Urinary tract infection: one lingering effect of childhood kidney diseases--review of the literature

Urinary tract infection (UTI) is a possible warning sign of the presence of anomalies of the urinary tract. Following a UTI there is concern with recurrences which can contribute to scarring which may lead to hypertension, pregnancy-induced hypertension and even renal failure in later years. Prospective studies using 99mTc-labeled dimercaptosuccinic acid (DMSA) have shown that 30%-40% of children will have renal scarring after febrile UTI, regardless of the presence or absence of vesicoureteral reflux (VUR). Many studies have demonstrated that VUR is an important risk factor for renal scarring after UTI. Hypertension affects at least 10% of children with renal scarring, and in adults with reflux nephropathy (RN), the prevalence of hypertension is also much higher (38%-50%). UTI, pregnancy-induced hypertension (PIH) or renal function deterioration alone or in some combination has been reported to be as high as 39% in women with renal scarring. RN is one of the important causes of end-stage renal disease (ESRD) worldwide. Prevention of renal scar development should reduce the incidence of hypertension in patients as they age. The appropriate management of childhood UTI includes education of parents, patients and general physicians to be sure that everyone is aware of not only the current condition, but also the possibility of future UTI-related situations. In conclusion: UTI itself is a warning sign of possible anomalies of the urinary tract, renal problems and/or chronic renal complications. Although VUR is primarily a disease of childhood, scarring from the disease can cause problems in later years, with the complicating factor that because only the renal scar remains, the VUR may be forgotten and not considered when diagnosing the current problem.     

Up-regulation of urinary UPIII mRNA levels in vesicoureteral reflux patients: Potential application as a screening test for vesicoureteral reflux

OBJECTIVES: Vesicoureteral reflux (VUR) is the most common congenital urinary tract anomaly. This disease can pose a major threat to the kidneys as twenty percent of patients with endstage renal disease are reported to have VUR. Although genetic studies for uroplakin III (UPIII) have been reported recently, no study has focused on UPIII gene expression in VUR patients. We describe here the up-regulation of UPIII mRNA in exfoliated urinary cells from primary VUR patients. METHODS: A real-time RT-PCR for UPIII mRNA was performed on exfoliated urothelial cells from 18 primary VUR and 38 control samples. UPIII mRNA copies were calculated for each sample. The statistical differences were assessed by the Mann-Whitney U test. Receiver operator characteristic curves were constructed for analysis of the diagnostic values. RESULTS: UPIII mRNA was found to be up-regulated to a greater extent in VUR than in control exfoliated urinary cells (mean +/- SE: 497.0 +/- 178.5 copies vs. 69.0 +/- 10.0 copies, respectively, P < 0.001). In evaluating the measurement of urinary UPIII mRNA as a screening test for VUR, the sensitivity was 77.8% and the specificity was 76.3% by the best diagnostic cutoff point. CONCLUSIONS: This is the first report demonstrating up-regulation of UPIII in mRNA levels in VUR patients. We submit that the quantitative measurement of urinary UPIII mRNA has a potential of developing into the first non-invasive screening test for VUR.     

Infections and vesicoureteral reflux

Vesicoureteral reflux (VUR) is a common condition in children. It may cause and maintain urinary tract infections, eventually leading to progressive renal damage and end-stage renal disease. Ideally, VUR should be detected and treated before renal scarring occurs. Although fetal hydronephrosis on antenatal ultrasound may be the first indicator, the role of further diagnostic investigations in these newborns is still controversial. Because VUR is an inherited condition, offspring of women with a family history of VUR and urinary tract infection should be screened closely for early detection of VUR. Once diagnosed, however, the optimal management of VUR (i.e. medical or surgical treatment) remains controversial. Evidence-based treatment recommendations, like the American Urological Association guidelines, may aid physicians in their therapeutic decision making, but cannot replace personal experience or surgical skill.     

Vesicoureteral reflux and urinary tract infections

Urinary tract infection is a common problem in children. The combination of vesico-ureteric reflux (VUR) and urinary tract infection may predispose children to pyelonephritis and subsequent complications. This review outlines the modifications suggested in the recent literature in the protocol for investigations and diagnosing VUR. Recent interest has been expressed in studying certain molecular markers to measure non-invasively renal damage in children with VUR. Long term results of comparative trials between medical and surgical management have been published recently.     

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。     

Vesico-ureteric reflux: using mouse models to understand a common congenital urinary tract defect

Vesico-ureteric reflux (VUR) is a common congenital urinary tract defect in which urine flows retrogradely from the bladder to the kidneys because of an abnormally formed uretero-vesical junction. It is associated with recurrent urinary tract infections, renal hypo/dysplasia, reflux nephropathy, hypertension, and end-stage renal disease. In humans, VUR is genetically and phenotypically heterogeneous, encompassing diverse renal and urinary tract phenotypes. To understand the significance of these phenotypes, we and others have used the mouse as a model organism and this has led to the identification of new candidate genes. Through careful phenotypic analysis of these models, a new understanding of the genetics and biology of VUR is now underway.     

Investigation of dysfunctional voiding in children with urgency frequency syndrome and urinary incontinence

PURPOSES: Dysfunctional voiding may result in lower urinary tract symptoms (LUTS) in children and is associated with urinary tract infection and vesicoureteral reflux (VUR). This study analyzed the videourodynamic investigations in children with urgency frequency syndrome and/or urinary incontinence. METHODS: Forty children, 1-13 years old, with urgency frequency syndrome and/or incontinence were investigated to determine their LUTS or for the assessment of VUR. Videourodynamic study was performed in all patients and the results were analyzed with clinical characteristics and underlying pathophysiology. RESULTS: Dysfunctional voiding was present in 75.7% of the children with detrusor overactivity, in 73.3% of the children with VUR, in 63% of the children with urinary incontinence, in 77% of the children with episodic urinary tract infection, and in all of the children with diurnal enuresis. Compared to children without dysfunctional voiding, the voiding pressure was significantly higher in children with dysfunctional voiding (with VUR, 61.1 +/- 29.8 vs. 24.8 +/- 15.8 cm H(2)O, p = 0.004; without VUR, 53.4 +/- 24.1 vs. 24.8 +/- 15.8 cm H(2)O, p = 0.010). Biofeedback pelvic floor muscle training and treatment with antimuscarinic agent effectively decreased detrusor pressure, increased bladder capacity and maximum flow rate, and reduced the grade of VUR in 5 children who had post-treatment urodynamic studies. CONCLUSIONS: This study has shown that dysfunctional voiding is highly prevalent in children with symptoms of urgency frequency and incontinence. Biofeedback pelvic floor muscle training is effective in treatment of dysfunctional voiding in children.     

THE MANY FACES OF VESICO-URETERIC REFLUX: FACTORS CONTRIBUTING TO RENAL DAMAGE*

Current controversies in the pathogenesis and management of vesico-ureteric reflux (VUR) and reflux-associated nephropathy (RAN) are critically reviewed, together with the advantages and limitations of surgical correction of reflux. Special emphasis is given to pitfalls in diagnosis and ongoing reassessment, to the importance of associated urinary tract abnormalities, and to the need for continuing long term chemoprophylaxis in the presence of persisting VUR.     

Assessment of vesicoureteral reflux in patients with self-retaining ureteral stents: implications for upper urinary tract instillation

PURPOSE: Conservative treatment of upper urinary tract tumors has been popularized during the last decade. Like in bladder cancer management, localized adjuvant therapy has been advocated to reduce the risk of disease recurrence or progression. In this study we tested the feasibility of creating vesicoureteral reflux (VUR) using a Double-J stent (Medical Engineering Corp., New York, New York) as a measure of efficacy for intravesical adjuvant treatment of the ureter and renal collecting system. MATERIALS AND METHODS: The cohort included 100 consecutive patients in whom a Double-J stent was inserted for renal obstruction. All the patients underwent cystography in the supine position by retrograde filling of the bladder with a 50% dilute solution of 300 mgI/ml iopromide in serial increments of 50 ml up to a maximum of 350 ml. A total of 41 patients underwent cystography immediately following stent insertion (early group) and 59 patients with indwelling stents underwent cystography before further endourological intervention (late group). The presence of VUR and the level along the ureter and renal collecting system were assessed fluoroscopically. RESULTS: Overall VUR was detected in 56 patients (56%), specifically 11 of the 41 (27%) in the early group and 45 of the 59 (76%) in the late group (p <0.001). There was no correlation between stent diameter or length and VUR, or between patient sex, age or particular side and the likelihood of reflux. Mean minimal intravesical volume required to obtain reflux was 171 +/- 11 ml, which was significantly higher in the early (255 +/- 21 ml) than in the late (146 +/- 11 ml) cystogram group. In 24 of the 56 patients (43%) with VUR, there was complete visualization of the entire ureter and renal collecting system. However, 15 patients (26%) had opacified renal pelves and calices without concomitant visualization of the ureters, whereas 7 patients (31%) had reflux to the ureter without opacification of the renal pelvis. CONCLUSIONS: VUR is not a guaranteed consequence of Double-J stent placement. Therefore, when upper urinary tract instillation with the Double-J technique is considered, a cystogram should be performed first to confirm the occurrence of reflux, determine the intravesical volume required to induce reflux and ascertain that the pertinent section of the ureter or pelvicaliceal system from which the tumor was initially removed is opacified during study. An interval that remains to be defined should be allowed between stent insertion and VUR assessment.     

Vesicoureteral reflux in male and female neonates as detected by voiding ultrasonography

BACKGROUND: Vesicoureteral reflux (VUR) is assumed to be congenital, and its early diagnosis is desired in order to prevent acquired renal damage. However, the incidence of VUR in neonates remains to be revealed. METHODS: Two thousand newborn babies (1048 boys and 952 girls) underwent voiding ultrasonography (an ultrasound examination of urinary tract during provoked voiding). Those who showed transient renal pelvic dilation during voiding, who had small kidneys, or who subsequently developed urinary infection underwent voiding cystourethrography. RESULTS: Transient renal pelvic dilation was observed in 16 babies (0.8%), including one boy with small kidneys. Among the rest of the babies, one boy had a small kidney, and nine babies subsequently developed urinary infection. Voiding cystourethrography revealed VUR in 24 ureters of 16 children (11 boys and 5 girls). Dimercaptosuccinate renoscintigraphy confirmed small kidneys, with generally reduced tracer uptake in a total of three boys, all having VUR. Voiding ultrasonography detected transient renal pelvic dilation in 17 (71%) of the 24 kidneys with VUR and, strikingly, 16 of the 17 (94%) kidneys with high-grade VUR (grade III or more). CONCLUSION: This study effectively detected VUR in 0.8% of the neonates (mostly of high grades and predominantly in males) and voiding ultrasonography showed a decided usefulness for the detection of VUR. The male preponderance of VUR in neonates was considered to be due to the occurrence of congenitally small kidneys, with reflux found exclusively in males and easier ultrasound detection of VUR in male neonates because the majority of diagnoses are reported to be high grades of VUR.     

A Snapshot of the Guidelines on Vesicoureteral Reflux in Children

The main goal in the management of patients with vesicoureteral reflux (VUR) is the preservation of kidney function by minimizing the risk of pyelonephritis. By defining and analyzing the risk factors for each patient depending on age, sex, grade of reflux, lower urinary tract dysfunction, anatomic abnormalities, and kidney status, it is possible to identify those patients with a potential risk of upper urinary tract infection and resulting renal scarring. This paper gives a brief overview of the European Association of Urology guidelines for the management and treatment of VUR in children. These guidelines are based on the best currently available knowledge and evidence.     

Remission of primary vesicoureteral reflux in children with medical management

We studied the spontaneous resolution rate in children with primary vesicoureteral reflux (VUR) and the interference of some specific factors. We reviewed the records of 110 children (14 days - 16 years) admitted in the 4th Pediatric Clinic Ia?i with primary VUR, between 1994 - 2003, which had exclusive medical management and minimum one follow-up cystogram. We used Kaplan-Meier curves to analyze the resolution rate of VUR during the follow-up in relation with initial grade, age at diagnosis, gender, recurrent urinary tract infections (UTIs) and the presence of renal scarring. The remission rate for all the cases was 70%, with differences based on the reflux grade: 100% for grade I and 45% for grade IV. The cases diagnosed during infancy recovered faster than those diagnosed after this period. The presence of renal scarring and breakthrough UTIs increased the remission time. In conclusion the majority of patients with VUR resolved during medical management, the remission rate being influenced by the reflux grade, presence of renal scarring and breakthrough UTIs.     

Vesicoureteric reflux is not a benign condition

Renal parenchymal defects may be congenital, usually associated with dilated vesicoureteric reflux (VUR), or they may appear in previously normal kidneys and be caused by reflux nephropathy due to VUR combined with urinary tract infection (UTI). A piglet model defined that the 70% of children with VUR and vulnerable pyramids would scar rapidly with their first UTI. Because most defects are present at first imaging after a UTI, and from the lack of benefit from apparently reasonable clinical interventions, many now believe that most defects are congenital, their association with VUR being a shared dysplasia rather than causal. Consequently, guidelines now argue for less assiduous management. These conclusions ignore adult human transplant evidence, adult pig studies, and clinical anecdotes, which indicate that scars may develop in infant kidneys quicker than urine culture can confirm the diagnosis, and that reflux nephropathy has no age limit. Its rarity over 4 years suggests that most vulnerable children develop scars before then, despite all medical efforts. I argue that preventing such scarring will require better diagnosis of infant UTI, quicker treatment, reliable imaging of scars and VUR, and subsequent protection until VUR resolves. To make a difference, we need more assiduous management, not less, and cannot afford to consider VUR to be a benign condition.     

输尿管囊肿内多发结石伴重复肾输尿管畸形1例并文献复习

目的：讨论输尿管囊肿的发生、诊断及其内镜治疗。方法：报道1例输尿管囊肿囊内多发结石伴同侧重复肾输尿管畸形病例的诊治,并复习这一疾病的相关文献。结果：输尿管囊肿是一种先天性畸形疾病,泌尿系B超、静脉泌尿系造影（IVP）、膀胱镜三者结合诊断符合率高,内镜治疗可有效的解除输尿管梗阻和控制术后膀胱输尿管反流（vesicoureteral reflux,VUR）的发生。结论：输尿管囊肿诊断并不困难,内镜治疗以其安全有效性已成为输尿管囊肿首选治疗方式。     

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.     

Vesicoureteral reflux and reflux nephropathy

Vesicoureteral reflux is an anatomic abnormality, mostly affecting a pediatric population, which may be the second leading cause of end-stage renal failure. Most cases of reflux are due to abnormalities in the insertion of the ureters into the bladder, either congenital or acquired. Most commonly, VUR is discovered during routine evaluation of urinary tract infections, but may also be present in patients with severe hypertension or chronic renal failure. The diagnosis is confirmed radiologically, utilizing either voiding cinecystography or radioisotopic methods. VUR can result in renal failure through scarring secondary to 'chronic pyelonephritis' or through a glomerulopathy, possibly immune in origin. In most series, the glomerulopathy is felt to be the cause of the end-stage renal failure. Treatment of VUR includes conservative (medical) management with the hope that maturation of the ureterovesical junction will cure reflux. Surgical therapy is reserved for those patients in whom this maturation is not expected to occur or in those whose urinary infections cannot be controlled. In those patients who have developed the glomerulopathy secondary to VUR, surgery may not halt the progression of the renal disease. VUR in a transplanted kidney may result in a higher risk of loss of the graft due to glomerulopathy or chronic rejection.     

Medical management of vesicoureteral reflux

Vesicoureteral reflux (VUR) in children is associated with increased risk of urinary tract infection (UTI). Recurrent UTI in the presence of the VUR is believed to cause renal scarring, which carries a risk of subsequent hypertension, toxemia of pregnancy, and significant renal damage, including end-stage renal disease. The natural history of VUR is to improve or resolve completely with time in most of the patients. The traditional management consists of prompt treatment of UTI, long-term anti-microbial prophylaxis until the VUR resolves, or surgical intervention in those with persistent high grade VUR, recurrent UTI in spite of prophylaxis with anti-microbial agent, allergy to anti-microbial agents, and patient/parent non-compliance with the medical management. Voiding dysfunction and constipation play an important role, and their diagnosis and appropriate management helps reduce the frequency of UTI and promote the resolution of the VUR. Patients with renal scarring need to be monitored for potential complications such as hypertension, proteinuria, and progression of the renal damage. In patients with hypertension and/or proteinuria, angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) are the drugs of choice, because of their reno-protective properties. Recent studies have revealed that there is no convincing evidence that UTI in the presence of VUR predicts renal injury or that the use of long-term anti-microbial prophylaxis or surgical intervention prevents renal scarring or its progression. However, until proven otherwise by a prospective, placebo-controlled, randomized study, it is advisable to err on the side of caution and consider VUR and UTI risk factors for renal scarring and treat each patient on individual basis.     

Evidence-based medicine and vesicoureteral reflux

Vesicoureteral reflux (VUR) remains one of the most controversial subjects in paediatric urology. Much literature has been published on VUR, making the understanding of this anomaly and its treatments quite opaque. Evidence-Based Medicine (EBM) should be helpful to clarify the various VUR approaches contained in the 6224 titles found on Medline using the keywords "vesicoureteral reflux" and "vesicoureteric reflux". These articles were critically reviewed and graded according to EBM scorings, with regard to their methodological designs. This review of VUR literature suggests that most of our knowledge is based on publications with a low level of evidence, and that EBM lacks arguments to support recommendations for VUR diagnostic and treatment. It appears yet that antenatal dilatation of the urinary tract and symptomatic urinary tract infections (UTI) justify VUR screening. Surgery should be discussed in recurrent UTIs or deterioration of renal function. There is no consensus in case of persistent asymptomatic VUR regarding indication and duration of antibio-prophylaxis, and selection of radical treatment.     

Predisposing factors for renal scarring in children with urinary tract infection

This study was undertaken to determine the predisposing factors for renal scarring in children with urinary tract infection. In this prospective cohort study, 176 children with documented urinary tract infection were categorized into four groups: ≤1 year old, 1-2 years old, 2-7 years and 7-14 years old. Ultrasonography and Technetium-99 m-DMSA scan were used to detect the possible abnormalities. Infants under 12 months old presented as the most common group for renal scarring (27 cases, 52.9%), and vesicoureteral reflux (VUR) was diagnosed in 29 cases (56.8%). Fifteen (41.67%) children between the ages of one and two years had renal scar, and VUR was detected in half of the patients. In the third group, 36.3%, and in fourth group, 41.6% of the patients had renal scar. Also, 38.6% in group three and 50% in the final group had VUR. A co-incidental finding that was observed in this study was the high incidence of pseudohypoaldesteronism (PHA) in our patients: in 39.2% of the children in group one, 22.2% in group two and 4% in group three. In group four however, none of the patients had PHA. Risk of scar formation with urinary tract infection (UTI) was higher in the younger age group and in those with recurrent UTIs.     

Kidney imaging in management of delayed febrile urinary tract infection

We report a cross-sectional study performed to evaluate the imaging findings of 40 children, aged one month to five years (16.65 ± 14.97 months), who presented with protracted fever of more than 48 hours due to urinary tract infection (UTI). About 85% of the patients had positive Tc99-Dimercaptosuccinic acid (DMSA) scan and 58% had vesicoureteral reflux (VUR). Kidney sonography aided in the diagnosis and treatment in 10% of the patients. Age, sex, presence or laterality of VUR did not contribute to defective DMSA scan (pyelonephritis) (P > 0.05). Delayed diagnosis and treatment of febrile UTI is associated with a high incidence of positive findings of DMSA scan irrespective of age, sex or presence/absence of VUR. In mild VUR, the DMSA scan may be normal while in patients with moderate and severe VUR the DMSA scan is almost always abnormal. Thus, our study shows that a normal DMSA scan can help in ruling out moderate to severe forms of VUR and that cystography remains an excellent and standard tool for the diagnosis of VUR.