Hypertension in autosomal dominant polycystic kidney disease

Abstract

Hypertension is common and occurs in a majority of autosomal dominant polycystic kidney disease (ADPKD) patients before the loss of kidney function. Hypertension relates to progressive kidney enlargement and is a significant independent risk factor for progression to ESRD. The pathogenesis of hypertension in ADPKD is complex and dependent on many factors that influence each other. Pkd1 and Pkd2 expression levels are highest in the major vessels and are present in the cilia of endothelial cells and in vascular smooth muscle cells. Decreased or absent polycystin 1 or 2 expression is associated with abnormal vascular structure and function. Pkd1/Pkd2 deficiency results in reduced nitric oxide (NO) levels, altered endothelial response to shear stress with attenuation in vascular relaxation. Ten percent to 20% of ADPKD children show hypertension and the majority of adults are hypertensive before any loss of kidney function. Cardiac abnormalities such as left ventricular hypertrophy and carotid intimal wall thickening are present before the development of hypertension in ADPKD. The activation of the renin-angiotensin-aldosterone system occurs in ADPKD because of decreased NO production as well as bilateral cyst expansion and intrarenal ischemia. With increasing cyst size, further activation of the RAAS occurs, blood pressure increases, and a vicious cycle ensues with enhanced cyst growth and hypertension ultimately leading to ESRD. The inhibition of the angiotensin aldosterone system is possible with angiotensin converting enzyme inhibitors and angiotensin receptor blockers. However, interventional studies have not yet shown benefit in slowing progression to renal failure in ADPKD. Currently, large multicenter studies are being performed to determine the beneficial effects of RAAS inhibition both early and late in ADPKD.

2010 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Proposed model for pathogenesis of hypertension in ADPKD. Reduction in polycystin 1 or 2 expression levels (PC1/PC2) result in endothelial, cardiac and carotid wall abnormalities in addition to renal cyst formation and expansion. Reduced nitric oxide (NO), cardiac relaxation and increased renal ischemia result in decreased renal blood flow and increased angiotensin II. Activation of the renin-angiotensin-aldosterone system results in increased blood pressure, tissue fibrosis and proliferation enhancing renal cyst growth.

Figure 2

a,b. SBP response (mmHg) in 7 hypertensive ADPKD patients to intravenous angiotensin I and II infusions. SBP increased significantly from baseline periods in placebo, enalapril and losartan treatment periods. No change in SBP during angiotensin I and II infusions was seen in the combined losartan/enalapril period. Peak SBP were significantly greater in placebo, enalapril and losartan periods vs. the losartan/enalapril period (p

Figure 2

a,b. SBP response (mmHg) in 7 hypertensive ADPKD patients to intravenous angiotensin I and II infusions. SBP increased significantly from baseline periods in placebo, enalapril and losartan treatment periods. No change in SBP during angiotensin I and II infusions was seen in the combined losartan/enalapril period. Peak SBP were significantly greater in placebo, enalapril and losartan periods vs. the losartan/enalapril period (p

Figure 3

a, b. Plasma aldosterone concentrations (PAC) (ng/dl) in 7 ADPKD hypertensive patients to intravenous angiotensin I and II infusions. PAC increased significantly from baseline in placebo, enalapril, and losartan treatment periods. No change in PAC was seen during angiotensin I and II infusions was seen in the combined losartan/enalapril period. Peak PAC was significantly greater in placebo, enalapril and losartan periods vs. the losartan/enalapril combined (p

Figure 3

a, b. Plasma aldosterone concentrations (PAC) (ng/dl) in 7 ADPKD hypertensive patients to intravenous angiotensin I and II infusions. PAC increased significantly from baseline in placebo, enalapril, and losartan treatment periods. No change in PAC was seen during angiotensin I and II infusions was seen in the combined losartan/enalapril period. Peak PAC was significantly greater in placebo, enalapril and losartan periods vs. the losartan/enalapril combined (p