How to Interpret a Deterioration of Split Function?

European Urology European Urology 47 (2005) 686 690 How to Interpret a Deterioration of Split Function? A. Piepsz a, *, K. Ismaili b, M. Hall b, F. Collier c, M. Tondeur a, H. Ham d a Department of Radioisotopes, University Hospital Saint-Pierre, 322 rue Haute, B-1000 Brussels, Belgium b Department of Pediatric Nephrology, Queen Fabiola University Hospital, Brussels, Belgium c Department of Pediatric Urology, Queen Fabiola University Hospital, Brussels, Belgium d Department of Radioisotopes, University Hospital, Rijksuniversiteit Ghent, Belgium Accepted 26 October 2004 Available online 7 December 2004 Summary Objective: A drop of split renal function often constitutes a criterion for pyeloplasty in hydronephrosis since it is considered as representing deterioration of the affected kidney. The aim of this work was to determine, in a selected population of patients with a drop of split function of at least 5%, if the evolution of single kidney glomerular filtration rate (SKGFR) was parallel to the one of split renal function. Methods: From a large data basis, we found retrospectively only 29 children (10 below and 19 above two years of age at first examination) having had at least two Tc-99m mertiatide (Tc-99m MAG3) renographic explorations for various urological diseases, with a decrease of split function of at least 5% between the two examinations. Evolution of split function was compared to evolution of SKGFR obtained by means of the combination of Tc-99m MAG3 split function and overall glomerular filtration rate as given by the chromium Cr 51 ethylenediamine tetraacetic acid (EDTA) clearance. Results: For the group above two years of age, SKGFR increased or remained stable in 63% of the cases, while in the children less than 2 years of age, a decrease of SKGFR was never observed, according to the maturation of overall GFR in this age group. Thus, the decrease of split function was not necessarily associated with a similar decrease of SKGFR. Conclusion: In patients with unilateral or bilateral urological disorders, deterioration of split renal function does not necessary correspond to a loss of function of the affected kidney. SKGFR often modifies the interpretation of split function. # 2004 Elsevier B.V. All rights reserved. Keywords: Tc-99m MAG3; Cr-51 EDTA; SKGFR; Split function; Child 1. Introduction * Corresponding author. Tel. +32 2 5354564; Fax: +32 2 5353137. E-mail Address: amypiepsz@yahoo.com (A. Piepsz). Split function, as obtained from a radionuclide renogram, is nowadays considered as a robust and well standardized parameter, rather easy to calculate [1,2]. It is routinely used by many urological departments in the management of various uropathies. In antenatally detected hydronephrosis conservatively treated, a drop of relative function is generally considered as a criterion of deterioration, and therefore constitutes a criterion for late pyeloplasty. Factors such as maturation of renal function or contralateral compensation may however give the false impression that the pathological kidney is deteriorating, although the true function, as determined on the basis of an absolute determination of single kidney glomerular filtration rate (SKGFR), may be unchanged or even improved. The aim of this work was to compare the evolution of split function and SKGFR, in a rather selected population of patients having undergone at least two 0302-2838/$ see front matter # 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2004.10.028

A. Piepsz et al. / European Urology 47 (2005) 686 690 687 renograms, with a drop of split function on the pathological side of at least 5%. 2. Material and methods 2.1. Selection of patients Starting from a large data base of 1600 renograms, we selected in a first step those patients having undergone at least two successive examinations. Were then selected the patients showing a change of split function of 5% or more (for instance, left split function passing from 45 to 38%). The first renogram and the latest one showing the change were systematically selected. We ended up with 29 children that were divided in two groups: group 1 (less than 2 years of age): 10 patients aged 2 to 22 months at the time of the first renogram; group 2 (2 years or more): 19 patients aged 2 to 10 years at the time of the first renogram. The diagnosis, on the side of the decreasing split function was, in group 1: pelviureteric junction stenosis (PUJ) [4], vesico-ureteral reflux [5] and megaureter [1];in group 2: pelviureteric junction stenosis [6], vesico-ureteral reflux [6], megaureter with or without vesico-ureteral reflux [5], duplex kidney [2]. Time interval between the two renograms was between 3 and 44 months (mean: 17 months) and between 4 and 64 months (mean: 28 months), respectively for group 1 and group 2. 2.2. Radioisotopic techniques For the renographic acquisition, the patient was in supine position and placed above the gamma camera. Tc-99m MAG 3 was administered intravenously at a maximal dose of 100 MBq, scaled on a body surface basis. A 20 min renogram acquisition was obtained, using 20 sec frames. The renal curves were corrected for background using a perirenal area. Split renal function was determined on the basis of the 1 to 2 minutes cumulative corrected renal activity, the sum of left and right split function being equal to 100%. According to previous work [3], a change of 5% or more was considered as significant. For the evaluation of overall glomerular filtration rate (GFR), Cr-51 EDTA was injected, together with MAG3, at a dose adapted to the body surface. GFR was determined using a single 120 minute blood sample in children [4]. Values, expressed in ml/min, were corrected for body surface. Single kidney glomerular filtration rate (SKGFR) was obtained by combining the split function obtained from the MAG3 renogram and the overall Cr-EDTA clearance, and also expressed in ml/min/1.73 m 2. For instance, if overall GFR was 120 ml/min/1.73 m 2 and split function was 50% on both sides, estimated SKGFR was then 60 ml/ min/1.73 m 2 for each kidney. According to the day to day variation of overall Cr-EDTA clearance [5], one can expect, for SKGFR, a maximal day to day variation between 5 and 10 ml/min. In this work, a cut-off level for change of 10 ml was chosen. 3. Results Individual results are described in Tables 1 and 2. Initial split function, on the side of the decreasing split function, was between 24 and 56% (mean: 42%) and between 21 and 89% (mean: 49%) respectively in group 1 and group 2. Overall GFR was between 37 and 100 ml/min/1.73 m 2 (mean: 69 ml/min) and between 46 and 104 ml/min/1.73 m 2 (mean: 82 ml/ min), respectively for group 1 and 2. The drop of split function was, in group 1, between 5 and 14% (mean: 8.7%) and in group 2, between 5 and 37% (mean: 10.0%). The change of overall GFR from Table 1 Data concerning the patients less than 2 years of age at the time of the first renogram Patient No. Age (years) GFR Abnormal kidney Split (%) SKGFR Contralateral kidney Diagnosis Split (%) SKGFR 1 1.9 62 39 24 PUJ 61 38 1 4.6 73 31 23 PUJ 69 50 2 1.2 78 56 44 reflux 44 34 2 2.6 94 50 47 reflux 50 47 3 0.4 55 24 13 reflux 76 42 3 1.3 90 11 10 reflux 89 80 4 0.1 37 45 17 PUJ 55 20 4 0.4 58 36 21 PUJ 64 37 5 1.0 100 48 48 megaureter 52 52 5 2.2 105 43 45 megaureter 57 60 6 0.9 68 55 37 reflux 45 31 6 4.5 83 41 34 reflux 59 49 7 1.5 75 43 32 PUJ 57 43 7 2.1 81 37 30 PUJ 63 51 8 1.1 88 52 46 reflux 48 42 8 1.7 97 47 46 reflux 53 51 9 0.2 45 26 12 reflux 74 33 9 1.2 57 14 8 reflux 86 49 10 0.2 52 34 18 PUJ 66 34 10 1.5 115 25 29 PUJ 75 86 For each patient, the numerical data of both renograms are successively provided.

688 A. Piepsz et al. / European Urology 47 (2005) 686 690 Table 2 Data concerning the patients 2 years of age at the time of the first renogram Patient No. Age (years) GFR Abnormal kidney Split (%) SKGFR Contralateral kidney Diagnosis Split (%) SKGFR 1 5.9 58 21 12 reflux, small kidney 79 46 1 9.7 66 12 8 reflux, small kidney 88 58 2 3.3 78 80 62 reflux 20 16 2 4.5 91 75 68 reflux 25 23 3 4.3 81 34 28 megaureter 66 53 3 5.0 79 16 13 megaureter 84 66 4 10.0 90 38 34 reflux 62 56 4 11.9 86 31 27 reflux 69 59 5 9.8 104 48 50 megaureter 52 54 5 10.4 96 34 33 megaureter 66 63 6 8.6 101 48 48 PUJ 52 53 6 9.0 77 11 8 PUJ 89 69 7 10.1 100 36 36 duplex 64 64 7 11.4 110 15 17 duplex 85 94 8 8.8 99 42 42 PUJ 58 57 8 10.3 93 31 29 PUJ 69 64 9 6.5 94 36 34 reflux, small kidney 64 60 9 9.4 101 31 31 reflux, small kidney 69 70 10 2.9 63 84 53 PUJ 16 10 10 5.9 69 77 53 PUJ 23 16 11 7.0 79 44 35 duplex 56 44 11 10.4 88 39 34 duplex 61 54 12 2.9 95 53 50 megaureter 47 45 12 8.0 104 46 48 megaureter 54 56 13 9.4 63 33 21 PUJ 67 42 13 11.1 64 25 16 PUJ 75 48 14 2.5 85 48 41 megaureter 52 44 14 3.4 93 43 40 megaureter 57 53 15 3.2 70 16 11 PUJ 84 59 15 5.3 79 7 6 PUJ 93 73 16 4.0 46 89 41 reflux 11 5 16 5.7 51 79 40 reflux 21 11 17 2.6 78 50 39 reflux 50 39 17 3.5 105 45 47 reflux 55 58 18 2.0 71 60 43 PUJ 40 28 18 7.3 89 54 48 PUJ 46 41 19 8.9 95 75 71 megaureter 25 24 19 13.9 128 69 88 megaureter 31 40 For each patient, the numerical data of both renograms are successively provided. first to second measurement was between +6 and +63 ml/min/1.73 m 2 (mean: +20 ml/min) and between 24 and +33 ml/min/1.73 m 2 (mean: +6 ml/min), respectively for group 1 and group 2. We compared split function change and SKGFR change on the side of decrease of split function (Fig. 1). In group 1, a decrease of SKGFR was never observed. In 9 patients, SKGFR remained unchanged while split function decreased. In 1 patient, SKGFR increased while split function decreased. In group 2, split function and SKGFR both dropped significantly in 5 patients; in 13 patients, SKGFR remained unchanged while split function decreased; in 1 patient, SKGFR increased while split function decreased. The choice of a cut-off level for SKGFR of 5 ml/min instead of 10 ml/min would have resulted in practically identical results (Fig. 1). The discordant or concordant character of both SKGFR and split function was not related to the clinical diagnosis. 4.Discussion It is not surprising that, from a large data base, we ended up with only a limited number of patients, since a significant change in split function is an infrequent phenomenon. Split function, calculated on the early

A. Piepsz et al. / European Urology 47 (2005) 686 690 689 Fig. 1. Comparison between split function change and SKGFR change on the side showing at least 5% decrease of split function between the two renograms. On y-axis, the difference between initial and last SKGFR (SKGFR1 SKGFR 2). On x-axis, the difference between initial and last split function (split1 split 2). The rhombus and the square indicate respectively the patients less and more than 2 years of age. Ten % cut-off levels for SKGFR change are indicated. images of a Tc-99m MAG3 renogram, is nowadays a robust and well-standardized technique [1,2]. The choice of a cut-off level of 5% was based on previous work in the department [3], a change of less than 5% representing the fluctuations related to the methodology rather than a real change of relative function. However, no agreement exists in the literature, as far as the cut-off level is concerned, some authors using the 5% cut-off level [6,7], some others a 10% variation [8 11]. GFR determination based on the injection of a glomerular tracer such as Tc-99m DTPA or Cr-51 EDTA, associated with measurement of residual activity in plasma samples, has been shown to be accurate, closely correlated with inulin clearance and reproducible. Simplified methods using two or even one blood samples have almost the same accuracy and reproducibility than the determination of the entire plasma disappearance curve by means of multiple blood samples [12]. Simple algorithms are available in both adults and children and are well accepted in international consensus [13] and guidelines [14]. The method used in the present work is based on a single blood sample at 2 h and allows accurate estimation of overall GFR in children [4], as long as the clearance is higher than 30 ml/min/1.73 m 2, which was the case in the present series of patients. In order to estimate the absolute function of each kidney, the overall Cr-51 EDTA GFR was combined with the split function determined on the renogram. One could argue about the use of a tubular tracer such as Tc-99m MAG3 to estimate split glomerular function. There are indeed some theoretical considerations suggesting that a change in filtration fraction observed in some diseases may result in a split function different for a tubular tracer such as MAG3 or for a glomerular tracer such as DTPA. There is however no hard evidence in the literature showing clearly discrepancy in split function, except in acute total obstruction. On the contrary it has been shown, using simultaneously both tracers, that DTPA and MAG3 split functions are almost identical in a large group of adult patients with various uro-nephrological diseases and a wide range of split function [15]. In young children with immature renal function, the estimation of split function using DTPA is inaccurate, because of the unfavorable signal to noise ratio, while the extraction rate of MAG3 is significantly higher, explaining why the preference is given to this latter tracer. Thus, unless new data in the future contradict the present option, the combined use of MAG3 split function and overall Cr-EDTA clearance is presently in our opinion the most accurate and simple way to get the absolute function of each kidney. In the literature, a decrease of split function is often considered as reflecting the deterioration of the function of that kidney. In the present study, the pathologies involved (reflux, megaureter, PUJ stenosis, duplex kidney) could all be associated with a deterioration of unilateral function. It is clear however that a decrease of split function may occur without concomitant deterioration of the absolute function of that kidney. Asymmetrical maturation of function during the first two years of life, as well as the development of functional compensation on the contralateral side may result in a significant decrease of split function, while unilateral renal function remains unchanged or even improves. As an example, the International Reflux Study in Children (IRSC) have used the technetium Tc-99m dimercaptosuccinic acid (DMSA) images as well as the split DMSA function to evaluate deterioration of the refluxing kidney. It became however clear that a drop of split function could be associated with an absence of change on the DMSA image. The change of split function was in these cases obviously related to some compensation developing on the contralateral side [16]. In the present study, the decrease of split function was not necessarily associated with a similar decrease of SKGFR. Above two years of age, SKGFR increased or remained stable in two third of the cases, while in those less than 2 years of age, no decrease of SKGFR was observed, as could be expected on the basis of the maturation of overall GFR in this young age group. Some authors will argue that it is unimportant to know whether the function of the affected kidney is decreasing or whether it is the contralateral kidney

690 A. Piepsz et al. / European Urology 47 (2005) 686 690 which develops functional compensation, since both phenomena may reflect a pathological behavior of the diseased kidney. It is however clear that SKGFR may improve considerably the information provided by split function. This is particularly true in case of bilateral disease. References [1] Prigent A, Cosgriff P, Gates GF, Granerus G, Fine EJ, Itoh K, et al. Consensus report on quality control of quantitative measurement of renal function obtained from the renogram: international consensus committee from the scientific committee of Radionuclides in Nephrology. Semin Nucl Med 1999;29:146. [2] Gordon I, Colarinha P, Fettich J, Fischer S, Frökier J, Hahn K, et al. Guidelines for standard and diuretic renography in children. Eur J Nucl Med 2001;28:BP21. [3] Piepsz A, Tondeur M, Ham H. Relative 99mTc-MAG 3 renal uptake: reproducibility and accuracy. J Nucl Med 1999;40:972. [4] Ham H, Piepsz A. Estimation of glomerular filtration rate in infants and children. J Nucl Med 1991;32:1294. [5] Piepsz A, Ham HR. How good is the slope of the second exponential for estimating 51Cr-EDTA renal clearance? Nucl Med Commun 1997;18:139. [6] Houben CH, Wischermann A, Borner G, Slany E. Outcome analysis of pyeloplasty in infants. Pediatr Surg Int 2000;16:189. [7] Chertin B, Fridmans A, Knizhnik M, Hadas-Halperin I, Hain D, Farkas A. Does early detection of ureteropelvic junction obstruction improve surgical outcome in terms of renal function? J Urol 1999; 162:1037. [8] Dhillon HK. Prenatally diagnosed hydronephrosis: the Great Ormond Street experience. Br J Urol 1998;81(Suppl. 2):39. [9] Capolicchio G, Leonard MP, Wong C, Jednak R, Brzezinski A, Salle JL. Prenatal diagnosis of hydronephrosis: impact on renal function and its recovery after pyeloplasty. J Urol 1999;162:1029. [10] Palmer LS, Maizels M, Cartwright PC, Fernbach SK, Conway JJ. Surgery versus observation for managing obstructive grade 3 to 4 unilateral hydronephrosis: a report from the Society for Fetal Urology. J Urol 1998;159:222. [11] Koff SA, Campbell KD. The nonoperative management of unilateral neonatal hydronephrosis: natural history of poorly functioning kidneys. J Urol 1994;152:593. [12] Piciotto G, Cacace G, Cesana P, et al. Estimation of chromium-51 ethylene diamine tetra-acetic acid plasma clearance: a comparative assessment of simplified techniques. Eur J Nucl Med 1992;19:30 5. [13] Blaufox MD, Aurell M, Bubeck B, Fommei E, Piepsz A, Russell C, et al. Report of the Radionuclides in Nephrourology Committee on renal clearance. J Nucl Med 1996;37:1883 90. [14] Piepsz A, Colarinha P, Gordon I, Hahn K, Olivier P, Sixt R, et al. Guidelines for glomerular filtration rate determination in children. Eur J Nucl Med 2001;28:BP31 6. [15] Granerus G, Moonen M, Ekberg S. A comparison between Tc-99m MAG3 and Tc-99m DTPA with special reference to the measurement of relative and absolute renal function. In: Schmidt HAE, van der Schoot JB, editors. Nuclear medicine: the state of the art of nuclear medicine in Europe. Stuttgart: Schattauer; 1991. p. 284 6. [16] Piepsz A, Tamminen-Mobius T, Reiners C, Heikkila J, Kivisaari A, Nilsson NJ, et al. Five-year study of medical or surgical treatment in children with severe vesico-ureteral reflux dimercaptosuccinic acid findings. International Reflux Study Group in Europe. Eur J Pediatr 1998;157:753.