Outcome at 10 years of severe vesicoureteric reflux managed medically: Report of the International Reflux Study in Children.

OBJECTIVE: To study the progress of vesicoureteric reflux (VUR) grade III or IV in children followed up prospectively over 10 years. STUDY DESIGN: One hundred forty-nine children (33 boys and 116 girls) with VUR were recruited for the International Reflux Study in Children and were treated with a medical regimen and monitored by means of serial cystograms. VUR disappearance was based on negative findings on 2 consecutive cystograms. RESULTS: At 5 years, VUR with dilatation was seen in 72 (48%) children and VUR without dilatation, in 55 (37%); 22 (15%) children had no reflux. At 10 years, VUR with dilatation was seen in 34 (23%) children and VUR without dilatation, in 37 (25%); 78 (52%) children had no reflux. Grade IV VUR persisted in 8 children. Absence of VUR was significantly associated with grade III versus grade IV VUR (P = .007), unilateral versus bilateral reflux (P = .0002), and age > or = 5 years at entry versus age < 5 years (P = .001). Neither sex nor renal scarring at entry individually affected resolution of VUR. Among 43 (29%) children with intermittent VUR, only 6 had reflux with dilatation at 10 years. CONCLUSION: Continuing reduction in the severity of VUR in children receiving careful medical treatment was observed over 10 years. On the basis of negative findings on 2 consecutive cystograms, VUR was absent in half of the children.

Medical versus surgical treatment in children with severe bilateral vesicoureteric reflux and bilateral nephropathy: a randomised trial.

BACKGROUND: Nephropathy associated with vesicoureteric reflux (VUR) and urinary tract infection can result in end-stage renal failure, hypertension, or both. Whether long-term VUR contributes to these outcomes is unknown. We compared, in a randomised trial, medical with surgical management of children with bilateral severe VUR and bilateral nephropathy. METHODS: We stratified by age and glomerular filtration rate (GFR) 25 boys and 27 girls aged 1-12 years and randomly assigned them to medical or surgical management. At enrolment and 4 years' follow-up we estimated GFR from the plasma clearance of 51Cr-labelled edetic acid (EDTA), and did intravenous urography. We also did a metastable 99mTc-labelled dimercaptosuccinic acid (DMSA) assay and contrast cystography. The change in GFR at 4 years, expressed as a percentage change between enrolment and 4 years, was available for 26 of 27 patients in the medical and 24 of 25 in the surgical group. We assessed GFR in 48 patients 10 years after enrolment. FINDINGS: Mean GFR at enrolment was 72.4 mL/min per 1.73 m(2) (SD 24.1) in the medical and 71.7 mL/min per 1.73 m(2) (22.6) in the surgical group. The mean percentage change in GFR at 4 years was 2.4% (SE 4.5) versus 4.7% (5.0) in the medical and surgical groups, respectively. The difference in change in GFR at 4 years between the two groups was not significant (7.1%, 95% CI 6.4% to 20.6%). INTERPRETATION: Our data do not lend support to the view that the outcome for renal function is improved by surgical correction of VUR in children with bilateral disease.

Renal growth in children with severe vesicoureteral reflux: 10-year prospective study of medical and surgical treatment: the International Reflux Study in Children (European branch).

PURPOSE: To determine whether medical or surgical treatment better promotes renal growth in children with severe vesicoureteric reflux (VUR) and to examine factors influencing renal growth. MATERIALS AND METHODS: Three hundred two children younger than 11 years with urinary tract infection and grade III or IV VUR were randomly assigned to surgical (n = 149) or medical (n = 153) treatment and were followed up at serial intravenous urography for up to 5 years; 223, for up to 10 years (surgical, n = 110; medical, n = 113). Renal size was measured planimetrically on serial intravenous urograms and was related to the virtual height of L1 through L3 by expressing it as an SD score. RESULTS: There was no significant difference in mean renal growth between patients treated surgically or those treated medically after 5- or 10-year follow-up. Bilateral renal size of 80 surgical and 75 medical patients remained within 1 SD score. In patients entering the study at 2 years of age or younger and in those with grade IV VUR, bilateral VUR, or renal scars, there was a trend toward improved renal growth in those treated medically, but this finding was not statistically significant. When renal scarring or thin parenchyma was unilateral, the affected kidney grew less well, irrespective of treatment. Bilateral renal scarring was usually asymmetrical, with a corresponding effect on renal growth. CONCLUSION: There was no significant difference in renal growth during 10 years between surgical and medical treatment in patients with severe reflux.

Five-year study of medical or surgical treatment in children with severe vesico-ureteral reflux dimercaptosuccinic acid findings. International Reflux Study Group in Europe.

UNLABELLED: The results of serial dimercaptosuccinic acid (DMSA) imaging over 5 years are reported in 287 children with severe vesico-ureteral reflux entered into the European Branch of the International Reflux Study in Children. The children were randomly allocated to medical (n=147) or surgical (n=140) management and DMSA studies were performed during the follow up period at least 6 months after any urinary tract infection. Abnormal images were classified into four types: (1) large polar hypodensity with normal renal outline; (2) peripheral photon deficient defect(s) in a non-deformed kidney; (3) small renal image with normal contour; and (4) peripheral defect(s) with resultant irregularity of the renal outline. The DMSA findings were abnormal at entry in 235 (82%) with no difference in incidence or severity between the two treatment groups. During follow up, deterioration was observed in 25 medically and 23 surgically treated patients and comprised image deterioration alone in 17, image deterioration with corresponding reduction in differential function in 16 and reduction in relative function without image change in 15, with similar distribution between the two treatment groups. Deterioration was more frequent in children entering the study under the age of 2 years and in those with grade IV rather than grade III reflux. These findings, showing no difference in outcome between children managed surgically or medically, are consistent with the radiological results already published. CONCLUSION: In the International Reflux Study the DMSA scintigraphic data showed no difference in outcome between children managed surgically or medically.

Childhood reflux and urinary infection: a follow-up of 10-41 years in 226 adults.

To ascertain the outcome of childhood vesicoureteric reflux (VUR), 226 adults (37 males), mean age 27 years, were studied after 10-35 years, extended to 41 years by postal questionnaire in 161. At presentation (mean age 5 years) all had VUR (grade III-V in 68) and urinary tract infection (UTI); there was renal scarring in 85 (acquired before referral in 11 and during follow-up in 1), hypertension in 6 and impaired renal function in 5. They were managed and followed prospectively by one paediatrician; 63% of these children remained free from UTI; VUR persisted in 63 and had resolved in 69% of 193 children managed medically. At follow-up, 61% of adults had remained free from infection; 17 adults had hypertension and/or raised plasma creatinine, 16 with scarred kidneys. Their deterioration was predictable because of scar type, blood pressure or plasma creatinine levels in childhood. No new scars developed after puberty. Renal growth rates were unaffected by initial severity or persistence of VUR. On the later questionnaire, 9 further adults, mean age 38 years, had moderate hypertension. The adults with complications were those with extensive renal scarring and/or at least borderline hypertension in childhood. Those with VUR, but no scarring, and managed carefully in childhood, did not suffer serious consequences as adults. There is a need for early recognition and treatment of children with VUR and UTI to limit scar development.

Nocturnal enuresis: a placebo controlled trial of two antidepressant drugs.

A multicentre, randomised, double blind treatment trial was set up comparing imipramine (a tricyclic antidepressant with anticholinergic action), mianserin (a quadricyclic antidepressant without anticholinergic activity), and placebo, (a) possibly to identify an effective alternative drug and (b) to elucidate the action of imipramine in enuretic children. Eighty children (65 boys, 15 girls) aged 5-13 years, wet three or more nights a week, were studied. Exclusions were a urinary tract infection or abnormality, other organic illness, or severe emotional disorders. After a four week assessment, 25 children were randomised to eight weeks' treatment with imipramine 25 mg, 26 to mianserin 10 mg and 29 to placebo, followed by four weeks without treatment. Dry nights and a wetness score were recorded throughout. During treatment, imipramine was superior to both placebo and mianserin (p < 0.001) in achieving dry nights and reducing wetness scores. It led to a definite improvement in 72% of children. Mianserin produced a mildly beneficial effect that was not superior to placebo. No side effects were recorded. Mianserin would not be a satisfactory alternative treatment for nocturnal enuresis. The efficacy of imipramine is unlikely to be the result of its antidepressant activity.

Technetium-99m-DMSA studies in pediatric urinary infection.

UNLABELLED: Urinary tract infection (UTI) is a common condition in children and may lead to renal scarring with a risk of later hypertension and renal insufficiency. We made a cross-sectional study of the 99mTc-DMSA findings in 496 children referred for following symptomatic UTI to a Department of Nuclear Medicine and we categorized the results, to provide a framework for further study. METHOD: A standard 99mTc-DMSA protocol was used to study 496 children (157 males, 339 females) aged from birth to 14 yr. Findings were classified according to the image appearance and relative function of each kidney. These were related to age, sex, history and timing of UTI and the results on micturating cysto-urethrography (MCU). RESULTS: Images were normal, with function within limits (45%-50% in one kidney), in approximately half the boys and girls studied. The other images were classified as equivocal in 68 children, abnormal unilaterally in 105 and bilaterally in 76, and they were subdivided according to the image appearance. No image changes could be identified that were specifically associated with acute UTI. Diffuse change alone was uncommon. A high proportion of abnormal images was found in infant boys, older girls with recurrent UTI and those children with vesico-ureteric reflux (VUR). Of the bilateral abnormal images, 98% were seen in children with VUR. CONCLUSION: Our findings suggest that infective renal change may be superimposed on underlying congenital lesions (perhaps detectable antenatally) or may be acquired following UTI in the presence of reflux and are thus potentially preventable. This study also suggests that VUR is almost certain to have occurred in a child who has bilateral abnormal 99mTc-DMSA images following UTI and is also commonly present in those with definite unilateral defects.

The intravenous urogram in the detection and evaluation of renal damage following urinary tract infection.

Intravenous urography (IVU) still provides the most comprehensive structural assessment of the urinary tract. In particular, the radiological renal appearances approximate closely to the morphology of the renal scarring of reflux nephropathy or chronic atrophic pyelonephritis. It also provides reproducible renal measurements for follow-up assessment of renal growth and scarring. It is now less often used for first-line investigation of the acute urinary tract infection (UTI) because the swelling accompanying acute renal involvement is less easily recognised than the areas of defective function demonstrated on 99mtechnetium-dimercaptosuccinic acid (DMSA) studies. Also IVU contributes a higher radiation dose when calculated for full IVU (dependent on the number of films exposed) and there is a slight risk of side effects from injected contrast media, reduced by using non-ionic compounds. Because of its value in confirming such a serious diagnosis as renal scarring, suspected on ultrasonography or DMSA scintigraphy, modification of the technique of IVU with adequate preparation and the use of a reduced number of films, or single films localised to the renal areas, should be considered. Expertise in the interpretation of IVU must also be maintained because of the ancillary information regarding bowel and bladder function, the spine and evidence of stones, pertinent to the management of children with UTI and renal scarring. IVU and DMSA study remain complementary investigations.

Urinary tract infection: a comparison of four methods of investigation.

The optimal regimen for investigating children with urinary tract infection (UTI) remains uncertain. Ultrasonography, contrast micturating cystourethrography (MCU), intravenous urography (IVU), and technetium-99m dimercaptosuccinic acid (DMSA) studies were performed in 58 children with UTI under 14 years of age attending two teaching hospitals and the results compared. All four investigations were normal in 12 children. In 36 with vesicoureteric reflux (VUR) on MCU, dilatation was reported on ultrasonography in eight children. Radiological renal scarring was seen in 20 children; it was suspected on ultrasonography in nine, with dilatation alone in four, and a normal report in seven. Duplex kidneys identified on IVU were unrecognised on ultrasonography or DMSA studies; ultrasonography showed no change corresponding to presumed acute defects on DMSA studies that later resolved. Disparities were observed at all ages. This study suggests that ultrasonography is unreliable in detecting VUR, renal scarring, or inflammatory change and, alone, is inadequate for investigating UTI in children.

Pitfalls in the investigation of children with urinary tract infection.

The histories and imaging results are presented in 10 children in whom errors had been made in the interpretation of early investigations. Ultrasonography may not detect either vesicoureteric reflux (VUR) or renal scars or inflammation. The reduced nephrogram or renal swelling following a first attack of acute pyelonephritis may not be recognised without renal measurement on an intravenous urogram. Renal scarring may be diagnosed incorrectly on the basis of functional defects of isotope uptake on a technetium 99m-dimercaptosuccinic acid study. In the absence of VUR, the micturating cystogram will not visualise the kidneys.

Retrospective study of children with renal scarring associated with reflux and urinary infection.

OBJECTIVE: To review the histories of children with bilateral renal scarring and severe vesicoureteric reflux to determine whether an improvement in early management might reduce the risk of scarring. DESIGN: Retrospective study of medical records and discussion with parents. SETTING: Outpatient departments of two teaching hospitals. PATIENTS: 52 children aged 1-12 years participating in a randomised comparison of medical and surgical management. All had a history of symptomatic urinary tract infection. Two thirds presented with fever and two with hypertension or renal failure. In only one out of 32 children examined by antenatal ultrasonography was an abnormality suspected. RESULTS: There was delay in diagnosis or appropriate imaging or effective treatment of urinary infection in 50 of the 52 children. In 41 there was delay in diagnosis; there was delay in treating a confirmed infection in 45; no antibacterial prophylaxis was prescribed before imaging in 28; and investigation of the urinary tract was delayed in 33. The severity of scarring was significantly related to delay in diagnosis (chi 2 for trend 7.43, P = 0.01). Four children of mothers known to have reflux nephropathy were not investigated until they developed urinary tract infection. CONCLUSIONS: Efforts to reduce the incidence and severity of renal scarring should be directed towards rapid diagnosis and effective early management of urinary tract infection in infancy and childhood. Siblings and offspring of known patients with severe reflux nephropathy should be investigated for reflux.

Differential excretion of urinary proteins in children with vesicoureteric reflux and reflux nephropathy.

We studied 40 children with a history of vesicoureteric reflux (VUR) without evidence of renal scarring, 93 children with a history of VUR and renal scarring and 10 children with previous urinary tract infections in whom the urinary tract was radiologically normal. Urine retinol-binding protein (RBP), albumin and N-acetyl-beta-D-glucosaminidase (NAG) were measured in each child. All were free from infection at the time of the analysis. Urinary RBP and NAG levels were significantly elevated (P < 0.001) in the group of children with renal scarring. Elevated RBP levels were detected in 51% of children with bilateral renal scarring compared with 7% of children with unilateral scarring. Urine RBP excretion increased progressively according to the type of scarring, best determined by the type of scarring of the less affected kidney. In children with renal scarring, elevated NAG levels were seen mostly in the 65 children with bilateral scarring and severe reflux. Urine albumin excretion was elevated in 10 children, 9 with bilateral scarring, all of whom had elevated RBP excretion. Urine protein excretion was unaffected by the presence or absence of persisting VUR. There was a strong negative correlation between glomerular filtration rate and RBP excretion (r = -0.69). We conclude that evidence of tubular dysfunction is common in children with bilateral renal scarring and usually precedes any glomerular protein leak. Tubular dysfunction may be the consequence of relative nephron hyperperfusion in the presence of bilateral scarring.

[Radiologic findings in the kidney of children with severe reflux. Five-year comparative study of conservative and surgical treatment]. / Radiologische Nierenbefunde bei Kindern mit schwerem Reflux. Fünfjahresvergleichsstudie konservativer und chirurgischer Behandlung.

The renal findings revealed by intravenous urography (IVU) in 306 children (73 boys, 233 girls) are reported. The children were seen at eight European centres and enrolled in an international study comparing medical and surgical management of children with urinary tract infection and severe vesico-ureteric reflux who were followed for 5 years. In all, 155 children were randomly allocated to medical and 151 to surgical treatment. The protocol and the investigative techniques were standardized, and randomization, data collection and analysis were performed centrally in Essen, Federal Republic of Germany. At entry 149 (49%) had established renal scarring (79 medical, 70 surgical). Presence of normal kidneys (105), areas of thinned parenchyma (52) and grade of reflux were also evenly distributed. IVU was repeated at 6, 18 and 54 months, and serial urine culture, 99mtechnetium-dimer-captosuccinic acid scans and plasma creatinine estimations were performed. Follow-up was complete in 272 children (89%). In 174 children (57%: 90 medical, 84 surgical) there was renal growth without morphological change. New renal scars developed in 19 children treated medically and 20 treated surgically; 12 (5 medical, 7 surgical) developed in previously normal kidneys. Six followed postoperative obstruction. No significant difference in outcome was found between medical and surgical management in terms of the development of new renal lesions or the progression of established renal scars.

Characteristics at entry of children with severe primary vesicoureteral reflux recruited for a multicenter, international therapeutic trial comparing medical and surgical management. The International Reflux Study in Children.

A total of 532 children, 401 from Europe and 131 from the United States, was recruited into an international multicenter study comparing the results of medical and surgical treatment of children with international grade III or IV vesicoureteral reflux and urinary tract infection. Patient age was less than 11 years, glomerular filtration rate was greater than 70 ml. per minute per 1.73 m.2 and there was no obstruction, renal malformation, previous urinary tract surgery or neuropathic bladder. A total of 80 children had less than grade III vesicoureteral reflux on a second pre-entry cystourethrogram required by the European protocol, and they were followed separately as a sideline group. At entry the age distribution, history of urinary tract infection and proportion of children with grade IV vesicoureteral reflux were similar in Europe and the United States. Of the European and United States children 48% and 54% had renal scarring, and 17% and 14% had parenchymal thinning, respectively. In each group renal length and planimetric area were normal in two-thirds and 5% had small kidneys (<2 standard deviations from normal). Differences included sex distribution (24% boys in Europe and 11% in the United States group), the proportion of children in whom vesicoureteral reflux was previously known (18% Europe and 69% United States) and the proportion of children with bilateral reflux (77% Europe and 57% United States). Randomization and stratification for treatment were successful.

Renal scars and parenchymal thinning in children with vesicoureteral reflux: a 5-year report of the International Reflux Study in Children (European branch).

A total of 321 children less than 11 years old with nonobstructive grade III or IV vesicoureteral reflux and with previous urinary tract infection was randomly allocated to medical or surgical treatment in the European branch of the International Reflux Study in Children. (Randomization was stratified for age, sex, grade of reflux, presence of renal scarring, interval since last urinary tract infection and treating hospital). The results of excretory urography are reported for 233 girls and 73 boys treated according to the random allocation, 89% of whom were followed for 5 years. After 5 years in the medical group (155 children) new renal scars were seen in 19 and new renal parenchymal thinning in 11. The proportions were almost identical among 151 children allocated to surgical treatment with 20 new scars and 15 new thinnings. Progression of established scars was also similar in both groups. However, the new scars developed sooner after surgery than during medical treatment. In 6 surgically treated children postoperative obstruction was followed by the development of new scars. In addition, 12 patients showed new scars approximately 6 months after successful surgery, while in only 2 children scars developed more than 6 months after surgery. In 11 children of the medical group new scars were seen more than 6 months after allocation. More new scars developed in the children with parenchymal thinning at entry (23%) than in those with scarred or normal kidneys at entry (10% each) (p < 0.05). The younger the patients at entry, the higher the frequency of new scars (less than 2 years 19.8%) 2 to 4 years 9.8% and 5 years or more 4.6%, p < 0.05).

Commentary: management of children with severe vesicoureteral reflux.

The main findings of the IRSC after 5 years of observation are summarized. Of the 434 children entered 128 were from centers in America and 306 from Europe. They were randomly allocated and stratified to a medical or surgical regimen. Of the children 50% had scarred kidneys at entry evenly distributed between the groups. After 5 years of observation there was no difference in outcome between the 2 treatment groups in terms of renal size and growth, the development of new radiological renal scars or areas of parenchymal thinning, or of progression of established scarring. In Europe infection recurred in equal numbers of children but pyelonephritic symptoms were more common in the medical group. Nevertheless, new scars developed in 19 of 155 children treated medically and 20 of 151 children treated surgically, including 5 and 7, respectively, with previously normal kidneys. Factors influencing the choice of treatment include patient age, availability of expert surgical care and experienced medical supervision, parental choice and compliance. Followup studies indicate that renal scarring rather than persistence of reflux determines the prognosis and, therefore, emphasis should be placed on the prevention of scarring.

Five-year study of medical or surgical treatment in children with severe reflux: radiological renal findings. The International Reflux Study in Children.

The renal findings on intravenous urography (IVU) are reported in 306 children (73 boys, 233 girls) from eight European centres entered into an international study comparing medical and surgical management of children with urinary tract infection and severe vesico-ureteric reflux followed for 5 years. One hundred and fifty-five children were randomly allocated to medical and 151 to surgical treatment. Protocol and investigative techniques were standardised and randomisation, data collection and analysis were performed centrally in Essen, Germany. At entry 149 (49%) has established renal scarring (79 medical, 70 surgical). Children with normal kidneys (105), areas of thinned parenchyma (52) and grade of reflux were also evenly distributed. IVU was repeated at 6, 18 and 54 months and serial urine culture, 99mtechnetium-dimercaptosuccinic acid scans and plasma creatinine estimations were performed. Two hundred and seventy-two children (89%) completed this follow-up. In 174 children (57%), (90 medical, 84 surgical) there was renal growth without morphological change. New renal scars developed in 19 children treated medically and 20 surgically; 12 (5 medical, 7 surgical) developed in previously normal kidneys. Six followed post-operative obstruction. No significant difference in outcome was found between medical or surgical management in terms of the development of new renal lesions or the progression of established renal scars.