Kidney Functional Reserve Changes Following Single vs. Recurrent Urinary Tract Infection (UTI) in a Mouse Model of Vesicoureteral Reflux

Background: Children with vesicoureteral reflux (VUR) are prone to recurrent UTIs and pyelonephritis. While kidney function is often maintained throughout childhood, they are at risk for progression to chronic kidney disease (CKD) later in life. VUR research has focused on macro-scale scarring by DMSA scan as a surrogate for kidney damage rather than kidney function. Microscopic changes are not well studied, and over half of the functional nephron mass must be lost before kidney function decreases to the CKD range. Methods: We used C3H/HeOuJ mice with VUR to compare changes in kidney function between single and recurrent UTI episodes, inducing pyelonephritis via transurethral inoculation of uropathogenic E. coli. Transcutaneous GFR (tGFR) was measured, then repeated following a 5 mg/g oral protein load at both baseline and 8 weeks post-infection. Kidney functional reserve (KFR) was calculated by subtracting the unstimulated from stimulated tGFR at each timepoint and compared within each group using paired t testing. Kidney sections were stained by trichrome staining to assess for scarring. Results: All groups had similar mean unstimulated tGFR measurements at the end of the study (Figure 1). For functional capacity, the control and single UTI groups showed no change in KFR from baseline to the end of the study, while KFR in the recurrent UTI group dropped significantly from pre-UTI baseline. Trichrome staining revealed ubiquitous interstitial fibrosis in the recurrent UTI group and moderate fibrosis in the single UTI group. Conclusion: We demonstrate that recurrent UTIs lead to increased scarring and a significantly diminished kidney functional reserve that remains undetected by a standard unstimulated GFR. This study is the first to measure KFR following UTI, and our findings highlight that CKD is a late manifestation of kidney damage. A kidney stress test may distinguish children at highest risk for CKD, who may benefit from more aggressive management of their VUR and recurrent UTI. Funding: NIDDK Support - NIDDK Support, NIDDK Support