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Kidney Week

Abstract: TH-PO933

Mouse Model of Progression to Chronic Kidney Injury from AKI

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Zhang, Jie, USF, Tampa, Florida, United States
  • Wei, Jin, USF, Tampa, Florida, United States
  • Wang, Lei, USF, Tampa, Florida, United States
  • Liu, Ruisheng, University of South Florida College of Medicine, Tampa, Florida, United States
Background

There is no animal model displaying the typical characteristics of CKD following an episode of AKI. Thus, the aim of the present study was to develop an AKI to CKD animal model.

Methods

We first tested whether current AKI models can induce CKD. Bilateral renal ischemia reperfusion (IR) and unilateral renal IR plus uninephrectomy with stepwise lengths of ischemic time were performed in C57BL/6 mice. Then we developed a two-stage AKI to CKD model in C57BL/6 mice. In stage I, IR induced AKI was performed in the left kidney with stepwise lengths of ischemic time, while the right kidney was kept intact. In stage II, after 2 week recovery for the injured left kidney, the intact right kidney was removed. Kidney function and renal injury were evaluated afterwards.

Results

In current IR induced AKI models, the animals either fully recovered if the renal injury was moderate with <18 min bilateral or <15 min unilateral ischemic time, or died if the renal injury was life-threatening with >21 min bilateral or >18 min unilateral ischemic time. No typical CKD feature was observed in these models. In two-stage AKI to CKD models, after removal of the intact right kidneys, the mice with 21 min or 24 min left renal ischemia exhibited the characteristics of CKD, including continuous decline in GFR (from 206.6±9.5 µl/min to 76.3±8.1 µl/min in 21 min group, from 199.2±6.7 µl/min to 49.5±11.3 µl/min in 24 min group), gradual increase in PCr (from 0.13±0.03 mg/dl to 0.43±0.05 mg/dl in 21 min group, from 0.09±0.03 mg/dl to 0.65±0.09 mg/dl in 24 min group), exacerbation in urine albumin-to-creatinine-ratio (from 13±6 μg/mg to 3457±342 μg/mg in 21 min group, from 9±5 μg/mg to 4841±375 μg/mg in 24 min group), histopathological changes including tubular atrophy, interstitial fibrosis, glomerular sclerosis, collapse of glomerular tufts and dilated Bowman's capsule, and transmission electron microscopy ultrastructural alterations including peritubular interstitium expansion, collagen deposition, cellular debris within Bowman’s space, GBM thickening, and podocyte foot process effacement. The mice with 15 min or 18 min left renal ischemia had a full recovery. All mice with 27 min or 30 min left renal ischemia died within 7 days after right kidney removal.

Conclusion

In conclusion, we successfully developed a novel mouse model with a direct transition from renal IRI induced AKI to subsequent progression of CKD.

Funding

  • NIDDK Support