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Abstract: TH-PO086

Mechanisms of Difference in AKI-CKD Transition due to Acute Cardiorenal Syndrome and Ischemia-Reperfusion Injury

Session Information

  • AKI: Mechanisms - I
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Funahashi, Yoshio, Oregon Health & Science University, Portland, Oregon, United States
  • Hebert, Jessica Faith, Oregon Health & Science University, Portland, Oregon, United States
  • Munhall, Adam C., Oregon Health & Science University, Portland, Oregon, United States
  • Nickerson, Megan N., Oregon Health & Science University, Portland, Oregon, United States
  • Hutchens, Michael, Oregon Health & Science University, Portland, Oregon, United States
Background

Cardiorenal syndrome type 1 (CRS1) is acute kidney injury (AKI) due to acute heart failure. Heart-specific cardiac LIM protein (CSRP3) is released into the plasma after cardiac arrest and is differentially endocytosed in the proximal tubule depending on megalin. We hypothesized that the phenotype of AKI-CKD transition differs between cardiac arrest and cardiopulmonary resuscitation (CA/CPR) and kidney-only ischemia due to renal uptake of heart-specific CSRP3.

Methods

8 to 12 weeks old C57BL/6J male mice and inducible proximal tubule-specific megalin knockout (iMegKO) mice (with littermate controls) were subjected to 8-minute CA/CPR or bilateral renal pedicle occlusion (IRI) with multiple durations. Glomerular filtration rate (GFR) and other outcomes were measured 24h and 49 days later.

Results

24h GFR was equivalent between 27-minute IRI and 8-minute CA/CPR. 8-minute IRI, the same ischemia duration as CA/CPR, resulted in higher 24h GFR than CA/CPR. 49 days after surgery, CA/CPR induced GFR was lower, and blood urea nitrogen (BUN) and cystatin-C (Cys-C) were higher than 8min IRI, suggesting milder chronic injury from 8min IRI. GFR, BUN and Cys-C were not different between CA/CPR and 27min IRI although survival. IRI induced late albuminuria and proteinuria, but CA/CPR did not. Cardiac CSRP3 was elevated after CA/CPR but not after IRI. Injection of recombinant CSRP3 after 8min IRI reduced the GFR 49 days following injection compared with 8min IRI. CA/CPR-exposed iMegKO mice demonstrated increased GFR compared to controls identical to that of 8min IRI compared with 8min CA/CPR. Inducible, cardiac-specific CSRP3 knockout (iCSRP3 KO) mice exhibited cre-recombinase expression and floxed Csrp3 genotype.

Conclusion

Cardiorenal AKI and focal ischemia (IRI)-induced AKI demonstrated different phenotypes in AKI-CKD transition, with different degrees of chronic filtration loss and albuminuria. CSRP3 may mediate this different phenotype. iCSRP3 KO mice are expected to delineate this important mechanism.

Funding

  • Veterans Affairs Support