Abstract: TH-PO928

Chymase and Neprilysin: Key Regulators of the Renin-Angiotensin System (RAS) in Kidney Allografts

Session Information

Category: Transplantation

  • 1702 Transplantation: Clinical and Translational

Authors

  • Kovarik, Johannes J., Medical University of Vienna, Vienna, Austria
  • Bohmig, Georg, Medical University Vienna, Vienna, Austria
  • Saemann, Marcus, Wilhelminen Hospital, Vienna, Austria
  • Kaltenecker, Christopher, Medical University of Vienna, Vienna, Austria
  • Kopecky, Chantal Maureen, University of New South Wales, Sydney, New South Wales, Australia
  • Domenig, Oliver, Attoquant Diagnostics, Vienna, Austria
  • Antlanger, Marlies, Medical University of Vienna, Vienna, Austria
  • Werzowa, Johannes, Medical University of Vienna, Vienna, Austria
  • Eskandary, Farsad Alexander, Medical University Vienna, Vienna, Austria
  • Kain, Renate, Medical University of Vienna, Vienna, Austria
  • Poglitsch, Marko, Attoquant Diagnostics, Vienna, Austria
Background

Angiotensin-converting enzyme inhibitors (ACEis) are well established to be beneficial in patients with heart failure and chronic kidney disease (CKD). Their role after kidney transplantation (KTx), however, remains ambiguous, and the effects of ACEis on plasma and intrarenal metabolites of the ‘classical’ and ‘alternative’ renin-angiotensin-system (RAS) in KTx recipients have not yet been studied.

Methods

This prospective study, which was designed to investigate allograft-specific RAS metabolism, included 48 kidney transplant recipients subjected to allograft biopsy for graft dysfunction, progression of proteinuria, and/or DSA detection early (0-24 months; n=14), intermediate (24-144 months; n=18) or late post-KTx (>144 months; n=16).

Results

Patients on ACEi therapy (n=24) had lower plasma levels of angiotensin (Ang) II (p<0.01), but higher levels of Ang I (p<0.05) and Ang-(1-7) (p<0.01) than patients without RAS blockade (n=24). Mass spectrometry-based renal biopsy analysis displayed a 2.8-fold increase in renal Ang II formation, with a stepwise increase from the early to the late biopsy group (p<0.005), paralleled by enhanced chymase activity (early group: 34±29%; late: 54±32%, p<0.005). Renal Ang-(1-7) formation via neprilysin (NEP) was dominant (59±13%) over Ang II-mediated Ang-(1-7) formation (15±10%).

Conclusion

Our study reveals a profound tissue-specific distortion of the RAS within renal allografts in a time-dependent fashion, with chymase and neprilysin being the predominant regulators of the RAS in kidney allografts. While the clinical significance of these results remains to be determined, a conspicuous role of chymase and neprilysin determining allograft survival may be hypothesized.