Cessation of Vesicoureteral Reflux For 5 Years in Infants and Children Allocated to Medical Treatment

Cessation of Vesicoureteral Reflux For 5 Years in Infants and Children Allocated to Medical Treatment

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0022-534 7/92/1485-1662$03.00/0 Vol. 148, 1662-1666, November 1992

THE JOURNAL OF UROLOGY

Printed in U.S.A.

Copyright© 1992 by AMERICAN UROLOGICAL ASSOCIATION, INC.

CESSATION OF VESICOURETERAL REFLUX FOR 5 YEARS IN INFANTS AND CHILDREN ALLOCATED TO MEDICAL TREATMENT T. TAMMINEN-MOBIUS, E. BRUNIER, K. D. EBEL, R. LEBOWITZ, H. OLBING, U. SEPPANEN AND R. SIXT ON BEHALF OF THE INTERNATIONAL REFLUX STUDY IN CHILDREN

ABSTRACT

A total of 401 children with severe vesicoureteral reflux (97 with grade III and 304 with grade IV) was entered into the European branch of the International Reflux Study in Children. Of these patients 37 with grade III and 43 with grade IY reflux '\'\'ere aJ!9cated to medical treatment as a sideline group because the reflux grade III or IV had improved to grade II or I, or it had disappeared during the preceeding 2 to 6 months (median 4). Of the remaining 321 patients with persistent grade III or IV reflux 158 were randomly allocated to medical treatment of whom 3 switched to surgery. We report on 235 children treated medically (155 random medical and 80 sideline), of whom 88% had a complete 5-year followup with x-ray and/or isotope voiding cystourethrography at 6, 18, 30 and 54 months. Seven children dropped out of the study after a followup of 6 months or less, including 6 with persistent vesicoureteral reflux. Cessation of vesicoureteral reflux was observed significantly more often in children with unilateral (40 of 74, 54%) than with bilateral (18 of 154, 12%) reflux (p <0.001). No significant difference between grades III and IV was noted. Vesicoureteral reflux ceased in 25 of 153 children (16%) from the random medical group and in 32 of 75 children (43%) in the sideline group. Of 194 children with vesicoureteral reflux detected for the first time at entry reflux resolved in 55 (28%). In only 2 of 34 children (6%) in whom vesicoureteral reflux was detected more than 1 year before entry did reflux resolve after 5 years. Among the children in whom vesicoureteral reflux either disappeared, diminished or remained unchanged the proportion with urinary tract infection recurrences was almost the same. Medical management of vesicoureteral reflux is based on the natural tendency of reflux to improve or cease with time. Earlier observations at the start of the International Reflux Study in Children (IRSC) showed that vesicoureteral reflux disappeared in more than 80% of the ureters that were undilated but that cessation of reflux was only about 40% when the ureters were dilated. 1 The Birmingham Reflux Study has reported their 5year followup results, showing 50% cessation of severe vesicoureteral reflux in medically managed children, based on 1 negative followup cystogram. 2 The study protocol of the IRSC included a second x-ray voiding cystourethrogram taken 2 to 6 months after the run-in period to confirm grade III or IV vesicoureteral reflux in children who were then to be randomly allocated to medical or surgical treatment. It was not envisaged that in many children with dilated ureters reflux would cease within this short period. However, reflux resolved in 5% of the cases and in another 15% the reflux grade decreased so that ureteral dilatation was no longer present after 2 to 6 months. All recruited children, including those in whom vesicoureteral reflux disappeared or Participating hospitals and principal investigators: University Children's Hospital, Bonn, Germany: Rudolf Mallmann. University Children's Hospital, Universite Libre de Bruxelles, Belgium: Michelle Hall. University Children's Hospital, Essen, Germany (Coordinating Center): Hermann Olbing (Chairman), Tytti Tamminen-Mobius (Coordinator) and Wolfgang Rascher. University Children's Hospital, Gothenburg, Sweden: Kelm Hjiilmas and Ulf Jodal. Department of Urology, University of Hamburg, Germany: Rainer Busch. University Children's Hospital, Helsinki, Finland: Olli Koskimies. University Children's Hospital, Oulu, Finland: Juhani Seppanen. Karolinska Institutet, St. Goran's and Sachska Children's Hospitals, Stockholm, Sweden: Anita Aperia. Data processing and statistical analysis: Institute for Medical Data Processing and Biomathemathics, University Essen, Germany: Hildegard Lax-GroE. and Herbert Hirche. Scientific advisors: Klaus-Dieter Ebel (pediatric radiology), Jan van Gool (pediatric urodynamics), Kalle V. Parkkulainen (pediatric surgery), Jean M. Smellie (pediatrics) and Jan Winberg (pediatrics). Supported by the VW-Foundation (Grants AZ 35 807, AZ 1/37 504) until 1985 and thereafter by the Bundesministerium fur Forschung und Technologie (Grant 07068343).

ceased to produce ureteral dilatation and who were relegated to a separate sideline study, were then followed for 5 years with yearly voiding cystourethrography mainly performed with quantitative isotope as long as reflux persisted. The persistence of vesicoureteral reflux was confirmed by an x-ray voiding cystourethrogram at the end of the 5-year followup. We report the results of the management of vesicoureteral reflux in all 235 medically treated children in 2 separate groups: random medical (155 cases) and sideline (80 cases). PATIENTS AND METHODS

Between 1980 and 1985, 401 children less than 11 years old were recruited for a therapeutic trial of medical compared with surgical treatment of grades III and IV vesicoureteral reflux. All subjects had a history of urinary tract infection. The clinical and radiographic characteristics are described elsewhere. 3 Of the children 163 randomly allocated to surgery and 3 who refused conservative therapy at allocation are not reported, leaving a total of 235 medically treated children analyzed. Of 155 patients treated medically according to random allocation (31 with grade III, 124 with grade IV vesicoureteral reflux) 90% completed the followup with a mean of 5.0 voiding cystourethrograms per patient. Additionally, a sideline group of 80 children was treated medically (37 with grade III and 43 with grade IV vesicoureteral reflux). They were separated from the random study because of disappearance or improvement in the grade of reflux to less than grade III during the 2 to 6-month run-in period. The number of followup voiding cystourethrograms in the sideline group was less than that in the medical random group (a mean of 3.4 voiding cystourethrograms per patient). Of the sideline patients 86% completed followup, that is voiding cystourethrography was performed after 5 years or 2 successive negative voiding cystourethrograms were obtained during the 5-year period. Thus, the number of children removed or lost during followup was small in both groups. There was no

1662

r CESSATION OF VESICOURETERAL REFLUX WITH MEDICAL TREATMENT

difference in the number of dropouts of children with unilateral or bilateral vesicoureteral reflux (table 1). Voiding cystourethrography followup. At entry to the study after a run-in period of 2 to 6 months an x-ray voiding cystourethrogram was repeated, using a standardized method. 4 The interval between the 2 investigations varied in the random medical group from 1 to 23 months (median 3.8 months) and in the sideline group from 1 to 15 months (median 3.8 months). Both entry voiding cystourethrograms were graded according to the international classification 4 by a panel of 3 radiologists. The cases were recorded according to maximum reflux grade at the 2 entry x-ray voiding cystourethrograms or according to the first entry x-ray voiding cystourethrogram, if the second study was performed only with isotopes (17 children). In children with bilateral vesicoureteral reflux the grading was based on the more severe side. The isotope voiding cystourethrogram was performed similarly to the x-ray voiding cystourethrogram with direct slow filling of bladder by gravity with 99"'technetium-pertechnetate labeled saline, using an infant feeding tube for the urethral catheter and a bottle height of 70 cm. The isotope voiding cystourethrogram facilitates measurement of the urine volume refluxing into the upper urinary tract and can be roughly equated with the grade of vesicoureteral reflux detected by xray voiding cystourethrography as follows: a volume less than 2 ml. compares with x-ray grade I or II, 2 to 5 ml. with grade II, 6 to 10 ml. with grade III and greater than 10 ml. with grade IV. All 235 children underwent 1 x-ray voiding cystourethrogram and 218 (93%) underwent 2 studies at entry. Both voiding cystourethrography methods were performed together in 98 of 235 children (42%) at entry. At the end of the followup 46 of 235 children (20%) underwent x-ray voiding cystourethrogram only, 25 (11%) underwent isotope voiding cystourethrogram only and in 164 (70%) both methods were used. The annual studies at 18, 30 and 42 months were performed using isotope voiding cystourethrogram only. Vesicoureteral reflux was considered diminished when a reduction of at least 1 grade was observed on x-ray and/or isotope voiding cystourethrogram, worse when reflux increased by 1 grade on x-ray voiding cystourethrogram and present when demonstrated by either of the 2 methods. In case of disparity between x-ray and isotope voiding cystourethrograms vesicoureteral reflux was considered diminished or unchanged according to the study showing the more severe grade. Cessation of reflux was considered when it was no longer demonstrable on 2 successive investigations (x-ray or isotope voiding cystourethrogram), with an interval of at least 6 months between them and a voiding phase in at least 1 of them. Additionally, in 3 random medical and 12 sideline children vesicoureteral reflux was recorded as ceased, even when confirmation of disappearance with additional voiding cystourethrography was still missing at the end of the 5-year period (8 patients) or the patient was lost to followup before 5 years (7 patients). 1. Followup of medically treated children (155 medical random plus 80 sideline) with x-ray and/or isotope voiding cystourethrogram

TABLE

Vesicoureteral Reflux at Entry Time ofFollowup Voiding Cystourethrogram Entry 6 mos.*

18 mos. 30 mos. 42 mos. 54 mos. % complete followup

Bilat.

Unilat.

III

IV

III

IV

41 22 39 (1) 36 (1) 33 (1) 32 85

119 95 115 112 (2) 109 (2) 104 91

27 8 26 24 (1) 22 (1) 21 85

48 28 48 45 (3) 41 37 83

Totals 235 153 228 (1) 218 (7) 205 (4) 194 88

Number in parentheses indicates no further voiding cystourethrogram mandatory because of 2 adequate negative studies. * Only medical random group had voiding cystourethrogram after 6 months of followup.

1663

Voiding cystourethrography quality. The quality of at least 1 of the 2 x-ray voiding cystourethrograms at study entry was good in 93 % of the patients (defined as complete bladder filling with voiding) and after 5 years it was good in 88%. Of the 235 children 2 had a poor x-ray voiding cystourethrogram (poor bladder filling and no documented voiding) at entry as did 7 of the 194 at 5-year followup. In 6% of the children at entry and in 12% after 5 years the bladder was completely filled during voiding cystourethrography but the voiding phase had not been adequately documented, that is no films were available showing the upper tract and urethra during voiding. Voiding was recorded in only 461 of 978 isotope voiding cystourethrograms (47%) performed and there were obvious differences between centers; the best center achieved a satisfactory examination in 177 of 245 (72%) and the worst in only 65 of 243 (27% ). The results of the isotope method in comparison with x-ray voiding cystourethrogram will be reported in detail elsewhere. Statistical methods. Comparison of frequencies and test of homogeneity of contingency tables on rank ordered scales were done by simple chi-square tests according to Brand/Snedecor or the chi-square trend test of Cochran. Life table analysis according to Kaplan and Meier, and generalized rank test of Gehan-Wilcoxon were performed to compare both groups in the primary outcome of exponential distributed events of vesicoureteral reflux cessation. Covariables were tested for interactions with a logistic linear regression model. 5 RESULTS

Vesicoureteral reflux between first and second entry voiding cystourethrography. By definition grades III and IV vesicoureteral reflux persisted in the random medical group between the 2 entry voiding cystourethrograms. In the sideline group vesicoureteral reflux was no longer demonstrable on the second voiding cystourethrography in 6 of the 41 children (15%) with bilateral and in 16 of the 39 children (40%) with unilateral reflux. Cessation of vesicoureteral reflux was permanent in 3 of 37 with bilateral and in 12 of 38 sideline children with unilateral involvement. Vesicoureteral reflux during the 5-year followup period. Life table analysis of the persistence of vesicoureteral reflux was performed separately in the random medical and the sideline groups (fig. 1). In the random group 75 of the 82 patients (91%) with bilateral grade III or IV reflux at entry still had reflux after 5 years. In those with bilateral vesicoureteral reflux but grade III or IV on only 1 side reflux persisted after 5 years in 31 of 35 cases (89% ). The persistence of unilateral grade III or IV reflux was observed in 22 of 36 randomly allocated patients (61 %). In the sideline group vesicoureteral reflux persisted in 30 of 37 children (81 %) with bilateral and 13 of 38 (31 %) with unilateral reflux at entry. The cessation rate of bilateral and unilateral vesicoureteral reflux in the sideline group was similar to the random medical group after the second voiding cystourethrography. In both groups bilateral vesicoureteral reflux persisted significantly more often (p <0.001) than unilateral reflux (table 2). Unilateral cessation ofreflux in children with bilateral vesicoureteral reflux was seen in 30 of 117 (26%) randomly allocated and 12 of 37 (32%) sideline patients. Vesicoureteral reflux grade at entry and cessation of reflux. The maximal grade of vesicoureteral reflux had no influence on the cessation of bilateral or unilateral reflux in either group (fig. 2). Reflux ceased in 16% of the children with grade IV and in 17% of those with grade III in the random medical group. In the sideline group 38% of the children with grade IV and 48% of those with grade III were free of vesicoureteral reflux after 5 years. The significant difference (p <0.01) between the groups is related to the higher proportion of patients with unilateral vesicoureteral reflux in the sideline group, especially those with unilateral grade III, than the random medical group. Age and sex associations with cessation of uesicoureteral reflux.

1664

TAMMINEN-MOBIUS AND ASSOCIATES

Random Medical 100

100

. .:;~-.:-.'c::-~·--=~c::"·~~-•· :a -.::::

80

c

Sideline

• • --·-•---·---·Wm.u:a.:.:~.:"--- ..,-

..

••

80

..

..·_·_··_·_··_·_·_··_·_··_·_··_·_··_·_··-·-··;;,;•;.:.·:.i·•1a---~ ,,

60

j -

c.,

60

if

40

~

40

20

20

0

0 0

10

5

15

--Bid

--·-· e In -Uni

111 111 111

20

25

30 __ 35_ Months

( n•l 2) ( n• 11) (n• 8)

40

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••••. BI d - - - Bin

4li_ 50

IV IV IV

••••• Un I

55

0

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--Bid ·-·-·BI n --Uni

( n•71) (n•25) (n•28)

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(n• 9) (n• 9) ( n• 1 9)

30 - 35 Months

40

••••. BI d - - - Bin ••••• Un I

IV IV IV

45

50

55

60

( n•1 O) ( n•13) (n•20)

FIG. 1. Life table analysis of vesicoureteral reflux persistence in medically treated children during 5 years. 0, time of entry voiding cystourethrography. Followup is given in months, with scheduled followup times of 3, 9, 21, 33, 45 and 57 months in random medical group (155 cases). In sideline group (80 cases) 9-month followup was not scheduled and others were same as in random medical group. Bid, bilateral reflux, both sides dilating, grade III/IV. Bin, bilateral reflux, 1 side dilating, grade III/IV. Uni, unilateral reflux, grade III/IV.

State of vesicoureteral reflux after 5-year followup of 153 random medical and 75 sideline children with grade III or IV reflux at entry

TABLE 2.

Vesicoureteral Reflux Status at Entry Sideline Group

Medical Random Group

Reflux After 5-Yr. Followup

Bilat. (both sides dilating grades III/IV)

Bilat. (1 side dilating grades III/IV)

Unilat. (grade III/IV)

7 30 45 1

4 10 21 1

14 10 12 0

25 50 78 2

83

36

36

155

Disappeared Diminished Unchanged No followup or followup 6 mos. or less Totals

Totals

Initial VUR Grade

Bilat. (both sides dilating grades III/IV)

30

3 2

3 8 9 2

25 9 4 1

32 27 16 5

19

22

39

80

Age at cessation of reflux in boys and girls Age at Cessation of Reflux

Less Than 2 Yrs. Boys Girls

40

Totals

4

TABLE 3.

so

Unilat. (grade III/IV)

10

m

IV No. of Children w m 70 ~ - - - - - - - - - - - , - - - - - - - - - - - - - - , Sideline Random Medical 60

Bilat. (1 side dilating grades III/IV)

6 2

2-4 Yrs. 2 11 (3*)

More Than 5 yrs. 4

32 (1*)

Total No. Cessated/Total (%)

12/50 (24) 45/178 (25)

* Reflux recurred.

20 10 0 30

disappeared diminished unchanged

D

123

35

40

5

20

17

15

12

38

12

15

13

65

6

10

disappeared

ffl

diminished

m

unchanged

FIG. 2. Change of reflux ( VUR) grade in medically treated children for 5 years. Worst side recorded. Random medical group consists of 153 patients (2 excluded because of 6-month or less followup). Sideline group includes 75 patients (5 excluded because of 6-month or less followup).

There was no overall difference between boys and girls in the proportions of patients with cessation of vesicoureteral reflux (table 3). However, in 30 boys the first entry x-ray voiding cystourethrogram was performed when they were less than 1 year old and 6 showed cessation of vesicoureteral reflux by the age of 1 year, 2 by the age of 2 years and 1 by the age of 5 years. Vesicoureteral reflux persisted for 5 years in the remaining 21 boys (70%). In 26 girls the first x-ray voiding cystourethrogram

was done when they were less than age 1 year. Permanent cessation of vesicoureteral reflux was observed in only 2 girls by age 1 year, in 4 by age 2 years and in 1 by age 5 years. Reflux persisted in the remaining 19 girls (73%). The median age at entry to the study was higher in girls than in boys (4.0 years, 1.3 years) and reflux ceased after a somewhat longer period in girls (mean 2.3 ± 1.7 years) than in boys (mean 1.7 ± 1.6 years). The age at entry showed no significant correlation with the cessation of vesicoureteral reflux during 5 years of followup. Vesicoureteral reflux disappeared sporadically at different times; in the sideline group reflux ceased at all ages at entry but in the random medical group no cessation was observed in children who entered the study at ages 2, 6 and 7 years (fig. 3). Vesicoureteral reflux history and cessation of reflux. Children who were recruited to the trial when grade III or IV vesicoureteral reflux was detected for the first time differed significantly from those in whom grade III or IV reflux was known to have been present for more than 1 year at recruitment. Of the children 33 of 155 (21 %) in the medical random group but only 2 of 80 (2.5%) in the sideline group were recruited with reflux history (p <0.01). Of the 200 patients without reflux history 55 (28%) and of the 35 patients with reflux history 2 (6%) were

1665

CESSATION OF VESICOURETERAL REFLUX WITH MEDICAL TREATMENT 30

Sideline

Random Medical

.,

25

C

L.

:2

::c u

....0 0

Z

-

20 15 10

5

o

1 2 3

4

5

6

7

s .,g

o

1 2 3 4 5

D persisting VUR

fil!l disapp. > 3. Year





disapp. 2.-3. Year

6 7

s .,g Age

disapp. 1. Year

FIG. 3. Age at entry and cessation of reflux (VUR) in medically treated children for 5 years. Same number of patients and exclusions in each group as in figure 2.

free of reflux after 5 years (p <0.01). The clinical characteristics of the patients without (age, sex, renal scar, urinary tract infection history) were not significantly different from those with reflux history. However, the proportion of unilateral vesicoureteral reflux was significantly higher in the group without (p <0.01) than in the group with reflux history. Reappearance of vesicoureteral reflux after confirmed cessation. Vesicoureteral reflux, defined as having ceased after 2 adequate negative voiding cystourethrograms (including a voiding phase), recurred in 4 children (after a symptomatic urinary tract infection in 2). The grade of vesicoureteral reflux at reappearance was lower than initially in 3 children in the random group and in the remaining child in the sideline group recurrent reflux was the same grade as initially. Reappearance of vesicoureteral reflux was also seen on 1 side in 9 additional children who still had reflux on the other side, including 1 case associated with a urinary tract infection. Recurrences of urinary tract infection. The frequency of different types of urinary tract infection recurrences during 5 years is shown in table 4. Urinary tract infection recurred during the 5-year followup in 36% of children with persistent unchanged vesicoureteral reflux, 38% of those with diminished reflux and 33% in whom reflux ceased. Thus, recurrent urinary tract infection did not affect the change of vesicoureteral reflux. The frequency of pyelonephritis was not significantly higher in children with persistent than in those with disappearance of reflux. However, after cessation of vesicoureteral reflux pyelonephritis was observed in only 4 of the 25 children in the random medical and 1 of the 32 in the sideline group. In children with cessation of vesicoureteral reflux the incidence of urinary tract infection recurrence per patient per followup year was 0.28 in the random medical group and 0.22 in the sideline group. In the children with persistent vesicoureteral reflux the respective incidences were 0.17 in the random medical group and 0.20 in the sideline group. Thus, there was no significant difference in the frequency of urinary tract infection recurrences in children with or without vesicoureteral reflux cessation during the 5-year followup. Change in vesicoureteral reflux grades. Changes of vesicoureTABLE 4.

teral reflux grade in patients of the random medical and the sideline groups are shown in figure 2. In the sideline group the proportion of children (36%) with diminished vesicoureteral reflux grade after the 5-year followup period was not higher than in the random medical group (32%), and there was no difference between grades III and IV. Overall in 77 children vesicoureteral reflux diminished based on isotope voiding cystourethrogram in 12 patients (16%) and on x-ray voiding cystourethrogram in 65; in 5 an x-ray voiding cystourethrogram showed no reflux and in 7 only an isotope voiding cystourethrogram had been performed. In the random medical group unchanged reflux was seen in half of the children with either grade III or IV reflux. In the sideline group vesicoureteral reflux was unchanged after 5 years in 17% of the children with grade III and 24 % with grade IV reflux, indicating that grade III or IV reflux recurred in these children. The difference between the random medical and sideline groups is significant (p <0.05) but no difference was observed between grades III and IV reflux. Overall in 94 children vesicoureteral reflux remained unchanged based on an isotope voiding cystourethrogram in 13 patients (14%) and on voiding cystourethrography in 81; in 7 the x-ray voiding cystourethrogram showed diminished grades and in 6 only an isotope voiding cystourethrogram had been performed. Bilateral worsening of vesicoureteral reflux was observed in 2 children of the random group and unilateral worsening in 3 (2 in the random group and 1 in the sideline group, all with xray voiding cystourethrogram). X-ray and isotope voiding cystourethrograms showed the same grade in 46% of 164 children after followup. X-ray voiding cystourethrogram grade was higher in 37% of the children and isotope voiding cystourethrogram grade was higher in 17% (maximum vesicoureteral reflux grade per child was recorded).

REMARKS

For this analysis the 21 cases of intermittent vesicoureteral reflux during followup, in which reflux was absent at times but still present on the last voiding cystourethrography with a lower grade than at entry, were recorded as diminished reflux. On the other hand, 34 children with variable vesicoureteral reflux, who still had grade III or IV reflux after 5 years, were regarded as unchanged. A more detailed analysis of all children with either intermittent or variable vesicoureteral reflux will be performed later. These patterns were often seen in children with persistent bladder dysfunction, which was discovered in 18% of the study children. The association between bladder dysfunction and cessation of vesicoureteral reflux is described in detail by van Gool et al. 6 Cystoscopy was performed in 53% of the medically treated children, and the results of its predictive value for vesicoureteral reflux persistence will be published separately. The relationship between vesicoureteral reflux grade and persistence with renal scarring and parenchymal thinning also will be published later.

Children with recurrent urinary tract infection during 5-year followup and change of reflux in 153 random medical and 75 sideline children Urinary Tract Infection Type

Vesicoureteral Reflux During 5 Yrs.

Disappeared Diminished Unchanged Missing Totals

Pyelonephritis (infection with high fever) 13 14 21 1

49

Asymptomatic Bacteriuria

No. Without Urinary Tract Infection

11

2 4

38 48

3 1

10 0

60

19

16

Symptomatic (not fulfilling criteria of acute pyelonephritis) 4

5 151

Total No. Children

57 77 94 7 235

1666

TAMMINEN-MOBIUS AND ASSOCIATES CONCLUSIONS

Of the 401 children recruited for the IRSC with grades III and IV reflux 235 were treated medically; 155 by random allocation and 80 because of the disappearance of reflux or its reduction below grade III. The latter patients in whom rapid improvement or disappearance was observed within the 2 to 6month run-in period were placed in a separate sideline group. Overall 19 of the 36 children (53 %) with unilateral grade III reflux, 20 of the 78 (26%) with unilateral grade IV, 18 of the 61 (30%) with bilateral grade III and 23 of the 226 (10%) with bilateral grade IV were placed in the sideline group (total refers to all 401 recruited children). The persistence of reflux, either unilateral or bilateral, after the 5-year followup was significantly lower (p <0.01) in the sideline group (57%) th~n_in the random medical group (84%). In the random medical group cessation of reflux was observed in only 9% of the children with bilateral and in 39% of those with unilateral reflux. The respective figures for the sideline group were 19% of children with bilateral and 66% of those with unilateral vesicoureteral reflux. The great majority of the children in the sideline group had absent (43%) or low grade vesicoureteral reflux (36%) even after the 5-year followup. Therefore, it is important to recognize such children before further therapeutic steps (cystoscopy or surgery) are contemplated. The initial vesicoureteral reflux grade had no significant in~uence o~ the disappearance rate of reflux in the 2 groups. Children with unchanged reflux associated with ureteral dilatation on 2 voiding cystourethrograms with an interval of more than 1 year at recruitment to the study had significantly lower cure rates than those who were recruited with the initial voiding cystourethrography (p <0.01). The higher rate of vesicoureteral reflux cessation in the latter patients can be partly explained by the larger proportion of children with unilateral reflux. Reflux ceased in 6 of the 30 boys but in only 2 of 26 girls less than age 2 years. The same incidence was observed in older age groups. The girls were older than the boys when they entered the study and the observed duration of vesicoureteral reflux was longer in girls than in boys. Age at entry did not significantly affect the cessation of reflux.

The numbers of children with urinary tract infection recurrence during the 5-year followup was about 35%, irrespective of the change of reflux grade or cessation. The incidence of urinary tract infection recurrences per patient followup year was not significantly different between the random medical and the sideline groups. Urinary tract infection recurrence was associated with vesicoureteral reflux recurrence in only 3 of the 13 children. Thus, the influence of urinary tract infection on vesicoureteral reflux seems to be insignificant. Favorable prognostic factors for the disappearance of severe vesicoureteral reflux during 5 years were unilateral involvement and initial detection of reflux at referral. Persistent grade III or IV reflux bilaterally on 2 successive voiding cystourethrograms (1-year interval) suggests poor prognosis of cessation. Each study patient had severe vesicoureteral reflux (grades III and IV-) at least on 1 side, Therefore, grade II or I reflux_was observed only in children with bilateral reflux, which was low grade on the other side. Consequently, no general conclusion can be drawn about cessation of grades II and I reflux. REFERENCES 1. Smellie, J. M., Edwards, D., Hunter, N., Normand, I. C. S. and

2. 3.

4. 5. 6.

Prescod, N.: Vesicoureteric reflux and renal scarring. Kidney Int., suppl. 8: S65, 1975. Birmingham Reflux Study Group: Prospective trial of operative versus non-operative treatment of severe vesicoureteric reflux in c~ildren: five years' observation. Brit. Med. J., 295: 237, 1987. Weiss, ~-, Tammi;1en-Mobius, T., Koskimies, 0., Olbing, H., Smelhe, J. M., Hirche, H. and Lax-Gross, H.: Characteristics at entry of children with severe primary vesicoureteral reflux recruited for a multicenter, international therapeutic trial comparing medical and surgical management. J. Urol., part 2 148: 1644, 1992. ' International Reflux Study in Children: International system of radiographic grading of vesicoureteric reflux. Ped. Rad. 15: 105 1985. ' ' SAS Institute Inc. Language Guide, release 6.03 ed. Cary, North Carolina, 1988. van Goo!, J. D., Hjalmas, K., Tamminen-Mobius, T. and Olbing, H._: H1stonca! clue~ to the complex of dysfunctional voiding, urmary tract mfect10n and vesicoureteral reflux. J. Urol., part 2, 148: 1699, 1992.