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Spontaneous Pyelonephritis and Struvite Urolithiasis in the Megabladder Mouse Model
Ahmad Z. Mohamed, MD, Brian Becknell, MD, PhD, Michael Wilhide, MS, Birong Li, MS, Susan Ingraham, MD, PhD.
Nationwide Children's Hospital, Columbus, OH, USA.

Obstructive nephropathy and bladder dysfunction are among the most common causes of ESRD in children. We study a unique mouse model, the megabladder (mgb) mouse, that in the homozygous (mgb-/-) state has a non-functional overdistended bladder at birth, with progressive hydronephrosis. This model mimics features of non-neurogenic neurogenic bladder, prune-belly syndrome or PUV. We previously reported that vesicostomy could be life saving to these mice. However, up to 35% of them developed urinary stones and the intravesical suture was identified as the nidus. In this work we report and investigate the incidence of spontaneous infection and stone formation in mgb-/- mice that have not undergone surgical intervention.
We identified 10 mgb-/- mice in our colony (8 females and two males) that had spontaneous bladder stones; two of them had also kidney stones. None had undergone any surgical intervention. Mean age at stone diagnosis was 42.2 days. We also identified spontaneous UTI without stones in 6 other mgb-/- mice. To study the incidence of spontaneous uronephrolithiasis and UTI we determined that a cohort of 17 animals would provide >80% power to detect the outcome at a frequency of 5% and 90% power to detect a frequency of 10%. We therefore examined a cohort of 19 consecutive mgb-/- female mice by ultrasonography at 4 weeks of age. A concurrent urine sample was obtained by percutaneous bladder tapping and tested for pH and culture. If no stones were present we repeated the ultrasound and urine tests at 6 and 8 weeks of age. At the termination of the 8-week period, or if a stone was discovered at any point, mice were euthanized and tissues collected for culture and histopathology. Stones were sent for chemical analysis.
In the general mgb colony, we identified a total of 16 mice with spontaneous stones over a 6 months period. All were mgb-/- genotype. We performed urine, stone and tissue cultures on 12 of them, and the results were positive in 11 (91.7%). In the same time period we also identified 11 mgb-/- mice with urinary infection and no stones. Recovered organisms included Coagulase negative Staphylococcus, Bacillus non anthracis, and Escherichia coli. Urine pH was consistently alkaline (7.5-8) in affected mice, as opposed to mice with no infection or stones (pH 5.5-6). When looking at the designated cohort of 19 consecutive Mgb-/- females, we identified bladder stones in 6 mice (cumulative incidence 31.6%), and urinary infection was diagnosed in 8 (cumulative incidence 42.1%) including the 6 mice with stones. The predominant stone composition was struvite, with up to 10% apatite. The average stone weight was 0.118g. Histopathology showed bladder and kidney inflammatory changes and scarring in some of the infected kidneys.
In contrast to our previous assumption that a stone would only develop in the megabladder mouse in the presence of a specific nidus, we are now finding spontaneous stones and infection in mgb-/- mice. We propose this as a novel animal model of UTI and uronephrolithiasis in bladder dysfunction and urinary stasis.

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