Clinical course of 735 children and adolescents with primary vesicoureteral reflux

The purpose of this retrospective cohort study was to report the clinical course of children with primary vesicoureteral reflux (VUR). Between 1970 and 2004, 735 patients were diagnosed with VUR and were systematically followed in a single tertiary renal unit. Patients were followed up for a mean time of 76 months (6 months to 411 months). The events of interest were reflux resolution, renal damage, urinary tract infection (UTI), chronic kidney disease (CKD), and hypertension. Survival analysis was performed in order to evaluate reflux resolution and CKD. Renal damage was detected at admission in 319 patients (43.4%). Continuous low-dose antibiotic prophylaxis was administered to 624 patients (91.2%); 499 (73%) patients subsequently had no UTI or fewer than three episodes. The median time of persistence of reflux according to Kaplan–Meier analysis was 38 months for grade I/II [95% confidence interval (95% CI), 33–43], 98 months for grade III (95% CI, 78.5–105), and 156 months for grade IV/V (95% CI, 122–189). Twenty patients (3%) developed hypertension. It was estimated that the probability of CKD was 5% at 10 years after diagnosis of VUR; for children diagnosed after 1990 the probability of CKD was only 2%. Renal function impairment occurred in patients with severe bilateral reflux or in patients with contralateral renal hypoplasia. There has been an improvement of prognosis for patients diagnosed in the past 15 years.     

Risk of hypertension in primary vesicoureteral reflux

The aim of this report was to estimate the risk of hypertension in children with primary vesicoureteral reflux (VUR). Between 1970 and 2004, 735 patients were diagnosed with VUR at a single tertiary renal unit. Of 735 patients, 664 (90%) were systematically followed and had multiple measurements of blood pressure. Hypertension was defined as values persistently above 95th for age, sex, and height in three consecutive visits. Risk of hypertension was analyzed by the Kaplan-Meier method. Of 664 patients followed, 20 (3%) developed hypertension. The estimated probability of hypertension was 2% (95%CI, 0.5%–3%), 6% (95%CI, 2%–10%), 15% (95%CI, 11%–20%) at 10, 15, and 21 years of age, respectively. The prevalence of hypertension has increased with age: it was 1.7% for patients with 1 yr–9.9 yr, 1.8% for adolescents with 10 yr–14.9 yr, 4.7% for patients with 15–19.9 yr, and 35% for patients >20 years at the end of the follow-up (P < 0.001). It was estimated by survival analysis that 50% of patients with unilateral and bilateral renal damage would have sustained hypertension at about 30 and 22 years of age, respectively. Hypertension increased with age and was strongly associated with renal damage at entry in an unselected population of primary VUR.     

Resolution of vesicoureteral reflux during medical management in children

A retrospective study was performed to evaluate the results of medical management of primary vesicoureteral reflux (VUR) in infants and children. The charts of 105 patients (74 boys, 31 girls) with 167 refluxing ureters were reviewed. The age at diagnosis ranged from 3 days to 9.2 years (mean 1.3±1.9 years). The mean duration of follow-up was 2.4±1.5 years. We found that the patient's sex did not influence the fate of VUR and its complications. Patients whose reflux improved while being managed medically were younger than those who did not improve, and the younger the patient the sooner the reflux resolved. Improvement and resolution of reflux were also related to grade, and the lower the initial grading the sooner the reflux resolved. Spontaneous resolution rates of reflux were 92.3%, 76.2%, 61.7%, and 32.0% for grades I, II, III, and IV, respectively. No ureters with grade V reflux resolved without complications. The most common complications in our series were renal scarring and secondary obstructive uropathy.     

Management of vesicoureteral reflux in children

Background. Vesicoureteral reflux (VUR) in children has been reported in many studies. However, the management of VUR is still controversial. Methods. One hundred and fourteen children with primary VUR were divided into two treatment groups: medical (group A) and surgical (group B). The clinical courses and X-ray films of cystography and intravenous pyelography of these children were reviewed retrospectively, using the International Reflux Study Committee Classification. Results. In children less than 1 year of age, VUR was observed more frequently in boys. However, this ratio was reversed in children aged 2 years or more. Sixty-three percent of all refluxing ureters had reflux of grade III or higher at the initial examination. Spontaneous cessation of VUR was observed in 17% of group A ureters, and all had grade III or less reflux. Renal parenchymal scars were already present at the initial examination in 23% of kidneys with refluxing ureters. Recurrent urinary tract infections became less frequent after anti-reflux surgery. The progression of renal scars and renal growth retardation was observed more frequently in group B children. Conclusions. From these observations, it appeared that surgical management of VUR did not prevent the progression of renal scarring or renal growth retardation. Early detection of and intervention in VUR may prevent the progression of renal scarring and renal growth retardation. However, a multicenter, prospective, randomized controlled study would be necessary to confirm these findings. Received: October 4, 1999 / Accepted: January 15, 2000     

Clinical course of prenatally detected primary vesicoureteral reflux

The purpose of this study was to report the clinical course of medium-long-term follow-up of children with prenatally detected vesicoureteral reflux (VUR). Between 1986 and 2004, 53 (41 males) children with VUR detected by investigation of prenatal hydronephrosis were followed up for a mean time of 66 months (range: 6–200 months). Newborns were investigated by ultrasound, voiding cystourethrogram (VCUG) and DMSA scan. Follow-up clinical visits were performed at 6-month intervals. After 24 months patients were investigated by conventional VCUG or direct isotope cystogram. Survival analysis was performed in order to evaluate the resolution of the reflux. Differences between subgroups (mild vs moderate/severe reflux) were assessed by the two-sided log rank test. Thirty (58%) infants presented bilateral VUR, for a total of 83 renal units. There was a predominance of severe reflux (54%). Renal damage was detected in 33.7% of the units on first renal scan. There was a significant correlation between severe reflux and renal damage scars (RR=3.4, 95% confidence interval [CI], 1.4–8, p=0.002). Forty-seven patients were treated with continuous prophylaxis. One patient developed systolic hypertension. Urinary tract infection occurred in 12 (25%) children conservatively managed. VUR resolution was evaluated in 56 renal units. Spontaneous resolution was observed in 25 units (45%). At 48 months after diagnosis, 75% of the cases of mild reflux (I–III) and 37% of severe reflux (IV–V) had resolved (log-rank, 5.6, p=0.017). There was an improvement of nutritional parameters between admission and the end of follow-up. In conclusion, the clinical course of prenatally detected VUR followed up on a medium-long-term basis is relatively benign. Our study corroborates the results obtained in other series of infants with reflux that emphasized the heterogeneity of this disorder.     

Role of the Teflon deposit in the recurrence of vesicoureteral reflux

A relationship between the Teflon deposit, visible with ultrasound, and long-term success of subureteric Teflon injection (STING) treatment was investigated. The study included only those patients with primary vesicoureteral reflux (VUR), in whom the reflux had disappeared and the Teflon deposits were visible 6 weeks following STING treatment. Cessation of VUR was proven by voiding cysto-urethrography (VCUG) in 99 patients (143 ureters). Average follow-up time was 9 (4–12) years. Patients were divided into two groups: group I, deposits visible with ultrasound [deposit (+)], and group II, no visible deposits at the end of the follow-up period [deposit (−)]. Reflux recurrence, the occurrence of urinary tract infection (UTI), and pyelonephritis were investigated, and technetium scintigraphy scans were examined. The deposit (+) group included 43 patients (65 ureters), and the deposit (−) group contained 56 patients (78 ureters). In the deposit (+) group there were no recurrences of VUR; however, 17 recurrences were found in the deposit (−) group (P < 0.05). Dimercaptosuccinic acid (DMSA) scintigraphy scans and occurrence of UTI showed significant difference between the groups (P < 0.05). A close relationship was found between the disappearance of the Teflon deposit and the recurrence of VUR. Disappearance of the Teflon deposit and repeated bacteriuria is a warning sign of the recurrence of VUR; therefore, VCUG might be warranted for these patients.     

Imaging strategies for vesicoureteral reflux diagnosis

The prevalence of vesicoureteral reflux (VUR), although reported to be low in the general population, is high in children with urinary tract infection (UTI), first degree relatives of patients with known VUR and children with antenatal hydronephrosis. In addition, it has been shown that VUR and UTIs are associated with renal scarring, predisposing to serious long-term complications, i.e., hypertension, chronic renal insufficiency and complications of pregnancy. Therefore, diagnostic imaging for the detection of VUR in the high-risk groups of children has been a standard practice. However, none of these associations has been validated with controlled studies, and recently the value of identifying VUR after a symptomatic UTI has been questioned. In addition, several studies have shown that renal damage may occur in the absence of VUR. On the other hand, some patients, mainly males, may have primary renal damage, associated with high-grade VUR, without UTI. Recently, increasing skepticism has been noted concerning how and for whom it is important to investigate for VUR. It has been suggested that the absence of renal lesions after the first UTI in children may rule out VUR of clinical significance and reinforces the redundancy of invasive diagnostic techniques. Therefore, the priority of imaging strategies should focus on early identification of renal lesions to prevent further deterioration.     

Predictive value of clinical and laboratory variables for vesicoureteral reflux in children

We aimed to determine the predictability of clinical and laboratory variables for vesicoureteral reflux (VUR) in children with urinary tract infection (UTI). Data of children with febrile UTI who underwent voiding cystoureterography between 2002 and 2005 were evaluated retrospectively for clinical (age, gender, fever ≥38.5°C, recurrent UTI), laboratory [leukocytosis, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), pyuria, serum creatinine (S_Cr)] and imaging (renal ultrasonography) variables. Children with VUR (group 1) vs. no VUR (group 2) and children with high-grade (III–V) VUR (group 3) vs. no or low-grade (I–II) VUR (group 4) were compared. Among 88 patients (24 male), 38 had VUR and 21 high-grade VUR. Fever ≥38.5°C was associated with VUR [odds ratio (OR): 7.5]. CRP level of 50 mg/l was the best cut-off level for predicting high-grade VUR (OR 15.5; discriminative ability 0.89 ± 0.05). Performing voiding cystourethrography based on this CRP level would result in failure to notice 9% of patients with high-grade VUR, whereas 69% of children with no/low-grade VUR would be spared from this invasive test. In conclusion, fever ≥38°C and CRP >50 mg/l seem to be potentially useful clinical predictors of VUR and high-grade VUR, respectively, in pediatric patients with UTI. Further validation of these findings could limit unnecessary voiding cystourethrography.     

Intermittent trimethoprim-sulfamethoxazole in children with vesicoureteral reflux

The effectiveness of intermittent low-dose trimethoprim-sulfamethoxazole (TMP-SMZ) for the prophylaxis of recurrent urinary infection is well established in adults. The present study assessed the effectiveness and safety of intermittent low-dose TMP-SMZ in 35 children (24 boys, 11 girls, aged 1 month to 9 years, median age 5 months) with vesicoureteral reflux; 18 children had bilateral reflux. A total of 53 refluxing ureters were graded as I in 2, II in 16, III in 19, IV in 14, and V in 2 cases. The children were given 1 mg/kg body weight of trimethoprim together with 5 mg/kg of sulfamethoxazole at bedtime every other day for 6 – 50 months (mean±SD, 22.9±11.7 months). None of the boys had a recurrence of urinary infection, while 2 of the 11 girls had a total of 7 recurrences during the prophylaxis period, with a recurrence rate of 0.027 per patient month in girls. Both girls were over 3 years and had a mildly unstable bladder. Transient neutropenia (<1,000/μl) developed in 2 infants during the prophylaxis period, but disappeared spontaneously. Intermittent low-dose TMP-SMZ seemed very effective for the prevention of recurrent urinary infection in children with ureteral reflux even of higher grades. Received September 11, 1996; received in revised form and accepted December 11, 1996     

Predictors of renal scar in children with urinary infection and vesicoureteral reflux

We evaluated the predictors of renal scar in children with urinary tract infections (UTIs) having primary vesicoureteral reflux (VUR). Data of patients who were examined by dimercaptosuccinic acid (DMSA) scintigraphy between 1995 and 2005 were evaluated retrospectively. Gender, age, reflux grade, presence/development of scarring, breakthrough UTIs, and resolution of reflux, were recorded. The relation of gender, age and VUR grade to preformed scarring and the relation of gender, age, VUR grade, presence of preformed scarring, number of breakthrough UTIs and reflux resolution to new scarring were assessed. There were 138 patients [male/female (M/F) 53/85]. Multivariate analysis showed that male gender [odds ratio (OR) 2.5], age ≥ 27 months in girls (OR 4.2) and grades IV–V reflux (OR 12.4) were independent indicators of renal scarring. On the other hand, only the presence of previous renal scarring was found to be an independent indicator for the development of new renal scar (OR 13.4). In conclusion, while the most predictive variables for the presence of renal scarring among children presenting with a UTI were male gender, age ≥ 27 months in girls, and grades IV–V reflux, the best predictor of new scar formation was presence of previous renal scarring.     

Summary of recent AUA guidelines for the management of vesicoureteral reflux in children

VUR is a common condition and it is a predisposing factor for pyelonephritis, and reflux nephropathy, which can cause end stage renal disease in children. Given the consequences and sequelae of UTI and VUR, and due to lack of consensus regarding management of this common condition, the American Urological Association (AUA) developed treatment guidelines for children with VUR in 1997 and 2012 to help physicians better manage children with VUR. In this review, the summary of the 1997 and 2012 AUA guidelines are discussed with a focus on the 2012 report. Recommendations about evaluation and management of children under and above one year with VUR, with and without bladder/bowel dysfunction, screening of siblings of patients with VUR, screening of the neonate/infant with prenatal hydronephrosis, and follow up of the children with VUR are discussed in this review. The identification and management of VUR in these groups, provide the potential opportunity to prevent renal damage and decrease the risk of UTI and pyelonephritis. According to these guidelines, risk assessment of renal injury/scarring in the individual patient based upon clinical factors is critical, and interventions should be appropriate to the risk profile. Informing families and healthcare providers of the potential risk of pyelonephritis and renal scarring and allowing them to participate in decision making is considered important.     

Asymptomatic vesicoureteral reflux detected by neonatal ultrasonographic screening

Renal ultrasonography was performed in 2,384 healthy and asymptomatic neonates. The definition and grading of hydronephrosis was according to the system of the Society for Fetal Urology. Voiding cystourethrography was performed in the cases with moderate to severe hydronephrosis or persistent mild hydronephrosis. In cases with vesicoureteral reflux (VUR), a dimercaptosuccinic acid (DMSA) renal scan was arranged immediately to evaluate the renal parenchyma. VUR was diagnosed in 30 infants with a prevalence of 1.26%; 7 had bilateral VUR. The male/female ratio was 4:1 and the right/left ratio was 1.85:1. Comparing with the abnormal ultrasonographic findings, VUR appeared ipsilaterally in 23 ureters and contralaterally in 14 ureters. Using ultrasonography for diagnosing VUR, the sensitivity, specificity, positive predictive value, and negative predictive value were 62.2%, 36.1%, 11.0%, and 88.2%, respectively. DMSA renal scan was perfomed in 31 refluxing kidneys, and congenital renal scarring was found in 9 (29.0%) kidneys. Six neonates underwent reimplantation surgery. We conclude that although ultrasonography is not a reliable tool for diagnosing VUR, it can detect many cases of VUR during the newborn stage using our screening program, which thus makes early treatment from the neonatal period possible. Whether our screening program can improve the outcome of VUR will require further follow-up. Received January 10, 1997; received in revised form September 2, 1997; accepted September 3, 1997     

Cyclic voiding urosonography in detecting vesicoureteral reflux in children

Three methods are currently used to identify vesicoureteral reflux (VUR) in children, namely X-ray voiding cystourethrography (VCUG), radionuclide voiding cystography (RVC), and, recently, echo-enhanced voiding urosonography (VUS). It is known that the sensitivity of VCUG and RVC for detecting VUR can be improved by using cyclic procedures, such as repeated bladder filling and voiding. The purpose of our prospective study was to evaluate whether the cyclic procedure is superior to the conventional (one cycle only) procedure in VUS also. VUS was performed in 49 patients, aged 1.4–15.8 years (mean 4.1 years). After the first micturition, the catheter was left in place and the whole procedure was repeated under the same conditions. The results of the first and second cycles and the combined procedure were compared. In the initial cycle, 7 of 35 (20%) refluxing renal units that were detected in the second cycle and 4 of 26 (15%) children with at least unilateral VUR were missed. Cyclic VUS detected 25% more VURs than the conventional (one cycle only) VUS (P=0.049) and revealed 50% more VUR III than the first cycle. Our results suggest that cyclic VUS is superior to conventional VUS.     

膀胱输尿管反流的精准诊治进展

膀胱输尿管反流( VUR)是儿童最为常见的泌尿系统疾病,该病使患儿更易出现肾盂肾炎,是儿童尿路感染后肾脏疤痕形成的最重要的风险因素。到目前为止,对VUR的诊断及治疗仍有很多争议,其争议内容主要是围绕着哪些儿童应该评估反流的有无,以及一旦确诊VUR时哪些儿童又应该接受治疗及接受何种治疗。VUR是一种遗传性疾病,但是该病具有种族差异性、遗传异质性等特点,迄今为止国际上尚没有公认的、一致的主要致病基因。明确不同基因突变所致的VUR的研究,有助于做出肾疤痕形成是先天性还是后天性的判断,从而在临床做出精确诊断及精准治疗。     

Indirect voiding urosonography for detecting vesicoureteral reflux in children

The purpose of our prospective study was to determine the value of indirect voiding urosonography without the use of contrast-media and without filling of the bladder through a catheter (IVUS) for detection of vesicoureteral reflux (VUR) in children, compared with echo-enhanced voiding urosonography (VUS). Among 57 children (45 girls and 12 boys, aged 2.7 to 12.0 years) admitted for echo-enhanced VUS either as part of routine evaluation after urinary tract infection (UTI) or follow-up of a previously detected VUR, IVUS was also successfully performed in 47 children. The results were considered positive when there was any increase in pelvis size and/or ureter lumen width during voiding. The overall sensitivity of IVUS in the detection of VUR was 49%, specificity 75%. The most accurate results were obtained with VUR grade III, where IVUS correctly detected 6 out of 7 cases, a sensitivity of 86%. The average increase of AP pelvis diameter during voiding was highly significant only in uretero-renal units with VUR grade III. Considering the obstacles in conducting the investigation and its relatively low overall sensitivity and specificity, it seems that IVUS is not sufficiently reliable to replace echo-enhanced VUS.     

The current status of screening for vesicoureteral reflux

Reflux nephropathy is responsible for a significant percentage of end-stage renal disease in late childhood as well as being the most common cause of severe hypertension in childhood and adolescence. To prevent reflux nephropathy, it is imperative to discover reflux at the youngest age possible and preferably before any urinary general population for reflux is not feasible, we have focused our efforts on the siblings of known refluxers and, more recently, the offspring of known refluxers. We have found high rates of reflux in both groups and have shown in the sibling population that early discovery of sibling reflux has significantly lowered the rate of renal damage compared with the index patients. It is imperative to screen these two risk populations at the youngest age possible, but we have recently made modifications in our recommendations for the older sibling and offspring. The results of these two screening studies are given as well as our current recommendations for screening for reflux in these risk groups.     

Urinary tract infections,VUR, and autosomal dominant polycystic kidney disease

This case series of 16 patients with autosomal dominant polycystic kidney disease (ADPKD) describes 4 girls who presented with a urinary tract infection (UTI). Radiological evaluation revealed that each of these patients had vesicoureteral reflux (VUR). The frequency of VUR was significantly higher in the patients with ADPKD compared with otherwise healthy age-matched children who underwent testing after a UTI (100% versus 15%, P<0.002). These findings suggest VUR is an associated somatic anomaly in children with ADPKD that may contribute to the occurrence of UTI in this patient population.     

The etiology of renal scars in infants with pyelonephritis and vesicoureteral reflux

We aimed to investigate, by means of dimercaptosuccinic acid (DMSA) scan, the relations between vesicoureteral reflux (VUR) and its degree, pyelonephritis during infancy, and renal parenchymal findings. Seventy-four infants with pyelonephritis, 44 girls and 30 boys (mean age at their first pyelonephritic episode 4.12 months, median 3 months), were enrolled in the study. Voiding cystourethrography (VCU) and ultrasonography (US) were performed within 6 weeks following the infection. DMSA was performed at least 4 months after the urinary tract infection (UTI). The renal parenchymal pathology was defined as focal or multifocal defects or as a split renal uptake of less than 45%. DMSA scintigraphy revealed that 19% (14/74) of the children had renal damage. Renal parenchymal findings were observed only when VUR was present, and its grade was above 3/5. No abnormality was found in 51 renal units without reflux, 9 with VUR grade 1/5, and 54 with grade 2/5. Renal pathology was observed in 9/24 renal units with VUR grade 3, 3/8 with grade 4, and 2/2 with grade 5. No correlation was found between renal parenchymal defects and clinical presentation of the pyelonephritis, type of the microorganism, presence of bacteremia, or the number of recurrent infections. In adequately treated infants, renal damage is probably due to a reflux-associated, preexisting, congenital renal parenchymal pathology and not to the inflammatory process. We suggest that DMSA scintigraphy should not be performed routinely in every infant with UTI and should be reserved primarily for children with VUR grade 3 and above. Received: 17 February 1999 / Revised: 30 June 1999 / Accepted: 7 July 1999     

Histopathological evidence of poor prognosis in patients with vesicoureteral reflux

Patients with vesicoureteral reflux (VUR) often develop reflux nephropathy with focal segmental glomerular sclerosis (FSGS), although the exact mechanisms leading to the development of this complication are unknown. To determine the early changes in glomeruli of VUR patients that ultimately cause poor renal outcome, we examined morphometrically renal biopsies of 16 young patients (age 10–20 years) with VUR at baseline pre-operatively. Patients were divided into two groups, those who subsequently showed good prognosis and those with poor renal prognosis at the end of a 10-year follow-up period. Patients with poor prognosis had worse proteinuria and lower creatinine at baseline than those with good prognosis. We also examined 40 age-matched control cases with previous temporal microhematuria and/or proteinuria but normal renal function and histology. Although the mean diameter of glomerular capillary did not change in VUR cases irrespective of prognosis, glomerular capillary length increased by 125% in cases with good prognosis, and 335% in cases with poor prognosis (P<0.01). Cystically expanded capillaries, with diameter ≥95% of that in age-matched control, were detected in five of eight patients with poor prognosis, but only in one of eight patients with good prognosis. In VUR, the number of podocytes/capillary diminished with increased length of the capillaries. Tuft adhesion to Bowman’s capsule and podocyte detachment were primarily found in patients with poor prognosis. Our results suggest that lengthening of glomerular capillaries in young patients with VUR is a compensatory reaction to hyperfiltration. The appearance of cystic capillary expansion, podocyte detachment and/or tuft adhesion to Bowman’s capsule in such glomeruli may be important indicators of renal prognosis in patients with VUR. These changes may lead to FSGS due to podocyte injury in patients with VUR, with subsequent deterioration of renal function. Received: 3 January 2000 / Revised: 18 January 2001 / Accepted: 18 January 2001