Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria.
School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia.
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.
血管紧张素转换酶抑制剂（ACEi）对慢性肾脏病（CKD）患者有益。然而，它们在肾移植（KTx）后的临床效果仍存在争议，局部肾素-血管紧张素系统（RAS）调节，包括“经典”和“替代”RAS，迄今为止尚未得到研究。在这里，我们使用串联质谱法在接受 KTx 且有或没有既定 ACEi 治疗的患者（n=48）中研究了全身和肾脏移植物特异性的肾内 RAS。将移植患者分为 KTx 后早期（<2 年）、中期（2-12 年）或晚期（>12 年）。无论移植物的使用时间如何，使用 ACEi 的患者的血管紧张素（Ang）II 血浆水平较低（P<0.01），Ang I（P<0.05）和 Ang-（1-7）（P<0.05）水平较高。与未使用 ACEi 的患者相比，无论 ACEi 治疗情况如何，都观察到大量的肾内 Ang II 合成。此外，我们发现晚期移植 Vintage 组的最大移植肾 Ang II 合成（P<0.005），这可能是由于移植肾糜酶活性增加（P<0.005）的结果。最后，我们可以确定 Neprilysin（NEP）是肾移植中“替代 RAS”代谢的中心酶。总之，糜酶依赖性 Ang II 合成的逐渐增加表明 KTx 后 RAS 调节发生了移植特异性扭曲，具有相当大的致病和治疗意义。
