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.
Sodium retention
Studies in ADPKD patients with preserved renal function have linked high blood pressure to sodium retention and volume expansion.30,31,41 However, this phenomenon reverses when there is significant renal impairment in ADPKD.
As evidence of this, a study demonstrated significantly more natriuresis in patients with renal failure due to ADPKD than in patients with a similar degree of renal failure due to chronic glomerulonephritis.31 Moreover, another study found that the prevalence of hypertension is higher in ADPKD patients than in those with other nephropathies with preserved renal function, but this association reverses with significant decline in kidney function.22
MANAGING HYPERTENSION IN ADPKD
Early diagnosis of hypertension and effective control of it, even before ADPKD is diagnosed, is crucial to reduce cardiovascular mortality. Aggressive blood pressure control in the prehypertensive phase of ADPKD will also help reduce the incidence of left ventricular hypertrophy and mitral regurgitation and slow the progression of renal failure (Figure 2).
A meta-analysis42 revealed hypertension to be present in 20% of ADPKD patients younger than 21, and many of them were undiagnosed. This study also suggests that patients at risk of hypertension (ie, all patients with ADPKD) should be routinely screened for it.
Ambulatory blood pressure monitoring may play an important role in diagnosing hypertension early in the prehypertensive stage of ADPKD.23
Target blood pressures: No consensus
Two well-powered double-blind, placebo-controlled trials, known as HALT-PKD Study A and HALT-PKD Study B, tested the effects of 2 different blood pressure targets and of monotherapy with an ACE inhibitor vs combination therapy with an ACE inhibitor plus an angiotensin II receptor blocker (ARB) on renal function, total kidney volume, left ventricular mass index, and urinary albumin excretion in the early (estimated glomerular filtration rate [eGFR] > 60 mL/min) and late (eGFR 25–60 mL/min) stages of ADPKD, respectively.43,44
HALT-PKD Study A43 found that, in the early stages of ADPKD with preserved renal function, meticulous control of blood pressure (95–110/60–75 mm Hg) was strongly correlated with significant reductions in left ventricular mass index, albuminuria, and rate of total kidney volume growth without remarkable alteration in renal function compared with standard blood pressure control (120–130/70–80 mm Hg). However, no notable differences were observed between the ACE inhibitor and ACE inhibitor-plus-ARB groups.43
Despite the evidence, universal consensus guidelines are lacking, and the available guidelines on hypertension management have different blood pressure goals in patients with chronic kidney disease.
The eighth Joint National Committee guideline of 2014 recommends a blood pressure goal of less than 140/90 mm Hg in patients with diabetic and nondiabetic chronic kidney disease.45
The National Institute for Health and Care Excellence 2011 guideline recommends a blood pressure goal of less than 130/80 mm Hg in chronic kidney disease patients.46
The European Society of Hypertension and European Society of Cardiology joint 2013 guideline recommends a systolic blood pressure goal of less than 140 mm Hg in diabetic and nondiabetic patients with chronic kidney disease.47
The 2016 Kidney Health Australia-Caring for Australians With Renal Impairment guideline for diagnosis and management of ADPKD48 recommends a lower blood pressure goal of 96–110/60–75 mm Hg in patients with an eGFR greater than 60 mL/min/1.73 m2 who can tolerate it without side effects, which is based on the findings of HALT-PKD Study A.43
Helal et al recommend that blood pressure be controlled to less than 130/80 mm Hg, until there is more evidence for a safe and effective target blood pressure goal in ADPKD patients.49
We recommend a target blood pressure less than 110/75 mm Hg in hypertensive ADPKD patients with preserved renal function who can tolerate this level, and less than 130/80 mm Hg in ADPKD patients with stage 3 chronic kidney disease. These targets can be achieved with ACE inhibitor or ARB monotherapy.43,44 However, no studies have established the safest lower limit of target blood pressure in ADPKD.
ACE inhibitors, ARBs are mainstays
Mainstays of antihypertensive drug therapy in ADPKD are ACE inhibitors and ARBs.
HALT-PKD Study B44 demonstrated that, in the late stages of ADPKD, target blood pressure control (110–130/70–80 mm Hg) can be attained with ACE inhibitor monotherapy or with an ACE inhibitor plus an ARB, but the latter produced no additive benefit.
Patch et al,50 in a retrospective cohort study, showed that broadening the spectrum of antihypertensive therapy decreases mortality in ADPKD patients. Evaluating ADPKD patients from the UK General Practice Research Database between 1991 and 2008, they found a trend toward lower mortality rates as the number of antihypertensive drugs prescribed within 1 year increased. They also observed that the prescription of RAAS-blocking agents increased from 7% in 1991 to 46% in 2008.50
However, a 3-year prospective randomized double-blind study compared the effects of the ACE inhibitor ramipril and the beta-blocker metoprolol in hypertensive ADPKD patients.51 The results showed that effective blood pressure control could be achieved in both groups with no significant differences in left ventricular mass index, albuminuria, or kidney function.51
Treatment strategies
Lifestyle modification is the initial approach to the management of hypertension before starting drug therapy. Lifestyle changes include dietary salt restriction to less than 6 g/day, weight reduction, regular exercise, increased fluid intake (up to 3 L/day or to satisfy thirst), smoking cessation, and avoidance of caffeine.47–49
ACE inhibitors are first-line drugs in hypertensive ADPKD patients.
ARBs can also be considered, but there is no role for dual ACE inhibitor and ARB therapy.43,48 A study found ACE inhibitors to be more cost-effective and to decrease mortality rates to a greater extent than ARBs.52
Beta-blockers or calcium channel blockers should be considered instead if ACE inhibitors and ARBs are contraindicated, or as add-on drugs if ACE inhibitors and ARBs fail to reduce blood pressure adequately.48,49
Diuretics are third-line agents. Thiazides are preferred in ADPKD patients with normal renal function and loop diuretics in those with impaired renal function.49
LEFT VENTRICULAR HYPERTROPHY IN ADPKD
Increased left ventricular mass is an indirect indicator of untreated hypertension, and it often goes unnoticed in patients with undiagnosed ADPKD. Left ventricular hypertrophy is associated with arrhythmias and heart failure, which contribute significantly to cardiovascular mortality and adverse renal outcomes.20,24
A 5-year randomized clinical trial by Cadnapaphornchai et al36 in ADPKD patients between 4 and 21 years of age showed strong correlations between hypertension, left ventricular mass index, and kidney volume and a negative correlation between left ventricular mass index and renal function.
Several factors are thought to contribute to left ventricular hypertrophy in ADPKD (Figure 1).
Hypertension. Two studies of 24-hour ambulatory blood pressure monitoring showed that nocturnal blood pressures decreased less in normotensive and hypertensive ADPKD patients than in normotensive and hypertensive controls.23,53 This persistent elevation of nocturnal blood pressure may contribute to the development and progression of left ventricular hypertrophy.
On the other hand, Valero et al54 reported that the left ventricular mass index was strongly associated with ambulatory systolic blood pressure rather than elevated nocturnal blood pressure in ADPKD patients compared with healthy controls.
FGF23. High levels of fibroblast growth factor 23 (FGF23) have been shown to be strongly associated with left ventricular hypertrophy in ADPKD. Experimental studies have shown that FGF23 is directly involved in the pathogenesis of left ventricular hypertrophy through stimulation of the calcineurin-nuclear factor of activated T cells pathway.
Faul et al55 induced cardiac hypertrophy in mice that were deficient in klotho (a transmembrane protein that increases FGF23 affinity for FGF receptors) by injecting FGF23 intravenously.
Yildiz et al56 observed higher levels of FGF23 in hypertensive and normotensive ADPKD patients with normal renal function than in healthy controls. They also found a lower elasticity index in the large and small arteries in normotensive and hypertensive ADPKD patients, which accounts for vascular dysfunction. High FGF23 levels may be responsible for the left ventricular hypertrophy seen in normotensive ADPKD patients with preserved renal function.
Polymorphisms in the ACE gene have been implicated in the development of cardiac hypertrophy in ADPKD.
Wanic-Kossowska et al57 studied the association between ACE gene polymorphisms and cardiovascular complications in ADPKD patients. They found a higher prevalence of the homozygous DD genotype among ADPKD patients with end-stage renal disease than in those in the early stages of chronic kidney disease in ADPKD. Also, the DD genotype has been shown to be more strongly associated with left ventricular hypertrophy and left ventricular dysfunction than other (II or ID) genotypes. These findings suggest that the DD genotype carries higher risk for the development of end-stage renal disease, left ventricular hypertrophy, and other cardiovascular complications.
