Secondary Hypertension

Hypertension and Hypokalemia

The coexistence of hypertension and spontaneous hypokalemia should always raise the possibility of secondary causes of hypertension. The approach should start with a clinical evaluation that confirms that the kidney is the source of potassium wasting. This can be achieved with measurement of the transtubular potassium gradient (TTKG) ([urine potassium/plasma potassium]:[urine osmolality/plasma osmolality]) or the urine potassium/creatinine ratio. In the presence of hypokalemia, a TTKG greater than 2 or a urine potassium/creatinine ratio greater than 13 mEq/g is diagnostic of renal potassium wasting. Once renal potassium wasting is confirmed, paired measurement of plasma renin activity (in ng/mL/h) and plasma aldosterone (in ng/dL) allows us to create a thoughtful differential diagnosis according to three different diagnostic patterns:

• 1

  High aldosterone (>15 ng/mL) with high plasma renin activity (>1.5 ng/mL/h). This combination results in a variable aldosterone-to-renin ratio, but it is usually <20. These patients have secondary hyperaldosteronism, commonly caused by diuretic therapy (thiazides, loop diuretics), renal artery stenosis (particularly unilateral), malignant hypertension (of any etiology), or the rare syndrome of primary reninism, which is usually caused by a benign renin-producing tumor of the juxtaglomerular cells, though several extrarenal tumors have been reported (teratomas, adenocarcinomas of the adrenal, lung, pancreas or ovary, or hepatocellular carcinoma).

• 2

  High aldosterone with suppressed renin activity (<0.6 ng/mL/h), leading to an aldosterone-to-renin ratio >30. This is diagnostic of primary aldosteronism and should lead to further subtype differentiation (see specific section below).

• 3

  Low aldosterone (often suppressed to undetectable levels) and low renin activity . These patients behave clinically as if they had hyperaldosteronism but have undetectable aldosterone levels. This implicates one of three possibilities: (1) an alternative source of mineralocorticoid activity (e.g., deoxycorticosterone or cortisol from a tumor, or congenital adrenal hyperplasia due to 11-beta hydroxylase or 21-hydroxylase deficiency); (2) a disorder of impaired degradation of cortisol, thus leaving it available to activate the mineralocorticoid receptor (e.g., licorice ingestion, posaconazole, or primary 11-beta-hydroxysteroid dehydrogenase type 2 deficiency); or (3) mutations in the epithelial sodium channel (Liddle syndrome) or the mineralocorticoid receptor (Geller syndrome). Some of these conditions are briefly presented in Table 65.2 .

  TABLE 65.2

  Clinical Clues to Guide the Investigation in Young Hypertensive Patients With a Potential Hereditary Cause

  Possible Causes of Familial Hypertension		Clinical Clues
  Catecholamine-Producing Tumors
  Pheochromocytoma/paraganglioma	Familial cases are responsible for up to 40% of cases	Paroxysmal palpitations, headaches, diaphoresis, pale flushing. Syndromic features of any of the associated disorders (see Pheochromocytoma/Paraganglioma section for details)
  Neuroblastomas (adrenal)	1%–2% of neuroblastomas are familial	Symptoms of the abdominal tumor (pain, mass) or catecholamine release (same as PPGL)
  Parenchymal Kidney Disease
  Glomerulonephritis	Alport disease (X-linked, AR or AD), familial IgA nephropathy (AD with incomplete penetrance)	Proteinuria, hematuria, low eGFR
  Polycystic kidney disease	ADPKD type 1 or 2, ARPKD	Multiple kidney cysts (as few as three in patients under the age of 30)
  Adrenocortical Disease
  Glucocorticoid-remediable aldosteronism (familial hyperaldosteronism type 1)	AD chimeric fusion of the 11-beta hydroxylase and aldosterone synthase genes	Cerebral hemorrhages at young age, cerebral aneurysms. Mild hypokalemia. High plasma aldosterone, low renin
  Familial hyperaldosteronism type 2	AD. Unknown defect	Severe hypertension in early adulthood. High plasma aldosterone, low renin. No response to glucocorticoid treatment
  Familial hyperaldosteronism type 3	AD mutation in the KCJN5 potassium channel	Severe hypertension in childhood with extensive target organ damage. High plasma aldosterone, low renin. Marked bilateral adrenal enlargement.
  Congenital adrenal hyperplasia	AR mutations in 11-beta hydroxylase or 21-hydroxylase	Hirsutism, virilization. Hypokalemia and metabolic alkalosis. Low plasma aldosterone and renin
  Monogenic Primary Renal Tubular Defects
  Familial hyperkalemic hypertension (Gordon syndrome)	AD mutations of KLHL3, CUL3, WNK1, WNK4. AR mutations of KLHL3	Hyperkalemia and metabolic acidosis with normal renal function
  Liddle syndrome	AD mutations of the epithelial sodium channel	Hypokalemia and metabolic alkalosis. Low plasma aldosterone and renin.
  Apparent mineralocorticoid excess	AD mutation in 11-beta-hydroxysteroid dehydrogenase type 2	Hypokalemia and metabolic alkalosis. Low plasma aldosterone and renin
  Geller syndrome	AD mutation in the mineralocorticoid receptor	Hypokalemia and metabolic alkalosis. Low plasma aldosterone and renin. Increased BP during pregnancy or exposure to spironolactone
  Unknown Mechanisms
  Hypertension-brachydactyly syndrome	AD mutation in the phosphodiesterase 3 (PDE3) gene	Short fingers (small phalanges) and short stature. Brainstem compression from vascular tortuosity in the posterior fossa

  AD, Autosomal dominant; Aldo, aldosterone; AR, autosomal recessive; PKD, polycystic kidney disease; PPGL, pheochromocytoma/paraganglioma.

  Modified from Peixoto AJ. Attending Rounds: A Young Patient with a Family History of Hypertension. Clin J Am Soc Nephrol. 2014; 9:2164–2172.

Hypertension with a Strong Family History of Hypertension Early in Life

Hypertension has a significant genetic component, with multiple genes associated with small effects on BP. However, patients who have a strong family history of hypertension early in life should be approached more carefully, as they may have a genetic disorder responsible for the hypertension. The most common of these conditions is autosomal dominant polycystic kidney disease (1:500 to 1:1000 live births), which can result in hypertension several years before producing symptoms or causing loss of kidney function. There are several rare monogenic causes of hypertension that the clinician should entertain in the right clinical setting; Table 65.2 summarizes their key clinical and genetic features.

Hypertension and Obesity

Obesity is strongly associated with hypertension, mediated by increased activity of the renin-angiotensin system and sympathetic nervous system, increased production of aldosterone by adipocytes, and impaired production of natriuretic peptides. Localized fat accumulation in the liver (as in nonalcoholic steatohepatitis) or kidney (renal sinus fat) is also associated with an increased prevalence of hypertension.

Weight gain often results in loss of BP control, and weight loss, when significant, can lead to resolution of hypertension. This can be achieved with lifestyle changes (dietary caloric restriction, exercise, behavioral modification to adjust caloric intake patterns), with or without the addition of drugs (orlistat, phentermine/topiramate, liraglutide, semaglutide naltrexone/bupropion) or bariatric surgery. It is important to remember that some drugs used to treat obesity, such as lorcaserin (a serotonin 5-HT2 receptor agonist no longer FDA approved), bupropion (a serotonin and dopamine reuptake inhibitor), and phentermine (a sympathomimetic amine), can induce significant hypertension in some patients. However, the net BP result of these drugs is usually favorable and reflects the achieved weight loss. Naltrexone/bupropion is the exception and should be avoided in obese patients with hypertension.

The impact of bariatric surgery on hypertension control in obese patients is well established. A meta-analysis of 57 studies in over 50,000 patients showed that 64% of patients had improved BP levels, and up to 50% were able to fully come off medications. In general, the amount of weight loss is greater with a Roux-en-Y gastric bypass than with other techniques that are purely restrictive (gastric banding, gastric sleeve) and, in many studies, this is also associated with greater BP reduction. However, a substantial portion of BP lowering occurs in the two initial postoperative weeks, before the majority of weight loss occurs. This implicates other mechanisms for BP reduction, such as decreased plasma leptin, leading to lower sympathetic tone, increased glucagon-like peptide 1 (GLP-1), and decreased reactive oxygen species as a result of caloric restriction, leading to improved endothelial function.

Drug-Induced Hypertension

Patients presenting with hypertension or whose BP control suddenly worsens should always be evaluated for exposure to hypertensogenic substances ( Table 65.3 ). These include substances of abuse as well as over-the counter and prescription drugs. Oral contraceptive pills (OCP), especially earlier-generation pills that had higher estrogen and progesterone content, can cause hypertension. Modern low-estrogen pills can also produce hypertension, though at rates much lower than with older preparations. Stopping the OCP cures the hypertension after several weeks to months in most but not all women. Nonsteroidal antiinflammatory drugs (NSAIDs) result in a modest average hypertensive effect (up to ∼5 mm Hg), but some patients can have very large BP responses. In addition, NSAID-induced hypertension often presents as loss of BP control in patients taking a diuretic or a blocker of the renin-angiotensin system, whereas the antihypertensive effect of calcium channel blockers tends to be less affected in NSAID users.

Sympathomimetic amines (legal or illegal) usually cause hypertension acutely, close to the time of ingestion. Alcohol has an acute hypotensive effect, but chronic use in large amounts (>4–5 drink-equivalents per day) is associated with increased BP. Glucocorticoids and mineralocorticoids can produce a dose-dependent rise in BP. Although generally seen only with systemic treatment, there are isolated reports of hypertension resulting from high-exposure topical therapy. Glucocorticoids with low mineralocorticoid activity (dexamethasone, budesonide) induce less pressor responses. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) can produce a modest increase in BP. SNRIs are more commonly culprits, and the hypertensive response in some patients can be severe. Interestingly, when used for hypertensive patients with depression, BP often improves as depressive symptoms improve.

Angiogenesis inhibitors, such as anti-VEGF antibodies (bevacizumab, ramucirumab) and tyrosine kinase inhibitors (sorafenib, sunitinib, axitinib), can produce hypertension that often persists despite discontinuation. Most cases are related to systemic therapy, though there are isolated reports following intravitreal administration of bevacizumab. Because hypertension during the use of these drugs correlates with better tumor responses (likely a reflection of successful antiangiogenesis), treatment is usually continued unless BP control to acceptable levels is not achievable or if severe kidney injury develops.

Labile Hypertension or Hypertension With Symptoms of Catecholamine Excess

Some patients present with paroxysmal hypertension (isolated episodes interspersed with normotension), labile hypertension (wide fluctuations in BP during any given time interval), or hypertension accompanied by stereotypical spells suggestive of catecholamine excess (headaches, palpitations, diaphoresis, pallor). In these situations, ruling out pheochromocytoma/paraganglioma (PPGL) is the initial step. However, because these symptoms are nonspecific and PPGL is rare, most patients turn out to have either an alternative diagnosis or, quite often, no specific etiology identified. Important considerations to be entertained in patients presenting as “pseudopheochromocytoma” include sympathomimetic drug use, alcohol withdrawal, hyperthyroidism, renal artery stenosis, carcinoid, intracranial hypertension, neurovascular brainstem compression, panic disorder, and baroreflex failure (as in patients with bilateral carotid sinus injury due to trauma, surgery, or irradiation). Further testing is based on specific symptoms and signs associated with each of these conditions.

Parenchymal Kidney Disease

Chronic kidney disease (CKD) of any etiology can lead to hypertension. Approximately 75% of patients with glomerular filtration rate (GFR) <45 mL/min are hypertensive. Patients with polycystic kidney disease and glomerulopathies tend to be hypertensive earlier in the course of the disease (at higher GFR) than patients with interstitial diseases. However, with progressive decline in kidney function, the prevalence of hypertension is relatively similar across all causes of CKD. Proteinuria is linked to increased sodium retention and hypertension. This relationship starts at relatively low levels of proteinuria and progressively strengthens with higher degrees of protein excretion. Low GFR and proteinuria have a synergistic association with higher BP.

The pathogenesis, diagnosis, and management of CKD (including hypertension), glomerular and interstitial diseases, and polycystic kidney disease are discussed elsewhere in this book.