Use Of Maximal Dosage Renin-Angiotensin-Aldosterone System Inhibitors In A Real Life Population Of Complicated Type 2 Diabetes – Contraindications And Opportunities

Objective Pharmacological inhibition of the renin-angiotensin-aldosterone-system (RAASi) is the cornerstone of hypertension treatment, renoprotection and secondary prevention of cardiovascular disease in patients with type 2 diabetes. Although there is a dose-dependent effect of RAASi with optimum protection when using maximal dose, little is known on actual use of maximal dosage RAASi in clinical practice. Here we investigate prevalence of maximal dosage RAASi, and contraindications for, optimizing RAASi dosage, in patients with complicated type 2 diabetes in a real-life clinical setting.Research Design and MethodsWe performed a retrospective analysis in 668 patients included in the DIAbetes and LifEstyle Cohort Twente (DIALECT). We grouped patients according to no RAASi, submaximal RAASi and maximal RAASi use. All potassium and creatinine measurements between January 1st 2000 and date of inclusion in DIALECT were extracted from patients files. We identified determinants of maximal RAASi use vs submaximal RAASi use with multivariate logistic regression analysis. ResultsMean age was 64 ± 10 years and 61% were men. In total, 460 patients (69%) used RAASi, and 30% used maximal RAASi. Maximal RAASi use was not statistically different between different indications for RAASi (i.e. hypertension, diabetic kidney disease, coronary heart disease and cerebrovascular disease; P>0.05). Per patient, 2 [1-4] measurements of potassium and 20 [13-31] measurements of creatinine were retrieved, retrospective follow-up time was -3.0 [-1.4 to -5.7] years. Pre-baseline hyperkalemia >5.0 mmol/l and acute kidney injury were found in 151 (23%) patients and 119 patients (18%), respectively. Determinants of maximal RAASi were prior acute kidney injury (OR 0.51 (0.30-0.87)), increased albuminuria (OR 1.89 (1.17-3.08)) and total number of used antihypertensives (OR 1.66 (1.33-2.06)).ConclusionsMaximal dose RAASi is used in almost one third of complicated type 2 diabetes patients in a real-life setting. The prevalence of contraindications is considerable, but relative in nature, suggesting that it is worthwhile to explore strategies aimed at maximizing RAASi while circumventing the alleged contraindications.

The circulating renin-angiotensin-aldosterone system is down-regulated in dogs with glomerular diseases compared to other chronic kidney diseases with low-grade proteinuria

Glomerular diseases (GD) lead to a variety of disorders of the vascular and the total body water volumes. Various pathomechanisms, including vascular underfill and overfill, have been suggested to explain these disturbances. Accordingly, the circulating renin-angiotensin-aldosterone system (cRAAS) is expected to be activated as either a cause or a result of these fluid disorders. The aim of this study was to characterize the activity of the cRAAS in dogs with GD and to evaluate its relationship with the vascular volume status. In a prospective study, we evaluated the plasma renin activity and the serum aldosterone concentration in 15 dogs with GD. Their fluid volume status was estimated with clinical variables reflecting volemia and hydration, echocardiographic volume assessment, N-terminal pro B-type natriuretic peptide, blood urea nitrogen:creatinine ratio, and the urinary fractional excretion of sodium. Ten dogs with chronic kidney disease (CKD) with matching degree of azotemia were recruited as controls. The activity of the cRAAS was low in 10 dogs, normal in 3 dogs, high in 1 dog and equivocal (high renin—low aldosterone) in 1 dog with GD. These dogs had a lower cRAAS activity than dogs with CKD (p = 0.01). The clinical evaluation showed 8 hypovolemic and 7 non-hypovolemic dogs; 3 dehydrated, 9 euhydrated and 3 overhydrated dogs. The cRAAS activity was not different between hypovolemic and non-hypovolemic dogs. The down-regulated cRAAS without obvious association with the clinical volume status of these dogs with GD, suggests different mechanisms of fluid volume dysregulation in dogs with GD than previously assumed. This finding however should be confirmed in a focused larger scale study, as it may influence the use of cRAAS blockers as part of the standard therapy of GD in dogs.

Impact of Renin-Angiotensin-Aldosterone-System Inhibitor Drugs on Mortality in Patients with Atrial Fibrillation and Hypertension

Background Renin-angiotensin-aldosterone-system inhibitors markedly played an active role in the primary and secondary prevention of atrial fibrillation (AF), but the impact of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) on the mortality of patients with AF remains unclear. This study aimed to examine the relationship between treatment with ACEIs or ARBs and the mortality in emergency department (ED) patients with AF and hypertension. Methods This multicenter study enrolled 2016 ED patients from September 2008 to April 2011; Total 1110 patients with AF and hypertension were analyzed. Patients were grouped according to whether they were treated with ACEI/ARB or not and completed a 1-year follow-up to evaluate outcomes including all-cause death, cardiovascular death, stroke, and major adverse events (MAEs). Results Among the 1110 patients with AF and hypertension, 574 (51.7%) received ACEI/ARB treatment. During the 1-year follow-up, 169 all-cause deaths (15.2%) and 100 cardiovascular deaths (9.0%) occurred, while 98 strokes (8.8%) and 255 MAEs (23.0%) occurred. According to the multivariate Cox regression analysis, ACEI/ARB therapy was significantly associated with a reduced risk of all-cause death (HR, 0.642; 95% CI, 0.466–0.884; P = 0.007). Moreover, ACEI/ARB therapy was independently associated with a reduced risk of cardiovascular death (HR, 0.649; 95% CI, 0.424–0.993; P = 0.046) and MAEs (HR: 0.701, 95% CI 0.541–0.907, P = 0.007) after adjusting for other risk factors. Conclusions Our results revealed that ACEI/ARB therapy was independently associated with a reduced risk of all-cause death, cardiovascular death, and MAEs in ED patients with AF and hypertension. These results provide evidence for a tertiary preventive treatment for patients with atrial fibrillation and hypertension.

Immunohistochemical and Transcriptional Analysis of SARS-CoV-2 Entry Factors and Renin-Angiotensin-Aldosterone System Components in Lethal COVID-19

<b><i>Introduction:</i></b> Since angiotensin converting enzyme-2 (ACE2) was discovered as an essential entry factor of SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2), there has been conflicting evidence regarding the role of renin-angiotensin-aldosterone system (RAAS) in COVID-19. This study elucidates pulmonary expression patterns SARS-CoV-2 entry factors (ACE2 and transmembrane protease serine subtype 2, TMPRSS2) and RAAS components in lethal COVID-19. <b><i>Methods:</i></b> Lung tissue from COVID-19 autopsies (<i>n</i> = 27) and controls (<i>n</i> = 23) underwent immunohistochemical staining for RAAS components (angiotensin receptors 1 and 2, ACE2 and Mas-receptor) and bradykinin receptors 1 and 2. Staining of individual cellular populations (alveolar pneumocytes [ALV], desquamated cells [DES] and endothelium [END]) was measured by a binary scale (positive/negative). SARS-CoV-2 was detected using immunohistochemistry against nucleocapsid protein, <i>in-situ</i> hybridization and quantitative reverse transcriptase polymerase chain reaction. Gene expression profiling for <i>ACE2, ACE</i> and <i>TMPRSS2</i> was performed. <b><i>Results:</i></b> Subtle differences were observed when comparing COVID-19 patients and controls not reaching statistical significance, such as a higher incidence of ACE2-positivity in END (52% vs. 39%) but lower positivity in ALVs (63% vs. 70%) and an overall downregulation of <i>ACE2</i> gene expression (0.25 vs. 0.55). However, COVID-19 patients with RAAS inhibitor (RAASi) intake had significantly shorter hospitalization times (5 vs. 12 days), higher viral loads (57,517 vs. 15,980/10⁶ RNase P-gene copies) and decreased <i>ACE/ACE2</i>-expression ratios (4.58 vs. 11.07) than patients without. <i>TMPRSS2</i> expression was significantly (1.76-fold) higher in COVID-19 patients than controls. <b><i>Conclusion:</i></b> Our study delineates the heterogeneous expression patterns of RAAS components in the lungs, which vary amongst cellular populations, and implies that COVID-19 patients with RAASi-intake present with a more rapid disease progression, although this requires further investigation.