Eric Judd

Management of Hypertension in CKD: Beyond the Guidelines

Hypertension (HTN) and CKD are closely associated with an intermingled cause and effect relationship. Blood pressure (BP) typically rises with declines in kidney function, and sustained elevations in BP hasten progression of kidney disease. This review addresses current management issues in HTN in patients with CKD including altered circadian rhythm of BP, timing of antihypertensive medication dosing, BP targets, diagnostic challenges in evaluating secondary forms of HTN, and the role of salt restriction in CKD. HTN in patients with CKD is often accompanied by a decrease in the kidneys ability to remove salt. Addressing this salt sensitivity is critical for the management of HTN in CKD. In addition to the well-established use of an ACEI or angiotensin receptor blocker, dietary salt restriction and appropriate diuretic therapy make up the mainstay of HTN treatment in patients with CKD. Bedtime dosing of antihypertensive medications can restore nocturnal dips in BP, and future clinical practice guidelines may recommend bedtime dosing of 1 or more antihypertensive medications in patients with CKD.

Pathophysiology and treatment of resistant hypertension: the role of aldosterone and amiloride-sensitive sodium channels.

Resistant hypertension is a clinically distinct subgroup of hypertension defined by the failure to achieve blood pressure control on optimal dosing of at least 3 antihypertensive medications of different classes, including a diuretic. The pathophysiology of hypertension can be attributed to aldosterone excess in more than 20% of patients with resistant hypertension. Existing dogma attributes the increase in blood pressure seen with increases in aldosterone to its antinatriuretic effects in the distal nephron. However, emerging research, which has identified and has begun to define the function of amiloride-sensitive sodium channels and mineralocorticoid receptors in the systemic vasculature, challenges impaired natriuresis as the sole cause of aldosterone-mediated resistant hypertension. This review integrates these findings to better define the role of the vasculature and aldosterone in the pathophysiology of resistant hypertension. In addition, a brief guide to the treatment of resistant hypertension is presented.

Hypertension and orthostatic hypotension in older patients

Outcome-based clinical trials have shown that reducing SBP below or near 150 mmHg in older patients (≥65 years of age) reduces stroke, coronary events, and cardiovascular-related mortality [1–4]. In addition, a recent subgroup analysis of the Felodipine Event Reduction (FEVER) trial demonstrates cardiovascular benefit of a lower SBP (mean on-treatment SBP of 139 mmHg) in Chinese hypertensive individuals greater than 65 years of age [5]. Current guidelines are in agreement of a goal blood pressure (BP) less than 140/90 mmHg in individuals with uncomplicated hypertension (HTN), regardless of age [6–8]. Clinicians, however, sometimes remain hesitant to treat older patients to recommended goals due to lack of outcome data targeting a SBP less than 140 mmHg and observational evidence suggesting that low DBP may be associated with an increased risk of death [9]. Orthostatic hypotension, a reduction in SBP by at least 20 mmHg or DBP by at least 10 mmHg within 3 min of standing [10], is another clinical concern during hypertensive treatment of older populations. Decreased baroreflex activation and loss of large artery compliance are thought to be age related, making older patients more susceptible to development of orthostatic hypotension. With the recognition that orthostatic hypotension has been associated with increased falls [11] and fears that intensive antihypertensive therapy can cause orthostatic hypotension, clinicians must weigh the risks and benefits of BP reduction in a population at risk for both HTN-related cardiovascular events and fall-related injuries. A recent consensus statement by the American Heart Association as well as European guidelines highlights this concern by recommending the measurement of standing BPs in the initial assessment of HTN in older patients [7, 8]. Clinical trials have reported a wide prevalence of orthostatic hypotension in older populations. In the 80 years and older patient population of the Hypertension in the Very Elderly Trial (HYVET), 8.3% of the 3845 patients had evidence of orthostatic hypotension at baseline [1]. In the over 60 patient population of the Systolic Hypertension in the Elderly Program (SHEP), 17.3% of the 4736 patients displayed orthostatic hypotension at baseline [12]. In a cross-sectional assessment of 653 home-dwelling Finnish individuals 75 year of age or older, Hiitola et al. [13] found that 34% met criteria for orthostatic hypotension. In this issue of the Journal of Hypertension, Valbusa et al. [14] report the prevalence of orthostatic hypotension in 994 French and Italian nursing home residents of at least 80 years of age. Associations between orthostatic hypotension and sitting BP, HTN medication use, central pulse pressure, and arterial stiffness were also assessed as part of the PARTAGE (predictive values of blood pressure and arterial stiffness in institutionalized very aged population) study. Patients with severe dementia (mini-mental state examination ≤12) were excluded and those unable to stand (136 patients) did not participate in the orthostatic hypotension portion of the study. The remaining 994 patients underwent mid-morning BP measurements (three seated and one at both 1 and 3 min after standing), pulse wave analysis, and determination of pulse wave velocity (PWV). The overall prevalence of orthostatic hypotension was 18% (175 of 994 participants). Interestingly, orthostatic hypotension was more often present in individuals with uncontrolled compared with controlled HTN (146 ±23/76 ± 12 vs. 136 ± 21/71 ±11 mmHg, respectively). Overall, individuals with orthostatic hypotension were not receiving more antihypertensive medications than those without orthostatic hypotension (2.2 ±1.0 vs. 2.2 ±1.2 medications, respectively). However, individuals with orthostatic hypotension were more likely to be receiving β-blockers, whereas they were less likely to be receiving angiotensin receptor blockers or nitrates. Importantly, there was no difference in diuretic use in individuals with and without orthostatic hypotension. Other comparisons showed a significantly higher central pulse pressure, but no significant difference in arterial stiffness as indexed by PWV between the 175 orthostatic hypotension-positive patients and the 819 orthostatic hypotension-negative patients. In the current findings, a direct association between orthostatic hypotension and level of SBP was observed. These finding are consistent with the report from Hiitola et al, who found in their study that the percentage of orthostatic hypotension diagnosed by systolic criteria increased with increasing baseline SBP, ranging from 20% with SBP more than 160 mmHg to 7% in individuals with SBP less than 120 mmHg [13]. An optimistic interpretation of these concordant results is that better BP control reduces the likelihood of developing orthostatic hypotension, such that clinicians need not be hesitant to intensively treat BP in older patients because of fear of inducing orthostatic hypotension. It is important to emphasize, however, that the current findings, being observational, support but do not confirm such an interpretation. The concern, of course, as with any observational study, is that the findings are confounded by a selection bias. Accordingly, a more pessimistic interpretation would be that maintaining a lower BP reduces the likelihood of developing orthostatic hypotension, whereas the relative risk of developing orthostatic hypotension with intensive BP lowering is unknown. Of course, distinguishing between these different possibilities will require a prospective assessment, randomizing older individuals to different goal BP levels. Although not designed to primarily address this issue, the Systolic Blood Pressure Interventional Trial (SPRINT) should be able to provide some insight into this issue, as it is randomizing nondiabetic individuals to a goal SBP of less than 140 mmHg or less than 120mmHg. Although the entry criteria is 50 years of age or older, it will include a large proportion of older individuals. Valbusa et al. found that β-blocker use was associated with increased likelihood of having orthostatic hypotension. From a mechanistic standpoint, one could speculate that the elderly rely more on increased cardiac output mediated by increased heart rate, as opposed to changes in vascular tone to maintain postural BP homeostasis. Hiitola et al. [13], however, did not find any difference in β-blocker use in their participants with and without orthostatic hypotension. If the positive association is proven correct, it would provide yet another reason to avoid use of β-blockers in older individuals, unless specifically indicated. Valbusa et al. and Hiitola et al. are in agreement in not finding an increased prevalence of orthostatic hypotension in individuals being treated with diuretics. This too has important clinical implications, if confirmed. Probably based largely on presumption, there is a belief among some clinicians that diuretics should be avoided in very old individuals because of risk of volume depletion and associated development of orthostatic hypotension. The findings of these two studies argue against such a fear. Giventhe outcome benefit strongly established with use of thiazide diuretics, particularly chlorthalidone, any bias against their use should be seriously considered. One important clinical consideration not addressed by observational studies is the significance of developing symptomatic vs. asymptomatic orthostatic hypotension. Presumably, it is symptomatic orthostatic hypotension that increases the risk of falling. The clinical relevance of a decrease in SBP by more than 20mmHg upon standing is unknown in the asymptomatic elderly population. Accordingly, checking orthostatic vital signs appears most relevant when used as a tool to diagnose intravascular volume contraction, dysautonomia, or overmedication in symptomatic patients. Overall, the findings of Valbusa et al. do provide important guidance in the management of HTN in very old patients. It is one of the few studies in which the SBP was below 140 mmHg in the majority of the study population. These controlled patients did not show an increase in orthostatic hypotension and tolerated diuretic use without increased risk of orthostatic hypotension. These results in combination with other similar trials [13] should allay fears of increasing orthostatic hypotension-related falls in older individuals when titrating antihypertensive medications to guideline BPs.

Aliskiren, amlodipine and hydrochlorothiazide triple combination for hypertension

Cardiovascular-related morbidity and mortality is linked to hypertension with proportional gains in cardiovascular risk factor reduction with the lowering of blood pressure. Clinical trial data has shown that attaining goal blood pressure requires, for most patients, at least two antihypertensive medications, with a significant proportion requiring regimens of three or more medications. Single-pill triple combinations have returned to the market following results of increased efficacy and adherence over dual- and mono-therapy. The combination of aliskiren, amlodipine and hydrochlorothiazide is a rational choice for combination therapy and recent studies suggest that it is safe and effective in lowering blood pressure in patients who fail dual combination therapy.

Novel strategies for treatment of resistant hypertension

Resistant hypertension, defined as blood pressure (BP) remaining above goal despite the use of 3 or more antihypertensive medications at maximally tolerated doses (one ideally being a diuretic) or BP that requires 4 or more agents to achieve control, occurs in a substantial proportion (>10%) of treated hypertensive patients. Refractory hypertension is a recently described subset of resistant hypertension that cannot be controlled with maximal medical therapy (⩾5 antihypertensive medications of different classes at maximal tolerated doses). Patients with resistant or refractory hypertension are at increased cardiovascular risk and comprise the target population for novel antihypertensive treatments. Device-based interventions, including carotid baroreceptor activation and renal denervation, reduce sympathetic nervous system activity and have effectively reduced BP in early clinical trials of resistant hypertension. Renal denervation interrupts afferent and efferent renal nerve signaling by delivering radiofrequency energy, other forms of energy, or norepinephrine-depleting pharmaceuticals through catheters in the renal arteries. Renal denervation has the advantage of not requiring general anesthesia, surgical intervention, or device implantation and has been evaluated extensively in observational proof-of-principle studies and larger randomized controlled trials. It has been shown to be safe and effective in reducing clinic BP, indices of sympathetic nervous system activity, and a variety of hypertension-related comorbidities. These include impaired glucose metabolism/insulin resistance, end-stage renal disease, obstructive sleep apnea, cardiac hypertrophy, heart failure, and cardiac arrhythmias. This article reviews the strengths, limitations, and future applications of novel device-based treatment, particularly renal denervation, for resistant hypertension and its comorbidities.

Renovascular Hypertension Associated With Pseudoaneurysm Following Blunt Trauma

We present the case of a 21-year-old man who developed a renal artery pseudoaneurysm following a 7-foot fall onto his back. He initially presented with gross hematuria, left flank pain, and back pain. He was observed in the hospital for 3 days and discharged. One week later, he was readmitted with headache, nausea, vomiting, seizure activity, and hypertension. Contrast-enhanced computed tomography of the abdomen showed a left renal artery pseudoaneurysm with associated arterial narrowing and delayed ipsilateral renal enhancement. He underwent percutaneous stent-graft placement with resolution of the pseudoaneurysm. He was free of complications and normotensive off antihypertensive medications after 36 months of follow-up. Renal artery pseudoaneurysms are rare and under-recognized complications of blunt abdominal or back trauma that can cause hypertension. Imaging modalities in renovascular hypertension have focused on detecting renal artery stenosis from atherosclerotic disease or fibromuscular dysplasia, with little attention given to renal artery pseudoaneurysms. In addition, first-line treatment for renal artery pseudoaneurysms historically has consisted of angioembolization, yet percutaneous stent-graft placement has emerged as an attractive alternative to preserve vessel patency. We discuss the role of imaging in renovascular hypertension with a focus on renal artery pseudoaneurysms and their prevalence, diagnosis, and treatment.

White-Coat Effect Is Uncommon in Patients With Refractory HypertensionNovelty and Significance

Refractory hypertension is a recently described phenotype of antihypertensive treatment failure defined as uncontrolled blood pressure (BP) despite the use of ≥5 different antihypertensive agents, including chlorthalidone and spironolactone. Recent studies indicate that refractory hypertension is uncommon, with a prevalence of ≈5% to 10% of patients referred to a hypertension specialty clinic for uncontrolled hypertension. The prevalence of white-coat effect, that is, uncontrolled automated office BP ≥135/85 mm Hg and controlled out-of-office BP <135/85 mm Hg, by awake ambulatory BP monitor in hypertensive patients overall is ≈30% to 40%. The prevalence of white-coat effect among patients with refractory hypertension has not been previously reported. In this prospective evaluation, consecutive patients referred to the University of Alabama at Birmingham Hypertension Clinic for uncontrolled hypertension were enrolled. Refractory hypertension was defined as uncontrolled automated office BP ≥135/85 mm Hg with the use of ≥5 antihypertensive agents, including chlorthalidone and spironolactone. Automated office BP measurements were based on 6 serial readings, done automatically with the use of a BpTRU device unobserved in the clinic. Out-of-office BP measurements were done by 24-hour ambulatory BP monitor. Thirty-four patients were diagnosed with refractory hypertension, of whom 31 had adequate ambulatory BP monitor readings. White-coat effect was present in only 2 patients, or 6.5% of the 31 patients with refractory hypertension, suggesting that white-coat effect is largely absent in patients with refractory hypertension. These findings suggest that white-coat effect is not a common cause of apparent lack of BP control in patients failing maximal antihypertensive treatment.

Obesity, African American Race, Chronic Kidney Disease, and Resistant Hypertension: The Step Beyond Observed Risk.

See related article, pp 387–396 The risk surrounding individuals with blood pressure (BP) that is difficult to control has now been characterized in many different populations in the United States. Prospective cohort studies,1,2 retrospective analyses of large clinical registries,3,4 and subgroup analyses of clinical trials5,6 have consistently identified a higher prevalence of obesity, African American race, chronic kidney disease (CKD), and diabetes mellitus among individuals with apparent treatment-resistant hypertension (ATRH). Despite subtle differences in defining ATRH between studies, individuals with difficult-to-control BP are at increased risk for cardiovascular and kidney events compared with individuals with hypertension being treated with <3 antihypertensive medications.1,2,5,7,8 In this issue of Hypertension , Thomas et al2 expand these risk associations into the CKD population by examining ATRH in the Chronic Renal Insufficiency Cohort (CRIC). The CRIC study included an ethnically diverse group of adults from across the United States with an estimated glomerular filtration rate 20–70 mL/min per 1.73 m2 Hypertension was present in 85.7% of the cohort, highlighting the strong, interdependent relationship between kidney disease and hypertension. Adhering to the American Heart Association definition of resistant hypertension,9 Thomas et al2 reported a prevalence of ATRH of 40.4% among CRIC study participants with hypertension. Although much higher than prevalence estimates for ATRH in general hypertensive populations (12.8%–21.5%), it is no surprise that ATRH is more common in CKD populations. In a cross-sectional analysis of the Kaiser Permanente Southern California health system, CKD had the strongest association with resistant hypertension with an adjusted odds ratio of 1.84 (95% confidence interval [CI] 1.78–1.90).3 When evaluated, CKD is inevitably associated with resistant hypertension.1,3,4 The analyses by Thomas et al2 are well suited to …

Chronic Kidney Disease Classification in Systolic Blood Pressure Intervention Trial: Comparison Using Modification of Diet in Renal Disease and CKD-Epidemiology Collaboration Definitions.

Background: Interventional trials have used either the Modification of Diet in Renal Disease (MDRD) or chronic kidney disease (CKD)-Epidemiology Collaboration (CKD-EPI) equation for determination of estimated glomerular filtration rate (eGFR) to define whether participants have stages 3-5 CKD. The equation used to calculate eGFR may influence the number and characteristics of participants designated as having CKD. Methods: We examined the classification of CKD at baseline using both equations in the Systolic Blood Pressure Intervention Trial (SPRINT). eGFR was calculated at baseline using fasting serum creatinine values from a central laboratory. Results: Among 9,308 participants with baseline CKD classification using the 4-variable MDRD equation specified in the SPRINT protocol, 681 (7.3%) participants were reclassified to a less advanced CKD stage (higher eGFR) and 346 (3.7%) were reclassified to a more advanced CKD stage (lower eGFR) when the CKD-EPI equation was used to calculate eGFR. For eGFRs <90 ml/min/1.73 m2, participants <75 years were more likely to be reclassified to a less advanced CKD stage; this reclassification was more likely to occur in non-blacks rather than blacks. Participants aged ≥75 years were more likely to be reclassified to a more advanced than a less advanced CKD stage, regardless of baseline CKD stage. Reclassification of baseline CKD status (eGFR <60 ml/min/1.73 m2) occurred in 3% of participants. Conclusions: Use of the MDRD equation led to a higher percentage of participants being classified as having CKD stages 3-4. Younger and non-black participants were more likely to be reclassified as not having CKD using the CKD-EPI equation.

Refractory Hypertension Is not Attributable to Intravascular Fluid Retention as Determined by Intracardiac VolumesNovelty and Significance

Refractory hypertension (RfHTN) is an extreme phenotype of antihypertensive treatment failure defined as lack of blood pressure control with ≥5 medications, including a long-acting thiazide and a mineralocorticoid receptor antagonist. RfHTN is a subgroup of resistant hypertension (RHTN), which is defined as blood pressure >135/85 mm Hg with ≥3 antihypertensive medications, including a diuretic. RHTN is generally attributed to persistent intravascular fluid retention. It is unknown whether alternative mechanisms are operative in RfHTN. Our objective was to determine whether RfHTN is characterized by persistent fluid retention, indexed by greater intracardiac volumes determined by cardiac magnetic resonance when compared with controlled RHTN patients. Consecutive patients evaluated in our institution with RfHTN and controlled RHTN were prospectively enrolled. Exclusion criteria included advanced chronic kidney disease and masked or white coat hypertension. All enrolled patients underwent biochemical testing and cardiac magnetic resonance. The RfHTN group (n=24) was younger (mean age, 51.7±8.9 versus 60.6±11.5 years; P=0.003) and had a greater proportion of women (75.0% versus 43%; P=0.02) compared with the controlled RHTN group (n=30). RfHTN patients had a greater left ventricular mass index (88.3±35.0 versus 54.6±12.5 g/m2; P<0.001), posterior wall thickness (10.1±3.1 versus 7.7±1.5 mm; P=0.001), and septal wall thickness (14.5±3.8 versus 10.0±2.2 mm; P<0.001). There was no difference in B-type natriuretic peptide levels and left atrial or ventricular volumes. Diastolic dysfunction was noted in RfHTN. Our findings demonstrate greater left ventricular hypertrophy without chamber enlargement in RfHTN, suggesting that antihypertensive treatment failure is not attributable to intravascular volume retention.