Natural history of renal scarring in susceptible mIL-8Rh−/− mice

Natural history of renal scarring in susceptible mIL-8Rh−/− mice. Background. Urinary tract infections (UTIs) cause end-stage renal disease (ESRD) but the molecular mechanisms have re- mained unclear. Recently, the interleukin (IL)-8 receptor was shown to control disease susceptibility in mice and low IL-8 receptor expression was observed in pyelonephritis-prone pa- tients. Methods. Intravesical Escherichia coli infection was estab- lished in mIL-8Rh−/− or Balb/c control mice. Survival, bacte- rial persistence, and histology were used as measurements of disease severity. Results. Within 2 days, 19/30 mIL-8Rh−/− mice developed lethal infection with bacteremia. Surviving mice remained in- fected and developed progressive renal damage with pathologic neutrophil accumulation and abscess formation first under the pelvic epithelium and then throughout the tissue. Recruited im- mune effector cells were unable to remove the dying neutrophils and frustrated macrophages formed foam cell aggregates. As a result, there was successive destruction of the mucosal barrier, medulla and cortex and necrosis of the renal papilla. The mIL- 8Rh+/+ mice all survived and infection was cleared within a few days without symptoms or tissue pathology. Conclusion. mIL-8Rh−/− mice develop acute bacteremic pyelonephritis and renal scarring due to a dysfunctional neu- trophil response. The tissue damage resembles human disease, and these mice offer a model system to study the molecular mechanisms of renal scarring.