Secondary Hypertension: Just as Essential as Primary

Background

We discussed primary HTN (previously known as essential HTN) in a prior blog post. Here, we’ll focus on secondary HTN (i.e., HTN resulting from an underlying cause.)

“A specific, remediable cause of hypertension can be identified in approximately 10% of adult patients with hypertension. If a cause can be correctly diagnosed and treated, patients with secondary hypertension can achieve a cure or experience a marked improvement in BP control, with reduction in cardiovascular disease risk.”

Whelton et al. J Am Coll Cardiol. 2018

There are many possible clues that can suggest the presence of secondary HTN, including

  • Onset of HTN that is new, abrupt, or present in patients <30yo (and especially if before puberty)
  • Onset of diastolic HTN in patients >65yo
  • Resistant, accelerated, or malignant HTN
  • Worsening of previously controlled HTN
  • Presence of disproportionate target-organ damage for the degree of HTN
  • Unprovoked or excessive hypokalemia

Common vs Uncommon Causes

The AHA’s 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults briefly discusses common and uncommon etiologies of secondary HTN. We discuss the common causes in detail below.

Source: Whelton et al. J Am Coll Cardiol. 2018

Obstructive Sleep Apnea

OSA is a risk factor for multiple forms of cardiovascular disease, including HTN, CAD, HF, and afib. An estimated 50% (!) of patients with HTN have concomitant OSA, and OSA is the most prevalent contributor to elevated BP in patients with resistant HTN. Furthermore, there appears to be a dose-response relationship between the severity of OSA and the cumulative incidence of HTN (i.e., the incidence of HTN increases as the severity of OSA increases.)

The pathophysiological relationship between OSA and HTN is complex, and likely depends on multiple mechanisms:

Source: Konecny et al. Hypertension. 2014

Interestingly, conflicting data exist regarding the role of CPAP in reducing BP in patients with OSA:

“Acute decreases in BP and sympathetic traffic during sleep can be achieved with effective OSA treatment; however, the data regarding long term, clinically meaningful BP reduction with CPAP treatment have been less clear. Meta-analyses previously conducted on this topic spoke to the modest but statistically significant beneficial effect of CPAP, and congruent with these findings was the recently published meta-analysis by Montesi et al. which included 28 studies representing 1948 patients, and reported weighted mean decrease in systolic and diastolic BP of 2.58 mm Hg and 2.01 mm Hg, respectively, favoring those treated with CPAP.”

Konecny et al. Hypertension. 2014

Primary Aldosteronism

Source: Encyclopedia Britannica

Primary aldosteronism (PA) is defined as inappropriately elevated aldosterone production in the setting of low plasma renin. The most common causes are bilateral adrenal hyperplasia and aldosterone-producing adenomas (aka Conn syndrome.)

The classic presenting signs of PA are HTN and hypokalemia, but the latter appears to occur only in the minority of patients. A 2004 study of patients on multiple continents found only 9-37% of patients with PA had hypokalemia.

The prevalence of PA is 8-20%, but may be even higher. Plus it appears our screening rates for PA leave A LOT to be desired.

Traditional guidance suggests screening for PA in specific situations:

  • HTN resistant to three conventional antihypertensive drugs
  • HTN and hypokalemia (spontaneous or diuretic-induced)
  • HTN and a family history of early-onset HTN or cerebrovascular accident at a young age (<40yo)
  • HTN and an adrenal tumor
  • Controlled BP on four or more antihypertensive drugs
  • Sustained BP above 150/100 mm Hg, measured on 3 different days
  • HTN and OSA
  • All hypertensive first-degree relatives of patients with PA

Guidelines suggest initial screening for PA with a plasma aldosterone/renin ratio (ARR); however, recent studies question the sensitivity of this test, not to mention its susceptibility to false-positive and false-negative results (see table below). In fact, a false-positive ARR occurs in 14-22% of screening tests in patients with resistant HTN, depending upon which antihypertensive medications are in use at the time of testing.

Source: Funder et al. J Clin Endocrinol Metab. 2016

Patients with PA are typically found with very low renin (<1 ng/mL/hr) and elevated aldosterone (usually >10 ng/dL), often leading to an ARR >20 ng/dL per ng/mL/hour (careful with the units!) However, there are potential pitfalls:

  • Since aldosterone is at its highest in the morning, the best time for this blood test to be drawn is after having been up for 2 hours. It is also recommended to be seated for 15 minutes before the test is drawn.
  • Hypokalemia inhibits aldosterone production, so potassium should be corrected to a level >4.0 prior to testing.
  • Different labs use different testing types and units, leading to potential confusion for providers trying to interpret the results (see quote below.)

“The most important pitfall of PA screening is that some laboratories report plasma renin activity (PRA) values to a lower limit of 0.1 ng/mL/h. In this circumstance, the ARR is disproportionately influenced by its denominator and can meet the threshold of 20 even when aldosterone is as low as 2 ng/dL – these values are not diagnostic of PA. Thus, caution should be used in interpreting the ARR when PRA is reported to values <0.6 ng/mL/h. Another potential pitfall in using the ARR is that many clinical laboratories are transitioning to replacing PRA with direct renin concentration (DRC), which yields different ARR values. The DRC in pg/mL is often roughly a factor of 10 higher and has a much wider linear dynamic range at high values.

Because of these potential pitfalls in interpreting the ARR, we recommend the following straightforward approach to interpreting the aldosterone and the renin when screening for PA. Our approach is based on the logic of the ARR but is designed to guard against false positives caused by very low renin measurements, while maintaining simplicity. Clinically, a PRA <1 ng/mL/h or DRC <10 pg/mL is considered suppressed and indicative of volume expansion, and a simultaneous aldosterone >10 ng/dL raises suspicion of PA. As previously mentioned, hypokalemia inhibits aldosterone production, so an even lower aldosterone could be present in hypokalemic PA. For that reason, correction of hypokalemia to a plasma K+ of 4.0 prior to testing is recommended. A practical approach to PA screening and triaging for patients with inadequate hypertension control is shown [below].”

Byrd et al. Circulation. 2018
Simplified algorithm for PA screening and triaging based primarily on plasma renin and secondarily on serum aldosterone. Aldo, aldosterone; DRC, direct renin concentration; FH, family history; MR, mineralocorticoid receptor; PA, primary aldosteronism; PRA, plasma renin activity.
Source: Funder et al. J Clin Endocrinol Metab. 2016

Patients who screen positive for PA should be referred to an endocrinologist or HTN specialist for confirmatory testing (most often salt-loading tests, which induce volume expansion and suppress aldosterone production in normal patients but not in those with PA); further evaluation also involves adrenal imaging and subtyping.

Depending on the underlying etiology, treatment for PA involves either surgery (usually in the presence of unilateral disease) or medical therapy with a mineralocorticoid-receptor antagonist (e.g., spironolactone or eplerenone).

Renovascular Disease

Renovascular disease as a cause of HTN refers to renal artery stenosis (RAS). RAS most often results from atherosclerosis (85% overall; usually older adults >50yo) and fibromuscular dysplasia (usually younger women <40yo).

Clinical clues that might suggest atherosclerotic RAS:

  • Onset of severe HTN (>180/120) after 55yo
  • Unexplained deterioration of kidney function during antihypertensive therapy, especially an acute and sustained elevation in serum creatinine by more than 50% occurring within one week of instituting therapy with an ACE inhibitor, ARB, or direct renin inhibitor
  • Severe HTN in patients with diffuse atherosclerosis, particularly those over age 50yo
  • Severe HTN in a patient with an unexplained atrophic kidney or asymmetry in kidney sizes of >1.5 cm
  • Severe HTN in patients with recurrent episodes of acute (flash) pulmonary edema or refractory HF with impaired kidney function
  • A systolic-diastolic abdominal bruit that lateralizes to one side (40% sensitivity but 99% specificity)

“Don’t screen for atherosclerotic renal artery stenosis in patients without resistant or accelerating hypertension, cardiac disturbance syndromes or rapidly deteriorating renal function.”

Society of Vascular Medicine, 2013; Choosing Wisely

Clinical clues that might suggest renal artery FMD:

  • Hypertensive patients <30 years of age, especially women
  • Accelerated, malignant, or grade 3 (>180/110 mmHg) HTN
  • Drug-resistant HTN (BP target not achieved despite 3-drug therapy at optimal doses including a diuretic)
  • Unilateral small kidney without a causative urological abnormality
  • Abdominal bruit in the absence of atherosclerotic disease or risk factors for atherosclerosis
  • Suspected renal artery dissection/infarction
  • Presence of FMD in at least 1 other vascular territory

Exam pearl for detecting abdominal bruits:

  • The patient should be supine, moderate pressure should be placed using the diaphragm of the stethoscope, and auscultation should be performed in the epigastrium and all four abdominal quadrants.

The prevalence of RAS as a secondary cause of HTN ranges from 5 to 34%, per the AHA, depending on the clinical situation: HTN alone, 5%; HTN in patients starting dialysis, 22%; HTN and peripheral vascular disease (PVD), 28%; HTN in the elderly with HF, 34%. Patients with RAS have significantly increased rates of CKD, CAD, stroke, and PVD.

Multiple testing options exist (note that testing for RAS is only indicated in a patient who would be amenable to a subsequent corrective procedure if clinically significant renovascular disease is detected):

  • Renal arteriography (gold standard, but invasive)
  • Duplex Doppler ultrasonography (most common initial test, but technically challenging)
  • Computed tomographic angiography (CTA)
  • Magnetic resonance angiography (MRA)

Importantly, medical therapy remains the cornerstone of treating RAS, regardless of cause. Revascularization, by percutaneous angioplasty with stenting or surgical revascularization in patients with complex lesions, may be reasonable in patients who have a high likelihood of benefitting from intervention; however, a 2016 meta-analysis found no benefit from percutaneous transluminal renal angioplasty on mortality, ESRD, or major cardiovascular events, and only modest effects on BP control.

Because the renin-angiotensin-aldosterone system is often activated in patients with renal-artery stenosis, a regimen including an inhibitor of this system is recommended in most patients. Additional agents may include an alpha-blocker or beta-blocker, a long-acting calcium-channel antagonist, and a diuretic. Although a renin-angiotensin-aldosterone system inhibitor may induce acute renal failure in some patients with bilateral severe stenosis, high-grade stenosis in one kidney, or advanced chronic kidney disease, the probability of this complication appears to be low, and in most cases, it is reversible with the discontinuation of treatment. Moreover, recent data from a large cohort of patients with renal-artery stenosis suggested a reduced risk of death among patients treated with an ACE inhibitor.”

Dworkin LD, Cooper CJ. N Engl J Med. 2009

Renal Parenchymal Disease

HTN is a frequent finding in both acute and chronic kidney disease, owing to multiple mechanisms:

  • Acute glomerular disease: Sodium retention leads to hypervolemia
  • Acute vascular disease (e.g., vasculitis, scleroderma): Ischemia-induced activation of the renin-angiotensin system
  • Chronic kidney disease (CKD): Sodium retention, increased activity of the renin-angiotensin system, and enhanced activity of the sympathetic nervous system, among others
Source: Middleton JP, Pun PH. Kidney Int. 2010

Accordingly, treatment of HTN in the presence of renal parenchymal disease depends on the underlying mechanism:

  • Acute glomerular disease: Treatment focuses on fluid removal with diuretics or, if necessary, dialysis
  • Acute vascular disease: Treatment with an ACE inhibitor is effective in many patients with vasculitis or scleroderma
  • CKD:
    • Proteinuric (protein excretion >500-1000 mg/day) non-diabetic CKD: RAS inhibitor is recommended as first-line therapy
    • Non-proteinuric non-diabetic CKD: Diuretics are first-line therapy in presence of edema; if no edema, RAS inhibitors are best

Drug- or Alcohol-Induced

MANY substances, including prescription medications, OTC medications, herbals, and food substances, can affect BP.

Source: Whelton et al. J Am Coll Cardiol. 2018

A 2021 study in JAMA found that 15% of patients overall and 19% of patients with HTN took a prescription medication that raises BP. The most commonly reported classes were antidepressants (8.7%; 95% CI, 8-9.5%), prescription NSAIDs (6.5%; 95% CI, 5.8-7.2%), steroids (1.9%; 95% CI, 1.6-2.1%), and estrogens (1.7%; 95% CI, 1.4-2.0%).

“In the clinical assessment of hypertension, a careful history should be taken with regard to substances that may impair BP control, with close attention paid to not only prescription medications, but also over-the-counter substances, illicit drugs, and herbal products. When feasible, drugs associated with increased BP should be reduced or discontinued, and alternative agents should be used.”

Whelton et al. J Am Coll Cardiol. 2018

Other Causes…

Uncommon causes briefly mentioned in the 2017 AHA guideline:

  • Pheochromocytoma / paraganglioma (0.1-0.6%)
  • Cushing syndrome (<0.1%)
  • Hypothyroidism (<1%)
  • Hyperthyroidism (<1%)
  • Aortic coarctation (0.1%)
  • Primary hyperparathyroidism (rare)
  • Congenital adrenal hyperplasia (rare)
  • Mineralocorticoid excess syndromes (rare)
  • Acromegaly (rare)

Additional causes not explicitly discussed in the guideline:

  • Preeclampsia
  • Drug withdrawal
  • Pain
  • Anxiety
  • Obesity
  • Neuroblastoma
  • Collagen vascular disease
  • Neurofibromatosis
  • Tuberous sclerosis

Blog post based on Med-Peds Forum talk by Madeleine Ward, PGY3

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