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Abstract: SA-PO114

Capillary Rarefaction Is Associated with CKD Progression in Cisplatin and Rhabdomyolysis AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Menshikh, Anna, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Scarfe, Lauren Nicolle, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Yang, Haichun, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • de Caestecker, Mark P., Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background

Incomplete recovery of renal function after AKI results in progressive CKD, but no therapies improve long-term outcomes in patients with AKI. For this reason there has been interest in pre-clinical models of AKI to CKD transition that mimic the pathophysiology of human AKI. One end point for pre-clinical interventions is renal fibrosis. However, reduced peritubular capillary density (PTCD) is also associated with CKD after ischemia-reperfusion AKI, and it is unknown whether PTCD is an independent predictor of CKD in models of AKI. Many studies have evaluated therapy in short term studies after cisplatin (CP), and glycerol-induced rhabdomyolysis (Rhabdo-AKI), but there are limited published data on long-term outcomes. In these studies we evaluated long-term renal outcomes, renal fibrosis and PTCD in mouse models repeat dose CP (RDCP) and Rhabdo-AKI.

Methods

RDCP was induced in male FVB/N mice with 7mg/kg CP weekly for four weeks, tissues harvested at 28 days. Rhabdo-AKI was induced by injecting 5.8ml/kg 50% glycerol IM in male BALB/c mice, tissues harvested at 36 and 66 days. Renal function: serial BUN, serum creatinine and transdermal GFR. Renal fibrosis: QRT-PCR for fibrosis markers, picro-sirius red (PSR) quantification. PTCD by quantifying CD31 immunostaining.

Results

There was a progressive decline in renal function with reduced GFR 110.69 (65.3) vs. 330.6 (36.8) microL/min (p<0.0001, T-test) and increased creatinine 28 days after RDCP-AKI. This was associated with increased expression of renal fibrosis markers, LoxL2, Col1a1 and Col1a3 mRNAs, but not PSR staining. In contrast, while mice treated with IM glycerol developed severe AKI, with peak BUN 161.6 (15.8) mg/dl at day 1, there was complete recovery of GFR at 36 and 66 days. This was associated with increased PSR staining, but unlike RDCP mice in which there was a reduction PTCD, PTCD was not reduced after Rhabdo-AKI.

Conclusion

These data demonstrate a dissociation between renal fibrosis and changes in GFR over time in different models of AKI to CKD transition, and that peritubular capillary rarefaction is more closely associated with changes in GFR than fibrosis. This provides insight into the potential role of capillary rarefaction as being the principal driver and candidate cellular target to prevent AKI to CKD progression, rather than renal fibrosis.

Funding

  • NIDDK Support