1.
Efficacy and Safety of Dual Blockade of the Renin-Angiotensin-Aldosterone System in Diabetic Kidney Disease: A Meta-Analysis.
Feng, Y, Huang, R, Kavanagh, J, Li, L, Zeng, X, Li, Y, Fu, P
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2019;(3):259-286
Abstract
INTRODUCTION Current guidelines recommend renin-angiotensin-aldosterone system (RAAS) inhibitors in the treatment of diabetic kidney disease (DKD). However, evidence suggests that the combined use of RAAS blockers may be associated with increased rates of adverse events. OBJECTIVES Our objective was to examine the efficacy and safety of dual blockade of the RAAS in patients with DKD. METHODS This was a systematic review and meta-analysis of randomized controlled trials (RCTs) published between January 1990 and January 2018 sourced via the PubMed, EMBASE, and Cochrane Library databases. RCTs were included if they investigated the efficacy and safety of dual blockade therapy compared with monotherapy in patients with DKD. Random effects models were used in meta-analysis to account for heterogeneities in effect sizes across the reviewed studies. Analyses were stratified by blood pressure and albuminuria. We further conducted subgroup analyses by considering various combinations of RAAS inhibitors. RESULTS Based on 42 RCTs with 14,576 patients, dual RAAS blockade therapy was associated with significant decreases in blood pressure, albuminuria, and proteinuria. However, dual therapy was not superior to monotherapy in terms of reductions in all-cause mortality, cardiovascular mortality, or progression to end-stage renal disease (ESRD). Significant increases in serum potassium and rates of hyperkalemia and hypotension were more common in patients treated with dual therapy. However, glomerular filtration rates (GFR) did not decrease significantly with dual therapy. In subgroup analysis, an angiotensin-converting enzyme inhibitor (ACEI) plus an angiotensin-receptor blocker (ARB) or a direct renin inhibitor (DRI) plus an ACEI/ARB did not significantly increase the risk of hyperkalemia, hypotension, and adverse events, and the risk of hypotension increased significantly within the normotensive subgroup but not within the hypertensive subgroup. The risk of hyperkalemia increased significantly in patients with DKD with macroalbuminuria but not in those with microalbuminuria. CONCLUSION Dual inhibition therapy is superior to monotherapy for blood pressure control and urine protein reduction, though such superiority does not translate into improvements in longer-term outcomes, such as reduced progression to ESRD, all-cause mortality, and cardiovascular mortality. An ACEI plus an ARB or a DRI plus an ACEI/ARB may be a safe and effective therapy for patients with DKD, and combination therapy may be suitable for patients with DKD and hypertension and microalbuminuria.
2.
Effect of sodium intake on renin level: Analysis of general population and meta-analysis of randomized controlled trials.
Rhee, OJ, Rhee, MY, Oh, SW, Shin, SJ, Gu, N, Nah, DY, Kim, SW, Lee, JH
International journal of cardiology. 2016;:120-6
Abstract
BACKGROUND We evaluated the association between sodium intake and plasma renin levels in the cross sectional study and meta-analysis of randomized controlled trials, whether there is a persistent elevation of plasma renin by longer-term sodium intake restriction. METHODS Plasma renin activity (PRA) and 24-h urine sodium (24HUNa) excretion were measured from individuals randomly selected from a community. Simple and multiple linear regression analyses adjusted for age, 24-h systolic blood pressure, 24-h average heart rate, fasting blood glucose and gender were performed. For meta-analysis, 74 studies published from 1975 to mid-2014 were identified in a systematic literature search using EMBASE, CINAHL, and MEDLINE. Random effects meta-analyses and a meta-regression analysis were performed. RESULTS Among the 496 participants recruited, 210 normotensive and 87 untreated hypertensive subjects were included in the analysis. There was no significant association between PRA and 24HUNa in the total population, or hypertensive and normotensive individuals. In the meta-analysis, the standard mean difference (SMD) of renin level by sodium intake reduction was 1.26 (95% CI: 1.08 to 1.44, Z=12.80, P<0.001, I(2)=87%). In the meta-regression analysis, an increase in a day of intervention was associated with a fall in SMD by -0.04 (95% CI: -0.05 to -0.02, Z=-5.27, P<0.001, I(2)=86%), indicating that longer duration of reduced sodium intake would lead to lesser SMD of renin level. CONCLUSIONS The present population based cross-sectional study and meta-analysis suggests that prolonged reduction in sodium intake is very unlikely associated with elevation of plasma renin levels.
3.
Genome-wide association study of CSF levels of 59 alzheimer's disease candidate proteins: significant associations with proteins involved in amyloid processing and inflammation.
Kauwe, JS, Bailey, MH, Ridge, PG, Perry, R, Wadsworth, ME, Hoyt, KL, Staley, LA, Karch, CM, Harari, O, Cruchaga, C, et al
PLoS genetics. 2014;(10):e1004758
Abstract
Cerebrospinal fluid (CSF) 42 amino acid species of amyloid beta (Aβ42) and tau levels are strongly correlated with the presence of Alzheimer's disease (AD) neuropathology including amyloid plaques and neurodegeneration and have been successfully used as endophenotypes for genetic studies of AD. Additional CSF analytes may also serve as useful endophenotypes that capture other aspects of AD pathophysiology. Here we have conducted a genome-wide association study of CSF levels of 59 AD-related analytes. All analytes were measured using the Rules Based Medicine Human DiscoveryMAP Panel, which includes analytes relevant to several disease-related processes. Data from two independently collected and measured datasets, the Knight Alzheimer's Disease Research Center (ADRC) and Alzheimer's Disease Neuroimaging Initiative (ADNI), were analyzed separately, and combined results were obtained using meta-analysis. We identified genetic associations with CSF levels of 5 proteins (Angiotensin-converting enzyme (ACE), Chemokine (C-C motif) ligand 2 (CCL2), Chemokine (C-C motif) ligand 4 (CCL4), Interleukin 6 receptor (IL6R) and Matrix metalloproteinase-3 (MMP3)) with study-wide significant p-values (p<1.46×10-10) and significant, consistent evidence for association in both the Knight ADRC and the ADNI samples. These proteins are involved in amyloid processing and pro-inflammatory signaling. SNPs associated with ACE, IL6R and MMP3 protein levels are located within the coding regions of the corresponding structural gene. The SNPs associated with CSF levels of CCL4 and CCL2 are located in known chemokine binding proteins. The genetic associations reported here are novel and suggest mechanisms for genetic control of CSF and plasma levels of these disease-related proteins. Significant SNPs in ACE and MMP3 also showed association with AD risk. Our findings suggest that these proteins/pathways may be valuable therapeutic targets for AD. Robust associations in cognitively normal individuals suggest that these SNPs also influence regulation of these proteins more generally and may therefore be relevant to other diseases.