia, Uppsala, Sweden), a purification step that reduced free 125I content in the injected dose to less than 1%. The 125I-labeled human serum albumin (6 to 8 Ci, SARI-125 A-2; SORIN Biomedica, Saluggia, Italy) was injected as a bolus after a 30-min rest in the supine position and blood was withdrawn from the contralateral arm at 5, 10, 15, 20, 25, 30, 40, 50, 55, and 60 min after the injection. Radioactivity was measured (Cobra 5000 ␥-counter; Packard, Downers Grove, IL) in duplicate in 1 mL of plasma for each sample. Transcapillary escape rate of albumin (TERalb) was expressed as the percentage decay per hour (%/h). The slope of the linear regression of radioactivity over time was used to calculate TERalb. One patient was excluded from the analysis because the correlation coefficient was lower than 0.85.
Between January 2000 and June 2002, all patients with primary hypertension attending the outpatient clinic of our institution were asked to participate in this study, which was part of a larger trial (MAGIC: Microalbuminuria: A Genoa Investigation on Complications). Details of the study have already been published.14 Three hundred hypertensive patients were (consecutively) seen at our clinic within that time period. Among them 180 met the study criteria, including 18 patients with microalbuminuria. Among these patients, 11 (7 men and 4 women) agreed to participate and were defined as microalbuminurics. A control group was established from among the entire cohort of screened patients by selecting 33 hypertensive patients with normal albumin excretion matched for gender, age (⫾ 5 years), and duration of hypertension (⫾ 60 months). Twenty-nine patients (22 men and 7 women) accepted and make up the group of normoalbuminurics. The study protocol was approved by the Ethical Committee of our Department, and written informed consent was obtained from each subject. Both groups of hypertensive patients underwent complete physical examination and routine biochemical blood and urine analyses. Twenty-four-hour urine collection was obtained from each subject on the day before the study to assess dietary sodium intake and measure potassium and aldosterone levels. All patients were on a salt-unrestricted diet at the time of the study. The LDL cholesterol was calculated using Friedewald’s formula.15 Creatinine clearance was estimated by the Cockcroft–Gault formula.16 Hypertension was defined as an average BP ⱖ140/90 mm Hg on at least three different occasions. Office BP was assessed by three consecutive readings and the average was recorded. Each patient also underwent a 24-h ambulatory BP recording (ABPM; Spacelabs Inc, Redmonds, WA).17 Left arm readings were taken with a standard cuff during a 24-h period as described in Pontremoli et al.6 The measurements were only taken into consideration if valid readings were no less than 80% of the expected readings, and if at least one valid reading per hour for at least 21 h was available. Systolic and diastolic BP load were defined as the percentage of BP readings that exceeded 130 and 80 mm Hg, respectively. Body mass index (BMI) was calculated using the formula: BMI ⫽ weight (in kilograms)/height (in meters) squared. Family history for hypertension and cardiovascular disease, the amount of physical activity, smoking habits, and alcohol consumption were assessed by means of a standardized questionnaire. The presence and extent of left ventricular hypertrophy and microalbuminuria were assessed in all patients as described in Viazzi et al,7 in agreement with European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines.18 Re-
Renal Hemodynamics and Renin-Angiotensin-Aldosterone System Hormonal Pattern We performed additional studies on a subset of 20 patients (10 patients with normoalbuminuria and 10 patients with microalbuminuria). On the morning of the study day, after an overnight fast and 30 min of rest in the supine position, blood was drawn to measure active renin and aldosterone. To evaluate glomerular filtration rate (GFR), 5 g of inulin (InutestR, Laevosan GmHB, Linz, Austria) was infused during 1 min. Blood samples were taken from the opposite arm at 0 (predosing), 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 210, and 240 min after the end of the infusion. Inulin in plasma samples was measured by means of the anthrone method after removing the glucose, essentially as described by Jung et al20 and Orlando et al.21 Renal clearance (GFR) was then calculated as the ratio of the amount excreted during the first 4 h to the corresponding area under the curve. Para-aminohippurate (PAH) (Monico SPA, Mestre (Ve) Italy) was measured by standard chemical methods as described in Schnurr et al.22 To measure renal plasma flow (RPF), PAH clearance was assessed by multiplying the infusion rate by the concentration in the infusate and dividing by the plasma concentration. The filtration fraction (FF) was calculated by expressing GFR as a percentage of RPF. Renal vascular resistance (RVR) was calculated by the Gomez formula: RVR ⫽ (mean BP ⫺ 10)/RPF ⫻ 60 ⫻ 1322 ⫻ (1 ⫺ hematocrit) as described in Zitta et al.23 Plasma active renin was measured by radioimmunoassay (Sanofi Diagnostic Pasteur, Milan, Italy). Plasma and
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Table 1. Descriptive characteristics of study patients on the basis of albumin excretion rate Variable
All
Patients with NA
Patients with MA
P
Number Sex (males, %) Age (ys) Duration of disease (months) BMI (kg/m2) Smoking habits (%) Office systolic BP (mm Hg) Office diastolic BP (mm Hg) 24-h systolic BP (mm Hg) 24-h diastolic BP (mm Hg) Serum glucose (mg/dL) Serum uric acid (mg/dL) Cholesterol (mg/dL) LDL-cholesterol (mg/dL) Triglycerides (mg/dL) Serum creatinine (mg/dL) Creatinine clearance (mL/min) ACR (mg/mmol) LVMI (g/m2) LVH (%) Renovascular resistive index
40 72 51 ⫾ 9 85 ⫾ 70 27 ⫾ 4 50 155 ⫾ 12 95 ⫾ 9 140 ⫾ 17 91 ⫾ 9 88 ⫾ 13 5.3 ⫾ 1.7 206 ⫾ 44 135 ⫾ 32 103 (33–330) 0.9 ⫾ 0.2 87 ⫾ 23 0.75 (0.10–10.6) 116 ⫾ 38 30 0.60 ⫾ 0.04
29 76 50 ⫾ 9 80 ⫾ 76 26 ⫾ 4 47 151 ⫾ 12 93 ⫾ 10 141 ⫾ 15 89 ⫾ 9 89 ⫾ 12 5.3 ⫾ 1.7 210 ⫾ 47 138 ⫾ 34 100 (33–330) 0.9 ⫾ 0.2 88 ⫾ 21 0.3 (0.1–2.0) 105 ⫾ 21 21 0.60 ⫾ 0.04
11 64 53 ⫾ 9 99 ⫾ 50 29 ⫾ 4 64 163 ⫾ 9 100 ⫾ 3 159 ⫾ 13 96 ⫾ 7 86 ⫾ 14 5.4 ⫾ 1.5 192 ⫾ 30 123 ⫾ 21 109 (62–314) 0.9 ⫾ 0.2 84 ⫾ 28 6.1 (3.4–10.6) 148 ⫾ 56 54 0.62 ⫾ 0.04
NS NS NS .038 NS .04 NS ⬍.001 .02 NS NS NS NS NS NS NS ⬍.001 ⬍.001 .02 NS
ACR ⫽ albumin creatinine ratio; BMI ⫽ body mass index; BP ⫽ blood pressure; LDL ⫽ low-density lipoprotein; LVH ⫽ left ventricular hypertrophy; LVMI ⫽ left ventricular mass index; MA ⫽ microalbuminuria; NA ⫽ normal albuminuria. Data are mean ⫾ SD or percentage except for triglycerides and urinary albumin excretion expressed as geometric mean and range.
urine aldosterone were measured by radioimmunoassay (Sorin Biomedica, Saluggia, Italy). Statistical Analysis Data are mean ⫾ SD or percentage except for triglycerides, urinary albumin excretion, RPF, renin, and plasma aldosterone, which are expressed as the geometric mean and range. Differences among variables were assessed using the appropriate statistical test based on the underlying distribution of the variables. The Student t test was used to analyze the data of the two study groups for parametric distribution. The Mann-Whitney U test was used for data that were not distributed normally. Comparisons of proportion among groups were performed using the 2 test. Analysis of covariance (ANCOVA) was performed to analyze the association between TERalb and albuminuria, with BMI, 24-h mean BP, and left ventricular mass index (LVMI) as covariates. Relations among variables were assessed using linear regression analysis and Pearson’s correlation coefficient. Logistic regression analysis was performed to assess the independent contribution of several variables (including TERalb and systolic BP) to the presence of microalbuminuria. All statistical analyses were performed using Statview for Windows (SAS Institute Inc., version 5.0.1, Cary, NC). P ⬍ .05 was considered statistically significant.
Results The geometric mean of urinary albumin-to-creatinine ratio (ACR) was 6.1 mg/mmol (3.4 to 10.7 mg/mmol) and 0.3
mg/mmol (0.1 to 2.0 mg/mmol) in hypertensive patients with and without microalbuminuria, respectively (Table 1). As a consequence of the selection procedures at entry, age, gender, and known duration of disease were super-imposable between study groups. There were no significant differences between the two groups with regard to serum glucose, uric acid, creatinine, lipid profile, and intrarenal vascular resistance (Tables 1 and 2). Moreover, within the group of patients who underwent additional studies, we found no differences in renal hemodynamics or reninangiotensin-aldosterone system (RAAS) activities on the basis of UAE (Table 2). The BMI, office systolic BP, as well as 24-h ambulatory systolic and diastolic BP values were higher in patients with microalbuminuria compared to those with normal UAE (Tables 1 and 2). Furthermore, microalbuminuric patients showed higher LVMI (Table 1) and were more likely to have left ventricular hypertrophy than normoalbuminuric patients (odds ratio [OR] 6.7, 95% CI 1.5–30.7 , P ⫽ .02). Finally, TERalb was significantly higher in patients with microalbuminuria compared to those without microalbuminuria, indicating an abnormal increase in vascular permeability (Fig. 1). This result remained statistically significant even after adjusting for BMI, 24-h mean BP, and LVMI (ANCOVA, P ⬍ .05; data not shown). Significant univariate correlations between urinary ACR or TERalb and selected clinical variables in the entire study group are shown in Tables 3 and 4. Albuminuria did not correlate to BMI, lipid profile, or renal function, whereas it related to smoking habits and 24-h ambulatory systolic and diastolic BP values, signs of early cardiovascular
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Table 2. Systemic and renal hemodynamics in hypertensive patients with and without microalbuminuria All (n ⴝ 20)
Variable Systemic Office systolic BP (mm Hg) Office diastolic BP (mm Hg) 24-h systolic BP (mm Hg) 24-h diastolic BP (mm Hg) Daytime systolic BP (mm Hg) Daytime diastolic BP (mm Hg) Night-time systolic BP (mm Hg) Night-time diastolic BP (mm Hg) Daytime/night-time systolic BP Daytime/night-time diastolic BP Renal Glomerular filtration rate (mL/min) RPF (mL/min) Filtration fraction (%) RVR (dyn/cm2) (mL/sec) Renovascular resistite index Plasma aldosterone (pg/mL) Urinary aldosterone (g/24 h) Plasma active renin (pg/mL) Urine sodium (mEq/24 h) Urine potassium (mEq/24 h)
158 97 154 95 155 95 137 82 1.14 1.17
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
Patients with NA (n ⴝ 10)
11 5 11 5 11 6 16 9 0.09 0.13
150 94 151 95 150 95 126 77 1.19 1.24
98 ⫾ 8 572 (433–952) 18 ⫾ 3 8817 ⫾ 1945 0.61 ⫾ 0.04 100 (23–324) 18 ⫾ 9 1.8 (0.24–25.3) 142 ⫾ 42 60 ⫾ 19
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
6 5 10 5 8 7 9 8 0.07 0.13
97 ⫾ 9 549 (433–952) 19 ⫾ 3 9099 ⫾ 2029 0.61 ⫾ 0.03 118 (46–324) 18 ⫾ 8 2.0 (0.7–14.0) 144 ⫾ 48 63 ⫾ 18
Patients with MA (n ⴝ 10)
P
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
⬍.001 .003 NS NS .023 NS ⬍.001 .008 .002 .008
165 100 158 95 161 95 150 88 1.07 1.09
9 3 12 6 11 7 12 8 0.06 0.05
99 ⫾ 8 597 (504–882) 17 ⫾ 3 8503 ⫾ 1916 0.62 ⫾ 0.04 83 (23–195) 17 ⫾ 9 1.6 (0.2–25.3) 139 ⫾ 36 57 ⫾ 21
NS NS NS NS NS NS NS NS NS NS
RPF ⫽ renal plasma flow; RVR ⫽ renovascular resistance by Gomezs formula. Other abbreviations as in Table 1. Data are mean ⫾ SD or percentage except for RPF, renin, and plasma aldosterone expressed as geometric mean and range.
damage, namely relative wall thickness and LVMI, and to TERalb (Table 3). On the other hand, capillary permeability did not correlate to any BP components and was positively related only to triglyceride levels and albuminuria (Table 4). Moreover, after adjusting for BMI, logistic regression analysis indicated that each 1% increment in TERalb or 10
12
P < 0.02
TERalb, %
11 10 9
8 7
+
mm Hg increase in systolic BP entailed an almost three times higher risk of being microalbuminuric (Table 5).
Discussion The present study shows that microalbuminuria is associated with greater BP load and vascular permeability in patients with primary hypertension. These findings may help understand the pathophysiologic mechanisms underlying the development of abnormal UAE and its association with increased cardiovascular mortality. The development of microalbuminuria may reflect the interplay of several pathogenetic mechanisms that modulate systemic and renal BP load as well as vascular selectivity. The degree of BP elevation seems to be a major
+
6
Table 3. Univariate correlation between albumin excretion rate and selected clinical variables
5
All
4 Patients with NA (n= 29)
Patients with MA (n=11)
FIG. 1. Transcapillary escape of albumin (TERalb) in hypertensive patients with (MA) and without microalbuminuria (NA). To provide more adequate information about data distribution, the results are presented as box-and-whisker plots. The central box encloses the middle 50% of the data; the horizontal line inside the box represents the median, and the mean is plotted as a cross. Vertical lines (whiskers) extend from each end of the box and cover the distance between the 10th and 90th percentiles.
Variable
r
P
Smoking habits 24-h systolic BP (mm Hg) 24-h diastolic BP (mm Hg) RWT LVMI Transcapillary escape rate (%)
0.36 0.51 0.37 0.41 0.57 0.32
.023 ⬍.001 .02 .01 ⬍.001 .046
RWT ⫽ relative wall thickness. other abbreviations as in Table 1.
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Table 4. Univariate correlation between TERalb and selected clinical variables All Variable
r
P
Smoking habits 24-h systolic BP (mm Hg) 24-h diastolic BP (mm Hg) Triglycerides (mg/dl) ACR (mg/mmol)
0.27 0.07 0.007 0.36 0.32
NS NS NS .029 .046
Abbreviations as in Table 1.
determinant of UAE. Pascual et al24 defined the temporal relationship between BP and microalbuminuria by showing that the persistence of higher than normal systolic BP precedes the development of microalbuminuria in primary hypertension. Other studies, however, have shown contrasting data, indicating that the occurrence of microalbuminuria may precede the development of hypertension.25 Furthermore, Mulè et al26 used 24-h ambulatory BP monitoring to demonstrate a worse hemodynamic profile in patients with microalbuminuria. In our study patients, office BP readings were higher in patients with microalbuminuria (Tables 1 and 2). Twenty-four-hour ambulatory BP monitoring clearly showed that increased UAE is associated to a worse systemic BP profile, namely a lower BP daytime-to-night-time ratio, indicating the lack of a physiologic BP decrease during the night (Table 2). Interestingly, linear regression analysis showed that ambulatory BP values correlated with UAE but not with TERalb (Tables 3 and 4). The latter finding is still under debate in the literature, with some studies reporting a linear correlation between TERalb and systolic but not diastolic and mean BP,12,13 and other studies failing to relate TERalb to ABPM indices.10,11 Whether microalbuminuric patients show an abnormal pattern of renal hemodynamics27,28 is currently a matter of debate. In the present study, we did not observe any differences in GFR, RPF, FF, and RVR in relation to the level of albuminuria (Table 2), although we cannot rule out that these abnormalities might become visible with conditions such as dietary protein load.23 Moreover, the activity of the RAAS might be implicated in the development of microalbuminuria.29 Angiotensin II promotes efferent vasoconstriction and mesangial cell contraction, thus favoring the progressive appearance of microalbu-
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minuria. Our study, however, does not confirm that RAAS activity is increased in association with microalbuminuria, at least at the systemic level (Table 2). The UAE is not, however, only dependent on renal hemodynamic factors, but also on vascular selectivity. In fact, microalbuminuria may signal the presence of a more widespread abnormality of endothelial function at the systemic level. On the basis of this hypothesis, it has been shown that leakage of albumin through the glomerular membrane is paralleled by systemic, transvascular, macromolecular leakage, a process that represents the earliest stage of atherosclerosis.9,30 The latter observation is strengthened by the correlation we found between UAE and TERalb (Table 4, Fig. 1). Previous studies, mainly conducted on male patients with primary hypertension,10,12 showed a dissociation of these variables. The discrepancy with our findings could be partially due to the inclusion of women in our study population. In fact, the positive correlation between UAE and TERalb held true for women (P ⬍ .04) but not for men when analyzed separately. The lack of correlation between BP values and transvascular permeability in our study (Table 4) partly confirms previous studies on hypertensive patients that reported that BP elevation per se does not induce increased vascular permeability. In fact, Pedrinelli et al10 described abnormal TERalb in patients with clinical atherosclerosis regardless of BP levels, and reported that patients with metabolic syndrome are characterized by higher transvascular permeability compared to essential hypertensives.11 Altogether these data corroborate the belief that TERalb may be considered a marker of preclinical atherosclerosis, regardless of hemodynamic load. Recent data suggest that a subclinical inflammatory process might be related to the diffuse vascular dysfunction observed in patients with microalbuminuria.31–33 Unfortunately, our study cannot help clarify this issue, as no data were collected on the inflammatory status of our patients. In the present study, multiple logistic regression analysis, including BMI in the model, showed an almost three times higher risk of being microalbuminuric for each 1% increment in TERalb and 10 mm Hg increase in 24-h systolic BP (Table 5), suggesting that microalbuminuria is independently influenced by both systemic BP load and capillary permeability. In addition, hypertensive patients with microalbuminuria were characterized by significantly higher BP levels, early signs of target organ damage, and abnormal TERalb (Table 1, Fig. 1). These data are even more noteworthy when we consider that the two study
Table 5. Multiple logistic regression analysis: dependent variable: microalbuminuria Variable
Increment
Relative risk
95% confidence interval
P
TERalb (1%/h) 24-h SBP (mm Hg)
1%, h 10 mm Hg
2.95 3.39
1.12–7.76 1.08–10.58
.028 .036
BMI ⫽ body mass index not significantly related to the presence of microalbuminuria; SBP ⫽ systolic blood pressure. Other abbreviations as in Table 1.
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groups were matched for a number of potentially confounding variables such as age, gender, and duration of hypertension. As a result, patients were also similar as per lipid profile and renal function, which are known to influence UAE, endothelial permeability, and the development of target organ damage. Thus, although the cross sectional design of our study precludes any conclusion on the pathogenesis of increased albumin excretion rate, we believe our data support a separate role of BP and vascular permeability in explaining the presence of microalbuminuria. In conclusion, by showing a close and independent relationship between UAE and BP load and TERalb, our study supports the view that microalbuminuria is an early renal manifestation of generalized vascular dysfunction, and may help explain its role as a predictor of cardiovascular events.
8.
9.
10.
11.
12.
13.
Acknowledgments The excellent technical advice of Professor Giuliano Mariani, MD, is gratefully acknowledged. Maura Ravera, Denise Parodi, and Simone Vettoretti are thanked for their invaluable support in the clinical assessment of patients. We thank Lorenzo Egildo Derchi and Carlo Martinoli for performing the ultrasound Doppler renal investigation, and Gian Paolo Bezante for performing the ultrasound cardiac evaluation on study patients.
14.
15.
16. 17. 18.
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