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Abstract: TH-PO082

Mineralocorticoid Receptor Antagonism Prevents the Acute and Chronic Effects of Ischemic AKI in the Large White Pig

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Barrera-Chimal, Jonatan, UNAM, Instituto de Investigaciones Biomedicas - Instituto Nacional de Cardiologia, Ignacio Chavez, Mexico City, Mexico
  • Giraud, Sebastien, INSERM U1082- CHU de Poitiers, service de biochimie, Poitiers, France
  • Kaaki, Sihem, INSERM U1082- CHU de Poitiers, service de biochimie, Poitiers, France
  • Jaisser, Frederic, INSERM U1138, Paris Cedex 13, France
  • Hauet, Thierry, Inserm / Université de Poitiers / CHU de Poitiers, Poitiers, France
Background

In rodent models of kidney ischemia/reperfusion (IR), mineralocorticoid receptor (MR) antagonism has shown beneficial effects against acute kidney injury (AKI) and its progression to chronic kidney disease (CKD); whether these findings might be translated to the human pathology remains to be clarified. The Large White pig is a useful preclinical animal model to test the effectiveness of therapeutic strategies aimed to protect against AKI due to the kidney similarities between the human and the pig. In this study we evaluated the effect of MR antagonism against the acute and chronic effects of ischemic AKI in the Large White pig.

Methods

Eighteen Large White male pigs were divided in three groups: sham, pigs that received vehicle and underwent bilateral renal ischemia for 60 min and a group of pigs subjected to renal ischemia and receiving Soludactone (potassium canreonate). Soludactone (7mg/kg, i.v.) or vehicle doses were given at 48 h, 24 h and 30 min before the induction of the ischemia and 24 h and 48 h after reperfusion. Urine collection and blood sampling was carried out at days 1, 3, 5, 7, 11, 14 and 90. Kidney biopsies were taken at days 14 and 90.

Results

Renal IR induced kidney dysfunction in the untreated pigs at day 1 (plasma creatinine: 443±7 mmol/L). In contrast, the pigs that received canrenoate showed an impressive prevention of plasma creatinine elevation (145±3 mmol/L). Tubular injury was evidenced by a significant increase in urinary NGAL, KIM-1, L-FABP and NAG excretion and by histological abnormalities at day 14 (tubular injury and increased inflammatory infiltrate). Canreonate treatment decreased by 50% the excretion of these markers and prevented the histological damage. At day 90, the untreated pigs presented kidney fibrosis which was absent in the canreonate-treated pigs. Plasma creatinine was higher in untreated pigs at day 90 (120±2 mmol/L) as compared to the treated pigs (92±4 mmol/L)

Conclusion

MR antagonism is effective against the acute and chronic kidney dysfunction and structural injury in a preclinical model of AKI in the Large White pig. These findings support clinical trials testing the potential benefits of MRAs in AKI.

Funding

  • Government Support - Non-U.S.