Flow chart of inclusion.

<p>Flow chart of inclusion.</p

Subject characteristics (n = 15).

<p>Subject characteristics (n = 15).</p

Effects of Direct Renin Blockade on Renal & Systemic Hemodynamics and on RAAS Activity, in Weight Excess and Hypertension: A Randomized Clinical Trial

<div><p>Aim</p><p>The combination of weight excess and hypertension significantly contributes to cardiovascular risk and progressive kidney damage. An unfavorable renal hemodynamic profile is thought to contribute to this increased risk and may be ameliorated by direct renin inhibition (DRI). The aim of this trial was to assess the effect of DRI on renal and systemic hemodynamics and on RAAS activity, in men with weight excess and hypertension.</p><p>Methods</p><p>A randomized, double-blind, cross-over clinical trial to determine the effect of DRI (aliskiren 300 mg/day), with angiotensin converting enzyme inhibition (ACEi; ramipril 10 mg/day) as a positive control, on renal and systemic hemodynamics, and on RAAS activity (n = 15).</p><p>Results</p><p>Mean (SEM) Glomerular filtration rate (101 (5) mL/min/1.73m²) remained unaffected by DRI or ACEi. Effective renal plasma flow (ERPF; 301 (14) mL/min/1.73m²) was increased in response to DRI (320 (14) mL/min/1.73m², P = 0.012) and ACEi (317 (15) mL/min/1.73m², P = 0.045). Filtration fraction (FF; 34 (0.8)%) was reduced by DRI only (32 (0.7)%, P = 0.044). Mean arterial pressure (109 (2) mmHg) was reduced by DRI (101 (2) mmHg, P = 0.008) and ACEi (103 (3) mmHg, P = 0.037). RAAS activity was reduced by DRI and ACEi. Albuminuria (20 [9–42] mg/d) was reduced by DRI only (12 [5–28] mg/d, P = 0.030).</p><p>Conclusions</p><p>In men with weight excess and hypertension, DRI and ACEi improved renal and systemic hemodynamics. Both DRI and ACEi reduced RAAS activity. Thus, DRI provides effective treatment in weight excess and hypertension.</p><p>Trial Registration</p><p>Dutch trial register, registration number: 2532 <a href="http://www.trialregister.nl/" target="_blank">www.trialregister.nl</a></p></div

RAAS parameters in plasma (upper panel) and urine (lower panel) at baseline and after 6-week treatment with ACEi and DRI.

<p>Data shown as geometric mean (95% CI).</p

Clinical parameters at baseline and after treatment with ACEi and DRI.

<p>Clinical parameters at baseline and after treatment with ACEi and DRI.</p

Renal angiotensinogen handling at baseline and after 6-week treatment with ACEi and DRI.

<p>Data shown as geometric mean (95% CI).</p

Blood pressure measured by ABPM at baseline and after 6-week treatment with ACEi and DRI.

<p>Individual data are shown as well as mean (SEM). ABPM measurement was unsuccessful in one patient during DRI treatment due to insufficient number of recordings (<80%). <u>Abbreviations</u>: SBP: systolic blood pressure; DBP: diastolic blood pressure; MAP: mean arterial pressure.</p

Renal hemodynamics and systemic blood pressure measurements at baseline and after treatment with ACEi and DRI.

<p>Renal hemodynamics and systemic blood pressure measurements at baseline and after treatment with ACEi and DRI.</p

Renal hemodynamic parameters at baseline and after 6-week treatment with ACEi and DRI.

<p>Renal hemodynamic data indexed for BSA. Data shown as mean (SEM). <u>Abbreviations</u>: BSA: body surface area; GFR: glomerular filtration rate; ERPF: effective renal plasma flow; FF: filtration fraction.</p

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways