Pathophysiology of Autosomal Dominant Polycystic Kidney Disease

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This entry is adapted from the peer-reviewed paper 10.3390/app13127175

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited kidney disease which leads to progressive kidney failure. About 5–10% of patients requiring renal replacement therapy are affected by ADPKD. Cardiovascular diseases are the main causes of morbidity and mortality in these patients with ADPKD; arterial hypertension (AH) is the first symptom with a very early onset. Anyway, some other cardiovascular abnormalities have been reported in ADPKD regardless of the presence of AH.

autosomal dominant polycystic kidney disease left ventricular hypertrophy cardiovascular risk carotid intima–media thickness cardiovascular disease

1. Introduction

Autosomal dominant polycystic kidney disease (ADPKD) is a heterogeneous genetic disorder included in ciliopathies. The cystic dilatation of renal tubules and the progressive destruction of renal parenchyma leads to end-stage renal disease (ESRD) in half of affected patients aged 50 to 60 years. Thus, ADPKD is the fourth most common cause of renal replacement therapy worldwide, with an estimated prevalence between 1:1000 and 1:2500. ADPKD is characterized by the age-dependent growth of kidney cysts, and it is mainly caused by mutations in the PKD1 and PKD2 genes encoding for polycystin 1 (PC1) and polycystin 2 (PC2), which regulate differentiation, proliferation, survival, apoptosis, and autophagy ^[1]. More recently identified genes such as GANAB (encoding glucosidase II subunit α (GIIα)), PMM2, DNAJB11, ALG9, and IFT140 are also responsible for the development of cysts.

Mutations in PC1 and PC2, transmembranes glicoproteins that are colocalized to the primary cilium of the kidney tubular epithelial cells, cause lower intracellular levels of calcium and increased intracellular cyclic adenosine monophosphate, with aberrant cell proliferation and fluid secretion into cysts. ADPKD is a systemic disease that may involve different organs, showing high phenotypic variability ^[2].

2. Pathophysiology

The advances in knowledge of multiple molecular pathways underlying the pathophysiology of ADPKD involve the understanding of multiple mechanisms associated with extrarenal manifestations, including cardiac manifestations.

Cardiovascular disease is a major cause of morbidity and mortality in patients with ADPKD, and cardiac-related death in these patients is estimated to be 1.6- to 3.2-fold higher compared to the general population, with 33% of deaths mainly due to ischemic heart disease and congestive heart failure ^[2].

Beyond the classic cardiovascular complications characterized by heart failure and coronary artery disease, well known in chronic kidney disease (CKD), ADPKD itself results in a genetically defined increased risk of cardiovascular complications.

Arterial hypertension (AH), a common finding in these patients, often occurs before the onset of renal failure and is associated with the most rapid progression to ESRD, with an increased cardiovascular risk.

The frequency of AH is increased at young age and is more frequent in patients with mutations in PKD1 than in PKD2 and in polycystic patients with hypertensive parents.

Early diagnosis is facilitated by the self-measurement of blood pressure or ambulatory BP monitoring (ABPM), particularly in those patients with masked hypertension who do not show a normal BP decrease at night-time (non-dippers) ^[3].

The pathogenesis of AH in ADPKD is not fully elucidated, but specific mechanisms such as the activation of the renin–angiotensin–aldosterone system (RAAS), impaired nitric oxide (NO)-related vasorelaxation, increased sympathetic nerve activity, increased plasma endothelin-1 concentrations, and insulin resistance have been revealed.

Sodium overload is also characteristic of ADPKD patients, and sodium-sensitive hypertension is described, associated with increased total kidney volume ^[3].

Left ventricular hypertrophy, a powerful, independent risk factor for cardiovascular morbidity and mortality, frequently occurs in patients with ADPKD. Both AH and left ventricular hypertrophy have important roles in cardiovascular complications in these individuals. The effect of cyst enlargement on renal vessels with parenchyma ischemia explains the activation of RAAS, which plays an important role in the development of hypertension in ADPKD ^[3]. Altered intrarenal hemodynamics cause endothelial dysfunction, NO production, and the hyperactivation of the sympathetic nervous system (SNS). The RAAS is stimulated at an early stage of the disease, even before the appearance of hypertension and other clinical findings. Similarly, increased left ventricular mass indices and diastolic dysfunction are reported in ADPKD patients with well-preserved renal function before the development of AH. Endothelial dysfunction, inflammation, and accelerated atherosclerosis are early-stage changes in ADPKD patients ^[4]. Biventricular diastolic dysfunction, endothelial dysfunction, increased carotid intima–media thickness (IMT), and increased arterial stiffness are present even in young ADPKD patients with normal blood pressure and well-preserved renal function ^[5]. Over the years, many innovations have been reported in renal imaging with computed tomography (CT) or magnetic resonance imaging (MRI) to evaluate, in addition, to renal volume, intermediate volume or renal fibrotic and perfusion volume ^[6]^[7] with important prognostic implications for ADPKD patients.

Intracranial aneurysm (ICA) is one of the cardiovascular manifestations of ADPKD, but information about the natural history of ICA in ADPKD patients comes from small, single-center observational studies. These mainly describe an increased prevalence of asymptomatic ICA detected via magnetic resonance angiography (MRA), with 9–12% of patients demonstrating ICA, compared with ~2–3% of the general population. The prevalence is higher in ADPKD patients with a positive family history compared to ADPKD patients with a negative family history. Family history is recognized as the main risk factor for ICA rupture as well, which occurs at the average age of 40, almost 10 years earlier than in the general population ^[8].

Data from pre-symptomatic screening demonstrated that the majority of ICA localize in the anterior circulation of the circle of Willis, with nearly all being of a small size <7 mm, falling in the low-risk category for rupture.

Therefore, guidelines suggest to only perform screening for ICA in ADKPK patients with family or personal history of ICA rupture. All patients with ADPKD should receive counseling about the risk of ICA, considering the pros and cons of pre-symptomatic screening and reserving diagnostic imaging for those individuals who remain anxious about their risk and individuals with high-risk professions ^[8]^[9].

Vascular disorders such as aneurysms and arterial dissections of large arteries, including aorta, coronary, and splenic arteries, are reported in ADPKD patients, representing an important cause of death. However, the prevalence of abdominal aortic aneurysms does not seem to be increased in patients with ADPKD.

Polycystin proteins have a role in epithelial cell/matrix interactions, and polycystin mutations are associated with collagen and extracellular matrix abnormalities. The high expression of PKD1 and 2 in the human adult vascular wall, particularly in the dense plaques of the smooth muscle cell, accounts for the risk of vascular wall modification. Characteristic phenotypes of some ADPKD patients showing arachnodactyly, high-arched palates, pectus deformities, joint laxity, flat feet, and positive thumb signs should alert clinicians toward an increased predisposition to vascular involvement ^[10].

There is no standard assessment suggested in these patients, and the clinical presentation of vascular disorders may be highly variable and mimic many common conditions. Given the high risk of complications in these patients, contrast-enhanced computed tomography should be considered when suggestive symptoms develop for differential diagnosis.

The other major extrarenal complications of ADPKD include hepatic and pancreatic cysts, colonic diverticula, dolichoectasias, abdominal wall hernias, cerebral and ascending thoracic aorta aneurysms, seminal vesicle cysts, and male infertility ^[2].

ADPKD is also associated with significant pain and discomfort, which may affect the quality of life of these patients. The quality of life (QOL) of patients with ADPKD could be associated with abdominal distention, pain, and anorexia caused by liver and kidney enlargement, even if other associated symptoms could also affect QOL such as sleep disturbance, heartburn, urinary tracts, fever, and hematuria ^[11].

Current treatment strategies include conservative therapy and reducing cyclic adenosine monophosphate levels, cell proliferation, and fluid secretion with somatostatin analogs and vasopressin V2 receptor antagonists that have been shown to slow the deterioration of renal function and the growth of renal and hepatic cysts ^[1].

References

Capuano, I.; Buonanno, P.; Riccio, E.; Amicone, M.; Pisani, A. Therapeutic advances in ADPKD: The future awaits. J. Nephrol. 2022, 35, 397–415.
Perrone, R.D.; Ruthazer, R.; Terrin, N.C. Survival after end-stage renal disease in autosomal dominant polycystic kidney disease: Contribution of extrarenal complications to mortality. Am. J. Kidney Dis. 2001, 38, 777–784.
Ecder, T. Cardiovascular complications in autosomal dominant polycystic kidney disease. Curr. Hypertens. Rev. 2013, 9, 2–11.
Lai, S.; Petramala, L.; Mastroluca, D.; Petraglia, E.; Di Gaeta, A.; Indino, E.; Panebianco, V.; Ciccariello, M.; Shahabadi, H.H.; Galani, A.; et al. Hyperaldosteronism and cardiovascular risk in patients with autosomal dominant polycystic kidney disease. Medicine 2016, 95, e4175.
Ecder, T.; Schrier, R.W. Cardiovascular abnormalities in autosomal-dominant polycystic kidney disease. Nat. Rev. Nephrol. 2009, 5, 221–228.
Caroli, A.; Antiga, L.; Conti, S.; Sonzogni, A.; Fasolini, G.; Ondei, P.; Perico, N.; Remuzzi, G.; Remuzzi, A. Intermediate volume on computed tomography imaging defines a fibrotic compartment that predicts glomerular filtration rate decline in autosomal dominant polycystic kidney disease patients. Am. J. Pathol. 2011, 179, 619–627.
Lai, S.; Mastroluca, D.; Letizia, C.; Petramala, L.; Perrotta, A.M.; DiGaeta, A.; Ferrigno, L.; Ciccariello, M.; D’Angelo, A.R.; Panebianco, V. Magnetic resonance imaging 3T and total fibrotic volume in autosomal dominant polycystic kidney disease. Intern. Med. J. 2018, 48, 1505–1513.
Haemmerli, J.; Morel, S.; Georges, M.; Haidar, F.; Chebib, F.T.; Morita, A.; Nozaki, K.; Tominaga, T.; Bervitskiy, A.V.; Rzaev, J.; et al. Characteristics and Distribution of Intracranial Aneurysms in Patients with Autosomal Dominant Polycystic Kidney Disease Compared with the General Population: A Meta-Analysis. Kidney360 2023, 4, e466–e475.
Chapman, A.B.; Devuyst, O.; Eckardt, K.U.; Gansevoort, R.T.; Harris, T.; Horie, S.; Kasiske, B.L.; Odland, D.; Pei, Y.; Perrone, R.D.; et al. Conference Participants. Autosomal-dominant polycystic kidney disease (ADPKD): Executive summary from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int. 2015, 88, 17–27.
Silverio, A.; Prota, C.; Di Maio, M.; Polito, M.V.; Cogliani, F.M.; Citro, R.; Gigantino, A.; Iesu, S.; Piscione, F. Aortic dissection in patients with autosomal dominant polycystic kidney disease: A series of two cases and a review of the literature. Nephrology 2015, 20, 229–235.
Lai, S.; Mangiulli, M.; Perrotta, A.M.; Gigante, A.; Napoleoni, L.; Cipolloni, E.; Mitterhofer, A.P.; Gasperini, M.L.; Muscaritoli, M.; Cianci, R.; et al. Cardiovascular Risk and Quality of Life in Autosomal Dominant Polycystic Kidney Disease Patients on Therapy with Tolvaptan: A Pilot Study. Curr. Vasc. Pharmacol. 2021, 19, 556–564.

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Subjects: Cardiac & Cardiovascular Systems

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Antonietta Gigante

Adolfo Marco Perrotta

Francesca Tinti

Eleonora Assanto

Maurizio Muscaritoli

Silvia Lai

Rosario Cianci

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Entry Collection: Hypertension and Cardiovascular Diseases

Update Date: 29 Jun 2023

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1. Introduction

2. Pathophysiology

References