Intrarenal Renin-Angiotensin-System Dysregulation after Kidney Transplantation

Abstract

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.

Local Action of Neprilysin Exacerbates Pressure Overload Induced Cardiac Remodeling

“…However, earlier studies on the distribution of NEP using whole organs and northern blot analyses showed that NEP mRNA expression levels were abundant in the kidney and lung, which were both much higher than heart. 27 However, histochemical examination revealed that NEP was mainly expressed in tubular epithelial cells in kidney 28,29 and in bronchial epithelial cells in lung, 17,30 which suggests that NEP expressed in these cells in kidney or lung could not be in direct contact with circulating natriuretic peptides. In contrast, NEP expressed in cardiomyocytes, fibroblasts, and capillary endothelial cells in heart would be in direct contact with ANP and BNP just after secretion from cardiomyocytes.…”

Hypertension in kidney transplant recipients

“…Renal sodium retention may be worsened by the use of immunosuppressive regimens, mainly corticosteroids[ 48 ] and calcineurin inhibitors (CNIs)[ 49 ] as well as during episodes of acute rejection, probably indicating ischemic allograft damage[ 50 ]. Dysregulation of the renin-angiotensin-aldosterone system[ 51 ] and sympathetic nerve overactivity, driven in the early post transplantation period by the native kidneys (since the graft is initially denervated before becoming later re-innervated[ 52 ]), also lead to increased peripheral vascular resistance and development of hypertension[ 5 , 53 , 54 ]. Increased arterial stiffness, endothelial dysfunction and imbalance between vasoconstrictive and vasodilating agents are also pertinent to CKD and further contribute to increased BP[ 55 , 56 ].…”

Renin–Angiotensin–Aldosterone System and Immunomodulation: A State-of-the-Art Review

“…In their study, Kovaric et al hypothesized that, in the first months, AngII occurs in the graft through moderate ACE activity, while Ang 1–7 formation occurs through NEP and ACE-mediated AngII (from AngI). Several years later, chymase activity becomes prominent and takes over the previously ACE-mediated AngII formation, alongside the persisting NEP-mediated Ang 1–7 formation [ 188 ].…”