Current Hypertension Reviews - Volume 9, Issue 1, 2013

Cardiovascular complications are a major cause of morbidity and mortality in patients with autosomal dominant polycystic kidney disease (ADPKD). Hypertension is a common finding of ADPKD occurring in 50-70% of patients before the impairment of renal function. Stimulation of the renin-angiotensin-aldosterone system plays a major role in the development of hypertension in ADPKD. Hypertension is associated with an increased rate of progression to end-stage renal disease and is the most important potentially treatable variable in these patients. Left ventricular hypertrophy, a major cardiovascular risk factor, is also common in patients with ADPKD. Both hypertension and left ventricular hypertrophy play a crucial role in the development of cardiovascular complications in these patients. Furthermore, endothelial dysfunction, impaired coronary flow velocity reserve, biventricular diastolic dysfunction, increased carotid intima–media thickness, and arterial stiffness are present even in young normotensive patients with ADPKD who have well-preserved renal function. These findings suggest that cardiovascular involvement starts very early in the course of ADPKD. Intracranial and extracranial aneurysms and cardiac valvular defects are other potential cardiovascular problems in patients with ADPKD. A multifactorial approach aiming at all cardiovascular risk factors, such as hypertension, smoking, dyslipidemia and obesity is extremely important in these patients. Early diagnosis and treatment of hypertension, with drugs that block the renin–angiotensin–aldosterone system, has the potential to decrease the cardiovascular complications and slow the progression of renal disease in ADPKD.

Autosomal dominant polycystic kidney disease is the most frequent life-threatening hereditary disease. Prognostic factors for progressive renal impairment have been identified such as gender, race, age, proteinuria, hematuria, hypertension. Hypertension is the only risk factor for renal dysfunction in autosomal dominant polycystic kidney disease, which is presently treatable. Better understanding of the pathophysiology of hypertension will help in defining appropriate interventions. The renin-angiotensin-aldosterone-system is the pivotal factor in the pathogenesis of hypertension in autosomal dominant polycystic kidney disease. Basic research and clinical studies in autosomal dominant polycystic kidney disease implicated activation of the renin-angiotensin-aldosterone-system. Therapy of hypertension in autosomal dominant polycystic kidney disease with angiotensin-converting enzyme inhibitors or angiotensin receptor blocker has the potential to prevent cardiovascular complications and slow the progression of renal disease. The results of two large multicenter double-blind placebo controlled randomized clinical trials (the HALT-PKD trials) possibly will elucidate the beneficial effects of the renin-angiotensin-aldosterone-system inhibition in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, affecting 1 in 1000 individuals. Previously termed “adult polycystic kidney disease”, ADPKD is now known to have important clinical manifestations beginning early in life and even in utero. Hypertension is an important risk factor for progressive renal and cardiovascular disease in children with ADPKD and may signify irremediable organ injury. The purpose of this article is to review current knowledge and treatment strategies in hypertension associated with pediatric ADPKD.

Left ventricular hypertrophy (LVH) has been recognized as an early and important complication in patients with autosomal dominant polycystic kidney disease (ADPKD). LVH is associated with arrhythmias, congestive heart failure, and increased cardiac mortality. The increase in left ventricular mass is attributed to the compensatory myocardial remodeling associated with systemic hypertension, which is also highly prevalent in those with ADPKD. Several observational studies over the past decades using echocardiography have estimated the prevalence of LVH in adults to range from 20-40%. More recently, the HALT-PKD study detected an LVH prevalence of less than 4% using magnetic resonance imaging. Some of the differences may relate to the imaging modality, variations in parameters used to define LVH, or demographic differences in the study populations. Nonetheless, there likely exists a shift in the pathophysiology of LVH in patients with ADPKD. Factors that explain this evolving trend include earlier detection and treatment of hypertension, more rigorous blood pressure control, and an increased use of renin-angiotensin-aldosterone system (RAAS) antagonists. The use of RAAS inhibitors has been shown to induce regression of LVH, and this may continue to play an important role in the cardiovascular risk management in patients with ADPKD. The results of ongoing studies will help elucidate these relationships.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially lethal hereditary disease. The hall mark of the disease is the development of innumerable cysts in kidneys and liver. However, a vascular phenotype including the early occurrence of hypertension, abnormalities in renal blood flow, intracranial and aortic aneurysms, spontaneous coronary and cervicocephalic artery dissections, and dolichoectasias of intracranial arteries is also part of the spectrum of ADPKD. While endothelial dysfunction occurs early in ADPKD and precedes the onset of hypertension, the pathogenesis of endothelial dysfunction has not been extensively studied. Development of endothelial dysfunction in ADPKD (as in other conditions characterized by endothelial dysfunction) has been linked to oxidative stress and vascular inflammation. Vascular dysfunction with increased contraction and decreased relaxation causes downstream tissue ischemia, a potent stimulus for angiogenesis. Evidence of angiogenesis on the surface of renal cysts has been documented in human ADPKD. In addition, high levels of angiogenic growth factors including vascular endothelial growth factor have been reported in cyst fluid and in the circulation of patients with ADPKD. In the following chapter we summarize recent studies examining the role and pathogenesis of endothelial dysfunction and neoangiogenesis in ADPKD.

The most important extra-renal manifestation of autosomal dominant polycystic kidney disease (ADPKD) in terms of debilitating injury and premature death is the development of intracranial aneurysms (IAs) and other vascular complications, resulting in subarachnoid hemorrhage (SAH). IAs are found at a rate approximately five times higher in ADPKD patients than in the general population and in patients with a family history of SAH/IAs the frequency is elevated further three to five times, indicating the importance of genetic factors in its etiology. Expression of the ADPKD gene products, polycystin-1 (PKD1) and polycystin-2 (PKD2), in vascular smooth muscle and the endothelium, and evidence that reduced levels of these proteins leads to IA development in mouse models, suggests a direct role of these proteins in the vascular disease. PKD1 and PKD2 patients seem equally likely to develop IAs, while patients with mutations to the 5’ half of PKD1 may more likely have vascular complications. Genome wide association and candidate studies of multiplex families with IAs without ADPKD have identified a number of genes/proteins that may be risk factors for the development of IAs. These candidate proteins largely have roles in the maintenance and remodeling of the arterial wall of small brain arteries. The development of the genetic methodologies of massively parallel sequencing mean it is now possible to test these and other candidates in ADPKD families with multiplex and singleton IA cases. Identifying strong modifiers of this phenotype will be important for prioritizing patients for presymptomatic screening and interventions.

The improvement of imaging techniques over the years has contributed to the understanding of the natural history of autosomal dominant polycystic kidney disease, and facilitated the observation of its structural progression. Advances in molecular biology and genetics have made possible a greater understanding of the genetics, molecular, and cellular pathophysiologic mechanisms responsible for its development and have laid the foundation for the development of potential new therapies. Therapies targeting genetic mechanisms in ADPKD have inherent limitations. As a result, most experimental therapies at the present time are aimed at delaying the growth of the cysts and associated interstitial inflammation and fibrosis by targeting tubular epithelial cell proliferation and fluid secretion by the cystic epithelium. Several interventions affecting many of the signaling pathways disrupted in ADPKD have been effective in animal models and some are currently being tested in clinical trials.

Hypertension is responsible for a significantly increased burden of cardiovascular events and it is cause and a consequence of Chronic Kidney Disease (CKD) and a determinant factor in its progression to End Stage Kidney Disease (ESKD). Therefore, nephrologists have been focusing their attention on hypertension control to prevent CKD progression, delaying it but with poor results on cardiovascular mortality reduction. An important effect is the difficulty to adequately reduce BP levels in CKD patients and especially in dialysis patients despite the polipharmacological therapy. We have to take into account other aspects influencing mortality risk in CKD patients .The first aspect to consider is whether brachial blood pressure (BP) measurement is sufficient to describe the complex relationship between the alteration of BP and outcomes in renal subjects. The second aspect to consider is the variability of BP (BPV). We think that BP measurement cannot only take into account brachial BP, because it represents a limited measure of a complex clinical condition in CKD or ESRD patients. The inability to evaluate hypertension in its complexity explains why several aspects are still unrecognized.

Arterial stiffness has been known to be a surrogate marker of arteriosclerosis, and also of vascular function. Pulse wave velocity (PWV) had been the most popular index and was known to be a predictor of cardiovascular events. But, it depends on blood pressure at measuring time. To overcome this problem, cardio-ankle vascular index (CAVI) is developed. CAVI is derived from stiffness parameter β by Hayashi, and the equation of Bramwell-Hill, and is independent from blood pressure at a measuring time. Then, CAVI might reflect the proper change of arterial wall by antihypertensive agents. CAVI shows high value with aging and in many arteriosclerotic diseases and is also high in persons with main coronary risk factors. Furthermore, CAVI is decreased by an administration of α1 blocker, doxazosin for 2-4 hours, Those results suggested that CAVI reflected the arterial stiffness composed of organic components and of smooth muscle cell contracture. Angiotensin II receptor blocker, olmesartan decreased CAVI much more than that of calcium channel antagonist, amlodipine, even though the rates of decreased blood pressure were almost same. CAVI might differentiate the blood pressure-lowering agents from the point of the effects on proper arterial stiffness. This paper reviewed the principle and rationale of CAVI, and the possibilities of clinical applications, especially in the studies of hypertension.

The role of innate and adaptive immunity in the pathogenesis of hypertension has received increasing recognition over the past few years. This review will focus on recent developments in this emerging area. In particular, the role of macrophages and lymphocytes will be highlighted.