Intrarenal Renin-Angiotensin-System Dysregulation after Kidney Transplantation

Sci Rep. 2019 Jul 5;9(1):9762. doi: 10.1038/s41598-019-46114-x.


Angiotensin-converting enzyme inhibitors (ACEis) are beneficial in patients with chronic kidney disease (CKD). Yet, their clinical effects after kidney transplantation (KTx) remain ambiguous and local renin-angiotensin system (RAS) regulation including the 'classical' and 'alternative' RAS has not been studied so far. Here, we investigated both systemic and kidney allograft-specific intrarenal RAS using tandem mass-spectrometry in KTx recipients with or without established ACEi therapy (n = 48). Transplant patients were grouped into early (<2 years), intermediate (2-12 years) or late periods after KTx (>12 years). Patients on ACEi displayed lower angiotensin (Ang) II plasma levels (P < 0.01) and higher levels of Ang I (P < 0.05) and Ang-(1-7) (P < 0.05) compared to those without ACEi independent of graft vintage. Substantial intrarenal Ang II synthesis was observed regardless of ACEi therapy. Further, we detected maximal allograft Ang II synthesis in the late transplant vintage group (P < 0.005) likely as a consequence of increased allograft chymase activity (P < 0.005). Finally, we could identify neprilysin (NEP) as the central enzyme of 'alternative RAS' metabolism in kidney allografts. In summary, a progressive increase of chymase-dependent Ang II synthesis reveals a transplant-specific distortion of RAS regulation after KTx with considerable pathogenic and therapeutic implications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Angiotensin I / blood
  • Angiotensin I / metabolism
  • Angiotensin II / blood
  • Angiotensin II / metabolism
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Biomarkers
  • Enzyme Activation / drug effects
  • Female
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Kidney / metabolism*
  • Kidney / physiopathology*
  • Kidney Transplantation* / adverse effects
  • Male
  • Middle Aged
  • Models, Biological
  • Peptide Fragments / blood
  • Peptide Fragments / metabolism
  • Postoperative Complications
  • Renin / blood
  • Renin / metabolism
  • Renin-Angiotensin System* / drug effects
  • Renin-Angiotensin System* / genetics


  • Angiotensin-Converting Enzyme Inhibitors
  • Biomarkers
  • Peptide Fragments
  • Angiotensin II
  • Angiotensin I
  • Renin
  • angiotensin I (1-7)