Split renal function does not change after successful treatment in children with primary vesico-ureteric reflux

Authors


F. Matsumoto, MD, Department of Urology, Osaka Medical Center and Research Institute for Maternal and Child Health, 840 Murodo-cho, Izumi, Osaka, 594-1101, Japan.
e-mail: fumim@mch.pref.osaka.jp

Abstract

OBJECTIVE

To evaluate the renal growth pattern in patients with primary vesico-ureteric reflux (VUR) using long-term measurements of split renal function with 99mTc-dimercaptosuccinic acid (DMSA) scintigraphy.

PATIENTS AND METHODS

In all, 712 children aged < 16 years (466 boys and 246 girls) with primary VUR were referred to our hospital from July 1991 to December 2000. VUR was diagnosed by voiding cysto-urethrography. The patients were treated either surgically (group 1) or conservatively (group 2) and followed with serial 99mTc-DMSA scintigraphy for up to 10 years. There were 942 examinations in 367 of 712 patients who had repeat scintigraphy. Patients with secondary VUR, VUR to a solitary or fused kidney, or upper urinary tract obstruction, were excluded. Five of 298 patients (1.7%) who had ureteric reimplantation had a febrile urinary tract infection (UTI) soon after surgery but none recurred (recurrence is an indication for surgery in children with VUR); there was no febrile UTI in the 69 patients in group 2. Planar scintigraphy with 99mTc-DMSA was used to assess the absolute uptake (AU) of each kidney, measured as a percentage of the injected dose, and the relative uptake (RU = AU of each kidney/AU of both kidneys) calculated. The initial examination was at least 4 weeks after any febrile UTI in most patients. Serial studies were conducted 1 year after surgery and then biannually in group 1. In group 2 the DMSA scan was repeated every 2–3 years. The change in split renal function was compared with the RU of the right kidney.

RESULTS

The RU of the right kidney at the initial scan correlated closely with those on repeated scans in both groups. The correlation coefficients were 0.99 in group 1 and 0.94–0.97 in group 2 at every study. The change of RU remained within 0.05 in all patients after treatment.

CONCLUSIONS

Under strict control of UTI, split renal function in children with primary VUR does not change. There may be no possibility of accelerated or compensatory growth of the kidney with reflux nephropathy, but no concern about deterioration and atrophy either.

Abbreviations
VCUG

voiding cysto-urethrography

AU

absolute uptake

RU

relative uptake.

INTRODUCTION

The most common congenital anomaly of the urinary tract is VUR, present in 29–50% of infants and children investigated for UTI [1,2]. Reflux nephropathy is irreversible and may result in hypertension, proteinuria and chronic renal failure. The detection of reflux nephropathy is important in assessing children with VUR. Although excretory urography (IVU) was historically used to evaluate the presence of reflux nephropathy, recent studies have shown that radionuclide studies using 99mTc-DMSA are more sensitive than the IVU for detecting renal cortical abnormalities [3–5].

99mTc-DMSA scintigraphy is also valuable in determining differential renal function, providing not only morphological information but also measurements of renal function. We used 99mTc-DMSA scintigraphy in children with primary VUR, calculating renal function from both absolute (AU) and relative (RU) radioisotope uptake, with the aim of evaluating the renal growth pattern in patients with primary VUR, by measuring serial changes in split renal function. The patients were treated either conservatively or surgically and followed with serial 99mTc-DMSA scintigraphy for up to 10 years.

PATIENTS AND METHODS

Renal growth was assessed retrospectively in children with primary VUR by analysing sequential DMSA findings. In all, 712 children aged < 16 years (466 boys and 246 girls) with primary VUR were referred to our hospital from July 1991 to December 2000. VUR was diagnosed by voiding cysto-urethrography (VCUG) and graded according to the criteria of the International Reflux Study Committee. The study comprised 367 of the 712 patients who had repeated radionuclide studies to evaluate renal damage (298 of 465 treated surgically, group 1; and 69 of 247 treated conservatively, group 2). Patients with secondary VUR, VUR to a solitary or fused kidney, or upper urinary tract obstruction were excluded. The indications for surgery in group 1 were high-grade reflux (grade 4–5), breakthrough UTIs, no compliance with prophylaxis and the parents’ request. They underwent ureteric reimplantation by Cohen's method, with a mean (range) age at surgery of 39 (1–141) months. Six months after surgery the children underwent VCUG to evaluate the result; all were cured and contralateral reflux developed in nine of 116 patients (7.8%) with unilateral VUR. All contralateral reflux was less than grade 2 and in six children it resolved spontaneously within a year; there was no permanent ureteric dilation. Five of 298 patients (1.7%) had febrile UTIs soon after surgery but none had recurrent UTI.

In group 2, antimicrobial prophylaxis was given to all infants but not to older children. VUR ceased in 28 of 69 patients (41%) in the study period. Recurrence of febrile UTIs is an indication for surgical treatment in children with VUR, so there was no febrile UTI in this group. The patients’ characteristics are shown in Table 1.

Table 1.  The patients’ characteristics
CharacteristicGroup 1Group 2
Maximum VUR grade
1  2  7
2 12 22
3 80 34
4140  5
5 64  1
Bilateral : unilateral182 : 116 39 : 30
Male : female198 : 100 49 : 20
Age at presentation (operation), years
0–1133 (108) 41
1–5 84 (105) 18
> 5 81 (85) 10
Total298 69

Scintigraphy was undertaken 2 h after an injection with 99mTc-DMSA in a dose adjusted for the child's height and weight. High-resolution, magnified images of the kidneys in one posterior, one anterior and two posterior oblique projections were obtained for 5 min using a γ-camera equipped with a pinhole collimator. From the posterior planar data the uptake of the each kidney was measured as a percentage of the injected dose (AU) and the RU calculated as (AU of each kidney/AU of both kidneys).

The initial examination was after the diagnosis of VUR and at least 4 weeks after any febrile UTI in most patients. The serial studies were obtained 1 year after surgery and then biannually in group 1; in group 2 the DMSA scan was repeated every 2–3 years. The change in split renal function was evaluated based on that of the right kidney, using the RU.

RESULTS

In group 1, 768 DMSA scan were taken in the 298 patients; a comparison of the DMSA uptake before and after surgery was available in 246 patients at < 2 years, in 166 at 2–5 years and in 58 at > 5 years. Linear regression analysis showed an excellent correlation (0.99) at every follow-up (Fig. 1a), for a mean (range) follow-up of 39.2 (12–118) months.

Figure 1.

Comparison of DMSA uptake before and after treatment (a, group 1; b, group 2). There was a close correlation at every assessment in both groups (< 2 years, green open circles; 2–5 years, red closed squares; > 5 years, red open squares). The respective fitted equations for each follow-up are: a,y = 0.007 + 0.99x; y = 0.014 + 0.97x; y = 0.004 + 1.0x; and b,y = 0.054 + 0.90x; y = 0.043 + 0.92x; y = 0.008 + 0.98x.

In group 2, 174 scans were available from the 69 patients, with comparisons available in 52 at < 2 years, 38 at 2–5 years and 15 at > 5 years of follow-up, with a mean (range) follow-up of 36.9 (12–95) months. There was a close correlation at each follow-up (coefficient 0.94–0.97; Fig. 1b). Only four patients in group 1 had a change of < 0.05 in RU soon after surgery but all were stable at repeat scans ≥ 2 years after surgery. The change in RU in group 2 was < 0.05 at every follow-up.

DISCUSSION

The correlation of reflux nephropathy, UTI and VUR is well established [6]; reflux nephropathy is irreversible and may lead to renal insufficiency, renin-mediated hypertension, chronic renal failure, decreased somatic growth and morbidity during pregnancy. To avoid further development of renal scarring these patients must be treated under strict control of UTI. However, there is controversy about its effect on individual renal growth after treatment. Until the early 1980s accelerated renal growth after surgical correction of VUR was reported by several authors [7–9]. Conversely, later large series reported that there was no significant difference between surgically and medically treated children with primary VUR [10–12]; these studies all based their findings on IVU.

Although serial measurements of renal length and/or parenchymal thickness by IVU used to be the standard method to evaluate renal growth, it is sometimes difficult to take clear images of the kidneys by excretory urography because of overlying bowel gas and poor urinary concentration in infants. DMSA isotope scintigraphy overcomes these problems and makes it possible to visualize functioning renal parenchyma. Many comparative studies have shown that DMSA scintigraphy is more sensitive than IVU for detecting renal scarring, especially in young children [3–5]. Morphological evaluation has been more popular than quantitative evaluation, using DMSA scanning [5,6]. Within the past two decades many authors have reported morphological changes in the kidney with VUR, using the detection of renal parenchymal loss. In 1999, Choi et al.[13] noted progressive renal scarring in two of 74 children (2.7%) with VUR at a median (range) of 43 (25–120) months after surgery. The rate of renal deterioration in that study using DMSA imaging was lower than in previous reports using IVU. In that study there was no upper urinary tract obstruction after surgery and only two episodes of UTI. However, detecting a small change is sometimes difficult and morphological judgement may be subjective.

DMSA is useful not only for morphological imaging but also for quantitative evaluation. The DMSA uptake in each kidney can be used as an index of individual renal function. Although some authors insist that the AU of DMSA correlates closely with renal function estimated by creatinine clearance [14], AU is affected by factors like the patient's age, kidney depth, positioning, etc.

There might be a potential problem when relying on the RU in cases of bilateral VUR. In the present study we always examined blood chemistry, including serum creatinine, at the same time as the DMSA scan. Although three of 298 patients in group 1 had a relatively high creatinine level, none had end-stage renal failure during the study period. Unilateral cases in group 1 and all patients in group 2 had normal creatinine levels for their age.

Schiepers et al.[15] recently reported the 5-year follow-up of children with VUR, where the RU correlated more closely than the AU before and after surgery, with coefficients of 0.99 and 0.89, respectively. Thus many investigators take RU as the more sensitive variable to evaluate split renal function.

From the European arm of the International Reflux Study in children, Piepsz et al.[16] reported the results of DMSA scintigraphy, defining evidence of renal deterioration on the DMSA scan as image deterioration or a decrease of RU by > 0.06 in both kidneys. Although the incidence of morphological change alone is unclear, there was no difference between medically and surgically treated groups in the rate of renal deterioration (18.5% and 17.5%, respectively). Using same criteria, Webster et al.[17] reported renal deterioration in 10 of 143 children (7%) after surgery. In the present study morphological changes on DMSA scan were not evaluated, but the data show an even lower incidence of renal deterioration after treatment; four of 246 children (1.6%) with ureteric reimplantation had a change of < 0.05 RU soon after surgery. The RU of more severely damaged kidneys decreased in two baby boys; one boy, who had unilateral massive reflux and recurrent UTI just before surgery, had another episode of UTI afterward and VCUG revealed contralateral reflux, which ceased 1 year later. The other boy had bilateral gross reflux and renal insufficiency before surgery. Both boys and two girls, whose RU of the more impaired kidney increased after surgery, showed no further change on repeat DMSA scans. The low incidence of surgical complications and UTIs after surgery in this study might have contributed to the difference in renal deterioration rate from that reported by others.

In conclusion, the present results strongly suggest that split renal function in children with primary VUR will not change if UTIs are strictly controlled. There was no difference in the change in RU between group 1 and 2. Although accelerated or compensatory growth of the affected kidney is not expected, small kidneys grow at a rate parallel to the contralateral kidney.

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