Pediatric Radiology
Pediat. Radiol. 7, 78-84 (1978)
9 by Springer-Verlag1978
A Gamma Camera Method for Quantitation of Split Renal Function in Children Followed for Vesicoureteric Reflux T. E. Tamminen, E. J. Riihim/iki, and E. E. T/ihti Children's Hospital and Radiodiagnostic Department of Meilahti Hospital, University of Helsinki, Helsinki, Finland
Abstract. A method for quantitative estimation of split renal function using a computerized gamma camera system is described. 42 children and adolescents with existing or preexisting vesicoureteric reflux and recurrent urinary tract infection were investigated. Total renal clearance of DTPA was calculated with a disappearance curve derived from the largest extrarenal area in the field of view of a gamma camera with diverging collimator. Split renal function was estimated with the slopes of second phase renograms. The plasma disappearance clearance of DTPA, calculated using one compartment model with two late blood samples, gave similar results with the clearance estimated from the body disappearance curves. The proportional planimetric renal parenchymal areas had good correlation with the split clearance estimated from renogram slopes. The method offers data on renal function and urinary tract dynamics which is very valuable in the follow-up of children with recurrent urinary tract infection and vesicoureteric reflux.
Key words: G a m m a camera renography - Split renal function - DTPA-Clearance - Vesicoureteric reflux - Planimetric kidney size Children with vesicoureteric reflux and urinary tract infection are a typical group of patients that needs long term follow-up and knowledge of split renal function. Intravenous urography has been the method for follow-up, although its value for measuring split renal function is limited [4, 5, 8]. On the other hand cumulative radiation dose when using radiographs for follow-up through childhood is considerably high [9, 25]. An accurate method for uncovering kidney pathology and measuring O3Ol-O449/78/ooo7/oo78/SOl.4O
split renal function without the hazard of a large radiation dose and allergic reactions is clearly needed [6, 23]. New Technetium marked radiopharmaceuticals are extremely suitable agents for scintillation camera studies. Their favorable radiation energy, short half-life (6 hours) and low ~-activity minimize the radiation dose [21]. We present a method for quantitative split renal function using 99mTc-DTPA (Sn) and a computerized gamma-camera system which can be used for measuring individual kidney function in childhood as well as later on. Material and Methods Forty-two children and adolescents (aged 2 to 23, mean 15) who have had urinary tract infections and vesicoureteric reflux since early childhood were investigated to estimate split and total renal function. In most cases reflux had been bilateral and the majority of the kidneys had local or generalized reduction of renal parenchyma. Kidney sizes were uneven in most cases. At the time of the study, 11/80 kidneys had reflux. None of the patients had obstruction in the urinary tract at the time of investigation, although many of them had dilated collecting tracts caused by preexisting reflux or obstruction or both. 99mTc-DTPA (Sn) (Solco, Basel) was chosen for clearance measurements because of its availability in a dry kit form that is easy to use in daily routine. DTPA escapes to the extravascular space and is excreted by glomerular filtration when chelated by tin or copper [7, 12, 14]. Its labeling efficiency is 98 % and the amount of free pertechnetate is negligible. Protein binding amounts to from 2 to 10% depending on the incubation time and preparation [14, 26]. Hence the clearance of 99mTc-Sn-DTPA gives a good estimate of glomerular filtration rate [3, 14]. The patients were investigated in the morning. 6 ml/kg fluid was given between half an hour and one hour prior to examination to get a moderate urine flow. The tracer dose administered was from 1 to 3 mCi according to the weight of the patient. The radiation dose produced was around 0.05
T. E. Tamminen et al.: Split Renal Function Measured with DTPA
79
Rad/study for the whole body and gonads [13, 25]. Dosage for the bladder, which is the critical organ, depends greatly on the voiding time after tracer injection. Six hour residence time will produce 1 Rad/study in the bladder. In our study the residence time averaged 2,5 h. Data were collected with a gamma-scintillation camera equipped with a diverging collimator from the backside of the lying patient and analysed by an on-line computing system (Digital Equipment Corporation Gamma 11). Frames were collected every 10 s for a total of 30 min. The information was stored on a magnetic tape for later analysis. Total 99mTc-DTPA clearance (body clearance) was estimated from the body disappearance curve with one blood sample between 20 and 30 min after injection (Fig. 2). Four different extra-renal areas of interest were marked with joy stick and the derived body curves were evaluated to find the best area for body curve in the camera field (Fig. 1). When marking the areas of interest, avoidance of kidney and urinary tract regions is mandatory. This can be checked by adding enough frames together to see whether the collecting tract intersects the area of interest. Thus abnormally dilated ureters which often have an unpredictable course are easily seen and can be avoided. (Normal ureters are not visible). Tho maximum of the body curves after the first circulation of the bolus was marked, and the measured body clearance at the time of blood sample was calibrated with this value (Fig. 2). Simultaneous clearance values for Tc 99m-DTPA were calculated from the plasma disappearance curve with one compartment model (plasma clearance) and from the urine excretion with declining plasma concentration (excretion clearance). Two late blood samples were taken between 1 and 4 h after injection (at least two hours between the samples) for plasma clearance. Two values for excretion clearance were calculated using these same samples, and the mean of the two values was taken. Micturition was performed about 2.5 h after injection in front of the gamma camera. The urine volume and its activity were measured. In case of incomplete bladder emptying the collected urine was not used for clearance calculations. The formulas used are given in Appendix. Creatinine and urea clearance were calculated from the urine collected at the time of renography. For creatinine clearance another value was derived from a 12-h urine collection prior to renography, and the mean of the two calculations was taken. Also an estimate of creatinine clearance (ml/rain/ 1,73 m2) was derived with the formula:
outline and the renal pelvic areas were drawn. The total renal cross sectional areas and the parenchymal cross sectional areas were measured with planimeter. The cross sectional areas were compared with DTPA-clearance values.
0.55 X body length (cm) [22]. plasma creatinine (mg/100 ml)
Table 1. Correlations between body clearances estimated from body curves A, B, C, and D (Fig. 1)
All clearance values were compared with each other. Split renal function was estimated as the ratio of the slopes of the linear uptake phase of renograms obtained from the exact renal areas marked with joy stick. The slopes were calculated by fitting a least squares line to the linear uptake phase of the renogram. The effect of background substraction on the split clearance values was studied. The background substraction curve was derived from an area above and aside of the left kidney where the spleen represents the vascular background inside the kidney (Fig. 1). The efficiency of this substraction was studied by marking an area similar to the area of the sole kidney (2 right-sided, 2 left-sided) in place of the nonexisting kidney. The proportional function of the sole kidney after adequate substraction should then be 100%. Recent intravenous urographs were available for 36 of the patients. These were carefully studied and the renal
Results
The total 99mTc-DTPA clearances estimated with the four different body curves derived from areas A, B, C, and D (Fig. 1) had only a small variation between them (Table 1). Area C had the largest mean absolute difference and about 10% higher mean value for the clearance. In this area the body curve does not have as fast a component in the beginning as the more vascularized areas A, B, and D. Also, the activity within area C was constantly lower, giving more statistical scatter to the body curve and the clearance value. This was most pronounced for thin patients. Area A is logical to use for the calculation since its definition is unambiguous (it is the largest extrareal area outside the urinary tract). The mean variability between clearance values when the stored information was analysed separately by the authors was 0.04 ml/s/1.73 m2 for the total body disappearance clearance values and for the percental split function from 0% to 9% (mean 5 %). The background substraction increased the clearance values of smaller kidneys on an average of 0.04 ml / s / 1.73 m2. Only in 3 / 25 pairs of clearly uneven-sized kidneys was the clearance of the smaller kidney slightly reduced after background substraction. The percental clearance values for the sole kidneys after background substraction were 94% and 96% for the right-sided kidneys,
Mean a stand, dev. Number of patients Area A
R Md
Area B
R Md
Area C
R Md
Area A
Area B
Area C
Area D
1.10 0.36 42
1.09 0.35 40
1.22 0.37 37
1.10 0.30 39
0.98 0.06
0.96 0.13
0.96 0.08
0.91 0.17
0.95 0.08
aMean clearance ml/s/1.73 m2 R - correlation coefficient Md = mean absolute difference
0.91 0.17
80
T.E. Tamminen et al.: Split Renal Function Measured with DTPA Area A
Area B 9
Area C
CD]PA =
"
Cpl
dA (ts) dt (ts) 9 A (to)
Area D
to
Fig. 2. The method of calculation for the body clearance using body disappearance curve and one blood sample between 10 to 30 min after tracer injection
Area for bockground
substraction
Fig. 1. Areas of interest used for the body curves A, B, C, and
A = regression line in present study Y = 19.4 + 48.9 X B = regression line in ct previous study (1) y : 23.6 + 43.8 X .
= time activity curve for extrarenal tissue = time of equilibrium in the vascular space of the injected activity
ts
= time of sample
Cpl
= Concentration of the activity in plasma in units of the injected activity
,//~/ , ~/ 9
,,,~ ,,7"~/
9
9
9
9
99 9
08
s
A (t) to
dA (ts) = slope of tangent at time ts dt
D, and for the background substraction
1.2
ts
9
99
OG (3.0_
r9 U
0.6
2 0
I
o
0.4
9
o_
u~
'
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9 9 1 4 9/ , / B
0.2
R= Q78 N = 68
~'/ 9 9
J 10
/
Y,"/ 20
/
,,
/"
I
I
I
I
I
I
30
40
50
60
70
80
Radiographicalty measured parenchymat area
( c m 2 9 1.73 / BSA "
90
Fig. 3. Correlation between split DTPA-clearance (body clearance from area A after background substraction) and the planimetric parenchymal cross sectional area. Line A is the regression line in our study, and the dotted line B is the corresponding regression line in a previous study where the split clearance was measured with inulin [1]. Points marked (a) are explained more closely in Results
T. E. Tamminen et al.: Split Renal Function Measured with DTPA
rs I ]
100 A
"~ 90
=
regression line y= -15.2 + 1.26 x
9 //'" ,f
oe
80
B = Line of i d e n t i t y
t3
9
9 Z'",
70
m
p
, ~ / " 9 //
E
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81
-
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,,"
-
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/A
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: 36
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0
I~
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20 30 Percenta[
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40 50 60 parenchyma[
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70 area
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80 90 (%)
100
Fig. 4. Correlation between the percental split DTPA clearance and percental parenchymal area of the right kidneys
and 101% and 102% for the left-sided kidneys. Hence the substraction was presumed to be satisfactory. The background substraction affected the side difference on average 6 %. The clearances calculated with one compartm e n t model after single injection gave values that were at the same level as those calculated with body disappearance curves. The correlations between all the calculated clearance values are given in Table 2. The three different isotope methods (body clearance, plasma clearance, and excretion clearance) had good correlation with each other. Mean creatinine clearance was about 60 % higher than the value for DTPA clearance. Creatinine clearance had only moderate correlation with other methods, and the standard deviation and mean differences were large. The formula estimate of creatinine clearance had good correlation with the other clearance values. The correlations with urea clearance were very poor. The kidney parenchymal area had good correlation with the estimated DTPA split clearances (Fig. 3). There were five kidneys that had considerably low clearance values when compared with their parenchymal areas. One of them had generalized deformity in most calices without concomitant reduction of renal parenchyma. One had a large area of reduced accumulation of the isotope in the lower pole, although the width of the parenchyma was normal (Fig. 5). One was rotated around its long axis which caused error
Fig. 5. The parenchymal width of the lower pole of the right kidney is normal in the radiograph A and in the gamma image B, although the accumulation of the tracer is considerably reduced in the function image C
in both planimetric area and radiographic measurement. The remaining two were radiographically normal kidneys in a patient who also had an abnormally low total clearance value. The clearance of the smaller kidney and its larger mate had equal correlation with their parenchymal areas. Also, the sum of the paten-
82
T . E . Tamminen et al.: Split Renal Function Measured with DTPA
Table 2. Correlations between different clearance methods
Meanb stand, dev. Number of patients DTPA body disappearance clearance
R Md N
DTPA plasma disappearance clearance
R Md N
DTPA excretion clearance
R Md N
DTPA body disappearance clearance
DTPA plasma disappearance clearance
DTPA excretion clearance
Creatinine clearance
Urea clearance
Creatinine clearance estimate a
1.10 0.36 42
1.12 0.26 33
1.18 0.27 27
1.81 0.50 35
0.95 0.46 34
1.95 0.42 41
0.92 0.12 28
0.84 0.16 22
0.69 0.48 30
0.45 0.33 28
0.78 0.64 33
0.86 0.09 24
0.70 0.39 26
0.44 0.38 25
0.76 0.58 29
0.64 0.38 22
0.45 0.41 22
0.70 0.57 23
body length (cm) aClearance estimate = 0.81 ;< ml/s/1.73 m2 plasma creatinine (lamol/1) bMean clearance values ml/s/1.73 m2 R = correlation coefficient Md = mean absolute difference N = number of patients
chymal areas of the kidney pairs correlated well with the total clearance values (R = 0.74). The percental proportion of renal function estimated from renogram slopes agreed well with the percental proportion of the cross sectional area of renal parenchyma (Fig. 4). Discussion
The clearance estimation from the body disappearance curve has several advantages over the plasma disappearance curve. Firstly, it is not possible to determine thr plasma curve adequately by external measurements, and several blood samples are therefore needed. However, only one blood sample taken 10 to 30 min after injection is required for the clearance calculation from the body curve. Secondly, only a short-term knowledge of the body curve at the time of the blood sample is required, whereas the plasma curve must be extrapolated to infinity by curve fitting methods in order to determine the exact clearance. The clearance principle using whole body curve has been shown to have excellent correlation with classical clearance methods [2, 8, 18]. Actual whole body disappearance curve is, of course, impossible to obtain since at least kidney and urinary tract areas must be excluded. Therefore, calibration of the measured curve is mandatory. In the field of view of the gamma camera equiped with diverging collimator there is enough extrarenal tissue to get adequate body curves, which must then be calibrated with the m a x i m u m
dispersed activity in the corresponding area. Marking the point of m a x i m u m activity after vascular mixing causes the main methodological variance in the clearance values. This can be minimized by using a curve from a maximal vascular area (like area D) when marking the time of m a x i m u m activity, because such a curve has a clear kink at the end of vascular mixing. In most cases the vascular mixing time was about one minute. After this calibration the clearance values of DTPA calculated from body curves were at the same level with the two other radioisotope methods used. The precordial curve is not a good estimate of the plasma curve since DTPA will also distribute into the extravascular spaces. Therefore, the clearances will be over-estimated if the precordial curve is used as plasma curve when measuring clearance with plasma sample at 20 min as suggested in a recent report [19]. We showed that the vascular curve D, which corresponds closely to the precordial curve, gives very similar results with the other possible body curves when using the body disappearance principle for the clearance calculation. The slope of the linear uptake phase of hippuran renogram gives an estimate of the division of clearance between the kidneys, and it has been shown to have excellent correlation with the hippuran clearance values using ureteral catheters [10, 18, 20]. In principle, an equivalent method is to use the total accumulated counts during the linear uptake phase for measuring the
T. E. T a m m i n e n et al.: Split R e n a l F u n c t i o n Measured with D T P A
proportional function of the kidneys [11, 15]. Since the uptake phase of the renogram is more linear and longer for an agent that is excreted by glomerular filtration than for hippuran, the slope of the linear part can be determined more accurately for DTPA. The patient's state of hydration affects the length of the linear uptake phase. Hence it is recommended by us to avoid water loading of the patient prior to examination. We prefer the slope method for the estimation of the side difference because of its simplicity and reliability. Most of the methodological variability for the proportional clearance values resulted from the poor statistics of the slopes of the kidneys with greatly reduced clearance. It has been suggested in previous reports [5, 10, 17] that background substraction is needed when the kidney function is very poor. We found that substraction affects the absolute clearances of poorly functioning kidneys only slightly. Background substraction can be used when absolute values are needed, but when patients are followed up, it is unnecessary. The triangular area beside the left kidney proved to be very satisfactory for background substraction. It has been shown previously with a group of patients similar to those in the present study [1] that parenchymal cross sectional area correlated well with split renal clearance measured with steady state inulin infusion and external compression of the opposite ureter. We also noticed that the corresponding correlation was good and that the regression line was even very close to that found by split inulin clearances (Fig. 3). This means that our method for split renal function seems to have good correlation with split inulin clearance with external compression, and also that the DTPA-clearance is at the same level as inulin clearance. Small kidneys were shown to have surprisingly high inulin clearance in another study with an eqivalent group of patients [4]. In contrast, our findings suggest that small kidneys function in proportion to their parenchymal size. In pyelonephritic kidneys glomerular function and tubular function are affected in about equal proportions [16] although concomitant obstruction and severe reflux might increase the relative tubular dysfunction. Nevertheless, a substance filtered by glomerulae can be used for measuring the overall renal function. 99mTc-DTPA-clearance is thus suitable for the measurement of renal function in the present group of patients. When using gamma-camera renography, the quantitative split renal clearance is available for follow-up of patients instead of the radiographical estimate of the kidney size. The split clearance values measured with radioisotopes are consider-
83
Table 3. T h e influence of the difference in kidney depth on the m e a s u r e d t e c h n e t i u m activity in kidney regions Difference in depths of kidney pair (cm)
Correction factor for the t e c h n e t i u m activity of the kidney closer to surface
1 2 3 4 5
0.86 0.74 0.64 0.55 0.47
ably affected by a difference of depths in the kidney pair [15]. Fortunately, most kidneys are located at equal depths [24]. When a difference in depth is known or suspected, it can be measured by ultrasound [24] and the correction to the side difference should be made according to Table 3. The scarred parenchymal areas are seen with reduced activity in the early gamma images and the ureters are only seen when they are abnormally dilated in the later gamma images [23]. The study can be completed by micturition in front of a gamma camera after waiting about two hours in order to get enough active urine into the bladder. This will disclose the presence of vesicoureteric reflux during micturition and the amount of residual urine. In our opinion gamma-scintillation camera renography combined with computer analysis yields the essential information on reflux, obstruction, and split renal function. Hence it could be used instead of intravenous urography and voiding cystography in the follow-up of children with recurrent urinary tract infection and vesicoureteric reflux. The cumulative gonadal radiation dosage would thereby be reduced considerably without lo osing significant information.
Appendix T h e following formulas were used for the clearance calculations using the two late plasma samples and urine collection: C = k V (1-Hcr) where k = disappearance constant for the tracer from blood V = tracer distribution volume Hcr = hematocrit T h e m o d e l assumes that the tracer disappearance from volume V is m o n o e x p o n e n t i a l . Therefore 1 V =- -
Cbl (ts)
exp (kts),
where %1 (t) = tracer concentration in blood at time t as a fraction of injected a m o u n t ts
= time of blood sample
T. E. Tamminen et al.: Split Renal Function Measured with DTPA
84
For the two-sample method [plasma clearance] the disappearance constant is k
= In (Cbl (tl)) / (t2-tl), cbl (t2) where tl,2 = times for the blood samples. For the urine collection method [excretion clearance] the disappearance constant is k
= in (1 - Vucu) / tu,
where Vu = urine volume Cu = urine tracer concentration as a fraction of injected amount tu = time from injection to voiding of the bladder. Acknowledgements. The authors wish to express their gratitude to Kaarlo Parkkulainen, M. D., and Jaakko J~i~iskelfiinen, M. D., for critical reading of the manuscript. This study was supported in part by a grant from the Foundation for Pediatric Research in Finland.
References 1. Aperia, A., Broberger, O., Ekengren, K., Ericsson, N. O., Wikstad, I.: Correlation between kidney parenchymal area and renal function in vesicoureteral reflux of different degrees. Ann. Radiol. (Paris) 20, 141 (1977) 2. Bahlman, J., Beuerlein, I., Just, G., Klement, V., Mariss, P.: A comparison of various methods for the estimation of the glomerular filtration rate. In: K. zum Winkel, M. D. 9 Blaufox, J.-L. Funck-Brentano (Eds.): Radionuclides in Nephrology,. Proceedings of the III international symposium in Berlin 1974. Stuttgart: Thieme 1975 3. Barbour, G. L., Crumb, C. K., Boyd, C. M., Reeves, R. D., Rastogi, S. P., Patterson, R. M.: Comparison of inulin, iodothalamate and 99m-Tc-DTPA for measurement of glomerular filtration rate. J. Nucl. Med. 17, 317 (1976) 4. Berg, U., Aperia, A., Broberger, O., Ekengren, K., Ericsson, N. O.: Relationship between glomerular filtration rate and radiological appearance of the parenchyma in children. Acta Paediatr. Scand. 59, 1 (1970) 5. Britton, K. E.: Renal function studies with radioisotopes. In: Dynamic studies with radioisotopes in medicine, Vol 1. Vienna: International Atomic Energy Agency 1974 6. Bueschen, A. J., Evans, B. B., Schlegel, J. U.: Renal scintillation camera studies in children. J. Urol. 111, 821 (1974) 7. Chervu, L. R., Lee, H. B., Goyal, Q., Blaufox, M. D.: Use of 99m-Tc-Cu-DTPA complex as a renal function agent. J. Nucl. Med. 18, 62 (1977) 8. Chisholm, G. D., Short, M. D., Glass, H. I.: The measurement of individual renal plasma flows using 123I-Hippuran and gamma-camera. Br. J. Urol. 46, 591 (1974) 9. Fendel, H.: Radiation exposure due to urinary tract disease. Prog. Pediatr. Radiol. 3, 116 (1970) 10. Fritjoffsson, A., l'crsson, J.-E., S6derholm, B., Vikter16f, K. J.: Quantitative determination of kidney function using radiorenography. Scand. J. Urol. Nephrol. 7, 215 (1973) 11. Hayes, M., Brosman, S., Taplin, G. V.: Determination of renal function by sequential renal scintigraphy. J. Urol. 111, 556 (1974)
12. Kempi, V., Persson, R. B. R.: Dry-kit preparation quality control and clearance studies. Nucl. Med. (Stuttg.) 13, 389 (1975) 13. Kereiakes, J. G., Feller, P. A., Ascoli, F. A., Thomas, S. R., Gelfand, M. J., Saenger, E. L.: Pediatric radiopharmaceutical dosimetry. In: Radiopharmaceutical dosimetry symposium, Proceedings of a conference held at Oak Ridge, Tenn. 1976. HEW publication (FDA) 76-8044 14. Klopper, J. F., Hauser, W., Atkins, H. L., Eckelman, W. C., Richards, P.: Evaluation of 99m-Tc-DTPA for the measurement of glomerular filtration rate. J. Nucl. Med. 13, 107 (1972) 15. Larsson, I., Lindstedt, E., Ohlin, P., Strand, S. E., White, T.: A scintillation camera technique for quantitative estimation of separate kidney function and its use before nephrectomy. Scand. J. Clin. Lab. Invest. 35, 517 (1975) 16. Meldolesi, U., Roncari, G., Conte, L., Mobelli, L.: Renal plasma flow and glomerular filtration rate as estimated through double radiocompound renography. Nucl. Med. (Stuttg.) 13, 279 (1975) 17. Nielsen, S. P., Moller, M. L., Trap-Jensen, J.: 99m-TcDTPA scintillation camera renography: A new method for estimation of single-kidney function. J. Nucl. Med. 18, 112 (1977) 18. Oberhausen, E., Berberich, R., Heinrich, W.: Nuklearmedizinische Bestimmung der Nierenclearance. Electro Medica 2, 42 (1972) 19. Piepsz, A., Dobbeleir, A., Erbsmann, F.: Measurement of separate kidney clearance by means of 99mTc-DTPA complex and scintillation camera. Eur. J. Nucl. Med. 2, 173 (1977) 20. Pixberg, H. U., Bahlman, J., Kluge, R.: Katheterlose Bestimmung der seitengetrennten Nierendurchblutung. Med. Klin. 66, 1015 (1971) 21. Saenger, E. L., Kereiakes, J. G.; In: A. E. James, Jr., H. N. Wagner, Jr., R. E. Cooke, (Ed.): Pediatric Nuclear Medicine. Philadelphia, London, Toronto: Saunders 1974 22. Schwartz, G. J., Haycock, G. B., Edelmann, C. M., Jr., Spitzer, A.: A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics 58, 259 (1976) 23. Shuler, S. E., Meckstroth, G. R., Maxfield, W. S.: Scintillation camera in pediatric renal disease. Am. J. Dis. Child. 120, 115 (1970) 24. Tonnesen, K. H., Munck, O., Hald, T., Mogensen, P., Wolf, H.: Influence on the radiorenogram of variation in skin to kidney distance and the clinical importance hereof. In: K. zum Winkel, M. D., Blaufox, J.-L., FunckBrentano (Eds.): Radionuclides in Nephrology, Proceedings of the III international symposium in Berlin 1974. Stuttgart: Thieme 1975 25. Webster, E. W., Alpert, N. M., Brownell, G. L.: Radiation doses in pediatric nuclear medicine and in diagnostic X-ray procedures. In: E. A. James, H. N. Wagner, R. E. Cooke, (Ed.): Pediatric Nuclear Medicine. Philadelphia, London, Toronto: Saunders 1974 26. Wiryosumarto, S., Pedersen, B.: 99m-Tc-DTPA quality control methods. In: Report 1A-4 1976, The isotope Pharmacy, The National Health Service of Denmark Date offinal acceptance: December 16, 1977 Tytti E. Tamminen Children's Hospital University of Helsinki SF-00290 Helsinki 29 Finland
Pediat. Radiol. 7, 78-84 (1978)
9 by Springer-Verlag1978
A Gamma Camera Method for Quantitation of Split Renal Function in Children Followed for Vesicoureteric Reflux T. E. Tamminen, E. J. Riihim/iki, and E. E. T/ihti Children's Hospital and Radiodiagnostic Department of Meilahti Hospital, University of Helsinki, Helsinki, Finland
Abstract. A method for quantitative estimation of split renal function using a computerized gamma camera system is described. 42 children and adolescents with existing or preexisting vesicoureteric reflux and recurrent urinary tract infection were investigated. Total renal clearance of DTPA was calculated with a disappearance curve derived from the largest extrarenal area in the field of view of a gamma camera with diverging collimator. Split renal function was estimated with the slopes of second phase renograms. The plasma disappearance clearance of DTPA, calculated using one compartment model with two late blood samples, gave similar results with the clearance estimated from the body disappearance curves. The proportional planimetric renal parenchymal areas had good correlation with the split clearance estimated from renogram slopes. The method offers data on renal function and urinary tract dynamics which is very valuable in the follow-up of children with recurrent urinary tract infection and vesicoureteric reflux.
Key words: G a m m a camera renography - Split renal function - DTPA-Clearance - Vesicoureteric reflux - Planimetric kidney size Children with vesicoureteric reflux and urinary tract infection are a typical group of patients that needs long term follow-up and knowledge of split renal function. Intravenous urography has been the method for follow-up, although its value for measuring split renal function is limited [4, 5, 8]. On the other hand cumulative radiation dose when using radiographs for follow-up through childhood is considerably high [9, 25]. An accurate method for uncovering kidney pathology and measuring O3Ol-O449/78/ooo7/oo78/SOl.4O
split renal function without the hazard of a large radiation dose and allergic reactions is clearly needed [6, 23]. New Technetium marked radiopharmaceuticals are extremely suitable agents for scintillation camera studies. Their favorable radiation energy, short half-life (6 hours) and low ~-activity minimize the radiation dose [21]. We present a method for quantitative split renal function using 99mTc-DTPA (Sn) and a computerized gamma-camera system which can be used for measuring individual kidney function in childhood as well as later on. Material and Methods Forty-two children and adolescents (aged 2 to 23, mean 15) who have had urinary tract infections and vesicoureteric reflux since early childhood were investigated to estimate split and total renal function. In most cases reflux had been bilateral and the majority of the kidneys had local or generalized reduction of renal parenchyma. Kidney sizes were uneven in most cases. At the time of the study, 11/80 kidneys had reflux. None of the patients had obstruction in the urinary tract at the time of investigation, although many of them had dilated collecting tracts caused by preexisting reflux or obstruction or both. 99mTc-DTPA (Sn) (Solco, Basel) was chosen for clearance measurements because of its availability in a dry kit form that is easy to use in daily routine. DTPA escapes to the extravascular space and is excreted by glomerular filtration when chelated by tin or copper [7, 12, 14]. Its labeling efficiency is 98 % and the amount of free pertechnetate is negligible. Protein binding amounts to from 2 to 10% depending on the incubation time and preparation [14, 26]. Hence the clearance of 99mTc-Sn-DTPA gives a good estimate of glomerular filtration rate [3, 14]. The patients were investigated in the morning. 6 ml/kg fluid was given between half an hour and one hour prior to examination to get a moderate urine flow. The tracer dose administered was from 1 to 3 mCi according to the weight of the patient. The radiation dose produced was around 0.05
T. E. Tamminen et al.: Split Renal Function Measured with DTPA
79
Rad/study for the whole body and gonads [13, 25]. Dosage for the bladder, which is the critical organ, depends greatly on the voiding time after tracer injection. Six hour residence time will produce 1 Rad/study in the bladder. In our study the residence time averaged 2,5 h. Data were collected with a gamma-scintillation camera equipped with a diverging collimator from the backside of the lying patient and analysed by an on-line computing system (Digital Equipment Corporation Gamma 11). Frames were collected every 10 s for a total of 30 min. The information was stored on a magnetic tape for later analysis. Total 99mTc-DTPA clearance (body clearance) was estimated from the body disappearance curve with one blood sample between 20 and 30 min after injection (Fig. 2). Four different extra-renal areas of interest were marked with joy stick and the derived body curves were evaluated to find the best area for body curve in the camera field (Fig. 1). When marking the areas of interest, avoidance of kidney and urinary tract regions is mandatory. This can be checked by adding enough frames together to see whether the collecting tract intersects the area of interest. Thus abnormally dilated ureters which often have an unpredictable course are easily seen and can be avoided. (Normal ureters are not visible). Tho maximum of the body curves after the first circulation of the bolus was marked, and the measured body clearance at the time of blood sample was calibrated with this value (Fig. 2). Simultaneous clearance values for Tc 99m-DTPA were calculated from the plasma disappearance curve with one compartment model (plasma clearance) and from the urine excretion with declining plasma concentration (excretion clearance). Two late blood samples were taken between 1 and 4 h after injection (at least two hours between the samples) for plasma clearance. Two values for excretion clearance were calculated using these same samples, and the mean of the two values was taken. Micturition was performed about 2.5 h after injection in front of the gamma camera. The urine volume and its activity were measured. In case of incomplete bladder emptying the collected urine was not used for clearance calculations. The formulas used are given in Appendix. Creatinine and urea clearance were calculated from the urine collected at the time of renography. For creatinine clearance another value was derived from a 12-h urine collection prior to renography, and the mean of the two calculations was taken. Also an estimate of creatinine clearance (ml/rain/ 1,73 m2) was derived with the formula:
outline and the renal pelvic areas were drawn. The total renal cross sectional areas and the parenchymal cross sectional areas were measured with planimeter. The cross sectional areas were compared with DTPA-clearance values.
0.55 X body length (cm) [22]. plasma creatinine (mg/100 ml)
Table 1. Correlations between body clearances estimated from body curves A, B, C, and D (Fig. 1)
All clearance values were compared with each other. Split renal function was estimated as the ratio of the slopes of the linear uptake phase of renograms obtained from the exact renal areas marked with joy stick. The slopes were calculated by fitting a least squares line to the linear uptake phase of the renogram. The effect of background substraction on the split clearance values was studied. The background substraction curve was derived from an area above and aside of the left kidney where the spleen represents the vascular background inside the kidney (Fig. 1). The efficiency of this substraction was studied by marking an area similar to the area of the sole kidney (2 right-sided, 2 left-sided) in place of the nonexisting kidney. The proportional function of the sole kidney after adequate substraction should then be 100%. Recent intravenous urographs were available for 36 of the patients. These were carefully studied and the renal
Results
The total 99mTc-DTPA clearances estimated with the four different body curves derived from areas A, B, C, and D (Fig. 1) had only a small variation between them (Table 1). Area C had the largest mean absolute difference and about 10% higher mean value for the clearance. In this area the body curve does not have as fast a component in the beginning as the more vascularized areas A, B, and D. Also, the activity within area C was constantly lower, giving more statistical scatter to the body curve and the clearance value. This was most pronounced for thin patients. Area A is logical to use for the calculation since its definition is unambiguous (it is the largest extrareal area outside the urinary tract). The mean variability between clearance values when the stored information was analysed separately by the authors was 0.04 ml/s/1.73 m2 for the total body disappearance clearance values and for the percental split function from 0% to 9% (mean 5 %). The background substraction increased the clearance values of smaller kidneys on an average of 0.04 ml / s / 1.73 m2. Only in 3 / 25 pairs of clearly uneven-sized kidneys was the clearance of the smaller kidney slightly reduced after background substraction. The percental clearance values for the sole kidneys after background substraction were 94% and 96% for the right-sided kidneys,
Mean a stand, dev. Number of patients Area A
R Md
Area B
R Md
Area C
R Md
Area A
Area B
Area C
Area D
1.10 0.36 42
1.09 0.35 40
1.22 0.37 37
1.10 0.30 39
0.98 0.06
0.96 0.13
0.96 0.08
0.91 0.17
0.95 0.08
aMean clearance ml/s/1.73 m2 R - correlation coefficient Md = mean absolute difference
0.91 0.17
80
T.E. Tamminen et al.: Split Renal Function Measured with DTPA Area A
Area B 9
Area C
CD]PA =
"
Cpl
dA (ts) dt (ts) 9 A (to)
Area D
to
Fig. 2. The method of calculation for the body clearance using body disappearance curve and one blood sample between 10 to 30 min after tracer injection
Area for bockground
substraction
Fig. 1. Areas of interest used for the body curves A, B, C, and
A = regression line in present study Y = 19.4 + 48.9 X B = regression line in ct previous study (1) y : 23.6 + 43.8 X .
= time activity curve for extrarenal tissue = time of equilibrium in the vascular space of the injected activity
ts
= time of sample
Cpl
= Concentration of the activity in plasma in units of the injected activity
,//~/ , ~/ 9
,,,~ ,,7"~/
9
9
9
9
99 9
08
s
A (t) to
dA (ts) = slope of tangent at time ts dt
D, and for the background substraction
1.2
ts
9
99
OG (3.0_
r9 U
0.6
2 0
I
o
0.4
9
o_
u~
'
A/~./
"a
9 9 1 4 9/ , / B
0.2
R= Q78 N = 68
~'/ 9 9
J 10
/
Y,"/ 20
/
,,
/"
I
I
I
I
I
I
30
40
50
60
70
80
Radiographicalty measured parenchymat area
( c m 2 9 1.73 / BSA "
90
Fig. 3. Correlation between split DTPA-clearance (body clearance from area A after background substraction) and the planimetric parenchymal cross sectional area. Line A is the regression line in our study, and the dotted line B is the corresponding regression line in a previous study where the split clearance was measured with inulin [1]. Points marked (a) are explained more closely in Results
T. E. Tamminen et al.: Split Renal Function Measured with DTPA
rs I ]
100 A
"~ 90
=
regression line y= -15.2 + 1.26 x
9 //'" ,f
oe
80
B = Line of i d e n t i t y
t3
9
9 Z'",
70
m
p
, ~ / " 9 //
E
?n
81
-
9 9
,,"
-
F- 50 /~0 30
.'"
20
,,
/A
I
l
N
: 36
(1) 10 i j / I s m '
0
I~
10
20 30 Percenta[
U
U
I
40 50 60 parenchyma[
I
70 area
I
I
80 90 (%)
100
Fig. 4. Correlation between the percental split DTPA clearance and percental parenchymal area of the right kidneys
and 101% and 102% for the left-sided kidneys. Hence the substraction was presumed to be satisfactory. The background substraction affected the side difference on average 6 %. The clearances calculated with one compartm e n t model after single injection gave values that were at the same level as those calculated with body disappearance curves. The correlations between all the calculated clearance values are given in Table 2. The three different isotope methods (body clearance, plasma clearance, and excretion clearance) had good correlation with each other. Mean creatinine clearance was about 60 % higher than the value for DTPA clearance. Creatinine clearance had only moderate correlation with other methods, and the standard deviation and mean differences were large. The formula estimate of creatinine clearance had good correlation with the other clearance values. The correlations with urea clearance were very poor. The kidney parenchymal area had good correlation with the estimated DTPA split clearances (Fig. 3). There were five kidneys that had considerably low clearance values when compared with their parenchymal areas. One of them had generalized deformity in most calices without concomitant reduction of renal parenchyma. One had a large area of reduced accumulation of the isotope in the lower pole, although the width of the parenchyma was normal (Fig. 5). One was rotated around its long axis which caused error
Fig. 5. The parenchymal width of the lower pole of the right kidney is normal in the radiograph A and in the gamma image B, although the accumulation of the tracer is considerably reduced in the function image C
in both planimetric area and radiographic measurement. The remaining two were radiographically normal kidneys in a patient who also had an abnormally low total clearance value. The clearance of the smaller kidney and its larger mate had equal correlation with their parenchymal areas. Also, the sum of the paten-
82
T . E . Tamminen et al.: Split Renal Function Measured with DTPA
Table 2. Correlations between different clearance methods
Meanb stand, dev. Number of patients DTPA body disappearance clearance
R Md N
DTPA plasma disappearance clearance
R Md N
DTPA excretion clearance
R Md N
DTPA body disappearance clearance
DTPA plasma disappearance clearance
DTPA excretion clearance
Creatinine clearance
Urea clearance
Creatinine clearance estimate a
1.10 0.36 42
1.12 0.26 33
1.18 0.27 27
1.81 0.50 35
0.95 0.46 34
1.95 0.42 41
0.92 0.12 28
0.84 0.16 22
0.69 0.48 30
0.45 0.33 28
0.78 0.64 33
0.86 0.09 24
0.70 0.39 26
0.44 0.38 25
0.76 0.58 29
0.64 0.38 22
0.45 0.41 22
0.70 0.57 23
body length (cm) aClearance estimate = 0.81 ;< ml/s/1.73 m2 plasma creatinine (lamol/1) bMean clearance values ml/s/1.73 m2 R = correlation coefficient Md = mean absolute difference N = number of patients
chymal areas of the kidney pairs correlated well with the total clearance values (R = 0.74). The percental proportion of renal function estimated from renogram slopes agreed well with the percental proportion of the cross sectional area of renal parenchyma (Fig. 4). Discussion
The clearance estimation from the body disappearance curve has several advantages over the plasma disappearance curve. Firstly, it is not possible to determine thr plasma curve adequately by external measurements, and several blood samples are therefore needed. However, only one blood sample taken 10 to 30 min after injection is required for the clearance calculation from the body curve. Secondly, only a short-term knowledge of the body curve at the time of the blood sample is required, whereas the plasma curve must be extrapolated to infinity by curve fitting methods in order to determine the exact clearance. The clearance principle using whole body curve has been shown to have excellent correlation with classical clearance methods [2, 8, 18]. Actual whole body disappearance curve is, of course, impossible to obtain since at least kidney and urinary tract areas must be excluded. Therefore, calibration of the measured curve is mandatory. In the field of view of the gamma camera equiped with diverging collimator there is enough extrarenal tissue to get adequate body curves, which must then be calibrated with the m a x i m u m
dispersed activity in the corresponding area. Marking the point of m a x i m u m activity after vascular mixing causes the main methodological variance in the clearance values. This can be minimized by using a curve from a maximal vascular area (like area D) when marking the time of m a x i m u m activity, because such a curve has a clear kink at the end of vascular mixing. In most cases the vascular mixing time was about one minute. After this calibration the clearance values of DTPA calculated from body curves were at the same level with the two other radioisotope methods used. The precordial curve is not a good estimate of the plasma curve since DTPA will also distribute into the extravascular spaces. Therefore, the clearances will be over-estimated if the precordial curve is used as plasma curve when measuring clearance with plasma sample at 20 min as suggested in a recent report [19]. We showed that the vascular curve D, which corresponds closely to the precordial curve, gives very similar results with the other possible body curves when using the body disappearance principle for the clearance calculation. The slope of the linear uptake phase of hippuran renogram gives an estimate of the division of clearance between the kidneys, and it has been shown to have excellent correlation with the hippuran clearance values using ureteral catheters [10, 18, 20]. In principle, an equivalent method is to use the total accumulated counts during the linear uptake phase for measuring the
T. E. T a m m i n e n et al.: Split R e n a l F u n c t i o n Measured with D T P A
proportional function of the kidneys [11, 15]. Since the uptake phase of the renogram is more linear and longer for an agent that is excreted by glomerular filtration than for hippuran, the slope of the linear part can be determined more accurately for DTPA. The patient's state of hydration affects the length of the linear uptake phase. Hence it is recommended by us to avoid water loading of the patient prior to examination. We prefer the slope method for the estimation of the side difference because of its simplicity and reliability. Most of the methodological variability for the proportional clearance values resulted from the poor statistics of the slopes of the kidneys with greatly reduced clearance. It has been suggested in previous reports [5, 10, 17] that background substraction is needed when the kidney function is very poor. We found that substraction affects the absolute clearances of poorly functioning kidneys only slightly. Background substraction can be used when absolute values are needed, but when patients are followed up, it is unnecessary. The triangular area beside the left kidney proved to be very satisfactory for background substraction. It has been shown previously with a group of patients similar to those in the present study [1] that parenchymal cross sectional area correlated well with split renal clearance measured with steady state inulin infusion and external compression of the opposite ureter. We also noticed that the corresponding correlation was good and that the regression line was even very close to that found by split inulin clearances (Fig. 3). This means that our method for split renal function seems to have good correlation with split inulin clearance with external compression, and also that the DTPA-clearance is at the same level as inulin clearance. Small kidneys were shown to have surprisingly high inulin clearance in another study with an eqivalent group of patients [4]. In contrast, our findings suggest that small kidneys function in proportion to their parenchymal size. In pyelonephritic kidneys glomerular function and tubular function are affected in about equal proportions [16] although concomitant obstruction and severe reflux might increase the relative tubular dysfunction. Nevertheless, a substance filtered by glomerulae can be used for measuring the overall renal function. 99mTc-DTPA-clearance is thus suitable for the measurement of renal function in the present group of patients. When using gamma-camera renography, the quantitative split renal clearance is available for follow-up of patients instead of the radiographical estimate of the kidney size. The split clearance values measured with radioisotopes are consider-
83
Table 3. T h e influence of the difference in kidney depth on the m e a s u r e d t e c h n e t i u m activity in kidney regions Difference in depths of kidney pair (cm)
Correction factor for the t e c h n e t i u m activity of the kidney closer to surface
1 2 3 4 5
0.86 0.74 0.64 0.55 0.47
ably affected by a difference of depths in the kidney pair [15]. Fortunately, most kidneys are located at equal depths [24]. When a difference in depth is known or suspected, it can be measured by ultrasound [24] and the correction to the side difference should be made according to Table 3. The scarred parenchymal areas are seen with reduced activity in the early gamma images and the ureters are only seen when they are abnormally dilated in the later gamma images [23]. The study can be completed by micturition in front of a gamma camera after waiting about two hours in order to get enough active urine into the bladder. This will disclose the presence of vesicoureteric reflux during micturition and the amount of residual urine. In our opinion gamma-scintillation camera renography combined with computer analysis yields the essential information on reflux, obstruction, and split renal function. Hence it could be used instead of intravenous urography and voiding cystography in the follow-up of children with recurrent urinary tract infection and vesicoureteric reflux. The cumulative gonadal radiation dosage would thereby be reduced considerably without lo osing significant information.
Appendix T h e following formulas were used for the clearance calculations using the two late plasma samples and urine collection: C = k V (1-Hcr) where k = disappearance constant for the tracer from blood V = tracer distribution volume Hcr = hematocrit T h e m o d e l assumes that the tracer disappearance from volume V is m o n o e x p o n e n t i a l . Therefore 1 V =- -
Cbl (ts)
exp (kts),
where %1 (t) = tracer concentration in blood at time t as a fraction of injected a m o u n t ts
= time of blood sample
T. E. Tamminen et al.: Split Renal Function Measured with DTPA
84
For the two-sample method [plasma clearance] the disappearance constant is k
= In (Cbl (tl)) / (t2-tl), cbl (t2) where tl,2 = times for the blood samples. For the urine collection method [excretion clearance] the disappearance constant is k
= in (1 - Vucu) / tu,
where Vu = urine volume Cu = urine tracer concentration as a fraction of injected amount tu = time from injection to voiding of the bladder. Acknowledgements. The authors wish to express their gratitude to Kaarlo Parkkulainen, M. D., and Jaakko J~i~iskelfiinen, M. D., for critical reading of the manuscript. This study was supported in part by a grant from the Foundation for Pediatric Research in Finland.
References 1. Aperia, A., Broberger, O., Ekengren, K., Ericsson, N. O., Wikstad, I.: Correlation between kidney parenchymal area and renal function in vesicoureteral reflux of different degrees. Ann. Radiol. (Paris) 20, 141 (1977) 2. Bahlman, J., Beuerlein, I., Just, G., Klement, V., Mariss, P.: A comparison of various methods for the estimation of the glomerular filtration rate. In: K. zum Winkel, M. D. 9 Blaufox, J.-L. Funck-Brentano (Eds.): Radionuclides in Nephrology,. Proceedings of the III international symposium in Berlin 1974. Stuttgart: Thieme 1975 3. Barbour, G. L., Crumb, C. K., Boyd, C. M., Reeves, R. D., Rastogi, S. P., Patterson, R. M.: Comparison of inulin, iodothalamate and 99m-Tc-DTPA for measurement of glomerular filtration rate. J. Nucl. Med. 17, 317 (1976) 4. Berg, U., Aperia, A., Broberger, O., Ekengren, K., Ericsson, N. O.: Relationship between glomerular filtration rate and radiological appearance of the parenchyma in children. Acta Paediatr. Scand. 59, 1 (1970) 5. Britton, K. E.: Renal function studies with radioisotopes. In: Dynamic studies with radioisotopes in medicine, Vol 1. Vienna: International Atomic Energy Agency 1974 6. Bueschen, A. J., Evans, B. B., Schlegel, J. U.: Renal scintillation camera studies in children. J. Urol. 111, 821 (1974) 7. Chervu, L. R., Lee, H. B., Goyal, Q., Blaufox, M. D.: Use of 99m-Tc-Cu-DTPA complex as a renal function agent. J. Nucl. Med. 18, 62 (1977) 8. Chisholm, G. D., Short, M. D., Glass, H. I.: The measurement of individual renal plasma flows using 123I-Hippuran and gamma-camera. Br. J. Urol. 46, 591 (1974) 9. Fendel, H.: Radiation exposure due to urinary tract disease. Prog. Pediatr. Radiol. 3, 116 (1970) 10. Fritjoffsson, A., l'crsson, J.-E., S6derholm, B., Vikter16f, K. J.: Quantitative determination of kidney function using radiorenography. Scand. J. Urol. Nephrol. 7, 215 (1973) 11. Hayes, M., Brosman, S., Taplin, G. V.: Determination of renal function by sequential renal scintigraphy. J. Urol. 111, 556 (1974)
12. Kempi, V., Persson, R. B. R.: Dry-kit preparation quality control and clearance studies. Nucl. Med. (Stuttg.) 13, 389 (1975) 13. Kereiakes, J. G., Feller, P. A., Ascoli, F. A., Thomas, S. R., Gelfand, M. J., Saenger, E. L.: Pediatric radiopharmaceutical dosimetry. In: Radiopharmaceutical dosimetry symposium, Proceedings of a conference held at Oak Ridge, Tenn. 1976. HEW publication (FDA) 76-8044 14. Klopper, J. F., Hauser, W., Atkins, H. L., Eckelman, W. C., Richards, P.: Evaluation of 99m-Tc-DTPA for the measurement of glomerular filtration rate. J. Nucl. Med. 13, 107 (1972) 15. Larsson, I., Lindstedt, E., Ohlin, P., Strand, S. E., White, T.: A scintillation camera technique for quantitative estimation of separate kidney function and its use before nephrectomy. Scand. J. Clin. Lab. Invest. 35, 517 (1975) 16. Meldolesi, U., Roncari, G., Conte, L., Mobelli, L.: Renal plasma flow and glomerular filtration rate as estimated through double radiocompound renography. Nucl. Med. (Stuttg.) 13, 279 (1975) 17. Nielsen, S. P., Moller, M. L., Trap-Jensen, J.: 99m-TcDTPA scintillation camera renography: A new method for estimation of single-kidney function. J. Nucl. Med. 18, 112 (1977) 18. Oberhausen, E., Berberich, R., Heinrich, W.: Nuklearmedizinische Bestimmung der Nierenclearance. Electro Medica 2, 42 (1972) 19. Piepsz, A., Dobbeleir, A., Erbsmann, F.: Measurement of separate kidney clearance by means of 99mTc-DTPA complex and scintillation camera. Eur. J. Nucl. Med. 2, 173 (1977) 20. Pixberg, H. U., Bahlman, J., Kluge, R.: Katheterlose Bestimmung der seitengetrennten Nierendurchblutung. Med. Klin. 66, 1015 (1971) 21. Saenger, E. L., Kereiakes, J. G.; In: A. E. James, Jr., H. N. Wagner, Jr., R. E. Cooke, (Ed.): Pediatric Nuclear Medicine. Philadelphia, London, Toronto: Saunders 1974 22. Schwartz, G. J., Haycock, G. B., Edelmann, C. M., Jr., Spitzer, A.: A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics 58, 259 (1976) 23. Shuler, S. E., Meckstroth, G. R., Maxfield, W. S.: Scintillation camera in pediatric renal disease. Am. J. Dis. Child. 120, 115 (1970) 24. Tonnesen, K. H., Munck, O., Hald, T., Mogensen, P., Wolf, H.: Influence on the radiorenogram of variation in skin to kidney distance and the clinical importance hereof. In: K. zum Winkel, M. D., Blaufox, J.-L., FunckBrentano (Eds.): Radionuclides in Nephrology, Proceedings of the III international symposium in Berlin 1974. Stuttgart: Thieme 1975 25. Webster, E. W., Alpert, N. M., Brownell, G. L.: Radiation doses in pediatric nuclear medicine and in diagnostic X-ray procedures. In: E. A. James, H. N. Wagner, R. E. Cooke, (Ed.): Pediatric Nuclear Medicine. Philadelphia, London, Toronto: Saunders 1974 26. Wiryosumarto, S., Pedersen, B.: 99m-Tc-DTPA quality control methods. In: Report 1A-4 1976, The isotope Pharmacy, The National Health Service of Denmark Date offinal acceptance: December 16, 1977 Tytti E. Tamminen Children's Hospital University of Helsinki SF-00290 Helsinki 29 Finland
