1030 ARTHRITIS & RHEUMATISM Vol. 39. No. 6, June 1996, pp 1030-1034 0 1996, American College of Rheumtology

RENAL, VASCULAR DAMAGE IN SYSTEMIC SCLEROSIS PATIENTS

WITHOUT CLINICAL EVIDENCE OF NEPHROPATHY

ROBERTO RIVOLTA, BARBARA MASCAGNI, VITTORIO BERRUTI, FILIPPO QUARTO DI PALO, ATTILIO ELLI, RAFFAELLA SCORZA, and DANIELA CASTAGNONE

Objective. To evaluate the use of color-flow Dopp- ler ultrasonography, a direct, noninvasive technique, for measurement of kidney blood flow in patients with systemic sclerosis (SSc).

Methods. Twenty-five normal volunteers and 25 SSc patients (median disease duration 8 years, range 2-21 years) were studied. All were free of clinical symptoms of renal damage. The resistance index (RI) was determined on main, interlobar, and cortical vessels.

Results. In SSc patients, the RI was significantly increased at every sampling site examined (P C 0.001). RI values were strongly correlated with disease duration (main artery r = 0.56, P C 0.04; interlobar artery r = 0.63, P < 0.02; cortical artery r = 0.75, P C 0.002). Regression analysis showed no relationship between RI and creatinine clearance values.

Conclusion. Color-flow Doppler ultrasonography is a sensitive and noninvasive technique for evaluating vascular damage of the kidney in patients with SSc.

Vascular lesions are prominent in systemic scle- rosis (SSc), and renal involvement with malignant hyper- tension and renal failure occurs in -20% of patients (1,2). The small and medium-sized arteries in the kidney are histologically involved, and blood flow is reduced by the intraluminal narrowing of renal arteries (3). During renal crisis, a condition of renal ischemia is present, as is

Roberto Rivolta, MD, Filippo Quarto di Palo, MD, Attilio Elli, MD, Daniela Castagnone, MD: Ospedale Maggiore di Milano, Milan, Italy; Barbara Mascagni, Vittorio Berruti, Raffaella Scorza: Istituto di Medicina Interna, Universita’ di Milano, Milan, Italy.

Address reprint requests to Daniela Castagnone, MD, Divi- sione di Radiologia Chirurgica, Pad. Monteggia, Ospedale Maggiore di Milano, V. F. Sforza, 35, 20122 Milan, Italy.

Submitted for publication June 12, 1995; accepted in revised form December 4, 1995.

almost always demonstrated by elevations in plasma renin levels (2).

To date, 2 different approaches have been used to evaluate vascular damage in these patients: kidney bi- opsy, a specific, invasive test which cannot be frequently repeated, and traditional clearance techniques, which give an indirect, quantitative evaluation of glomerular filtration rate and renal plasma flow. Creatinine clear- ance and plasma creatinine levels are the clinical tests most commonly used to evaluate renal function. Unfor- tunately, they are not very sensitive or accurate, which limits their diagnostic usefulness. The vascular lesion in SSc patients becomes evident with these methods only when the disease has caused a loss of parenchymal function.

Color-flow Doppler ultrasonography is a tech- nique developed for exploring the vascular tree (43). Doppler waves show the blood flow of each kidney, in a direct and noninvasive manner. This approach, which is sensitive but not specific, has been used extensively for the diagnosis of renal transplant rejection (6-9), for the screening of arterial disease (lO,ll), in diabetic ne- phropathy (5 ) , and in hepatorenal failure (12-14). Its usefulness in these conditions prompted us to investigate its potential clinical usefulness in detecting vascular intraparenchymal lesions of the kidney in patients with SSc. We studied a group of SSc patients with apparently normal renal function and a control group matched for age, sex, and blood pressure, to evaluate the sensitivity of ultrasonographic results compared with plasma cre- atinine levels and endogenous creatinine clearance.

PATIENTS AND METHODS

Subjects. Twenty-five SSc outpatients without hyper- tension or diabetes, with a median disease duration of 8 years (range 2-21 years), were selected. Clinical features of the patients, subdivided into two groups according to the classifi-

RENAL VASCULAR DAMAGE IN SSc 1031

Table 1. patients, according to SSc subgroup’

Immunopathologic findings in the systemic sclerosis (SSc)

dcSSc ICSSC ( n = 9) (n = 16)

2 (12) Anti-topoisomerase I antibodies 7 (78)

Esophageal involvement 9 (100) 12 (75) Lung involvement 5 (56) 1(6) Calcinosis 5 (56) 7 (44)

Pulmonary hypertension 4 (44) 3 (19)

10 (62) Anticentromere antibodies 0

Telangiectasias 8 (89) 14 (87)

*The LeRoy classification system (15) was used to classify each patient’s disease as diffuse cutaneous SSc (dcSSc) or limited cutaneous SSc (IcSSc). Values are the number (76).

cation system of LeRoy et a1 (15), are shown in Table 1. All patients were free from clinical symptoms of renal damage: urinanalysis results, plasma creatinine levels, and endogenous creatinine clearance, corrected for 1.73 mz body surface area, were within normal limits.

Twenty-five normal volunteers, matched for age, sex, and blood pressure, served as the control group.

Assessment of renal function. At 9:00 AM, after 1 hour of rest in a supine position in a suitable environment (20- 23°C) to achieve uniform basal conditions, brachial arterial pressure was measured on fasting patients who had not received any medication for at least 12 hours. Mean arterial pressure was calculated by the formula [systolic pressure + (2 X diastolic pressure)]/3. Color-flow Doppler scans of both kidneys were all performed by the same ultrasonographer (RR), using an ATL Ultramark 9HDI scanner with a 2-4-MHz broadband convex probe (Bothell, Seattle, WA).

Resistance index (RI) was determined from the analy- sis of the spectral waveform, as follows: the peak systolic frequency shift minus the lowest diastolic frequency shift was divided by the peak systolic frequency shift (43). Doppler sample width was set at 1.5 mm. RI was calculated as an average value obtained with 5 waveforms on the main renal artery and interlobar artery. The measure of RI on cortical vessels was obtained by color imaging, positioning the explor- ing probe externally to the visualized arcuate vessels. The value represented the mean of 6 waveforms measured: 2 on the upper, 2 on the medial, and 2 on the lower pole of the organ. The variation between R I at different sites was not great (mean 2 SD 3.5 5 2.1%).

Doppler waveforms were made on the lowest pulse repetition frequency possible without aliasing. This maximized the size of the Doppler spectrum and decreased the percentage of error in the measurements. All reported R I values are multiplied by a factor of 100.

Statistical analysis. Patient characteristics were com- pared by means of SPSS software and processed by t-test for independent groups. Categorical data were analyzed by chi- square test. A three-way analysis of variance (ANOVA) pro- cedure was used to analyze the outcome variable (RI) with respect to the selected factors: site of sampling (i.e., renal, interlobar, cortical artery), control group or SSc group, and right or left kidney. Scheffe’s multiple comparison procedure

was chosen to identify significant differences in these factors. The interaction between the factors was also calculated. Mul- tiple linear regression was used to assess the association between RI and creatinine clearance, disease duration, and SSc subtype. Data shown are the mean ? ISD unless otherwise indicated. P values less than 0.05 were considered significant.

RESULTS

Table 2 presents clinical and demographic find- ings in the control group and the SSc group. No differ- ence between the 2 groups in mean age, male/female distribution, mean arterial brachial pressure, plasma creatinine level, or creatinine clearance rate was ob- served. Body weight (P < 0.004) and surface area (P < 0.01) were significantly lower in SSc patients.

The three-way ANOVA procedure showed no significant difference in RI between the right and the left kidney, while there was a significant difference in RI between normal subjects and SSc patients (P < 0.0001) and between sampling sites (P = 0.04). No interactions between the factors considered were observed, so a one-way analysis of variance was performed on those for which there were significant differences, utilizing the mean value of the 2 kidneys of every subject examined.

The RI was significantly increased in patients with SSc compared with controls (Table 3 and Figure 1). RI values tended to decrease from the main renal artery to the interlobar artery to the kidney cortex in both groups (Figure 2). In normal controls, a significant difference was observed between the main artery and cortical vessels (P < 0.01). In SSc patients, cortical vessel RI was different from both the interlobar and the main artery values (P < 0.01).

In SSc patients, RI was related to disease dura- tion (main artery r = 0.56, P < 0.04; interlobar artery r = 0.63, P < 0.02; cortical artery r = 0.75, P < 0.002).

Table 2. control group*

Characteristics of the systemic sclerosis (SSc) group and the

~

Age, years No. malelno. female Weight, kg Body surface area, mz Mean arterial pressure,

Plasma creatinine, pmoles/liter creatinine clearance/l.73 mz

body surface area, m b i n u t e

mni Hg

SSc patients (n = 25)

53.2 i- 9.3 2/23

56.7 ? 7.2 1.65 -t 0.16 92.5 2 6.7

96.8 ? 13.2 80i- 16

Controls (n = 25)

51.9 2 9.6 2/23

67.2 -t 6.1 1.76 5 0.22 90.2 -t 4.8

101.3 i- 12.5 87 i- 14

P

NS NS

<0.004 co.01

NS

NS NS

* Except for no. malelno. female, values are the mean ? 1SD. NS = not significant.

1032 RIVOLTA ET AL

Table 3. Resistance index values (X100) in the systemic sclerosis (SSc) group and the controls group"

SSc patients (n = 25)

Controls (n = 25) Pt

Renal artery 70.8 -C 5.7 (68.5-73.1) 57.6 t 4.2 (55.9-59.3) <0.0001 Interlobar artery 69.9 t 5.8 (67.5-72.3) 55.3 * 5.0 (53.2-57.4) <0.0001 Cortical artery 65.0 * 5.9 (62.6-67.4) 51.8 i 5.1 (49.7-53.9) <0.001 PS <0.001 <0.001

" Values are the mean f 1SD (95% confidence interval). t One-way analysis of variance of the significance of the difference between patients and controls. $ One-way analysis of variance of the significance of the difference between sites, by Scheffe's test for multiple comparisons. In the SSc group, P < 0.01, cortical vessels versus interlobar and renal arteries. In the control group, P < 0.01, cortical vessels versus renal arteries.

The degree of correlation increased along with the reduction of the vessel caliber; this was most evident on cortical arteries (Figure 3 ) . Regression analysis showed no relationship between RI and creatinine clearance rate (P = 0.48) or SSc subtype (P = 0.2).

DISCUSSION

In this trial, kidney blood flow measurements obtained by color-flow Doppler ultrasonography and results of other renal function tests currently in use were compared between a group of healthy subjects and a group of systemic sclerosis patients with overt disease of long duration. None of the subjects had clinical signs of renal involvement. The 2 groups were matched for age,

:

J- 0 q T 0

0 0

*u I

Renal Interlobar Cortical

sex, and blood pressure. Mean body weight in the SSc group was lower than that in the control group, probably because of the disease chronicity.

To allow an adequate comparison of results in individuals of differing heights and weights, values ob- tained with all clearance techniques must be corrected for an identical surface area. In several diseases, such as SSc, patients with longstanding disease are frequently

75 8ol I -

s 0 70i ? * r x x 0 U - E 60 -

-h

45 1 40 ! I I I 1

Renal Interlobar Cortical

Figure 2. Variations in resistance index values (X100) from the main renal artery to the interlobar artery to the cortical vessels in 25 systemic sclerosis patients (closed circles) and 25 normal controls

Figure 1. Distribution of resistance index values (X100) in 25 sys- temic sclerosis patients (closed circles) and 25 normal controls (open circles). Horizontal lines represent the means.

(open circles) with normal renal function. Values are the mean i 1SEM). * = P < 0.01 versus main renal artery and versus interlobar artery; ** = P < 0.01 versus main renal artery.

RENAL VASCULAR DAMAGE IN SSc 1033

statistically significant reduction of the RI between the interlobar artery and the cortical vessels was found. These results reveal an increased resistance to flow after the interlobar arteries. This is consistent with the histo- logic picture of the kidney in SSc, in which a symmetric and widespread vascular narrowing in the caliber of small and medium arteries is demonstrated.

Another important finding of this study was the observed relationship between the degree of RI increase and disease duration, suggesting a slow progression of the vascular lesion over time. This hypothesis might be in accordance with the reported finding of normal results of Doppler sonography when it was performed in the early phase of the disease (17). Nevertheless, in some patients, we observed an elevated RI also early in the disease, probably because variable degrees of vascular involvement were present at that time. This might be related to the increased urinary excretion of the vaso- active compounds thromboxane A2 and prostacyclin metabolites observed during Raynaud’s phenomenon in SSc patients (18).

In conclusion, RI determined by color-flow Doppler ultrasonography is a noninvasive, sensitive, and reproducible parameter for evaluating renal vascular damage in SSc patients because it directly explores the blood flow changes in the various kidney vascular branches. This explains its greater sensitivity with re- spect to many other diagnostic methods in use. More experience is needed to define its practical usefulness in the diagnosis and treatment of these patients and in the early diagnosis of renal crisis.

X Q) U c Q) 0 C m v)

a dl

- c. .- K

0 0

- .- ” b 0

60 65i

80 -

75 -

70 -

r - n75 302

I

I - V..

p c 0.1

5 5 1 :, 50 ! I I I I I I

0 5 1 0 1 5 2 0 2 5 3 0

Disease Duration (years)

Figure 3. Relationship between resistance index values ( X loo), mea- sured on cortical vessels, and disease duration in patients with systemic sclerosis.

underweight, making this correction a potential cause of error. In our study, serum creatinine levels and creati- nine clearance, corrected for body surface area, were not significantly different in the 2 groups.

Among the various Doppler parameters, RI was selected because it is the ultrasonographic index most frequently used. RI represents the systolic component of the Doppler wave and is a measure of the resistance to the downstream flow. RI gives quantitative and highly reproducible results (6,lO) that are not influenced by the angle of insonation. This allows its direct measurement in every kidney vascular site, from main artery to cortical vessels.

Determination of RI on 3 different vascular sites (main, interlobar, and cortical arteries), allowed us to detect not only the severity, but also the site of vessel narrowing. In the control group, a small reduction of renal vascular resistance between the main renal and the cortical vessels was found. Resistance remained elevated on the kidney cortex area, at the level of the afferent and efferent arteries (16). In SSc patients, a statistically significant increase in the RI compared with control values was found at every site explored. This increment was identical and symmetric in the 2 kidneys and was not correlated with creatinine clearance values, showing that the observed vascular changes were not yet accompanied by loss of function. Moreover, in the SSc group, a

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