|Year : 2017 | Volume
| Issue : 2 | Page : 253-260
|Update on pathogenesis, management, and treatment of hypertension in autosomal dominant polycystic kidney disease
Imed Helal1, Fadel Al-Rowaie2, Ezzedine Abderrahim1, Adel Kheder1
1 Department of Medicine A (M8), Charles Nicolle Hospital; Laboratory of Kidney Pathology (LR00SP01), Charles Nicolle Hospital; Faculty of Medicine, University of Tunis El Manar, Tunis, Tunisia
2 Department of Nephrology, King Fahad Medical City, Riyadh, Saudi Arabia
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|Date of Web Publication||23-Mar-2017|
| Abstract|| |
Hypertension is a common early finding in autosomal dominant polycystic kidney disease (ADPKD). Improvements in screening and diagnosis of ADPKD have allowed earlier diagnosis, later onset of end-stage renal disease, and better survival. However, the main and most effective therapy remains control of hypertension. Hypertension is the most important modifiable risk factor in ADPKD. Therefore, early management of hypertension reduces the incidence of cardiovascular events in ADPKD patients. Stimulation of the renin–angiotensin–aldosterone system (RAAS) plays a central role in the pathogenesis of hypertension in ADPKD. Therapies that block the RAAS have improved patient management, blood pressure control, and ADPKD patient survival. This review highlights the current understanding of the epidemiology, potential pathogenetic mechanisms and proposes a strategy for the treatment and management of hypertension in ADPKD.
|How to cite this article:|
Helal I, Al-Rowaie F, Abderrahim E, Kheder A. Update on pathogenesis, management, and treatment of hypertension in autosomal dominant polycystic kidney disease. Saudi J Kidney Dis Transpl 2017;28:253-60
|How to cite this URL:|
Helal I, Al-Rowaie F, Abderrahim E, Kheder A. Update on pathogenesis, management, and treatment of hypertension in autosomal dominant polycystic kidney disease. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2021 Jun 17];28:253-60. Available from: https://www.sjkdt.org/text.asp?2017/28/2/253/202774
| Introduction|| |
Autosomal dominant polycystic kidney disease (ADPKD) is the most common, life-threatening single-gene disease in adults. It affects over 15 million people worldwide and is responsible for 5%–10% of end-stage renal disease (ESRD).,
Patients with ADPKD have an increased incidence of hypertension, left ventricular hypertrophy (LVH), and cardiovascular abnormalities., The reported relative mortality rate in patients with ADPKD is 1.6-fold [95% confidence interval (CI) 1.3–2.0] and 3.2-fold higher (95% CI 2–4.8) in comparison to the general population. Hypertension represents the most important modifiable risk factor of ADPKD Therefore, early and effective treatment of hypertension is very important to slow down kidney progression and decrease morbidity and mortality of ADPKD patients.
Recently, exciting molecular pathogenesis breakthrough and new treatments halting disease progression have been discovered. In this review, we highlight the current understanding of the epidemiology, potential pathogenetic mechanisms, and therapeutic strategies and propose an approach to the treatment and management of hypertension in ADPKD.
| Epidemiology of Hypertension in ADPKD|| |
Hypertension occurs early in the natural history of ADPKD, and in 50%–70%, it actually appears even before kidney function decline., However, the development of hypertension and its complications begins even earlier in the course of natural history of this disease. The median age at diagnosis of hypertension in ADPKD is 32 years for male and 34 years for female and occurs at an earlier age in comparison with general population. Young ADPKD patients have also significantly higher ambulatory blood pressure (BP) and left ventricular mass index than control population. Furthermore, hypertension occurs in 30% of children with ADPKD.,,,
Hypertension occurs earlier and more frequently in PKD1 than in PKD2, and with ADPKD patients whose parents have hypertension, whether they have ADPKD or not. Hypertension is more frequent and more severe in men than women. BP monitoring allows earlier diagnosis of hypertension and identifies nondipping circadian BP rhythm. Currently, ambulatory BP monitoring represents the best tool for the diagnosis and follow-up of patients with hypertension according to the new clinical guidelines, and we have to apply this recommendation to our ADPKD patients.
Patients with essential hypertension are less frequently affected by end-organ damage than hypertensive ADPKD patients. Other cardiovascular abnormalities such as LVH, early diastolic dysfunction, carotid intimal wall thickening, and impaired coronary flow velocity reserve have also been demonstrated in ADPKD., Therefore, a cardiovascular risk assessment must be systematic in ADPKD patients. However, lower incidence of LVH using cardiac magnetic resonance has recently been reported in HALT-PKD study. This low prevalence has been attributed to the high usage of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARBs).
Current published data confirm that patients with ADPKD in the United Sates,, Denmark, and Great Britain have a better prognosis than in the past. There has been an earlier diagnosis, better control of BP, more use of renin–angiotensin–aldosterone system (RAAS) inhibitors, better preservation of kidney function, later onset of ESRD, and better survival.,,, Early and effective treatment of hypertension is very important in patients with ADPKD to slow down renal failure progression and prevent the occurrence of cardiovascular events. This improved prognosis no doubt involves other factors in addition to the better control of BP.
| Pathogenesis of Hypertension in ADPKD|| |
Hypertension is common in most chronic kidney diseases (CKD). However, the pathogenesis is somewhat different in ADPKD. The pathogenesis of hypertension in ADPKD involves several interactive factors. Activation of the RAAS of the vascular dysfunction related to ciliopathy and other factors have all been found to be involved in the development of hypertension in ADPKD [Figure 1].
|Figure 1: Potential pathogenetic mechanisms of hypertension in ADPKD.|
ADPKD: Autosomal dominant polycystic kidney disease, RAAS: Renin–angiotensin–aldosterone system.
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Activation of the RAAS
The pathogenesis of hypertension in ADPKD patients is dominated by activation of RAAS. CRISP (the consortium for radiologic imaging studies of polycystic kidney disease) trial and other previous studies demonstrated that the decline of kidney function in ADPKD patients is directly related to progressive enlargement of multiple cysts.,,, It is believed that distortion of the renal parenchyma leads to structural damage, tubular dysfunction, and renal vascular ischemia and results in activation of the RAAS.
There are several explanations for the involvement of RAAS in the development of hypertension in ADPKD patients. Plasma renin activity and plasma aldosterone concentrations are higher the in supine and upright positions in patients with ADPKD compared with patients with essential hypertension matched for age, sex, kidney function, sodium intake, and degree of hypertension. All components of the RAAS have been identified in kidneys from patients with ADPKD. In addition, higher renin activity has been demonstrated in the cyst fluid.
The roles of vascular abnormalities in the pathogenesis of hypertension have been investigated. There is growing evidence confirming that GFR decline occurs after extensive vascular remodeling.,,,, Recently, several studies have demonstrated an altered intimamedia thickness of carotid arteries, impaired endothelial-dependent vascular relaxation and vascular ultrasound thickness in ADPKD 36,38-42 patients.
Recent studies have demonstrated that some proteins such as polycystin-1 and polycystin-2 are expressed in vascular smooth muscle cells., and play an important role in maintaining the integrity of dense plaques of the arterial wall. Histological study of specimens of cerebral aneurysms in ADPKD patients demonstrated an altered expression of polycystins in arterial smooth muscle cells. Furthermore, cardiovascular abnormalities were related to functional alteration of polycystins.,,, Evidence for endothelial dysfunction has been reported in both animal models and human studies of ADPKD.
Cilia are a local regulator of blood vessel. The alteration of cilia in ADPKD may be responsible for defective autoregulation of BP in ADPKD.,,,,,,
Other pathogenic factors are involved in ADPKD hypertension. Intrarenal ischemia/ hypoxia is increased which may affect renal tubular sodium handling and increases the activity of the sympathetic nervous system.
The chronic intrarenal ischemia and capsular stretch caused by cyst growth activate the renal sympathetic nervous system, potentially contributing to hypertension. Adrenaline and noradrenaline are significantly increased in ADPKD patients even when the kidney function is normal. Other factors that may contribute to the development of hypertension in ADPKD include insulin resistance.
| Treatment of Hypertension in ADPKD|| |
Currently, there is no effective treatment to slow down the progression of ADPKD but are some promising drugs under study. Hypertension is the most important modifiable risk factor in ADPKD. Early management of hypertension reduces the progression of kidney disease and onset of cardiovascular events.
An unresolved issue in ADPKD is the optimal BP for patients with hypertension. In patients with CKD, the goal is a BP of less than 130/80 mm Hg, based on NICE guidelines for hypertension published in 2011. However, other clinical practice guidelines differ on this recommendation. The 2013 ESH/ ESC guidelines for the management of arterial hypertension propose a target systolic BP (SBP) <140 mm Hg for patients with CKD and <130 mm Hg when overt proteinuria is present. The 2014 Evidence-based Guideline for the Management of High Blood Pressure in Adults (JNC 8) states that for patients with CKD, it is recommended that pharmacologic treatment is needed to lower BP at SBP <140 mm Hg or diastolic BP (DBP) <90 mm Hg and treat to goal SBP <140 mm Hg and goal DBP <90 mm Hg. Both clinical practice guidelines acknowledge that there is a lack of high-quality evidence. Until more evidence is available, in patients with ADPKD, we recommend adopting BP target of less than 130/80 mm Hg and should be pursued as soon as microalbuminuria or LVH is present.
Diet and lifestyle changes should be the first-line treatments for hypertensive ADPKD patients. Dietary salt restriction <6 g/day, avoidance of caffeine intake, smoking cessation, and maintenance of adequate fluid intake (3 L/day) should be recommended to all ADPKD patients. High water intake has been shown to decrease cyst growth in animal models and human studies by suppressing cAMP pathway.,
In addition to lifestyle changes, pharmacologic therapy is often necessary to control hypertension in ADPKD. Unfortunately, we do not have enough studies that examined the effect of hypertension control on kidney disease progression and occurrence of cardiovascular events. The HALT-PKD trial is a prospective randomized study to test whether dual blockade of the RAAS using ACEI and ARB combination therapy delay normal progression of kidney disease compared to ACEI monotherapy. The results have been published recently and showed that in the early stages of ADPKD, the dual inhibition of RAAS by a combination of ACEI and ARB did not significantly decrease the rate of total kidney volume growth. Rigorous BP control was associated with a slower rate of total kidney volume growth in comparison with standard BP control, a greater decline in the left ventricular mass index, and greater reduction in urinary albumin excretion. However, no effect on kidney function was observed. In later stages of ADPKD, monotherapy blockade of RAAS with an ACEI was associated with BP control in ADPKD patients with Stage 3 CKD. The addition of an ARB did not affect the kidney function progression.
Based on the current understanding of the pathogenesis of hypertension and results of clinical trials in ADPKD,,,,,,, we suggest that the optimal treatment of this disease is RAAS inhibitors with ACEI or ARBs. These agents remain the most recommended drugs to treat hypertension in patients with ADPKD although clinical studies have not convincingly demonstrated evident benefit.
We suggest the following treatment algorithm [Figure 2], an ACEI or ARB should be the initial antihypertensive agent. Careful monitoring is indicated in ADPKD patients at advanced stage of CKD after institution of a RAAS inhibitor or following an episode of volume depletion. Patients who develop a significant decline in renal function may be more safely treated with another agent such as a beta-blocker or calcium channel blocker; we prefer to use a beta blocker as a second agent given the potentially detrimental effects of calcium blockers on cyst formation.
|Figure 2: Treatment algorithm of hypertension in ADPKD.|
ADPKD: Autosomal dominant polycystic kidney disease, ACEI: Angiotensin-converting enzyme inhibitor, ARB: Angiotensin receptor blockers, CCB: Calcium channel blockers, BB: â-Blockers, BP: Blood pressure.
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Beta blockers and calcium channel blockers also reduce BP in ADPKD patients and are effective in those with concomitant cardiac disease, and as second line in those with uncontrolled hypertension under ACEI or ARBs. There is a sodium retention in ADPKD patients related to higher level of aldosterone than in patients with essential hypertension. Diuretics, used in conjunction with inhibitors of the RAAS, may be effective in reducing BP in ADPKD patients, particularly those with established CKD where the capacity to excrete sodium is reduced, and BP is maintained through intravascular volume expansion. In hypertensive ADPKD patients with normal kidney function, thiazide diuretics are the first choice. In those with impaired kidney function, long-acting loop diuretics must be the first choice. Diuretics should be considered as second- or third-line treatment in hypertensive ADPKD.
To the best of our knowledge, alpha blockers and direct vasodilators have not been tested and compared with RAAS inhibitors in ADPKD population.
| Conclusions|| |
Hypertension occurs early in ADPKD patients, even before impairment of renal function. Hypertension is associated with a faster progression to ESRD and represents the most important potentially treatable factor in ADPKD. Cardiovascular disease represents the first cause of death in ADPKD. Various animal and human studies confirm the important of RAAS in the genesis of hypertension in ADPKD. More prospective randomized studies are needed to determine the most appropriate agents for the treatment of hypertension in these patients.
Conflict of interest:
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Department of Medicine A (M8), Charles Nicolle Hospital, Tunis
[Figure 1], [Figure 2]
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