Abstract: TH-PO094
Using Transdermal Measurement of GFR to Evaluate Long-Term Outcomes in Mouse Models of AKI
Session Information
- AKI: Inflammation, New Technologies, Omics
October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Scarfe, Lauren Nicolle, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Finney, Charlene, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Menshikh, Anna, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Delgado, Rachel, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- de Caestecker, Mark P., Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background
There are no specific treatments for patients with acute kidney injury (AKI). In part this relates to the preclinical studies that have been used to assess therapeutic efficacy: these are often short-term studies, commonly using cisplatin or ischemia reperfusion (IR) injury. However, to identify target populations with meaningful long-term outcomes, therapeutic efficacy should be tested in a range of models over longer periods, including the long-term effects of therapy on the development of progressive chronic kidney disease (CKD) after episodes of AKI.
Methods
We established a range of mouse models of AKI that reflect the diverse injuries seen in human AKI and allow long-term functional analyses of CKD progression: 1) unilateral IR with a delayed contralateral nephrectomy (Nx), modeling profound renal hypoperfusion; 2) repeat-dosing cisplatin, modeling the injury in patients receiving cisplatin chemotherapy; 3) reversible UUO with delayed contralateral Nx, modeling the relief of urinary obstruction; and 4) rhabdomyolysis, modeling crush injury, sepsis and cardiopulmonary bypass-associated AKI. We are currently developing new models in female and diabetic mice, to recapitulate more complex clinical scenarios. To evaluate the effects of these injuries on CKD progression, we used transdermal monitors to assess glomerular filtration rate (GFR) in conscious mice by detecting the clearance of exogenous FITC-sinistrin through the skin 26-46 days after the initial injury.
Results
Here, we present for the first time, data on the long-term effects of AKI on GFR in multiple mouse models of AKI. GFR was significantly reduced in several models, but not in the rhabdomyolysis model (Table).
Conclusion
We have assessed the use of transdermal GFR measurement in a range of mouse models of AKI. This method of assessing renal function is more clinically relevant than standard methods and will be useful for preclinical efficacy testing of novel therapeutics on long-term renal outcomes in mouse models of AKI.
Transdermal GFR measurement in a range of mouse models of AKI
| Injury Model | Mean GFR (μl/min) | p-value | |
| Control mice | Injured mice | ||
| IR-AKI with delayed Nx (day 26) | 306.21 n=5 | 153.16 n=5 | 0.0001 |
| Repeat-dosing cisplatin (day 26) | 355.84 n=4 | 180.63 n=7 | 0.0133 |
| Reversible UUO (day 46) | 432.54 n=4 | 166.02 n=9 | <0.0001 |
| Rhabdomyolysis (day 26) | 314.50 n=6 | 266.48 n=8 | 0.1395 |
Funding
- NIDDK Support