Association of O-Antigen Serotype with the Magnitude of Initial Systemic Cytokine Responses and Persistence in the Urinary Tract.

UNLABELLED: Urinary tract infection (UTI) is one of the most common ailments requiring both short-term and prophylactic antibiotic therapies. Progression of infection from the bladder to the kidney is associated with more severe clinical symptoms (e.g., fever and vomiting) as well as with dangerous disease sequelae (e.g., renal scaring and sepsis). Host-pathogen interactions that promote bacterial ascent to the kidney are not completely understood. Prior studies indicate that the magnitude of proinflammatory cytokine elicitation in vitro by clinical isolates of uropathogenic Escherichia coli (UPEC) inversely correlates with the severity of clinical disease. Therefore, we hypothesize that the magnitude of initial proinflammatory responses during infection defines the course and severity of disease. Clinical UPEC isolates obtained from patients with a nonfebrile UTI elicited high systemic proinflammatory responses early during experimental UTI in a murine model and were attenuated in bladder and kidney persistence. Conversely, UPEC isolates obtained from patients with febrile UTI elicited low systemic proinflammatory responses early during experimental UTI and exhibited prolonged persistence in the bladder and kidney. Soluble factors in the supernatant from saturated cultures as well as the lipopolysaccharide (LPS) serotype correlated with the magnitude of proinflammatory responses in vitro. Our data suggest that the structure of the O-antigen sugar moiety of the LPS may determine the strength of cytokine induction by epithelial cells. Moreover, the course and severity of disease appear to be the consequence of the magnitude of initial cytokines produced by the bladder epithelium during infection. IMPORTANCE: The specific host-pathogen interactions that determine the extent and course of disease are not completely understood. Our studies demonstrate that modest changes in the magnitude of cytokine production observed using in vitro models of infection translate into significant ramifications for bacterial persistence and disease severity. While many studies have demonstrated that modifications of the LPS lipid A moiety modulate the extent of Toll-like receptor 4 (TLR4) activation, our studies implicate the O-antigen sugar moiety as another potential rheostat for the modulation of proinflammatory cytokine production.

Is VCUG still indicated following the first episode of urinary tract infection in boys?

OBJECTIVES: To determine if voiding cystourethrogram (VCUG) following first episode of urinary tract infection (UTI) offers any incremental diagnostic advantage in boys if a comprehensive renal and bladder ultrasonogram (RBUS) revealed no abnormalities. METHODS: All boys less than 10 years of age whose first evaluation for UTI included RBUS and VCUG were retrospectively studied over a 10-year period. Those with a disorder of the urinary tract known before imaging were excluded. RBUS and VCUG results were analyzed. RESULTS: Of the 77 who met the inclusion criteria, 58 (77%) were <1 year old. 45 (58%) boys had normal RBUS and VCUG. In 16 (21%) both studies were abnormal: 15 had vesicoureteral reflux (VUR) and one had posterior urethral valves. The remaining 16 (21%) had one abnormal study: 10 had pelvicaliectasis on RBUS without VUR; 6 had normal RBUS with VUR. No urethral abnormality was diagnosed on VCUG when RBUS was normal. Of the six who had VUR and normal RBUS, the one who required surgical intervention had recurrent febrile UTI. CONCLUSIONS: If a well-performed RBUS is normal in a boy with first UTI, the likelihood of a significant finding in VCUG is low. A VCUG is likewise of no apparent screening benefit for obstructive uropathy. With the uncertainties surrounding the benefit of chemoprophylaxis, omitting a VCUG when a RBUS is normal in boys with a first UTI avoids the morbidity without missing important pathologies or altering evolving management protocols.

Relationship among bacterial virulence, bladder dysfunction, vesicoureteral reflux and patterns of urinary tract infection in children.

PURPOSE: We hypothesized that virulence levels of Escherichia coli isolates causing pediatric urinary tract infections differ according to severity of infection and also among various uropathies known to contribute to pediatric urinary tract infections. We evaluated these relationships using in vitro cytokine interleukin-6 elicitation. MATERIALS AND METHODS: E. coli isolates were cultured from children presenting with urinary tract infections. In vitro cytokine (interleukin-6) elicitation was quantified for each isolate and the bacteria were grouped according to type of infection and underlying uropathy (neurogenic bladder, nonneurogenic bowel and bladder dysfunction, primary vesicoureteral reflux, no underlying etiology). RESULTS: A total of 40 E. coli isolates were collected from children with a mean age of 61.5 months (range 1 to 204). Mean level of in vitro cytokine elicitation from febrile urinary tract infection producing E. coli was significantly lower than for nonfebrile strains (p = 0.01). The interleukin-6 response to E. coli in the neurogenic bladder group was also significantly higher than in the vesicoureteral reflux (p = 0.01) and no underlying etiology groups (p = 0.02). CONCLUSIONS: In vitro interleukin-6 elicitation, an established marker to determine bacterial virulence, correlates inversely with clinical urinary tract infection severity. Less virulent, high cytokine producing E. coli were more likely to cause cystitis and were more commonly found in patients with neurogenic bladder and nonneurogenic bowel and bladder dysfunction, whereas higher virulence isolates were more likely to produce febrile urinary tract infections and to affect children with primary vesicoureteral reflux and no underlying etiology. These findings suggest that bacteria of different virulence levels may be responsible for differences in severity of pediatric urinary tract infections and may vary among different underlying uropathies.

Pathogenesis of renal injury in the megabladder mouse: a genetic model of congenital obstructive nephropathy.

Congenital obstructive nephropathy (CON) is the most common cause of chronic renal failure in children often leading to end-stage renal disease. The megabladder (mgb) mouse exhibits signs of urinary tract obstruction in utero resulting in the development of hydroureteronephrosis and progressive renal failure after birth. This study examined the development of progressive renal injury in homozygous mgb mice (mgb-/-). Renal ultrasound was used to stratify the disease state of mgb-/- mice, whereas surgical rescue was performed using vesicostomy. The progression of renal injury was characterized using a series of pathogenic markers including alpha smooth muscle isoactin (α-SMA), TGF-ß1, connective tissue growth factor (CTGF), E-cadherin, F4/80, Wilm's tumor (WT)-1, and paired box gene (Pax) 2. This analysis indicated that mgb-/- mice are born with pathologic changes in kidney development that progressively worsen in direct correlation with the severity of hydronephrosis. The initiation and pattern of fibrotic development observed in mgb-/- kidneys appeared distinctive from previous animal models of obstruction. These observations suggest that the mgb mouse represents a unique small animal model for the study of CON.

Pathophysiology and management of urinary incontinence in case of distal penile epispadias.

PURPOSE: We evaluated boys with distal epispadias and urinary incontinence to determine the cause, and designed a simplified bladder neck reconstruction to restore urinary continence. MATERIALS AND METHODS: Six boys with epispadias of the glans or distal penile shaft whose incontinence persisted after successful single stage epispadias repair were evaluated with cystoscopy and urodynamics after failed attempts at toilet training. Surgical management--simplified bladder neck reconstruction--involved suprapubic excision of an identified deformity of the roof of the bladder neck and posterior urethra, followed by reapproximation of the remaining normal bladder neck and posterior urethral tissues. RESULTS: All boys displayed a characteristic deformity of the roof of the bladder neck and posterior urethra, which extended distally through the membranous urethral sphincter toward the urethral meatus. Five of the 6 boys were treated surgically, and promptly achieved normal continence and urinary control that remained durable through a mean followup of 9.6 years. Histologically, the roof deformity exhibited abnormalities including attenuation and reduction of smooth muscle. CONCLUSIONS: The meatus is not the only site involved in distal epispadias, which presents as a field defect that deforms the roof of the urethra distal to the bladder neck. Incontinence in distal epispadias has a dual etiology, namely anatomical dilatation and distortion of the bladder neck and posterior urethra, and histological abnormality of the roof tissues. These conditions combine to affect adversely coaptive and constrictive functions of the posterior urethra and urinary sphincter. Excision and reapproximation of the roof deformity appears to be proof in principle of the cause of incontinence, and offers an alternative approach to treating incontinence in these patients without the need for more invasive surgical procedures.

A novel technique for ureteral catheterization and/or retrograde ureteroscopy after cross-trigonal ureteral reimplantation.

PURPOSE: A criticism of the Cohen cross-trigonal reimplantation is the potential difficulty of retrograde access to the ureter. With the advent of modern endourological equipment, we devised a novel technique that obviates the aforementioned difficulty and permits even retrograde ureteroscopy. MATERIALS AND METHODS: Cystoscopy is performed and a curved tip vascular access catheter is directed towards the ureteral orifice. An angle tipped glide wire with a torque device attached is passed through the catheter and directed into the orifice. The combination of the curved catheter and angled glide wire permits passage of the wire in an axis perpendicular to that of the cystoscope. Once the glide wire has been passed into the proximal ureter it is exchanged for a super stiff guide wire. The latter literally straightens the ureter permitting direct retrograde passage of a catheter, stent or rigid ureteroscope. RESULTS: This technique was successful in 6 children. Of the patients 4 underwent retrograde ureteroscopy with stone extraction, 1 underwent retrograde studies followed by stent insertion and 1 underwent retrograde catheterization alone for radiographic studies. CONCLUSIONS: It is distinctly uncommon to have to access a ureter in a retrograde fashion after cross-trigonal reimplantation. However, when required the technique described reliably permits retrograde access and should dispel fears of long-term consequences of the Cohen ureteral reimplantation.