!~11 it',l~Qr
European Journal of I ~IIIL~I~,./I~.#r....~L/
Eur. J. Nucl. Med. 2, 63-66 (1977)
Medicine O by Springer-Verlag 1977
An Analysis of the Diagnostic Contribution of Double-Radiocompound Renography* U g o M e l d o l e s i 1, R u g g e r o C a s u c c i 1, a n d L o r e n z o C o m o t t i 2 1 Istituto di Scienze radiologiche dell'Universitfi di Milano, Cattedra di Medicina nucleare, Curamn, Viale L. Borri, 57, 1-21100 Varese, Italy 2 Ufficio di Statistica e Organizzazione sanitaria dell'Ospedale di Circolo di Varese, Italy
Abstract. T h e d i a g n o s t i c c o n t r i b u t i o n o f d o u b l e - r a d i o c o m p o u n d r e n o g r a p h y w a s t e s t e d b y a p p l y i n g disc r i m i n a n t a n a l y s i s t o t h e d a t a o b t a i n e d in o n e g r o u p o f n o r m a l s u b j e c t s a n d in s o m e g r o u p s o f selected p a t h o l o g i c a l cases w h i c h i n c l u d e d g l o m e r u l o n e p h r i t i s , p y e l o n e p h r i t i s , a n d h y p e r t e n s i o n . T h e results o b t a i n e d c o n f i r m t h e r e l i a b i l i t y o f t h e test a n d g i v e evid e n c e o f its u s e f u l n e s s in d i a g n o s t i c clinical w o r k .
Introduction I n 1974 a m e t h o d was p r o p o s e d ( M e l d o l e s i et al., 1974) f o r c a r r y i n g o u t r e n o g r a p h i e s u s i n g t w o t r a c e r s , i o d i n e 131 H i p p u r a n a n d y t t e r b i u m 169 D T P A , in o r d e r to o b t a i n f r o m t h e c l e a r a n c e r a t e s o f t h e t w o radiocompounds an estimate of the renal plasma flow a n d t h e g l o m e r u l a r f i l t r a t i o n r a t e r e s p e c t i v e l y for e a c h k i d n e y . O u r a i m in c a r r y i n g o u t this s t u d y w a s to e v a l u a t e t h e d i a g n o s t i c c o n t r i b u t i o n o f this t e c h n i q u e by c o m p a r i n g t h e r e s u l t s o b t a i n e d f r o m a f e w g r o u p s o f s e l e c t e d p a t h o l o g i c a l cases w i t h t h o s e f r o m a g r o u p o f n o r m a l subjects.
Material and Methods Double-radiocompound renography is based upon a method (Meldolesi et al., 1973, 1974) which allows the estimation of the clearance rates by renography provided a precordial tracing is also recorded and provided the radioactivity of the urine collected at the end of the examination is measured and expressed as a fraction of the injected dose. Figure 1 schematically illustrates the method of elaboration, where an estimate of the fraction of the injected radioactivity cleared by each kidney during the first minute after the injection is obtained. This fraction approximates the fractional clearance of the radiocompound. In fact, it turns out to be propor* Report presented at the First E.N.M.S. Congress, Lausanne, May 1976 For offprints contact: Prof. Ugo Meldolesi
A
0
I
I 5
I 10
I 15 tlmin)
hl.Etp (t) dt
p-
0
I
5
10
15t(min)
Fig. 1. Schema of the elaboration used to calculate the fraction of the injected radioactivity cleared by each kidney in the first minute [D~(1) and Dz(1)]. P(t) indicates the precordial tracing whereas h,. and hz indicate the coefficients that normalize the integral function of the precordial curve (which is proportional to the curve of inflow into the kidneys) on the renographic tracings of the right side and left side respectively, after correction for blood background. The curves reproduced in the figure are then normalized on the injected radioactivity by means of a factor: =(A +B)/(fraction of the injected radioactivity excreted during the examination)
tional to the clearance rate corrected to the body surface area by a factor which is close to the standard volume of plasma. The method was successfully tested using either ~ali_Hippuran or S~Cr-EDTA. Later on, in order to estimate both the renal blood flow and the glomerular filtration rate by only one examination, ~69Yb-DTPA was used instead of SlCr-EDTA since the gamma radiation of the former could be discriminated from that of the Hippuran labeling iodine 131. The problems related to the separate measurement of the two radionuclides in vivo were considerably simplified, if the injections of the two substances were not simultaneous (Meldolesi et al., 1974). In fact, by injecting first the ~69yb-DTPA and then, after
64
U. Meldolesi et al. : Diagnostic Contribution of Double-Radiocompound Renography
a few minutes, the 13li_Hippuran, onIy one double channel analyzer was needed in connection with the precordial probe and, in addition, the in vivo interference of the iodine on the measurement of the ytterbium could be calculated for each single patient and therefore correctly substracted. In this way double-radiocompound renography resulted in a sufficiently simple and accurate examination to be applied in routine clinical work. Using this method over 3000 patients have so far been studied. The test is normally performed by means of three-probe equipment coupled with a multi-channel analyzer which is used as an intermediate memory. One gCi of 169yb-DTPA and 0.7 gCi of 13q-Hippuran are injected intravenously with an interval of 3-4 min between them. At the end of a 30-min examination, the urine is collected and measured. The complete emptying of the bladder is checked by external measurement. The data are then transferred to the computer using punched tape. For this study one group of 39 normal subjects and a few groups of selected pathological cases were considered. The pathological groups included 16 cases of acute and 24 cases of chronic glomerulonephritis, 36 cases of pyelonephritis, and 6 cases of renal tuberculosis. We also considered one group of 29 patients who had been suffering from hypertension for over five years with a diastolic pressure of more than 100 mm Hg, but who did not show any signs of renal damage. The diagnostic contribution of double-radiocompound renography was tested in these groups by applying discriminant analysis. The latter is a statistical test introduced by Fisher (1936, 1943) whereby if certain measurements are taken from two separate groups of individuals, an estimate can be made of the frequency
of misclassification of the individuals in each group when such measurements are used as a means of discrimination. In our study the results obtained from each pathological group were compared with those from the group of normal subjects.
Results Table 1 reports the mean clearance rates and standard d e v i a t i o n s in t h e s t u d i e d g r o u p s , w h i l e T a b l e 2 r e p o r t s the results of discriminant analysis. D i s c r i m i n a n t a n a l y s i s w a s c a r r i e d o u t o n t h e following data obtained from double-radiocompound r e n o g r a p h y : (1) t h e l o w e r o f t h e t w o u n i l a t e r a l clearance rates, for Hippuran
and DTPA;
(2) t h e r a t i o
of lower to higher unilateral clearance rates, for Hipp u r a n a n d D T P A ; a n d (3) f i n a l l y , w e t o o k i n t o account the sums of the clearance rates of the two kidneys, in o r d e r to identify the p a r t i c u l a r c o n t r i b u t i o n of the renogram compared with that of other methods which s i m p l y give a g l o b a l e s t i m a t e o f t h e c l e a r a n c e r a t e s o f b o t h sides. A s is t o b e e x p e c t e d , in t h e c a s e o f g l o m e r u l o n e phritis the diagnostic contribution of the unilateral and
Table 1. Mean clearance rates and standard deviations in the studied groups. The total clearance rates and the lower of the two unilateral clearance rates for Hippuran and DTPA are considered
Normal subjects Acute glomerulonephritis Chronic glomerulonephritis Pyelonephritis Tuberculosis Hypertension
Total clearance rates (cm 3 min-1)
Unilateral clearance rates (cm 3 min-1)
Hippuran
Hippuran
DTPA
DTPA
Mean values
Standard deviations
Mean values
Standard deviations
Mean values
Standard deviations
Mean values
Standard deviations
486 448 348 352 335 387
126 172 164 150 175 92
94 60 61 72 59 77
24 29 26 31 29 18
231 210 163 145 142 179
61 80 80 61 67 47
47 27 28 30 25 37
13 13 14 13 14 11
Table 2. Frequency of misclassification resulting from discriminant analysis applied to single or combined data obtained from doubleradiocompound renography. Results of the comparison between each pathological group and the group of normal subjects are shown. The following data are considered: C/~ the lower of the two unilateral clearance rates of Hippuran; Co the lower of the two unilateral clearance rates of DTPA; Rn the ratio of lower to higher unilateral clearance rates of Hippuran; RD the ratio of lower to higher unilateral clearance rates of DTPA; TCn the total clearance rate of Hippuran, i.e., the sum of the Hippuran clearance rates of the two kidneys; TCD the total clearance rate of DTPA, i.e., the sum of the DTPA clearance rates of the two kidneys Total clearance rates
Unilateral clearance rates Groups
C~,
CD
CLr,CD RH
RD
CH, Rn CD, RD CH, R•, CD, Ro
TCH
TCD
TC~, TCD
Acute glomerulonephritis Chronic glomerulonephritis Pyelonephritis Tuberculosis Hypertension
0.44 0.31 0.24 0.24 0.31
0.22 0.24 0.26 0.21 0.34
0.12 0.24 0.24 0.21 0.31
0.34 0.33 0.31 0.25 0.46
0.43 0.31 0.17 0.18 0.31
0.45 0.32 0.31 0.31 0.33
0.25 0.25 0.34 0.25 0.34
0.16 0.25 0.31 0.25 0.32
0.46 0.43 0.23 0.32 0.39
0.21 0.24 0.24 0.18 0.34
0.12 0.24 0.17 0.17 0.31
U. Meldolesi et al. : Diagnostic Contribution of D o u b l e - R a d i o c o m p o u n d Renography .o_ i
800
600
400
200 -
~:
I
I
J
20
40
60
I
80 Age
B
(J
150
100
50
10 b
I
I
I
20
40
60
I
80 Age
Fig. 2a and b. Linear regressions and 90% confidence limits of the clearance rates (in cm 3 min 1 per 1.73 m 2 of surface area) of both Hippuran (a) and D T P A (b) with an increase in age (in years) of normal subjects
total clearance rates is comparatively similar. Only in the acute cases is there an appreciable difference with the error in classification passing from 12 to 16%. The best discrimination is obtained by taking into consideration both the clearance rates, although that of DTPA, which estimates the glomerular filtration rate, obviously plays a major r61e in this process. In the diagnosis of pyelonephritis and tubercolosis there exist, on the other hand, a noticeable difference between the contribution of the unilateral clearance rates and that of the total clearance rates. In the case of the total clearance rates, the minimum error in classification is 31% for pyelonephritis and 25% for tuber-
65
culosis, while in the case of the unilateral clearance rates the same error is reduced to 17% for both pathological forms. An important factor in this reduction of error is the ratio between the clearance rates of the two sides, since pyelonephritis and tuberculosis generally affect the two kidneys to different degrees. Finally, for the cases of hypertension the results are unsatisfactory with both the unilateral and the total clearance rates. In the hope of obtaining an all-round improvement in our results we looked for a regression in the clearance rates with an increase in age which would enable us to reduce the variance for this quota due to a physiological process such as aging. As a matter of fact we obtained significant linear regressions of the clearance rates of both Hippuran and D T P A with age increase in the group of normal subjects. These regressions are illustrated in Figure 2 together with their 90% confidence limits. We therefore repeated the discriminant analysis with the same groups substituting the values of the original clearance rates with those corrected for age based on the linear regression already obtained. Table 3 reports the mean clearance rates and standard deviations after such a correction, while Table 4 reports the results of discriminant analysis. In the case of glomerulonephritis the maximum power of discrimination is offered by the clearance rate of DTPA, while that of Hippuran is negligible. The frequency of misclassification is about 10% in the acute forms and 20% in the chronic forms. In cases of pyelonephritis and tuberculosis the differences in the power of discrimination between the total and unilateral clearance rates are even more significant than before. The misclassification is in fact approximately 20% for the total clearance rates and about 10% for the unilateral clearance rates. With regard to this last result, the informative contribution made by the clearance rates of both the Hippuran and D T P A is almost identical. This, therefore, underlines the greater diagnostic efficiency of a renogram using two tracers instead of just Hippuran. Finally, the poor capacity of discrimination in patients suffering from hypertension is again evident. Most likely, these patients do not form a homogeneous group and a significant difference with respect to normal subjects only results when comparing the mean values.
Discussion
The linear regressions of the clearance rates with an increase in age which we have shown are in close agreement with those obtained by Davies and Shock (1950) using Diodrast and inulin and by Watkin and
66
U. Meldolesi et al. : Diagnostic Contribution of Double-Radiocompound Renography
Table 3. Mean clearance rates and standard deviations in the studied groups after correction to the age of 20 years, according to the regression functions illustrated in Figure 2. The total clearance rates and the lower of the two unilateral clearance rates for Hippuran and DTPA are considered
Normal subjects Acute glomerulonephretis Chronic glomerulonephretis Pyelonephritis Tuberculosis Hypertension
Total clearance rates (cm 3 min- 1)
Unilateral clearance rates (cam 3 min 1)
Hippuran
Hippuran
DTPA
DTPA
Mean values
Standard deviations
Mean values
Standard deviations
Mean values
Standard deviations
Mean values
Standard deviations
631 488 451 435 401 556
108 187 219 160 184 130
118 64 75 87 70 106
21 30 33 34 34 25
299 228 212 179 170 256
48 87 108 67 71 66
59 29 34 36 29 50
11 14 18 15 16 16
Table 4. Same items as in Table 1 after correction of clearance rates for age of patients Unilateral clearance rates
Total clearance rates
Groups
Cn
Co
C,~, Co Rn
Ro
Cn, RH Co, Re
CR, Rn, Co, Ro
TCR
TCo
TCH, TCo
Acute Glomerulonephritis Chronic glomerulonephritis Pyelonephritis Tuberculosis Hypertension
0.30 0.29 0.15 0.15 0.36
0.12 0.20 0.20 0.15 0.38
0.10 0.20 0.15 0.13 0.35
0.34 0.33 0.31 0.25 0.46
0.16 0.26 0.14 0.14 0.34
0.10 0.20 0.11 0.10 0.34
0.31 0.29 0.23 0.21 0.38
0.14 0.21 0.28 0.19 0.39
0.12 0.21 0.23 0.19 0.37
0.46 0.43 0.23 0.32 0.39
Shock (1955) using PAI and inulin, applying the constant infusion technique. This agreement becomes even more marked if one bears in mind that the latter results regard adult males, while our studies were made on subjects of both sexes (21 men and 18 women). This fact possibly accounts for our estimates of the clearance rates being slightly lower on average than those obtained by the authors mentioned above. The proportionate regression with age shown in our data further validates the method used for measuring renal clearances by renography (Meldolesi et al., 1973, 1974) and confirms the property of 131IHippuran (Mombelli et al., 1969) and 169yb-DTPA (Hosain et al., 1969) to act as substitutes for the more classical PAI and inulin. The results of the discriminant analysis, taken as a whole, demonstrate that the diagnostic contribution of the clearance rates increases appreciably if both radiocompounds are taken into account instead of just one and also that the unilateral clearance rates contribute in the discrimination between normal and pathological cases much more than the global clearance rates of both kidneys. These results therefore confirm the fundamentals of double-radiocompound renography and give evidence of its usefulness in diagnostic clinical work. We feel that above all the results concerning pyelonephritis deserve to be stressed, since this test would seem to make a notable contribu-
0.12 0.20 0.16 0.14 0.34
tion in the screening procedure of such a serious and diffused disease. References Davies, D.F., Shock, N.W.: Age changes in glomerular filtration rate, effective renal plasma flow and tubular excretory capacity in adult males. J. clin. Invest. 29, 496~98 (1950) Fisher, R.A. : The use of multiple measurement in taxonomic problems. Ann. Eugen. (Lond.) 7, 87-104 (1936) Fisher, R.A.: Statistical methods for research workers. Edinburg: Oliver & Boyd 1943 Hosain, F., Reba, R.C., Wagner, H.N. : Measurement of glomerular filtration rate using chelated ytterbium 169. J. appl. Radiat. Isotopes 20, 517-521 (1969) Meldolesi, U., Conte, L., Mombelli, L., Roncari, G. : La determinatione della clearance in corso di radionefrografia. Radiol. med. (Torino) 60, 149-160 (1974a) Meldolesi, U., Mombelli, L., Roncari, G., Conte, L.: A simple method of estimating renal clearance by renography. J. nucl. Biol. Med. 1"7, 79-83 (1973) Meldolesi, U., Roncari, G., Conte, L., Mombelli, L.: Tlae renal plasma fl0w and glomerular filtration rate as estimated through double radiocompound renography. Nucl.-Med. (Stuttg.) 13, 279-287 (1974b) Mombelli, L., Roncari, G., Fidanza, M.A., Comotti, L. : Confronto fra clearance dell'Hippuran lZSI e del PAI. Radiol. med. (Torino) 55, 761-771 (1969) Watkin, D,M., Shock, N.W.: Agewise standard value for CIN, CpAn and TmpA H in adult males. J. clin. Invest. 34, 969 (1955)
Received August 2, 1976
European Journal of I ~IIIL~I~,./I~.#r....~L/
Eur. J. Nucl. Med. 2, 63-66 (1977)
Medicine O by Springer-Verlag 1977
An Analysis of the Diagnostic Contribution of Double-Radiocompound Renography* U g o M e l d o l e s i 1, R u g g e r o C a s u c c i 1, a n d L o r e n z o C o m o t t i 2 1 Istituto di Scienze radiologiche dell'Universitfi di Milano, Cattedra di Medicina nucleare, Curamn, Viale L. Borri, 57, 1-21100 Varese, Italy 2 Ufficio di Statistica e Organizzazione sanitaria dell'Ospedale di Circolo di Varese, Italy
Abstract. T h e d i a g n o s t i c c o n t r i b u t i o n o f d o u b l e - r a d i o c o m p o u n d r e n o g r a p h y w a s t e s t e d b y a p p l y i n g disc r i m i n a n t a n a l y s i s t o t h e d a t a o b t a i n e d in o n e g r o u p o f n o r m a l s u b j e c t s a n d in s o m e g r o u p s o f selected p a t h o l o g i c a l cases w h i c h i n c l u d e d g l o m e r u l o n e p h r i t i s , p y e l o n e p h r i t i s , a n d h y p e r t e n s i o n . T h e results o b t a i n e d c o n f i r m t h e r e l i a b i l i t y o f t h e test a n d g i v e evid e n c e o f its u s e f u l n e s s in d i a g n o s t i c clinical w o r k .
Introduction I n 1974 a m e t h o d was p r o p o s e d ( M e l d o l e s i et al., 1974) f o r c a r r y i n g o u t r e n o g r a p h i e s u s i n g t w o t r a c e r s , i o d i n e 131 H i p p u r a n a n d y t t e r b i u m 169 D T P A , in o r d e r to o b t a i n f r o m t h e c l e a r a n c e r a t e s o f t h e t w o radiocompounds an estimate of the renal plasma flow a n d t h e g l o m e r u l a r f i l t r a t i o n r a t e r e s p e c t i v e l y for e a c h k i d n e y . O u r a i m in c a r r y i n g o u t this s t u d y w a s to e v a l u a t e t h e d i a g n o s t i c c o n t r i b u t i o n o f this t e c h n i q u e by c o m p a r i n g t h e r e s u l t s o b t a i n e d f r o m a f e w g r o u p s o f s e l e c t e d p a t h o l o g i c a l cases w i t h t h o s e f r o m a g r o u p o f n o r m a l subjects.
Material and Methods Double-radiocompound renography is based upon a method (Meldolesi et al., 1973, 1974) which allows the estimation of the clearance rates by renography provided a precordial tracing is also recorded and provided the radioactivity of the urine collected at the end of the examination is measured and expressed as a fraction of the injected dose. Figure 1 schematically illustrates the method of elaboration, where an estimate of the fraction of the injected radioactivity cleared by each kidney during the first minute after the injection is obtained. This fraction approximates the fractional clearance of the radiocompound. In fact, it turns out to be propor* Report presented at the First E.N.M.S. Congress, Lausanne, May 1976 For offprints contact: Prof. Ugo Meldolesi
A
0
I
I 5
I 10
I 15 tlmin)
hl.Etp (t) dt
p-
0
I
5
10
15t(min)
Fig. 1. Schema of the elaboration used to calculate the fraction of the injected radioactivity cleared by each kidney in the first minute [D~(1) and Dz(1)]. P(t) indicates the precordial tracing whereas h,. and hz indicate the coefficients that normalize the integral function of the precordial curve (which is proportional to the curve of inflow into the kidneys) on the renographic tracings of the right side and left side respectively, after correction for blood background. The curves reproduced in the figure are then normalized on the injected radioactivity by means of a factor: =(A +B)/(fraction of the injected radioactivity excreted during the examination)
tional to the clearance rate corrected to the body surface area by a factor which is close to the standard volume of plasma. The method was successfully tested using either ~ali_Hippuran or S~Cr-EDTA. Later on, in order to estimate both the renal blood flow and the glomerular filtration rate by only one examination, ~69Yb-DTPA was used instead of SlCr-EDTA since the gamma radiation of the former could be discriminated from that of the Hippuran labeling iodine 131. The problems related to the separate measurement of the two radionuclides in vivo were considerably simplified, if the injections of the two substances were not simultaneous (Meldolesi et al., 1974). In fact, by injecting first the ~69yb-DTPA and then, after
64
U. Meldolesi et al. : Diagnostic Contribution of Double-Radiocompound Renography
a few minutes, the 13li_Hippuran, onIy one double channel analyzer was needed in connection with the precordial probe and, in addition, the in vivo interference of the iodine on the measurement of the ytterbium could be calculated for each single patient and therefore correctly substracted. In this way double-radiocompound renography resulted in a sufficiently simple and accurate examination to be applied in routine clinical work. Using this method over 3000 patients have so far been studied. The test is normally performed by means of three-probe equipment coupled with a multi-channel analyzer which is used as an intermediate memory. One gCi of 169yb-DTPA and 0.7 gCi of 13q-Hippuran are injected intravenously with an interval of 3-4 min between them. At the end of a 30-min examination, the urine is collected and measured. The complete emptying of the bladder is checked by external measurement. The data are then transferred to the computer using punched tape. For this study one group of 39 normal subjects and a few groups of selected pathological cases were considered. The pathological groups included 16 cases of acute and 24 cases of chronic glomerulonephritis, 36 cases of pyelonephritis, and 6 cases of renal tuberculosis. We also considered one group of 29 patients who had been suffering from hypertension for over five years with a diastolic pressure of more than 100 mm Hg, but who did not show any signs of renal damage. The diagnostic contribution of double-radiocompound renography was tested in these groups by applying discriminant analysis. The latter is a statistical test introduced by Fisher (1936, 1943) whereby if certain measurements are taken from two separate groups of individuals, an estimate can be made of the frequency
of misclassification of the individuals in each group when such measurements are used as a means of discrimination. In our study the results obtained from each pathological group were compared with those from the group of normal subjects.
Results Table 1 reports the mean clearance rates and standard d e v i a t i o n s in t h e s t u d i e d g r o u p s , w h i l e T a b l e 2 r e p o r t s the results of discriminant analysis. D i s c r i m i n a n t a n a l y s i s w a s c a r r i e d o u t o n t h e following data obtained from double-radiocompound r e n o g r a p h y : (1) t h e l o w e r o f t h e t w o u n i l a t e r a l clearance rates, for Hippuran
and DTPA;
(2) t h e r a t i o
of lower to higher unilateral clearance rates, for Hipp u r a n a n d D T P A ; a n d (3) f i n a l l y , w e t o o k i n t o account the sums of the clearance rates of the two kidneys, in o r d e r to identify the p a r t i c u l a r c o n t r i b u t i o n of the renogram compared with that of other methods which s i m p l y give a g l o b a l e s t i m a t e o f t h e c l e a r a n c e r a t e s o f b o t h sides. A s is t o b e e x p e c t e d , in t h e c a s e o f g l o m e r u l o n e phritis the diagnostic contribution of the unilateral and
Table 1. Mean clearance rates and standard deviations in the studied groups. The total clearance rates and the lower of the two unilateral clearance rates for Hippuran and DTPA are considered
Normal subjects Acute glomerulonephritis Chronic glomerulonephritis Pyelonephritis Tuberculosis Hypertension
Total clearance rates (cm 3 min-1)
Unilateral clearance rates (cm 3 min-1)
Hippuran
Hippuran
DTPA
DTPA
Mean values
Standard deviations
Mean values
Standard deviations
Mean values
Standard deviations
Mean values
Standard deviations
486 448 348 352 335 387
126 172 164 150 175 92
94 60 61 72 59 77
24 29 26 31 29 18
231 210 163 145 142 179
61 80 80 61 67 47
47 27 28 30 25 37
13 13 14 13 14 11
Table 2. Frequency of misclassification resulting from discriminant analysis applied to single or combined data obtained from doubleradiocompound renography. Results of the comparison between each pathological group and the group of normal subjects are shown. The following data are considered: C/~ the lower of the two unilateral clearance rates of Hippuran; Co the lower of the two unilateral clearance rates of DTPA; Rn the ratio of lower to higher unilateral clearance rates of Hippuran; RD the ratio of lower to higher unilateral clearance rates of DTPA; TCn the total clearance rate of Hippuran, i.e., the sum of the Hippuran clearance rates of the two kidneys; TCD the total clearance rate of DTPA, i.e., the sum of the DTPA clearance rates of the two kidneys Total clearance rates
Unilateral clearance rates Groups
C~,
CD
CLr,CD RH
RD
CH, Rn CD, RD CH, R•, CD, Ro
TCH
TCD
TC~, TCD
Acute glomerulonephritis Chronic glomerulonephritis Pyelonephritis Tuberculosis Hypertension
0.44 0.31 0.24 0.24 0.31
0.22 0.24 0.26 0.21 0.34
0.12 0.24 0.24 0.21 0.31
0.34 0.33 0.31 0.25 0.46
0.43 0.31 0.17 0.18 0.31
0.45 0.32 0.31 0.31 0.33
0.25 0.25 0.34 0.25 0.34
0.16 0.25 0.31 0.25 0.32
0.46 0.43 0.23 0.32 0.39
0.21 0.24 0.24 0.18 0.34
0.12 0.24 0.17 0.17 0.31
U. Meldolesi et al. : Diagnostic Contribution of D o u b l e - R a d i o c o m p o u n d Renography .o_ i
800
600
400
200 -
~:
I
I
J
20
40
60
I
80 Age
B
(J
150
100
50
10 b
I
I
I
20
40
60
I
80 Age
Fig. 2a and b. Linear regressions and 90% confidence limits of the clearance rates (in cm 3 min 1 per 1.73 m 2 of surface area) of both Hippuran (a) and D T P A (b) with an increase in age (in years) of normal subjects
total clearance rates is comparatively similar. Only in the acute cases is there an appreciable difference with the error in classification passing from 12 to 16%. The best discrimination is obtained by taking into consideration both the clearance rates, although that of DTPA, which estimates the glomerular filtration rate, obviously plays a major r61e in this process. In the diagnosis of pyelonephritis and tubercolosis there exist, on the other hand, a noticeable difference between the contribution of the unilateral clearance rates and that of the total clearance rates. In the case of the total clearance rates, the minimum error in classification is 31% for pyelonephritis and 25% for tuber-
65
culosis, while in the case of the unilateral clearance rates the same error is reduced to 17% for both pathological forms. An important factor in this reduction of error is the ratio between the clearance rates of the two sides, since pyelonephritis and tuberculosis generally affect the two kidneys to different degrees. Finally, for the cases of hypertension the results are unsatisfactory with both the unilateral and the total clearance rates. In the hope of obtaining an all-round improvement in our results we looked for a regression in the clearance rates with an increase in age which would enable us to reduce the variance for this quota due to a physiological process such as aging. As a matter of fact we obtained significant linear regressions of the clearance rates of both Hippuran and D T P A with age increase in the group of normal subjects. These regressions are illustrated in Figure 2 together with their 90% confidence limits. We therefore repeated the discriminant analysis with the same groups substituting the values of the original clearance rates with those corrected for age based on the linear regression already obtained. Table 3 reports the mean clearance rates and standard deviations after such a correction, while Table 4 reports the results of discriminant analysis. In the case of glomerulonephritis the maximum power of discrimination is offered by the clearance rate of DTPA, while that of Hippuran is negligible. The frequency of misclassification is about 10% in the acute forms and 20% in the chronic forms. In cases of pyelonephritis and tuberculosis the differences in the power of discrimination between the total and unilateral clearance rates are even more significant than before. The misclassification is in fact approximately 20% for the total clearance rates and about 10% for the unilateral clearance rates. With regard to this last result, the informative contribution made by the clearance rates of both the Hippuran and D T P A is almost identical. This, therefore, underlines the greater diagnostic efficiency of a renogram using two tracers instead of just Hippuran. Finally, the poor capacity of discrimination in patients suffering from hypertension is again evident. Most likely, these patients do not form a homogeneous group and a significant difference with respect to normal subjects only results when comparing the mean values.
Discussion
The linear regressions of the clearance rates with an increase in age which we have shown are in close agreement with those obtained by Davies and Shock (1950) using Diodrast and inulin and by Watkin and
66
U. Meldolesi et al. : Diagnostic Contribution of Double-Radiocompound Renography
Table 3. Mean clearance rates and standard deviations in the studied groups after correction to the age of 20 years, according to the regression functions illustrated in Figure 2. The total clearance rates and the lower of the two unilateral clearance rates for Hippuran and DTPA are considered
Normal subjects Acute glomerulonephretis Chronic glomerulonephretis Pyelonephritis Tuberculosis Hypertension
Total clearance rates (cm 3 min- 1)
Unilateral clearance rates (cam 3 min 1)
Hippuran
Hippuran
DTPA
DTPA
Mean values
Standard deviations
Mean values
Standard deviations
Mean values
Standard deviations
Mean values
Standard deviations
631 488 451 435 401 556
108 187 219 160 184 130
118 64 75 87 70 106
21 30 33 34 34 25
299 228 212 179 170 256
48 87 108 67 71 66
59 29 34 36 29 50
11 14 18 15 16 16
Table 4. Same items as in Table 1 after correction of clearance rates for age of patients Unilateral clearance rates
Total clearance rates
Groups
Cn
Co
C,~, Co Rn
Ro
Cn, RH Co, Re
CR, Rn, Co, Ro
TCR
TCo
TCH, TCo
Acute Glomerulonephritis Chronic glomerulonephritis Pyelonephritis Tuberculosis Hypertension
0.30 0.29 0.15 0.15 0.36
0.12 0.20 0.20 0.15 0.38
0.10 0.20 0.15 0.13 0.35
0.34 0.33 0.31 0.25 0.46
0.16 0.26 0.14 0.14 0.34
0.10 0.20 0.11 0.10 0.34
0.31 0.29 0.23 0.21 0.38
0.14 0.21 0.28 0.19 0.39
0.12 0.21 0.23 0.19 0.37
0.46 0.43 0.23 0.32 0.39
Shock (1955) using PAI and inulin, applying the constant infusion technique. This agreement becomes even more marked if one bears in mind that the latter results regard adult males, while our studies were made on subjects of both sexes (21 men and 18 women). This fact possibly accounts for our estimates of the clearance rates being slightly lower on average than those obtained by the authors mentioned above. The proportionate regression with age shown in our data further validates the method used for measuring renal clearances by renography (Meldolesi et al., 1973, 1974) and confirms the property of 131IHippuran (Mombelli et al., 1969) and 169yb-DTPA (Hosain et al., 1969) to act as substitutes for the more classical PAI and inulin. The results of the discriminant analysis, taken as a whole, demonstrate that the diagnostic contribution of the clearance rates increases appreciably if both radiocompounds are taken into account instead of just one and also that the unilateral clearance rates contribute in the discrimination between normal and pathological cases much more than the global clearance rates of both kidneys. These results therefore confirm the fundamentals of double-radiocompound renography and give evidence of its usefulness in diagnostic clinical work. We feel that above all the results concerning pyelonephritis deserve to be stressed, since this test would seem to make a notable contribu-
0.12 0.20 0.16 0.14 0.34
tion in the screening procedure of such a serious and diffused disease. References Davies, D.F., Shock, N.W.: Age changes in glomerular filtration rate, effective renal plasma flow and tubular excretory capacity in adult males. J. clin. Invest. 29, 496~98 (1950) Fisher, R.A. : The use of multiple measurement in taxonomic problems. Ann. Eugen. (Lond.) 7, 87-104 (1936) Fisher, R.A.: Statistical methods for research workers. Edinburg: Oliver & Boyd 1943 Hosain, F., Reba, R.C., Wagner, H.N. : Measurement of glomerular filtration rate using chelated ytterbium 169. J. appl. Radiat. Isotopes 20, 517-521 (1969) Meldolesi, U., Conte, L., Mombelli, L., Roncari, G. : La determinatione della clearance in corso di radionefrografia. Radiol. med. (Torino) 60, 149-160 (1974a) Meldolesi, U., Mombelli, L., Roncari, G., Conte, L.: A simple method of estimating renal clearance by renography. J. nucl. Biol. Med. 1"7, 79-83 (1973) Meldolesi, U., Roncari, G., Conte, L., Mombelli, L.: Tlae renal plasma fl0w and glomerular filtration rate as estimated through double radiocompound renography. Nucl.-Med. (Stuttg.) 13, 279-287 (1974b) Mombelli, L., Roncari, G., Fidanza, M.A., Comotti, L. : Confronto fra clearance dell'Hippuran lZSI e del PAI. Radiol. med. (Torino) 55, 761-771 (1969) Watkin, D,M., Shock, N.W.: Agewise standard value for CIN, CpAn and TmpA H in adult males. J. clin. Invest. 34, 969 (1955)
Received August 2, 1976
