Autosomal dominant polycystic kidney disease and the heart and brain
ABSTRACT
Autosomal dominant polycystic kidney disease (ADPKD) has numerous systemic manifestations and complications. This article gives an overview of hypertension, cardiac complications, and intracranial aneurysms in ADPKD, their pathophysiology, and recent developments in their management.
KEY POINTS
- Hypertension and left ventricular hypertrophy are common complications of ADPKD.
- Cardiovascular disease is a major cause of morbidity and death in ADPKD.
- Early diagnosis and aggressive management of high blood pressure, specifically with agents that block the renin-angiotensin-aldosterone system, are necessary to prevent left ventricular hypertrophy and progression of renal failure in ADPKD.
- Timely screening and intervention for intracranial aneurysm would lessen the rates of morbidity and death from intracranial hemorrhage.
CORONARY ARTERY DISEASE AND ANEURYSM IN ADPKD
Atherosclerosis sets in early in ADPKD, resulting in coronary artery disease and adverse cardiovascular outcomes.
Coronary flow velocity reserve is the ability of coronary arteries to dilate in response to myocardial oxygen demand. Atherosclerosis decreases this reserve in ADPKD patients, as shown in several studies.
Turkmen et al, in a series of studies,76–78 found that ADPKD patients had significantly less coronary flow velocity reserve, thicker carotid intima media (a surrogate marker of atherosclerosis), and greater insulin resistance than healthy controls. These findings imply that atherosclerosis begins very early in the course of ADPKD and has remarkable effects on cardiovascular morbidity and mortality.76
Aneurysm. Although the risk of extracranial aneurysm is higher with ADPKD, coronary artery aneurysm is uncommon. The pathogenesis of coronary aneurysm has been linked to abnormal expression of the proteins polycystin 1 and polycystin 2 in vascular smooth muscle.11,79 The PKD1 and PKD2 genes encode polycystin 1 and 2, respectively, in ADPKD. These polycystins are also expressed in the liver, kidneys, and myocardium and are involved in the regulation of intracellular calcium, stretch-activated ion channels, and vascular smooth muscle cell proliferation and apoptosis.11,16 Abnormally expressed polycystin in ADPKD therefore has an impact on arterial wall integrity, resulting in focal medial defects in the vasculature that eventually develop into micro- and macroaneurysms.11
Hadimeri et al79 found a higher prevalence of coronary aneurysm and ectasia in ADPKD patients than in controls. Most coronary aneurysms are smaller than 1 cm; however, a coronary aneurysm measuring 4 cm in diameter was found at autopsy of an ADPKD patient.11
Spontaneous coronary artery dissection is very rare in the general population, but Bobrie et al reported a case of it in an ADPKD patient.9
ATRIAL MYXOMA, CARDIOMYOPATHY, AND PERICARDIAL EFFUSION IN ADPKD
Atrial myxoma in ADPKD patients has been described in 2 case reports.15,80 However, the association of atrial myxoma with ADPKD is poorly understood and may be a coincidental finding.
Cardiomyopathy in ADPKD has been linked to abnormalities in the intracellular calcium pathway, although a clear picture of its involvement has yet to be established.
Paavola et al16 described the pathophysiology of ADPKD-associated cardiomyopathy in PKD2 mutant zebrafish lacking polycystin 2. These mutants showed decreased cardiac output and had atrioventricular blocks. The findings were attributed to abnormal intracellular calcium cycling. These findings correlated well with the frequent finding of idiopathic dilated cardiomyopathy in ADPKD patients, especially with PKD2 mutations.16 Also, 2 cases of dilated cardiomyopathy in ADPKD have been reported and thought to be related to PKD2 mutations.81,82
Pericardial effusion. Even though the exact pathophysiology of pericardial effusion in ADPKD is unknown, it has been theorized to be related to defects in connective tissue and extracellular matrix due to PKD1 and PKD2 mutations. These abnormalities increase the compliance and impair the recoil capacity of connective tissue, which results in unusual distention of the parietal pericardium. This abnormal distention of the parietal pericardium together with increased extracellular volume may lead to pericardial effusion.17
Qian et al17 found a higher prevalence of pericardial effusion in ADPKD patients. It was generally asymptomatic, and the cause was attributed to these connective tissue and extracellular matrix abnormalities.
EMERGING THERAPIES AND TESTS
Recent trials have investigated the effects of vasopressin receptor antagonists, specifically V2 receptor blockers in ADPKD and its complications.
Tolvaptan has been shown to slow the rate of increase in cyst size and total kidney volume.83,84 Also, a correlation between kidney size and diastolic blood pressure has been observed in ADPKD patients.85 Reducing cyst volume may reduce pressure effects and decrease renal ischemia, which in turn may reduce RAAS activation; however, the evidence to support this hypothesis is poor. A major clinical trial of tolvaptan in ADPKD patients showed no effect on blood pressure control, but the drug slowed the rate of increase in total kidney volume and fall in eGFR.83
Endothelin receptor antagonists are also in the preliminary stage of development for use in ADPKD. The effects of acute blockade of the renal endothelial system with bosentan were investigated in animal models by Hocher et al.28 This study showed a greater reduction in mean arterial pressure after bosentan administration, resulting in significantly decreased GFR and renal blood flow. Nonetheless, the mean arterial pressure-lowering effect of bosentan was more marked than the reductions in GFR and renal blood flow.
Raina et al,86 in a pilot cross-sectional analysis, showed that urinary excretion of ET-1 is increased in ADPKD patients, and may serve as a surrogate marker for ET-1 in renal tissue and a noninvasive marker of early kidney injury.
