INTRODUCTION — Hypertension is common in most chronic progressive kidney diseases. However, the pathogenesis is somewhat different in autosomal dominant polycystic kidney disease (ADPKD).
Hypertension is a common early finding in ADPKD, occurring in 50 to 70 percent of cases before any significant reduction in glomerular filtration rate (GFR), with an average age onset of 30 years [1-3]. However, the tendency to develop hypertension and its complications begins even earlier (eg, left ventricular hypertrophy) [4]. Affected young adults have a higher ambulatory blood pressure and left ventricular mass index than age-matched controls, even though the values remain within the normal range [5,6]. This raises the possibility that treatment of normotensive ADPKD patients may be beneficial.
PATHOGENESIS — Increased activity of the renin-angiotensin system (RAS) and extracellular volume expansion are often present early in ADPKD (ie, prior to loss of kidney function) and may play an important role in the rise in blood pressure [7]. It has been suggested that cyst expansion, leading to focal areas of kidney ischemia and enhanced renin release, is largely responsible for at least the initial rise in blood pressure [1,2]. Two observations are compatible with this hypothesis:
●Renin-containing cells are present in the attenuated arteries in the walls of the cysts and in cells in the connective tissue surrounding cysts [8,9]. Renin can also be produced by the epithelial cells lining the cysts, and active renin is often present within the cyst fluid [9]. Renin may directly promote epithelial cell proliferation and cyst growth since angiotensin II is a growth factor.
●The degree of early hypertension varies with the degree of structural change as patients with normal serum creatinine with an elevated blood pressure tend to have a higher total kidney volume than those who are normotensive [10].
The role of sodium retention and vasoactive hormones in the genesis of hypertension is less clear. Although aldosterone and vasopressin levels may be elevated in hypertensive ADPKD patients and patients with ADPKD may be slightly volume expanded, their plasma volume is similar to normotensive patients with ADPKD [1,7,11]. The circulating levels of prostaglandins and norepinephrine are not different between hypertensive and normotensive patients [1]. Importantly, measurement of renal blood flow utilizing para-aminohippurate (PAH) clearance techniques or breath-held magnetic resonance (MR) angiography demonstrates a relative decline in total renal blood flow that correlates with cyst burden (kidney volume) that responds to inhibition of the RAS. Renal blood flow, similar to hypertension, is a risk factor for progressive kidney disease in ADPKD [12].
METHODS OF BLOOD PRESSURE MONITORING — Blood pressure is commonly monitored by using office (OBPM) and/or self-measured home readings (HBPM). Twenty-four-hour ambulatory blood pressure monitoring (ABPM) is considered as the gold-standard noninvasive method but, due to its high cost and inconvenience for patients, is only indicated in cases of suspicion for white-coat or masked hypertension, noncompliance, or drug resistance or hypotensive symptoms while on antihypertensive therapy [13]. (See "Out-of-office blood pressure measurement: Ambulatory and self-measured blood pressure monitoring".)
Available data from essential hypertensives suggest that blood pressures are comparable when measured by ABPM or HBPM and that both of these methods are more accurate than OBPM. The effect of antihypertensive therapy on systolic blood pressure (SBP; and diastolic blood pressure [DBP]) can be 10 points higher in the office than at home [14].
In ADPKD, ABPM is superior to OBPM in diagnosing hypertension and prehypertensive states [15]. A study of 36 young (age 21 to 31 years) ADPKD patients with normal kidney function and office blood pressure of <140/90 mmHg revealed that 6 of 36 patients (16.7 percent) were hypertensive based on ABPM. ABPM is the only method that provides information on nocturnal blood pressure levels and "the nocturnal dipping" (>10 percent drop in SBP during the night compared with daytime), which has been suggested as a protective factor against the development of end organ damage. Amplitude of nocturnal dipping is lower [16], and nondipping is more common in ADPKD (present in 40 percent of prehypertensive/hypertensive subjects) [17]. However, the reproducibility of nocturnal dipping is modest in ADPKD, limiting its clinical significance [17,18]. One study has shown a positive correlation between average 24-hour SBP and left ventricular mass index in normotensive and hypertensive ADPKD patients [19]. Another study showed a positive correlation between ABPM readings, kidney volume, and the number of kidney cysts [20].
TREATMENT — The large number of widely available antihypertensive agents and increased clinician awareness of the importance of blood pressure control have resulted in a dramatic increase in the use of antihypertensive medications (particularly renin-angiotensin system [RAS] inhibitors) over the last 30 years. Data from the University of Colorado ADPKD center (a tertiary subspecialized referral center) comparing the two periods of 1985 to 1989 and 1995 to 1999 showed an increase in the use of RAS inhibitors from 19 to 67 percent [21]. In addition, registry data from Denmark demonstrate a four- to five-year delay to end-stage kidney failure in those individuals receiving RAS inhibitors [22]. Incremental cost-effectiveness ratios indicated that, compared with angiotensin receptor blockers (ARBs), angiotensin-converting enzyme (ACE) inhibitors may be more cost effective due to lower costs and similar life expectancy [23].
In addition, a comprehensive review of the electronic patient records of 1877 adults with ADPKD from the United Kingdom General Practice Database between 1991 and 2008 showed a dramatic increase (from 32 to 62 percent) in the use of antihypertensive therapy in patients with ADPKD. The use of RAS inhibitors increased from 7 to 46 percent. The management of hypertension resulted in a drop in average blood pressure from 142/85 mmHg in 1991 to 133/80 in 2008. More interestingly, mortality rates decreased significantly during the same time period, most likely due to a better control of blood pressure [24].
Choice of agent
Overview — If there are no contraindications, an ACE inhibitor should be the initial antihypertensive agent. An ARB could be considered in patients who are intolerant of ACE inhibitors. However, combination therapy with an ACE inhibitor and ARB provides no additional benefit to that of an ACE inhibitor alone.
Careful monitoring is indicated in high-risk patients after institution of an ACE inhibitor or following an episode of volume depletion or cyst hemorrhage in someone already being treated with one of these agents. Patients who develop an acute, clinically significant elevation in the plasma creatinine concentration may be more safely treated with another agent, such as a calcium channel blocker; however, some experts prefer to use a beta blocker as a second agent, given the potentially detrimental effects of calcium blockers on cyst formation. Diuretics may be considered for patients who do not have adequate blood pressure control on an ACE inhibitor alone.
Angiotensin-converting enzyme inhibitors — Patients with hypertension and ADPKD generally respond well to an ACE inhibitor (and probably ARBs) since, as described above, focal ischemia induced by the cysts stimulates the RAS [2,25]. A separate issue is whether ACE inhibitors or ARBs protect against secondary glomerular injury, as they do in other chronic kidney diseases, in part by reducing the intraglomerular pressure and/or glomerular hypertrophy. Secondary glomerular injury appears to be less important in ADPKD since glomerulosclerosis is not a feature of progressive kidney disease [26]. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and "Autosomal dominant polycystic kidney disease (ADPKD): Treatment".)
It is possible that ADPKD patients who have proteinuria might have a slower rate of progression of kidney disease when treated with ACE inhibitors. A meta-analysis of eight randomized trials of progression of nondiabetic chronic kidney disease (CKD) provided some evidence in support of this hypothesis [27]. There were 142 patients with a diagnosis of ADPKD; mean protein excretion was 920 mg/day, which, in a larger study of patients with ADPKD, was present in <20 percent of cases [28]. This suggests possible selection bias for ADPKD patients with proteinuria or proteinuric patients who might have secondary glomerular injury or other factors. (See "Autosomal dominant polycystic kidney disease (ADPKD): Kidney manifestations", section on 'Proteinuria'.)
At a mean follow-up of 2.3 years, urinary protein excretion significantly decreased in the ACE inhibitor group compared with the control group (-0.33 g/day versus +0.19 g/day). This benefit was greater in those with higher levels of baseline urine protein excretion. There was also a nonsignificant trend for a decreased incidence of progression of kidney dysfunction with ACE inhibitor therapy (29 versus 41 percent, p = 0.17).
A study that was not included in the previous meta-analysis found that effective blood pressure control with an ACE inhibitor (or a calcium channel blocker) appeared to delay the onset of kidney failure. In this prospective study, 24 patients with ADPKD, hypertension, and creatinine clearances >50 mL/min/1.73 m2 were randomly assigned to either amlodipine (a calcium channel blocker) or enalapril [29]. At five years, there was a similar degree of blood pressure control and preservation of kidney function, with a mean yearly decline in creatinine clearance of approximately 3.4 mL/min/1.73 m2. These findings compare favorably with the rate of progression in patients with ADPKD but uncontrolled hypertension (declines of 5.8 and 5.3 mL/min/1.73 in Modification of Diet in Renal Disease [MDRD] studies A and B, respectively) [30]. In addition, enalapril, but not amlodipine, had a consistent antiproteinuric effect, but the ability to lower proteinuria did not correlate with the preservation of kidney function in these patients.
A nonrandomized trial comparing the kidney outcomes of 14 patients on a diuretic and 19 patients on an ACE inhibitor showed similar blood pressure control with both agents over a mean follow-up period of 5.2 years, but the annual decrease in creatinine clearance was significantly higher in the diuretic group (5.3 versus 2.7 mL/min/1.73 m2). Additionally, urinary protein excretion was significantly increased in the diuretic group but not in the ACE inhibitor group [31]. This small study suggested that diuretics may not be an optimal first-line choice for treatment of hypertension in ADPKD.
Angiotensin receptor antagonists — There are limited data on the use of ARBs in ADPKD. A randomized trial of 49 hypertensive patients with ADPKD compared amlodipine with candesartan [32]. The blood pressure was equally well controlled in both groups. At mean follow-up of 36 months, creatinine clearance had declined significantly less in the candesartan group (-5 versus -21 mL/min in the amlodipine group).
Angiotensin-converting enzyme inhibitor plus angiotensin receptor antagonist — The addition of an ARB to an ACE inhibitor, although safe, does not provide renoprotective benefit to ADPKD patients [33,34]:
●In a large, randomized trial, 486 patients with estimated GFR (eGFR) 25 to 60 mL/min/1.73 m2 were randomly assigned to receive either an ACE inhibitor (lisinopril) plus placebo or lisinopril and an ARB (telmisartan) [34]. Target blood pressure in both groups was 110/70 to 130/80. There was no difference between groups in the composite endpoint of death, end-stage kidney disease, or 50 percent reduction in eGFR. Rates of decline in eGFR were not different between groups. Albumin excretion and adverse events, including hyperkalemia and acute kidney injury, were infrequent and not different between groups. Therefore, although well tolerated and safely administered, there is no indication to combine ACE inhibitor and ARB therapy in hypertensive ADPKD individuals.
●In a second trial with a 2x2 factorial design, 558 patients with eGFR >60 mL/min/1.73 m2 were randomly assigned to either an ACE inhibitor (lisinopril) plus an ARB (telmisartan) or to lisinopril plus placebo [33]. There were no differences between groups in the annual percentage increase in total kidney volume, the rate of decline of eGFR, the urinary albumin excretion, or left ventricular mass index.
Complications of angiotensin inhibition — A potential complication of angiotensin inhibition in patients with ADPKD is a reversible, acute decline in GFR, with the serum creatinine usually rising by <1.5 mg/dL (132 micromol/L) [35]. This complication occurs in less than 5 percent of cases and is seen primarily in patients with underlying kidney function impairment and massive cystic disease. Concurrent diuretic use and hemorrhage into a cyst (which can lead to intravascular volume contraction) are additional risk factors.
The fall in GFR related to angiotensin inhibition probably results from interference with autoregulation via a mechanism similar to that seen in bilateral renal artery stenosis. In ADPKD, however, the vascular disease is intrarenal due primarily to vascular sclerosis of uncertain etiology that appears to be associated with progressive ADPKD [26]. It is not clear if the vascular lesions are the result or in part the cause of the hypertension [26]. (See "Renal effects of ACE inhibitors in hypertension".)
An important consideration in selecting an antihypertensive agent is that hypertensive women with ADPKD are frequently of childbearing age. Since exposure to ACE inhibitors and ARBs may be associated with serious adverse fetal effects that can occur in the earliest stages of pregnancy, women in childbearing years should be counseled about the potential risks of ACE inhibitors and ARBs and, if possible, should switch to alternate antihypertensive drugs prior to planned pregnancy. (See "Adverse effects of angiotensin converting enzyme inhibitors and receptor blockers in pregnancy".)
Blood pressure goal — An unresolved issue in ADPKD is the optimal blood pressure among those with hypertension. This matter is further complicated by defining the appropriate modality (office, home, or 24-hour ambulatory) of blood pressure monitoring. (See 'Methods of blood pressure monitoring' above.)
For all ADPKD patients, we believe that goal blood pressure should be <130/80 mmHg, based on office blood pressure readings. For selected patients (particularly young, healthy individuals with relatively intact kidney function), we believe a lower blood pressure target (ie, <110/75 mmHg) can provide cardiovascular benefit and reduce the rate of cyst growth. However, although safe, achieving such low blood pressures is likely to be associated with an increased frequency of symptoms of dizziness and fatigue. Usually, such symptoms occur during dose titration and can be managed by temporary dose reduction until symptoms abate.
Two studies have compared kidney outcomes of various blood pressure goals [33,36]. In the largest trial to date, 558 young, hypertensive ADPKD patients (15 to 49 years of age) who had an eGFR >60 mL/min/1.73 m2 were randomly assigned to a standard blood pressure target (120/70 to 130/80 mmHg) or to a low blood pressure target (95/60 to 110/75 mmHg) and to either an ACE inhibitor (lisinopril) plus an ARB (telmisartan) or lisinopril plus placebo [33].
Compared with the standard-target group, the annual percentage increase in total kidney volume (TKV) was lower in the low-target group (6.6 versus 5.6 percent, respectively, with an overall reduction in TKV growth of 14.2 percent). In addition, compared with the standard-target group, the left ventricular mass index decreased more in the low-target group (-0.57 versus -1.17 g per m2 per year, respectively). Albumin excretion decreased (by 3.9 percent) in the low-target group and increased (by 2.4 percent) in the standard-target group. Although there was a significant short-term decline in eGFR in the low blood pressure group in the first four months of treatment, the rate of eGFR decline in the long-term phase of the trial was lower in the low versus standard blood pressure group (-2.71 versus -3.0 mL/min/year, respectively). The combination of the short- and long-term changes in eGFR resulted in an overall change in the eGFR that was the same between groups, although there was a nonsignificant trend over time toward better preservation of eGFR in the low-target group.
The percentage of patients with side effects including dizziness and lightheadedness was higher in the low-target group (81 versus 69 percent in the standard-target group).
While these data show the beneficial effect of the lower blood pressure target on surrogate endpoints (eg, TKV), their effect on patient-important endpoints, such as risk of end-stage kidney disease or mortality, is not known. However, designing a trial that is inclusive of such patient-important endpoints may be infeasible for this population (young patients with preserved eGFR) due to the slow nature of their disease progression.
The addition of telmisartan to lisinopril did not alter the rate of increase in kidney volume in this study. (See 'Angiotensin-converting enzyme inhibitor plus angiotensin receptor antagonist' above.)
We do not agree with the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for blood pressure management or with recommendations of the Joint National Committee (JNC)-8 [37] that the optimal target blood pressure is <140/90 mmHg for all CKD patients who do not have proteinuria (including moderately increased albuminuria [formerly called "microalbuminuria"]), which includes many ADPKD patients.
A separate issue is when to initiate antihypertensive therapy, a decision that is complicated by the observation that left ventricular mass often begins to increase in children and young adults prior to the onset of overt hypertension.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypertension in adults".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Polycystic kidney disease (The Basics)")
●Beyond the Basics topic (see "Patient education: Polycystic kidney disease (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Hypertension is a common early finding in autosomal dominant polycystic kidney disease (ADPKD), occurring in 50 to 70 percent of cases before any significant reduction in glomerular filtration rate (GFR), with an average age onset of 30 years. (See 'Introduction' above.)
●Increased activity of the renin-angiotensin system (RAS), possibly caused by focal ischemia due to cyst expansion, and extracellular volume expansion may play an important role in the rise in blood pressure. (See 'Pathogenesis' above.)
●Ambulatory blood pressure may be helpful to diagnose hypertension and is indicated in untreated (and especially young adults) with borderline high office blood pressure and suspicion of white-coat hypertension.
●If there are no contraindications, an angiotensin-converting enzyme (ACE) inhibitor should be the initial antihypertensive agent. Careful monitoring is indicated in high-risk patients after institution of an ACE inhibitor or following an episode of volume depletion or cyst hemorrhage in someone already being treated with one of these agents. An angiotensin receptor antagonist (ARB) could be considered in patients who are intolerant of ACE inhibitors. Dual therapy with an ACE inhibitor and ARB provides no additional benefit to that provided by an ACE inhibitor alone. (See 'Choice of agent' above.)
●Patients who develop a clinically significant elevation in the plasma creatinine concentration may be more safely treated with another agent, such as a calcium channel blocker; some experts prefer to use a beta blocker as a second agent given the potentially detrimental effects of calcium blockers on cyst formation. Use of diuretics should be considered after using an RAS inhibitor. (See 'Choice of agent' above.)
●Goal blood pressure should be to <130/80 mmHg based on office blood pressure readings. It is possible that a blood pressure goal <110/75 mmHg may decrease the rate of increase in kidney volume and provide cardiovascular benefit among young, healthy hypertensive ADPKD patients. (See 'Blood pressure goal' above.)
