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Background Our objective was to analyze the evolution of kidney damage over time in small children with urinary tract infection (UTI) and factors associated with progression of renal damage. Methods From a cohort of 1003 children

INTRODUCTION Urinary tract infections (UTI) during childhood can result in permanent renal damage, with possible implications for future pregnancies. The aim of this prospective study was to investigate pregnancy outcomes in women followed after their first UTI in childhood. MATERIAL AND METHODS A cohort of 72 parous women was followed from their first UTI in childhood up to a median age of 41 years. Clinical data were obtained from antenatal and hospital records. Renal damage was evaluated by a (99m) Tc-dimercaptosuccinic acid scan. Pregnancy blood pressure (BP), complications and UTIs were compared between women with and without renal damage. RESULTS All women completed the investigations, 48 with and 24 without renal damage. No woman, irrespective of presence or absence of renal damage, was diagnosed with hypertension before the first pregnancy. Pregnancy-related hypertension was diagnosed in 10 of 151 pregnancies, all in women with renal damage. Preeclampsia occurred in four women. Women with renal damage had significantly higher systolic BP measured at the last antenatal visit of their first pregnancy, compared with women without renal damage (p = 0.005). During subsequent pregnancies both systolic and diastolic BP were significantly higher in women with than without renal damage (p = 0.02 and p = 0.03, respectively). CONCLUSION In this population-based follow-up study we found a large proportion of women with renal damage after UTI in childhood. Women with renal damage had significantly higher BP during pregnancy compared with women without renal damage. Pregnancy-related hypertension was recorded only in women with renal damage. However, pregnancy complications, including preeclampsia, were few.

In national guidelines for urinary tract infection (UTI) in children, different cut-off levels for defining bacteriuria are used. In this study, the relationship between bacterial count in infant UTI and inflammatory parameters, frequency of vesicoureteral reflux (VUR), kidney damage, and recurrent UTI was analyzed. We conducted a population-based retrospective study of 430 infants age

Urine biomarkers are commonly used in the evaluation of acute kidney injury, and are gaining attention as tools for studying urinary tract infections (UTIs). We analyzed neutrophil gelatinase-associated lipocalin (NGAL) and seven other urine biomarkers to evaluate their usefulness in the diagnosis of UTI in infants. Eight urine biomarkers were analyzed in 108 infants with UTI. Controls were 64 febrile children without UTI and 13 healthy children. Logistic regression and construction of receiver operating characteristic (ROC) curves were performed for UTI patients versus febrile controls for all biomarkers. The best biomarkers to differentiate between UTI and febrile controls were NGAL and interleukin 8 (IL8). Urine NGAL in absolute concentration and adjusted for creatinine had a sensitivity of 93% and 96% and a specificity of 95% and 100% for diagnosing UTI, with a cut-off concentration of 38 ng/mL and 233 ng/mg respectively. Urine biomarkers, particularly NGAL, can aid in the diagnosis of UTI among febrile infants. The results suggest that in infants with fever and high NGAL, UTI is most likely, whereas in infants with fever and low NGAL, other causes of fever should be looked for.

Urinary tract infection (UTI) is a common bacterial disease in small children in which treatment with antimicrobials is used. The worldwide increase of bacterial resistance to these drugs is threatening the efficacy of such treatment and may increase the risk for long-term damage. The aim of this retrospective study was to analyse the development of resistance to oral antimicrobials over a 10-year period in an unselected outpatient population of small children with first-time UTI. The patient material included 494 boys and 512 girls below 2 years of age with community acquired symptomatic UTI. Escherichia coli bacteria were isolated in 96 % of girls and 89 % of boys (p

Objective Functional urinary incontinence causes considerable morbidity in 8.4% of school-age children, mainly girls. To compare oxybutynin, placebo, and bladder training in overactive bladder (OAB), and cognitive treatment and pelvic floor training in dysfunctional voiding (DV), a multi-center controlled trial was designed, the European Bladder Dysfunction Study. Methods Seventy girls and 27 boys with clinically diagnosed OAB and urge incontinence were randomly allocated to placebo, oxybutynin, or bladder training (branch I), and 89 girls and 16 boys with clinically diagnosed DV to either cognitive treatment or pelvic floor training (branch II). All children received standardized cognitive treatment, to which these interventions were added. The main outcome variable was daytime incontinence with/without urinary tract infections. Urodynamic studies were performed before and after treatment. Results In branch I, the 15% full response evolved to cure rates of 39% for placebo, 43% for oxybutynin, and 44% for bladder training. In branch II, the 25% full response evolved to cure rates of 52% for controls and 49% for pelvic floor training. Before treatment, detrusor overactivity (OAB) or pelvic floor overactivity (DV) did not correlate with the clinical diagnosis. After treatment these urodynamic patterns occurred de novo in at least 20%. Conclusion The mismatch between urodynamic patterns and clinical symptoms explains why cognitive treatment was the key to success, not the added interventions. Unpredictable changes in urodynamic patterns over time, the response to cognitive treatment, and the gender-specific prevalence suggest social stress might be a cause for the symptoms, mediated by corticotropin-releasing factor signaling pathways. Neurourol. Urodynam. 33:482-487, 2014. (c) 2013 Wiley Periodicals, Inc.

The aim of this study was to describe the pattern of urinary tract infection (UTI) and bladder function in women who had experienced recurrent UTI in childhood, with and without consequent renal damage, and followed for three to four decades. A population-based cohort of women who had been followed from the first UTI in childhood and previously studied at a median age of 27 years was studied at a median age of 41 years. Renal damage was evaluated by 99mTc-dimercaptosuccinic acid scan. Clinical data were collected on the pattern of recurrent UTIs and bladder function. A total of 86 women were investigated, of whom 58 had suffered renal damage and 28 were without. Febrile UTI in adulthood had occurred in 22 patients, once in 15 women and twice or more in seven women. There was a change in the infection pattern over time, evident already in childhood, that was characterized by a decrease in UTI frequency and a shift from febrile to non-febrile infections. A significant association was found between renal damage and febrile UTI (p = 0.046), and between abnormal bladder function and recurrent non-febrile UTI (p = 0.002). There was no relationship between persisting vesicoureteral reflux (VUR) and proneness to either symptomatic UTI (p = 0.99) or febrile UTI in adulthood (p = 0.14). Among this study cohort there was a continuously decreasing rate of febrile UTI in adulthood. Persisting VUR was not related to UTI in adulthood. Abnormal bladder function was related to non-febrile UTI but not to febrile UTI.

To evaluate prophylaxis and endoscopic injection for children with dilating vesicoureteral reflux (VUR) compared to surveillance, regarding urinary tract infection (UTI) recurrence, new renal damage, VUR outcome, and impact of lower urinary tract (LUT) dysfunction on these outcomes.203 children (128 girls and 75 boys), aged 1 to2 years, with VUR grade III or IV were randomized to antibiotic prophylaxis (n = 69), endoscopic injection (n = 66) or surveillance (n = 68). Voiding cystourethrography, dimercaptosuccinic acid scintigraphy and optional LUT function assessment were performed before randomization and after 2 years.There were 67 febrile UTIs in 42 girls and 8 in 7 boys (p = 0.0001). In girls, recurrence rate was 19% on prophylaxis, 23% with endoscopic treatment and 57% on surveillance (p = 0.0002). In boys, there was no difference between treatment groups. New damage was seen in 13 girls: 8 on surveillance, 5 in the endoscopic group and none on prophylaxis (p = 0.0155), and in 2 boys. In 13 children with no or non-dilating VUR after 1 injection, dilating VUR reappeared at the 2-year follow up. LUT dysfunction at follow up was associated with persistence of VUR.In girls, prophylaxis reduced the rate of UTI recurrence and new renal damage, and endoscopic injection the rate of UTI recurrence. Boys did not benefit from active treatment.

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.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.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.As far as parental satisfaction and preferences are concerned, antibiotic prophylaxis, surveillance and injection treatment are equivalent treatment strategies in children with VUR.

We analyzed clinical data for prediction of permanent renal damage in infants with first time urinary tract infection.This population based, prospective, 3-year study included 161 male and 129 female consecutive infants with first time urinary tract infection. Ultrasonography and dimercapto-succinic acid scintigraphy were performed as acute investigations and voiding cystourethrography within 2 months. Late scintigraphy was performed after 1 year in infants with abnormality on the first dimercapto-succinic acid scan or recurrent febrile urinary tract infections. End point was renal damage on the late scan.A total of 270 patients had end point data available, of whom 70 had renal damage and 200 did not. Final kidney status was associated with C-reactive protein, serum creatinine, temperature, leukocyturia, non-Escherichia coli bacteria, anteroposterior diameter on ultrasound and recurrent febrile urinary tract infections. In stepwise multiple regression analysis C-reactive protein, creatinine, leukocyturia, anteroposterior diameter and non-E.coli bacteria were independent predictors of permanent renal damage. C-reactive protein 70 mg/l or greater combined with anteroposterior diameter 10 mm or greater had sensitivity of 87% and specificity of 59% for renal damage. An algorithm for imaging of infants with first time urinary tract infection based on these results would have eliminated 126 acute dimercapto-succinic acid scans compared to our study protocol, while missing 9 patients with permanent renal damage.C-reactive protein can be used as a predictor of permanent renal damage in infants with urinary tract infection and together with anteroposterior diameter serves as a basis for an imaging algorithm.

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.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.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.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.

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.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.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.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.

We studied variables with impact on cessation of congenital high grade vesicoureteral reflux in univariate analyses and provide a multivariate model for prediction of reflux resolution.A total of 80 male and 35 female infants (median age 2.7 months) were included in this prospective observational study. Of the cases 71% were diagnosed after urinary tract infection and 26% after prenatal ultrasound. Reflux was bilateral in 70% of the patients and maximum grade was III in 16%, IV in 45% and V in 39%. The study protocol included repeat videocystometries, renal scintigrams, chromium edetic acid clearances and free voiding observations. Median followup was 36 months.Overall spontaneous reflux resolution, including cases downgraded to grade I to II, was 38%. Variables significantly negatively correlated to resolution were breakthrough febrile urinary tract infection, bladder dysfunction, higher grade of reflux at inclusion, renal abnormality, subnormal renal function, increased bladder capacity, residual urine and passive occurrence of reflux. Multivariate Cox proportional hazard model with stepwise selection identified 3 independent predictors--renal abnormality (hazard ratio 0.45, 95% CI 0.31-0.64, p0.0001), bladder dysfunction (hazard ratio 0.43, 95% CI 0.29-0.64, p0.0001) and breakthrough urinary tract infection (hazard ratio 0.38, 95% CI 0.18-0.78, p = 0.009). Performance of the model was evaluated by the receiver operating characteristic curve, with a calculated area under the curve of 83%.Overall resolution rate in congenital high grade vesicoureteral reflux is high during the first years of life. By multivariate analyses renal abnormality, bladder dysfunction and breakthrough febrile urinary tract infection were identified as strong independent negative predictive factors for reflux resolution.

We sought to study renal abnormality and renal function through time in infants with high grade vesicoureteral reflux.This prospective observational study included 115 infants (80 boys and 35 girls) younger than 1 year with grade III to V vesicoureteral reflux. The diagnosis was made after prenatal ultrasound in 26% of the patients and after urinary tract infection in 71%. Patients were followed by renal scintigraphy, 51chromium edetic acid clearance and video cystometry. Median followup was 62 months.Renal abnormality, which was found in 90% of the children at followup, was generalized in 71% and focal in 29%. The abnormality was bilateral in 28% of the affected patients. Total glomerular filtration rate was less than 80% of expected in 30% of the patients. Single kidney function was less than 40% of expected total glomerular filtration rate in 71% of the patients. Renal status (parenchymal abnormality and function) remained unchanged through time in 84 of 108 available cases (78%), improved in 5 (5%) and deteriorated in 19 (18%). Predictive factors for deterioration were recurrent febrile urinary tract infection, bilateral abnormality and reduced total glomerular filtration rate. Deteriorated renal status was more common in cases diagnosed prenatally than in those detected after urinary tract infection.Among these infants with high grade vesicoureteral reflux renal abnormality was frequent and was associated with subnormal filtration of one of the kidneys. Decreased total glomerular filtration rate was seen in about a third of the patients. Overall deterioration of renal status was seen in only a fifth of the patients. Infection control seems to be an important factor to minimize the risk.

Jodal, U. (Institute of Medical Microbiology and Department of Pediatrics, University of Goteborg, Goteborg, Sweden). The immune response to urinary tract infections in childhood. I. Serological diagnosis of primary symptomatic infection in girls by indirect hemagglutination. Acta Paediatr Scand, 64:96, 1975.–Determination of antibodies to E. coli O antigen by indirect hemagglutination for detection of acute pyelonephritis was investigated in sequences of sera from 94 girls with their first known attack of symptomatic urinary tract infection. Using O antigen from the infecting bacterial strain or a standard strain increased antibody titres were found among pyelonephritis patients in 89% in unreduced sera (mainly 19 S antibodies) and in 81% in reduced sera (mainly 7 S antibodies) compared to a control material of 643 healthy children. Significant changes of these antibody titres occurred in 74 and 39% respectively. Analysis of maximal titres as well as titre changes in both unreduced and reduced sera showed diagnostic-ally significant changes in two or more of these four parameters in 89% of patients with pyelonephritis. In contrast one parameter with such changes was found among the cystitis patients in only 5%. Employing a pool of 8 common O antigens, increased antibody titres were detected in 76% of patients with pyelonephritis. A larger pool of 68 antigens was no better and had a low capacity to detect 7 S antibodies. Optimal time for blood sampling was 2 to 3 weeks after onset of symptoms.

The aim was to analyse the psychosocial factors of teenagers and young adults with myelomeningocele with at least 5 years' experience of clean intermittent catheterization (CIC).A qualitative interview technique with semi-structured questions was used in 22 participants aged 13-26 years (median 17) and issues addressed were information given to others, integrity, attitudes to other disabilities, friendship, partnership and sexuality.The participants wanted to inform their peers about the disability but often did not have the courage. Ignorance of the principle of self-CIC among medical staff was confusing. Urinary incontinence after the introduction of the self-CIC regimen was not seen as a problem in comparison with other major disabilities. Half of the participants had peers that they could call a best friend. The subjects wanted more specific information regarding their own sexual function. Finding a partner and becoming a parent were strongly desired but considered problematic.The participants wished to acquire more knowledge about CIC as a bladder-emptying method from the medical staff and also to have the respect to perform self-CIC at examinations. This study did not find any negative psychosocial factors associated with CIC.

We studied the relationship among vesicoureteral reflux, urinary tract infection and permanent renal damage in children.We retrospectively analyzed 303 children younger than 2 years with a first time, nonobstructive, culture verified urinary tract infection. The protocol included ultrasonography and voiding cystourethrography within 3 months after urinary tract infection, and (99m)technetium dimercapto-succinic acid scintigraphy after 1 to 2 years.Vesicoureteral reflux was found in 36 of 163 boys (22%) and in 44 of 140 girls (31%). Of the 303 patients 80 (26%) had permanent renal damage according to dimercapto-succinic acid scintigraphy. The rate of abnormality increased significantly with grade of vesicoureteral reflux in boys and girls. The relative risk of renal damage was significantly increased in patients with vesicoureteral reflux grade II and higher. Maximum C-reactive protein concentration, maximum temperature during urinary tract infection, presence of vesicoureteral reflux and febrile recurrences of urinary tract infection were significantly related to permanent renal damage. In stepwise logistic regression vesicoureteral reflux was the only independent variable for boys, while C-reactive protein and vesicoureteral reflux were independent factors for girls.There was a significant relationship between grade II vesicoureteral reflux and higher and permanent renal damage in boys and girls. However, while the association between renal damage and vesicoureteral reflux was evident in boys, the role of urinary tract infection and renal inflammation seemed to be equally or more important in girls. These findings support the concept that renal damage is associated with vesicoureteral reflux and is often congenital in boys, while in girls it is more related to urinary tract infection with vesicoureteral reflux as a reinforcing factor.

A critical survey of the literature on treatment of children with vesico-ureteric reflux was carried out in order to create a basis for the new Swedish management policy. There are few studies that meet modern standards of scientific methodology and provide adequate patient numbers. The only large investigations that randomized patients to operative or non-operative treatment were the Birmingham Reflux Study and the International Reflux Study in Children. In these studies, long-term outcome of renal status and renal function, as well as the number of recurrent infections, were independent of treatment modality. Although pyelonephritic recurrences were less common in the surgically managed group, this did not influence appearance of renal damage. There is no evidence to indicate clear superiority of either medical or surgical management. Further studies are needed to address such questions as the optimal duration of antibacterial prophylaxis and the effect of a dilating reflux that persists into adulthood.

UNLABELLED The aim of this study was to investigate whether birth size is associated with permanent renal damage in children with urinary tract infection (UTI). A cohort of 1221 children under 16 y of age was diagnosed with their first symptomatic UTI between 1970 and 1979. Of these, 74 had urographic renal scarring in childhood and 57 were re-examined as adults. The birth files of 48 of these patients (35F, 13M) were available, and birthweight and birthlength in relation to gestational age were analysed and compared with a Swedish reference population. Children who had renal damage without vesicoureteric reflux were significantly smaller at birth (median weight, -0.76 SDS) compared with both children who had renal damage and reflux (median weight, -0.01 SDS) and the reference population. CONCLUSION The demonstration of low birthweight among children with UTI and renal damage but no reflux suggests that low birthweight may be a risk factor for the development of renal damage.

UNLABELLED Short courses of antibiotics are often recommended to treat children with acute cystitis despite lack of firm evidence to support such management. The aim of this study therefore was to analyse the short-term outcome of such treatment. The retrospective analysis included 300 children (252F, 48M) fulfilling the criteria of first-time acute cystitis and managed according to a protocol recommending 5 d treatment. In 214 (71%) the treatment was given according to the protocol and in the others for 7 or 10 d. Nitrofurantoin was used in 150 (50%) and trimethoprim without or with sulfonamide in 129 (43%). The short-term results were excellent with 96% of the children being free from symptoms at the first follow-up visit after a median of 6 d. Only 2 girls had persisting bacteriuria and thus the frequency of bacteriological treatment failure was 1%. Recurrence within 30 d occurred in 4 girls (2%). CONCLUSION A 5 d treatment with antibiotics is adequate in children with acute cystitis. Routine follow-up visits after a first acute cystitis may not be necessary, providing that the bacteria causing the infection are sensitive to the prescribed antibiotic and that there is no history of defective bladder or bowel emptying.

The risk of deterioration of renal function in patients with urinary tract infection (UTI)-associated renal damage over several decades is incompletely known but of importance in regard to follow-up.A population-based cohort of women followed from their first UTI in childhood was studied at median age of 27 years and now at 41 years. Renal damage was evaluated by (99m)Tc-dimercaptosuccinic acid scan and glomerular filtration rate (GFR) by (51)Cr-edetic acid clearance. Extent of individual kidney damage was graded as class 1 to 3.Eighty-six women completed the investigation, 58 with renal damage, and 28 without. Of those with damage, one had chronic kidney disease (CKD) stage 3, 14 stage 2, and 43 stage 1. Women with bilateral damage had lower GFR than those with no or unilateral damage (p 0.0001). Women with class 3 damage had numerically but not significantly lower GFR than the others with damage (p = 0.07). Between the two studies there was significant decrease of GFR in the group with bilateral damage (p = 0.01).Women with UTI-associated renal damage had remarkably well preserved renal function, but those with bilateral or severe individual kidney damage may be considered for regular monitoring of GFR and blood pressure.

For the comparison of long-term outcome of the management of medical or surgical treatment of children with severe vesicoureteral reflux (VUR), children aged

Purpose: We study the ability of dimercapto-succinic acid (DMSA) scintigraphy to predict the presence of dilating vesicoureteral reflux (VUR) in infants with urinary tract infection (UTI) to simplify the evaluation protocol. Materials and Methods: A retrospective analysis of the records of 303 children younger than 2 years with initial UTI investigated with DMSA scintigraphy and voiding cystourethrography (VCU) within 3 months after UTI was performed. Results: In 156 of the 303 children (51%) DMSA scintigraphy showed renal lesions. VUR was found in 80 patients (26%) and VUR grade significantly correlated with the presence of renal lesions. A normal DMSA scintigraphy and dilating VUR (grade III) occurred in 7 infants. At followup after 1 to 2 years, 6 of these 7 patients had normal DMSA scans and 1 had a scarred duplex kidney. VUR resolved spontaneously in 5 and improved spontaneously to grade 1 in 2 patients. None of the 7 children had recurrent UTI. Conclusions: DMSA scintigraphy in infants with UTI may replace VCU as a first line investigation. A strategy to perform VCU in only patients with renal lesions is proposed. In this study 147 of 303 VCUs would have been unnecessary as only 1 child with a damaged kidney was missed.

The International Reflux Study in Children was set up to compare prospectively the outcome of medical or surgical management of children with grade III or IV vesicoureteral reflux and a history of symptomatic urinary tract infection. Development of new radiological scars was the main end point. Of the 306 children randomized, 302 (153 medical, 149 surgical) were available for radiological follow-up at 5 years. New scars had developed in 19 medically and 21 surgically treated children. Among 223 patients (113 medical, 110 surgical) who continued follow-up with urography at 10 years, only 2 further new scars developed. Overall, 47 new scars were acquired in 42 patients (20 medical, 22 surgical), 25 of them in children with unscarred kidneys at entry (13 medical, 12 surgical). New scars occurred mostly in children under 5 years of age and were observed more frequently in children with grade IV than grade III reflux. We conclude that with careful management, only a small proportion of children with severe reflux developed new scars and rarely after the first 5-year follow up period, and that there was no difference between children treated medically or surgically.

Objective Ultrasonography (US) is commonly used to visualize the upper urinary tract in children and adolescents with meningomyelocele (MMC). The aim of this investigation was to prospectively evaluate US in those with spinal angulation or obesity and compare it to the corresponding results obtained by mercaptoacetyltriglycine renography. Patients and methods Twenty-five children and adolescents with MMC and pronounced angulation of the spine or obesity, were prospectively investigated with both US and renography during the period 2006 to 2008. Results In 13 (52%) patients the kidneys could not be fully evaluated; in 4 (16%) neither renal size nor pelvic dilation, in 12 (48%) renal length and in 5 (20%) dilation was not accessible. In 23 individuals where dilatation could be evaluated uni- or bilaterally, US was compared to OEE% (%outflow excretion efficiency) at renography. In 1 of these individuals there was normal OEE% while slight dilatation on US was noticed. In 2/15 individuals, split function at renography did not correlate with renal length on US. Conclusion Severe spinal angulation and obesity in individuals with MMC reduced the possibility to evaluate the urinary tract by US. However, it seems that renography could be a reliable alternative to evaluate renal condition in those patients where US is insufficient.

To study 24-h ambulatory blood pressure (BP) and development of hypertension over four decades in women with childhood urinary tract infection (UTI) associated with renal damage.A population-based group of 111 women was followed from their first UTI in childhood. The cohort was investigated at a median age of 27 years using standardized office BP measurement and was reinvestigated 15 years later with 24-h ambulatory BP monitoring (ABPM) and Tc-dimercaptosuccinic acid scan for evaluation of renal damage.Eighty-six women with median age 41 years completed the reinvestigation. Hypertension occurred in 26 women, four of 28 (14%) without and 22 of 58 (38%) with renal damage (P = 0.04). The hypertension was diagnosed before entry in seven and in the study by ABPM in another 19 women. In 78 women, of which 50 had renal damage, the ABPMs were correlated to renal damage. There was significant difference between the groups without and with renal damage when mean 24-h systolic, mean daytime systolic and mean night-time SBP were compared (P = 0.03, P = 0.04, P = 0.01, respectively). The results remained significant when the group with damage was divided into subgroups with increasing extent of damage: class 1, 2 and 3 (P = 0.01, P = 0.02, P = 0.008, respectively).Women with UTI-associated renal damage but well preserved function had significantly higher 24-h ambulatory BP and more often hypertension than comparable women without damage. This shows that women with UTI-associated renal damage are at increased risk of hypertension and should be considered for regular BP screening, preferably with 24-h ABPM.

We report the detection and progression of renal scars in girls prospectively followed from their first recognized urinary tract infection. There were 107 infection-prone subjects with a median age of 7.1 years at the first and 21.7 years at the last urography. Of 51 females who ultimately had lesions, 38 had established scars at the first urography. In 18 subjects, new scars were found in previously undamaged kidneys, 5 already with unilateral scarring. There had been a normal urography after the 5th birthday in 8 of those with later scarring. Worsening of scarring was seen in 10 of the 38 subjects with established scars. The renal damage was in most cases slight or moderate. By stepwise logistic regression analysis, grade of reflux and number of pyelonephritic attacks correlated with scarring, and number of pyelonephritic attacks with new scars and worsening of the lesions. In summary, of the females who ultimately had renal lesions, one-third developed new scars. In most of those with established scars at the first urography, the focal character of lesions suggests that most were also acquired. Since reflux and number of pyelonephritic attacks were identified as risk factors, prevention of renal deterioration should be possible.

Renal duplication is the most common malformation of the urinary tract and is frequently seen among children with urinary tract infection (UTI).To evaluate problems in the interpretation of dimercaptosuccinic acid (DMSA) scintigraphy and to establish the range of relative function in uncomplicated unilateral duplication.Retrospective analysis of 303 children less than 2 years of age with first time non-obstructive urinary tract infection investigated by both urography and DMSA scintigraphy. At DMSA scintigraphy, renal lesions and/or relative function below 45% was considered abnormal. Urography was used as reference for the diagnosis of duplication.Duplex kidneys were found in 22 of 303 patients (7%). Of the 16 children with unilateral duplication, 10 had bilaterally undamaged kidneys with a range of relative function varying between 51% and 57% in the duplex kidney. In two of the children with unilateral duplication the imaging results were discordant.There was risk of underdiagnosis as well as overdiagnosis of renal damage at scintigraphy. Although it is important to be aware of this risk, the rate of misinterpretation was low. A range of 51% to 57% can be used as the limit for normality of the relative function of a unilateral duplex kidney.

There are considerable variations in the management of children with urinary tract infection and reflux. These new guidelines were written after critical review of the literature, but are also based on clinical experience, since there are issues that have not been otherwise adequately studied. The aim is to limit renal damage and future complications, with minimal discomfort to the child, and to avoid unnecessary costs. The recommendations include increased attention to bladder dysfunction, shortening of the time of antibacterial prophylaxis and focus on renal development and function rather than on reflux.

Purpose: We studied the urodynamic pattern in infants with urinary tract infection and evaluated the influence of the infection.Materials and Methods: Cystometry was combined with voiding cystourethrography (video cystometry) and 90 male and 68 female infants admitted to the hospital with first time urinary tract infection. Evaluation was performed 1 to 30 days (mean 11) and 32 to 78 days (mean 46) after diagnosis in 93 and 65 infants, respectively.Results: Bladder instability was found in two-thirds of male and female infants. Compared to older children male infants had high voiding detrusor pressure and low bladder capacity (hypercontractility). Female infants also had increased voiding pressure levels but they were significantly lower than those in male infants. The voiding detrusor pressure was even higher in both sexes when evaluation was delayed after the infection.Conclusions: Infants with urinary tract infection have bladder instability and hypercontractility compared to older children. Bl...

The identification of bacteria 1 century ago soon led to the finding of microorganisms in the urine and to the description of children with urinary tract infection (UTI). An early report by Goppert described different clinical presentations and pointed out that it is a common disease of endemic character. 5 He also described a mortality rate of 20% in infants and small children with febrile UTI. Effective therapy was not available until the introduction of the sulfonamides during the 1930s, but since then the further development of antibiotics and an increased awareness of the high frequency of UTI in children together with improved diagnostic methods have decreased acute mortality to close to zero in industrialized countries. Urinary tract infection is the term used for a mixture of diseases of different causes with growth of bacteria within the urinary tract in common. There is a great variation in the clinical presentation. In some individuals, bacteriuria causes no symptoms and only screening of healthy children can reveal its existence. Symptoms vary from foul smelling urine, dysuria, and loin pain to peaking fever and signs of circulatory shock. Many children have only one episode of UTI; others have repeated infections. Some children develop permanent renal damage that potentially can lead to hypertension, pregnancy complications, and even renal failure. It is a complex pattern dominated by benign episodes of UTI but with a large proportion of potentially serious infections; these children need to be diagnosed, treated, investigated, and followed-up on. Our knowledge of the natural history of UTI in childhood is still incomplete. There are several reasons for this. Most children with UTI are managed at the primary care level, each practitioner handling only a restricted number of children. It is therefore difficult to create population-based registries that are necessary for large epidemiologic studies. Furthermore, the course of UTI often runs over several decades, and to follow patients over such long periods of time is difficult. Finally, there is the continuous change in the management that influences and hopefully improves the long-term prognosis but which also can make comparisons between different time periods difficult. An example of this is the switch from urography to dimercaptosuccinic acid (DMSA) scanning to study renal damage that is going on in many centers. 4 During the first half of the 1960s, Jan Winberg et al performed pioneering studies on UTI in children in Goteborg. They introduced a standardized protocol for diagnosis, treatment, investigation, and follow-up and encouraged the primary care doctors to refer children suspected to have UTI to the Children's Hospital. A special UTI clinic was created to provide an instrument for efficient long-term follow-up but also to manage the children whenever a recurrence was suspected. A close cooperation evolved, especially with the departments of pediatric radiology and microbiology and several important papers were published. 34,35 The Goteborg Childhood UTI Research Group has been continuously functioning since 1960 and still uses basically the same protocol, although the focus of interest and the members have changed over the years. This article describes the local organization and the protocol for management of children with UTI in Goteborg. Further, it gives selected aspects of the natural history of UTI in childhood focusing on results from the authors' study group.

We studied echocardiographically 17 children with depletion of carnitine due to treatment over 1–3 years with antibiotics containing pivalic acid. When the children were depleted of carnitine, the left ventriclar posterior wall was significantly thickened in diastole when compared to a reference group. Six months later, after normalisation of the concentrations of carnitine, the left ventricular posterior wall was significantly thinner and did not differ from the reference group. We conclude that drugs containing pivalic acid, when given for several months, decrease the stores of carnitine to levels where cardiac involvement occurs.

Objective To study changes in the urodynamic pattern during the first year of life in patients with myelomeningocele (MMC) and to correlate these to deleterious effects on the upper urinary tract. Patients methods Thirty-four infants with MMC were investigated using cystometry, micturating cysto-urethrography and urography at 1, 4 and 10 months of age. Results Detrusor contractility was characterized by an increase in activity, with hyper-reflexia in 45% initially, increasing to 65% at the 4-month investigation. During the same period, the number of infants with areflexia decreased from 25% to 12%. Between 4 and 10 months, there were only minor changes in detrusor contractility. The number of patients with poorly compliant bladders also increased between the first and fourth month. The number of patients with elevated outlet resistance increased only slightly during the first year, from 32% of all infants at the initial investigation to 40% at the 10-month follow-up. Vesico-ureteric reflux was detected in 12 of the patients during the year, with five already diagnosed at the first investigation. Almost all refluxes were cured with clean intermittent catheterization, with additional pharmacological therapy in two patients; one patient required a vesicostomy. Conclusions This study indicates that detrusor activity, and to some extent outlet resistance, change during the first year of life in infants with MMC. The changes were mainly increases in activity and occurred mostly between the first and fourth months of age. There was a strong correlation between the occurrence of reflux and poor compliance, hypercontractility and outlet obstruction.

This prospective study analyzed the intestinal carriage of P fimbriated Escherichia coli as a host susceptibility factor in urinary tract infection (UTI). P fimbriation was defined by the pap and G adhesin (papG1A2, prsGJ96) genotypes. Children with UTI carried pap+ E. coli in the fecal flora more often than healthy controls both at diagnosis (86% vs. 29%) and during infection-free intervals (approximately 40%; P < .01). P1 blood group-positive children carried pap+ E. coli in the fecal flora more often (88%) than those with P2 blood group (40%; P < .05). A pap+ E. coli strain caused UTI in 53 of 55 patients who carried both pap+ and pap- strains in their fecal flora. These results suggest that persons who develop UTI have an increased tendency to carry pap+ E. coli in the large intestine and that these pap+ E. coli cause UTI more often than pap E. coli strains in the fecal flora of the same host.

To assess life situation, and bladder and bowel management in individuals with myelomeningocele (MMC) after transferal to adult medical care.All individuals (134) with myelomeningocele from western Sweden, born before 1981, and assessed on at least two occasions by a pediatric urologist, were invited to participate in a telephone interview according to a structured protocol. Sixty-nine individuals (32 males, 37 females) with a median age of 34 years (range 27-50) agreed to participate.Sixty-two individuals (90%) passed high school or had university education and 46 (67%) were employed. Fifty-three (77%) had their own apartment and 27 (39%) lived with a partner. Clean intermittent catheterization was used by 49 (71%), more commonly in females (p 0.05). Pads were used by 60 (87%) individuals. Ten (14%) had urotherapy support. Of those operated on, 16 (53%) had a consultation with a urologist every 3 years; the corresponding number for the non-operated was 12 (31%). Eight individuals were treated with anticholinergic drugs. None had support for improvement of the fecal emptying regimen.Of the participants in the study, one third had no or rare contact with a urologist, few had urotherapy support and none had support for bowel regimen.

Long-term treatment with pivalic acid prodrug results in impaired ketone-body production. Therefore, it was of interest to investigate whether short-term treatment had any influence on the fatty acid oxidation. In this study six healthy males were given 1200 mg per day of pivmecillinam for 12 days to induce carnitine deficiency. The concentration of free carnitine in serum was reduced from a mean of 42.8 mumol/liter (range, 31-48) to 11.6 mumol/liter (range, 7.0-24), but the muscle carnitine concentration was not reduced. A 36-h fasting test was performed before and after drug administration to study the effect on ketone-body production. After treatment, the two subjects with the lowest level of serum free carnitine at the end of the fasting period had impaired ketogenesis. This indicates a carnitine deficiency in the liver which was reflected in the free carnitine concentration for by mobilization of muscle carnitine. We conclude that there is a substantial risk to develop carnitine deficiency and impaired fatty acid oxidation in the liver during short-term treatment with drugs conjugated with pivalic acid.

Hemolysins are cytolytic proteins which have been extensively characterized at the molecular level, however, their in vivo functions remain unclear. This study analyzed the association of hemolysin production with the inflammatory response in patients with urinary tract infection (UTI). Infants and children with their first episode of UTI (n = 644) were followed prospectively. The body temperature, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), urinary leucocyte count and renal concentrating capacity were used as measures of the inflammatory response. The hemolytic genotype (hly) of the Escherichia coli strain from each UTI episode was defined by DNA-DNA hybridization, and the phenotype by hemolysis in blood agar. There was no significant increase in the level of fever, CRP, ESR, or decrease in renal concentrating capacity during UTI episodes caused by hly positive compared to hly negative E. coli. Multiple regression analysis did not demonstrate significant associations of hly with elevated fever, CRP, ESR or reduced renal concentrating capacity. In contrast, patients infected with P fimbriated E. coli strains had higher fever, CRP, ESR and lower renal concentrating capacity than those infected with other strains. This association was not influenced by the hly genotype of the P fimbriated strains. The frequency of hly+ strains was not significantly higher in the subset of patients assigned a diagnosis of acute pyelonephritis compared to asymptomatic bacteriuria. This was in contrast to P fimbriae, which were accumulated in acute pyelonephritis. The results suggested that the acute inflammatory response to E. coli UTI is independent of hemolysin production. The inflammatogenic potential of uropathogenic E. coli clones was better described by the presence or absence of P-fimbriae than by hemolysin.

The mucosal immune system identifies and fights invading pathogens, while allowing non-pathogenic organisms to persist. Mechanisms of pathogen/non-pathogen discrimination are poorly understood, as is the contribution of human genetic variation in disease susceptibility. We describe here a new, IRF3-dependent signaling pathway that is critical for distinguishing pathogens from normal flora at the mucosal barrier. Following uropathogenic E. coli infection, Irf3−/− mice showed a pathogen-specific increase in acute mortality, bacterial burden, abscess formation and renal damage compared to wild type mice. TLR4 signaling was initiated after ceramide release from glycosphingolipid receptors, through TRAM, CREB, Fos and Jun phosphorylation and p38 MAPK-dependent mechanisms, resulting in nuclear translocation of IRF3 and activation of IRF3/IFNβ-dependent antibacterial effector mechanisms. This TLR4/IRF3 pathway of pathogen discrimination was activated by ceramide and by P-fimbriated E. coli, which use ceramide-anchored glycosphingolipid receptors. Relevance of this pathway for human disease was supported by polymorphic IRF3 promoter sequences, differing between children with severe, symptomatic kidney infection and children who were asymptomatic bacterial carriers. IRF3 promoter activity was reduced by the disease-associated genotype, consistent with the pathology in Irf3−/− mice. Host susceptibility to common infections like UTI may thus be strongly influenced by single gene modifications affecting the innate immune response., Author Summary The host immune system must identify pathogens and defeat them through TLR-dependent signaling pathway activation, while distinguishing them from commensal flora. Contrary to current dogma, the host cannot solely use “pattern recognition” since the microbial molecules involved in such recognition are present on pathogens and commensals alike. We identify here a pathogen-specific mechanism of TLR4 activation and signaling intermediates in this pathway, leading to IRF3-dependent transcription of innate immune response genes. We show in knockout mice that Irf3 deficiency causes severe tissue pathology and that effector functions controlled by IFNβ are involved. Finally, in highly disease-prone pyelonephritis patients we found a high frequency of IRF3 promoter polymorphism compared to asymptomatic bacterial carriers or controls. The polymorphisms influenced promoter activity in reporter assays, suggesting that they are functionally important. Urinary tract infections are among the most common bacterial infections in man, and are a major cause of morbidity and mortality. A subset of disease-prone individuals is at risk for recurrent disease, severe renal dysfunction and end-stage renal disease. At present, there is no method to identify disease-prone infants and to prevent future morbidity and renal damage. The genetic and functional studies described here indicate that genetic variation in IRF3 influences individual susceptibility to kidney infection and might serve as a new tool for future risk assessment in this patient group.

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.

Reference values are reported for maximal renal concentrating capacity in children using intranasally administered desmopressin. The report is based on 591 tests in 473 healthy children aged 0.5-13 years. The concentrating capacity increased markedly during the first years of life and reached a plateau at the age of 3 years. The mean value minus two standard deviations was 525 mosmol/kg at 1 year of age and 825 mosmol/kg at 3 years of age.

In a prospective study 101 children aged less than 2 years (median age 10 months), were examined the first time they were admitted to a paediatric ward for asthmatic symptoms. Two-thirds were boys and 58 had parents or siblings with allergic symptoms. During winter-spring, respiratory syncytial (RS) virus was verified in 50% of children. Other viral agents were adenovirus, parainfluenza 3, coxsackie B 2, ECHO 6 and rotavirus. At the acute stage, 54% of the children displayed changes on pulmonary X-ray. The total IgE value was greater than or equal to +2 SD score units in 14 children. At reinvestigation after 3-4.5 years, when the children were aged 3.3-6.3 years, 53% were free from asthmatic symptoms; the median age for the last episode was 2 years. A total of 33% had mild asthma, 8% moderate and 6% severe asthma. The factors which correlated significantly with persistent asthma were: (1) The need for daily medication for at least 6 months. (2) A young age in conjunction with the first wheezing episode and on the first admission to a paediatric ward because of asthmatic symptoms. (3) Other past or present atopic symptoms. Heredity, tobacco smoking at home, having a furry pet, RS virus infection, or high total IgE at the time of the first admission did not correlate significantly with the persistence of asthma 3-4.5 years later. The results emphasize the good overall prognosis of wheezing in early childhood, even when the wheezing is severe enough to lead to inpatient treatment.

Treatment of 17 children aged 2-9.5 years with a combination of pivmecillinam and pivampicillin (250-500 mumol 24 h-1) for more than 1 year resulted in a reduction of the free carnitine concentration in serum and muscle to less than 10% of the mean reference value. The decline in serum was slow, with an estimated half-life of about 5 months. Spontaneous replenishment occurred at about the same slow rate. Thus, there is no increase in endogenous carnitine synthesis as a response to increased demand of carnitine for detoxification. Supplementation with carnitine during treatment required at least a four-fold molar excess over pivalic acid to achieve and sustain a normal carnitine concentration. The replenishment of carnitine occurred with a half-life of 1.1-3.0 months. From determination of muscle-carnitine concentration in patients treated with pivaloyl-containing antibiotics and in patients with organic aciduris, we conclude that serum carnitine is a good predictor of carnitine stores in the body. Six non-supplemented patients with a serum free-carnitine concentration of 0.7-2.6 mumol l-1 had an inadequate ketone-body increase during a 24-h fast. Vomiting, nausea and tiredness occurred in three cases following the fasting period. After normalization of the serum-carnitine concentration, a normal response to fasting was observed. Thus, in some organic acidurias, for example medium-chain acyl-CoA dehydrogenase deficiency, a low liver concentration of carnitine may be an important contributing factor to hypoglycaemic and Reye-like attacks. We believe that prodrugs which contain pivalic acid should be avoided if acceptable alternatives exist. If used, supplementation with at least four-fold molar excess of carnitine is advisable.