Molecular remodeling of the renin-angiotensin system after kidney transplantation

Objective: We aimed at assessing the molecular adaptation of the renin-angiotensin system (RAS) after successful kidney transplantation (KTX). Materials and methods: In this prospective, exploratory study we analyzed 12 hemodialysis (HD) patients, who received a KTX and had excellent graft function six to 12 months thereafter. The concentrations of plasma Angiotensin (Ang) peptides (Ang I, Ang II, Ang-(17), Ang-(15), Ang-(28), Ang-(38)) were simultaneously quantified with a novel mass spectrometry-based method. Further, renin and aldosterone concentrations were determined by standard immunoassays. Results: Ang values showed a strong inter-individual variability among HD patients. Yet, despite a continued broad dispersion of Ang values after KTX, a substantial improvement of the renin/Ang II correlation was observed in patients without RAS blockade or on angiotensin receptor blocker (HD: renin/Ang II R2 = 0.660, KTX: renin/Ang II R2 = 0.918). Ang-(17) representing the alternative RAS axis was only marginally detectable both on HD and after KTX. Conclusions: Following KTX, renin-dependent Ang II formation adapts in non-ACE inhibitor-treated patients. Thus, a largely normal RAS regulation is reconstituted after successful KTX. However, individual Ang concentration variations and a lack of potentially beneficial alternative peptides after KTX call for individualized treatment. The long-term post-transplant RAS regulation remains to be determined.(VLID)456375

Effects of direct renin inhibition versus angiotensin II receptor blockade on angiotensin profiles in non-diabetic chronic kidney disease

<p><b>Background:</b> Direct renin inhibition (DRI) is clinically inferior to other blockers of the renin–angiotensin system (RAS). Thus far, the underlying molecular causes of this finding remain unknown.</p> <p><b>Methods:</b> Twenty four patients with non-diabetic chronic kidney disease (CKD) stages III–IV and albuminuria were randomized to DRI or angiotensin receptor blocker (ARB). Employing a novel mass-spectrometry method, the concentrations of renin, aldosterone and plasma angiotensin peptides [Ang I, Ang II, Ang-(1-7), Ang-(1-5), Ang-(2-8), Ang-(3-8)] were quantified before and after an 8-week treatment.</p> <p><b>Results:</b> While blood pressure, renal function and albuminuria decreased comparably in both groups, profound RAS component differences were observed: DRI led to a massive renin increase, while suppressing both vasoconstrictive (Ang I and Ang II) and vasodilatory RAS metabolites (Ang-(1-7) and Ang-(1-5)). In contrast, ARB led to a four-fold increase of Ang I and Ang II, while Ang-(1-7) and Ang-(1-5) increased moderately but significantly. With ARB treatment, a decreased aldosterone-to-Ang II ratio suggested efficacy in blocking AT1 receptor.</p> <p><b>Conclusions:</b> DRI therapy abolishes all RAS effector peptides. ARB increases both vasoconstrictive and vasodilative angiotensins, while this is accompanied by efficient blockade of vasoconstrictive effects. These differential molecular regulations should be considered when selecting optimal antihypertensive and disease-modifying therapy in CKD patients.Key messages</p><p>Direct renin inhibition leads to a complete and lasting abolition of both classical and alternative RAS components.</p><p>Angiotensin receptor blockade leads to effective receptor blockade and up-regulation of alternative RAS components.</p><p>Differential molecular regulations of the RAS should be considered when selecting optimal antihypertensive and disease-modifying therapy in CKD patients.</p><p></p> <p>Direct renin inhibition leads to a complete and lasting abolition of both classical and alternative RAS components.</p> <p>Angiotensin receptor blockade leads to effective receptor blockade and up-regulation of alternative RAS components.</p> <p>Differential molecular regulations of the RAS should be considered when selecting optimal antihypertensive and disease-modifying therapy in CKD patients.</p

HDL Cholesterol Efflux Does Not Predict Cardiovascular Risk in Hemodialysis Patients

The cardioprotective effect of HDL is thought to be largely determined by its cholesterol efflux capacity, which was shown to inversely correlate with atherosclerotic cardiovascular disease in populations with normal kidney function. Patients with ESRD suffer an exceptionally high cardiovascular risk not fully explained by traditional risk factors. Here, in a post hoc analysis in 1147 patients with type 2 diabetes mellitus on hemodialysis who participated in the German Diabetes Dialysis Study (4D Study), we investigated whether the HDL cholesterol efflux capacity is predictive for cardiovascular risk. Efflux capacity was quantified by incubating human macrophage foam cells with apoB-depleted serum. During a median follow-up of 4.1 years, 423 patients reached the combined primary end point (composite of cardiac death, nonfatal myocardial infarction, and stroke), 410 patients experienced cardiac events, and 561 patients died. Notably, in Cox regression analyses, we found no association of efflux capacity with the combined primary end point (hazard ratio [HR], 0.96; 95% confidence interval [95% CI], 0.88 to 1.06; P=0.42), cardiac events (HR, 0.92; 95% CI, 0.83 to 1.02; P=0.11), or all-cause mortality (HR, 0.96; 95% CI, 0.88 to 1.05; P=0.39). In conclusion, HDL cholesterol efflux capacity is not a prognostic cardiovascular risk marker in this cohort of patients with diabetes on hemodialysis

Enrollment and randomization of the SAPT-NODAT and ITP-NODAT trial participants at the Medical University of Vienna.

<p>Enrollment and randomization of the SAPT-NODAT and ITP-NODAT trial participants at the Medical University of Vienna.</p

Adverse events, insulin therapy-related only.

<p>Adverse events, insulin therapy-related only.</p