Per Brandström

The Swedish Reflux Trial in Children: IV. Renal Damage

PURPOSE We compared the development of new renal damage in small children with dilating vesicoureteral reflux randomly allocated to antibiotic prophylaxis, endoscopic treatment or surveillance as the control group. MATERIALS AND METHODS Included in the study were 128 girls and 75 boys 1 to younger than 2 years with grade III-IV reflux. Voiding cystourethrography and dimercapto-succinic acid scintigraphy were done before randomization and after 2 years. Febrile urinary tract infections were recorded during followup. Data analysis was done by the intent to treat principle. RESULTS New renal damage in a previously unscarred area was seen in 13 girls and 2 boys. Eight of the 13 girls were on surveillance, 5 received endoscopic therapy and none were on prophylaxis (p = 0.0155). New damage was more common in children with than without febrile recurrence (11 of 49 or 22% vs 4 of 152 or 3%, p <0.0001). CONCLUSIONS In boys the rate of new renal damage was low. It was significantly higher in girls and most common in the control surveillance group. There was also a strong association between recurrent febrile UTIs and new renal damage in girls.

The Swedish Reflux Trial in Children: III. Urinary Tract Infection Pattern

PURPOSE We evaluated the difference in the febrile urinary tract infection rate in small children with dilating vesicoureteral reflux randomly allocated to 3 management alternatives, including antibiotic prophylaxis, endoscopic treatment or surveillance only as the control. MATERIALS AND METHODS At 23 centers a total of 203 children were included in the study, including 128 girls and 75 boys 1 to younger than 2 years. Vesicoureteral reflux grade III in 126 cases and IV in 77 was detected after a febrile urinary tract infection (194) after prenatal screening (9). Voiding cystourethrography and dimercapto-succinic acid scintigraphy were done before randomization and after 2 years. The febrile urinary tract infection rate was analyzed by the intent to treat principle. RESULTS We noted a total of 67 febrile recurrences in 42 girls and a total of 8 in 7 boys (p = 0.0001). There was a difference in the recurrence rate among treatment groups in girls with febrile infection in 8 of 43 (19%) on prophylaxis, 10 of 43 (23%) with endoscopic therapy and 24 of 42 (57%) on surveillance (p = 0.0002). In girls the recurrence rate was associated with persistent reflux after 2 years (p = 0.0095). However, reflux severity (grade III or IV) at study entry did not predict recurrence. CONCLUSIONS In this randomized, controlled trial there was a high rate of recurrent febrile urinary tract infection in girls older than 1 year with dilating vesicoureteral reflux at study entry but not in boys. Antibiotic prophylaxis and endoscopic treatment decreased the infection rate.

The Swedish Reflux Trial in Children: II. Vesicoureteral Reflux Outcome

PURPOSE We compared reflux status in children with dilating vesicoureteral reflux treated in 3 groups, including low dose antibiotic prophylaxis, endoscopic therapy and a surveillance group on antibiotic treatment only for febrile urinary tract infection. MATERIALS AND METHODS A total of 203 children 1 to younger than 2 years with grade III-IV reflux were recruited into this open, randomized, controlled trial. Endoscopic treatment was done with dextranomer/hyaluronic acid copolymer. The main end point was reflux status after 2 years. Data were analyzed by the intent to treat principle. RESULTS Reflux status improved in all 3 treatment arms. Of patients in the prophylaxis, endoscopic and surveillance groups 39%, 71% and 47%, respectively, had reflux resolution or downgrading to grade I-II after 2 years. This was significantly more common in the endoscopic than in the prophylaxis and surveillance groups (p = 0.0002 and 0.0030, respectively). After 1 or 2 injections 86% of patients in the endoscopic group had no or grade I-II reflux but recurrent dilating reflux was seen in 20% after 2 years. CONCLUSIONS Endoscopic treatment resulted in dilating reflux resolution or downgrading in most treated children. After 2 years endoscopic treatment results were significantly better than the spontaneous resolution rate or downgrading in the prophylaxis and surveillance groups. However, of concern is the common reappearance of dilating reflux after 2 years.

The Swedish Reflux Trial in Children: V. Bladder Dysfunction

PURPOSE We investigated the prevalence and types of lower urinary tract dysfunction in children with vesicoureteral reflux grades III and IV, and related improved dilating reflux, renal damage and recurrent urinary tract infection to dysfunction. MATERIALS AND METHODS A total of 203 children between ages 1 to less than 2 years with reflux grades III and IV were recruited into this open, randomized, controlled, multicenter study. Voiding cystourethrography and dimercapto-succinic acid scintigraphy were done at study entry and 2-year followup. Lower urinary tract function was investigated by noninvasive methods, at study entry with 4-hour voiding observation in 148 patients and at 2 years by structured questionnaire and post-void residual flow measurement in 161. RESULTS At study entry 20% of patients had lower urinary tract dysfunction, characterized by high bladder capacity and increased post-void residual urine. At 2 years there was dysfunction in 34% of patients. Subdivision into groups characteristic of children after toilet training revealed that 9% had isolated overactive bladder and 24% had voiding phase dysfunction. There was a negative correlation between dysfunction at 2 years and improved dilating reflux (p = 0.002). Renal damage at study entry and followup was associated with lower urinary tract dysfunction at 2 years (p = 0.001). Recurrent urinary tract infections were seen in 33% of children with and in 20% without dysfunction (p = 0.084). CONCLUSIONS After toilet training a third of these children with dilating reflux had lower urinary tract dysfunction, mainly voiding phase problems. Dysfunction was associated with persistent reflux and renal damage while dysfunction at study entry did not predict the 2-year outcome.

Low bacterial counts in infants with urinary tract infection

We analyzed the number of colony-forming units in urine cultures obtained by suprapubic aspiration in a group of 366 unselected infants with symptomatic urinary tract infection to relate these findings to factors such as pyuria and vesicoureteric reflux. Seventy-three (20%) of 366 infants had fewer than 100,000 colony-forming units per milliliter. Such low counts were significantly related to low numbers of leukocytes in the urine. Vesicoureteric reflux was equally distributed among children, irrespective of the number of bacteria in quantitative culture. The findings emphasize the importance of sampling technique; in infants, the method of choice is suprapubic aspiration, or catheterization, which eliminates the risk that urinary tract infection is overlooked because of low bacterial counts.

The Swedish Reflux Trial in Children: I. Study Design and Study Population Characteristics

PURPOSE We compared the rates of febrile urinary tract infection, kidney damage and reflux resolution in children with vesicoureteral reflux treated in 3 ways, including antibiotic prophylaxis, endoscopic therapy and surveillance with antibiotics only for symptomatic urinary tract infection. MATERIALS AND METHODS Children 1 to younger than 2 years with grade III-IV reflux were recruited into this prospective, open, randomized, controlled, multicenter study and followed for 2 years after randomization. The main study end points were recurrent febrile urinary tract infection, renal status on dimercapto-succinic acid scintigraphy and reflux status. Outcomes were analyzed by the intent to treat principle. RESULTS During a 6-year period 128 girls and 75 boys entered the study. In 96% of cases reflux was detected after urinary tract infection. The randomization procedure was successful and resulted in 3 groups matched for relevant factors. Recruitment was slower than anticipated but after patients were entered adherence to the protocol was good. Of the children 93% were followed for the intended 2 years without a treatment arm change. All except 2 patients completed 2-year followup scintigraphy. CONCLUSIONS Recruitment was difficult but a substantial number of children were entered and randomly assigned to 3 groups with similar basic characteristics. Good adherence to the protocol made it possible to address the central study questions.

Parental experiences and preferences regarding the treatment of vesicoureteral reflux

Abstract Objective. Dilating vesicoureteral reflux (VUR) has been linked to febrile urinary tract infection (UTI) and renal scarring. It is unclear, however, whether children with reflux should be treated surgically or medically, or just kept under close surveillance with prompt treatment of UTIs. This lack of evidence makes parental preferences a crucial factor in the choice of therapy. The Swedish Reflux Trial was set up to compare the three treatment alternatives prospectively. This paper focuses on parental experience and satisfaction after completing the trial. Material and methods. A group of 203 children aged 12–24 months with reflux grade III or IV were randomly assigned to antibiotic prophylaxis (n = 69), surveillance (n = 68) or endoscopic injection treatment (n = 66) and followed closely for 2 years. Afterwards, the families were interviewed by an investigator not involved in the care of the children about their experience of the study. Results. Parental satisfaction with the treatment given was high, with 53% scoring 5 and 35% 4 on a five-grade scale, with no difference between the three groups (p = 0.5). Recurrence of febrile UTI or new kidney scarring did not influence parental satisfaction. Even though the satisfaction was high regardless of therapy, parents of children in the prophylaxis group more often than others would have chosen another treatment if given a choice. Conclusions. As far as parental satisfaction and preferences are concerned, antibiotic prophylaxis, surveillance and injection treatment are equivalent treatment strategies in children with VUR.

Diagnosis and management of bladder bowel dysfunction in children with urinary tract infections: a position statement from the International Children’s Continence Society

BackgroundWe present a consensus view from the International Children’s Continence Society (ICCS) on the evaluation and management of bladder bowel dysfunction (BBD) in children with urinary tract infection (UTI). The statement aims to highlight the importance of BBD in the development and recurrence of childhood UTI and its management to reduce its associated morbidity and sequelae.MethodsA systematic literature search was done on PubMed, Embase, and Scopus databases until August 15, 2016. Relevant publications concerning BBD and its relationship with UTI among children were reviewed and aggregated for statements of recommendation. Discussion by the ICCS Board and a multi-disciplinary core group of authors resulted in a document available on its website for all ICCS members to review. Insights and feedback were considered with consensus and agreement reached to finalize this position statement.ResultsBBD in children with UTI is summarized. Details regarding epidemiology, pathophysiology, and recommendations for general and family practitioners and pediatricians relating to the evaluation and management of this condition are presented.ConclusionsThis document serves as the position statement from ICCS, based on literature review and expert opinion providing our current understanding of BBD in children with UTI.

Uropathogen Resistance and Antibiotic Prophylaxis: A Meta-analysis

The benefit of prophylaxis must be weighed against its risks. In this meta-analysis, we quantify the risk of developing a multidrug-resistant recurrent UTI. CONTEXT: Limited data exist regarding uropathogen resistance in randomized controlled trials of urinary tract infection (UTI) prevention and antibiotic prophylaxis. OBJECTIVE: To assess the effect of prophylaxis on developing a multidrug-resistant first recurrent UTI among children with vesicoureteral reflux. DATA SOURCES: Cochrane Kidney and Transplant Specialized Register through May 25, 2017. STUDY SELECTION: Randomized controlled trials of patients ≤18 years of age with a history of vesicoureteral reflux being treated with continuous antibiotic prophylaxis compared with no treatment or placebo with available antibiotic sensitivity profiles. DATA EXTRACTION: Two independent observers abstracted data and assessed quality and validity per Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Adjusted meta-analyses were performed by using a mixed-effects logistic regression model. RESULTS: One thousand two hundred and ninety-nine patients contributed 224 UTIs. Patients treated with prophylaxis were more likely to have a multidrug-resistant infection (33% vs 6%, P < .001) and were more likely to receive broad-spectrum antibiotics (68% vs 49%, P = .004). Those receiving prophylaxis had 6.4 times the odds (95% confidence interval: 2.7–15.6) of developing a multidrug-resistant infection. One multidrug-resistant infection would develop for every 21 reflux patients treated with prophylaxis. LIMITATIONS: Variables that may contribute to resistance such as medication adherence and antibiotic exposure for other illnesses could not be evaluated. CONCLUSIONS: Prophylaxis increases the risk of multidrug resistance among recurrent infections. This has important implications in the risk-benefit assessment of prophylaxis as a management strategy and in the selection of empirical treatment of breakthrough infections in prophylaxis patients.

Novel de novo AVPR2 Variant in a Patient with Congenital Nephrogenic Diabetes Insipidus

Early diagnosis and treatment of congenital nephrogenic diabetes insipidus (CNDI) are essential due to the risk of intellectual disability caused by repeated episodes of dehydration and rapid rehydration. Timely genetic testing for disease-causing variants in the arginine vasopressin receptor 2 (AVPR2) gene is possible in at-risk newborns with a known family history of X-linked CNDI. In this study, a Swedish male with no family history was diagnosed with CNDI at 6 months of age during an episode of gastroenteritis. We analyzed the coding regions of AVPR2 by PCR and direct DNA sequencing and identified an 80-bp duplication in exon 2 (GenBank NM_000054.4; c.800_879dup) in the proband. This variant leads to a frameshift and introduces a stop codon four codons downstream (p.Ala294Profs*4). The variant gene product either succumbs to nonsense-mediated decay or is translated to a truncated nonfunctional vasopressin V2 receptor. This variant was absent in four unaffected family members, including his parents, as well as in 100 alleles from healthy controls, and is thus considered a novel de novo disease-causing variant. Identification of the disease-causing variant facilitated precise diagnosis of CNDI in the proband. Furthermore, it allows future genetic counseling in the family. This case study highlights the importance of genetic testing in sporadic infant cases with CNDI that can occur due to de novo variants in AVPR2 or several generations of female transmission of the disease-causing variant.