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Select Considerations for Secondary Hypertension
  JOHTN
REVIEW ARTICLE
Select Considerations for Secondary Hypertension
Geetha M. Nair, Jigy Joseph
Department of Nephrology, PRS Hospital, Trivandrum, Kerala, India
Address for correspondence: Geetha M. Nair, Department of Nephrology, PRS Hospital, Trivandrum, Kerala, India.
E-mail: malugeetha@hotmail.com
Received: 14-12-2018; Accepted: 02-01-2019
doi: 10.15713/ins.johtn.0148
 
ABSTRACT
Hypertension assumes a dominant position among chronic non-communicable diseases worldwide. Of this, secondary hypertensionconstitutes only 5-10% of the total disease burden. In routine clinical practice, physicians come across hypertensive cases which aredifficult to control despite optimal therapy. In this backdrop, the present paper reviews the less frequently encountered etiologies ofhypertension which can pose difficulties to both the patient and treating clinician. This is classified as secondary hypertension andthe major entities include renal parenchymal diseases, renovascular diseases, primary hyperaldosteronism, and sleep-disorderedbreathing. Among patients with resistant hypertension, investigations such as urine analysis, renal function tests, electrolytes,sonogram for kidneys, duplex ultrasound for renal artery stenosis, plasma aldosterone concentration/plasma renin activity (PAC/PRA) ratio, and sleep study may be done in serial manner depending on the individual patient to identify a secondary cause. Druginducedhigh blood pressure should also be addressed, especially in young ladies due to oral contraceptives pills and in chronicobstructive pulmonary disease patients on long-term steroids. Many a time, a proper evaluation and diagnosis can reduce the pillburden and long-term consequences of resistant hypertension.
Keywords: Endocrine, renovascular, secondary hypertension, sleep disorder
How to cite this article: Nair GM, Joseph J. SelectConsiderations for Secondary Hypertension. Hypertens2019;5(1): 35-39.
Source of support: Nil
Conflict of interest: None
 
 

Introduction

Increasing prevalence of hypertension is a global epidemiologicalconcern, as the disease already tops the burden of chronicdiseases across the world. Indian scenario turns out to be moreworrying due to several reasons; specifically, the growing size ofthe urban population and economic burdens leading to stressedlifestyles. Hypertension has been marked as the most commonsingle diagnosis by the primary care providers.[1-3] An overridingmajority of these hypertension cases (90-95%) fall underessential or idiopathic hypertension category.

Secondary hypertension is the effect of a definite, identifiablepredisposing cause and accounts for approximately 5-10% ofcases. Secondary hypertension often goes underdiagnosed,leading to lifelong medications. End-organ damage is earlier andmore prevalent due to the resistant nature of hypertension inthese patients. This deems important, particularly in countriessuch as India, where the likelihood of obesity is increasing at analarming rate due to change in lifestyle patterns, consumerism,and related factors.[4-6] Unlike patients with primary or essentialhypertension those with secondary hypertension need extensiveinvestigations, resulting in greater psychological distress andfinancial burden which leads to a vicious cycle of irregularfollow-up and poor compliance. However, proper case selection,evaluation, and focused treatment strategies lead to complete orpartial cure in good proportion of patients.[7]

 
Evidence reveals an array of causes for secondary hypertensionwhich broadly could be classified into renal, endocrine,cardiovascular/pulmonary, and drug induced. The present reviewmakes an attempt to focus on, the major etiologies of secondaryhypertension such as renovascular hypertension (RVHTN),endocrine hypertension due to primary hyperaldosteronism, andhypertension due to sleep-disordered breathing.

An Updated Overview of Management Protocols for
Secondary Hypertension


Secondary hypertension is strongly suspected in the followingsituations:

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Nair and Joseph Secondary hypertension

  1. Persistent hypertension in spite of concurrent use of optimaldoses of at least three antihypertensive drugs belongingto three different classes, of which one is a diuretic. This istermed as resistant hypertension.
  2. Labile hypertension or acute rise in blood pressure in aperson with previous optimal control.
  3. Sudden onset of hypertension in persons with no familyhistory or risk factors, who are < 30 years of age and are nonobeseor in patients more than 55 years of age.
  4. Malignant or accelerated hypertension accompanying a targetorgan damage such as heart failure, acute kidney injury, retinalhemorrhage, papilledema, or neurological disturbances.
  5. Hypertension with dyselectrolytemia - hypokalemia andmetabolic alkalosis.
  6. Well-documented age of onset before puberty.

Major Causes of Secondary Hypertension

Renal causes
  • Renal parenchymal hypertension
  • RVHTN.

Endocrine causes

Primary hyperaldosteronism
  • Cushing's syndrome
  • Pheochromocytoma
  • Hypothyroidism
  • Hyperparathyroidism.

Cardiovascular or cardiopulmonary causes
  • Coarctation of aorta
  • Obstructive sleep apnea (OSA).

Drugs
  • Glucocorticoids, NSAIDs, combined oral contraceptivepills, calcineurin inhibitors, caffeine, phenyl ephedrine, anderythropoietin.
  • Inherited rare causes such as Liddle's syndrome and Gordon'ssyndrome.

Renal parenchymal diseases

Primary renal disease is the most common cause of secondaryhypertension and can happen in acute as well as chronic kidneydisease (CKD). Hypertension is present in more than 80% ofpatients with CKD. Out of this, glomerular diseases cause moresevere hypertension than tubulointerstitial diseases. Clues fordiagnosis are the presence of proteinuria, especially more than1000 mg/day, active urine sediment (with RBCs, WBCs, andcasts) and other sonological and histological features favoring arenal pathology. On the other hand, long-standing uncontrolledblood pressure can also cause nephrosclerosis and then many atime, clinicians find it difficult to identify whether hypertensionor renal disease was the initial problem. The etiology ofhypertension in CKD could be clinically discernible from theoccurrence of one or more of such symptoms as extracellularvolume overload, increased renin-angiotensin-aldosteroneactivity, endothelial cell dysfunction, oxidative stress, increasedvasopressin release, and hypertensinogenic drugs such aserythropoietin and steroids.

 
Detailed evaluation of primary renal disease withappropriate tests (sonogram, urinalysis, histopathology, etc.)is required. Uncontrolled hypertension adds on to significantmorbidity and mortality in CKD, across all stages, by causingrapid progression of renal failure and its associated hugecardiovascular risk. The target blood pressure recommendsin patients with significant proteinuria (500-1000 mg/day)is 130/80 mmHg. Angiotensin receptor blockers (ARBs)and angiotensin-converting enzyme inhibitors (ACEIs) arepreferred agents in CKD, but periodic monitoring of creatinineand serum potassium is advised.[8,9]

RVHTN

It caused by occlusive lesion of a renal artery resulting inreduction of renal artery perfusion pressure. It is most often apotentially curable cause of hypertension. RVHTN is relativelyuncommon in patients with mild hypertension but quitecommon in patients with severe or refractory hypertension,especially in patients with other atherosclerotic diseases suchas aortic disease, peripheral occlusive arterial disease, andcoronary disease. Renal artery disease if progressive can causedecline in glomerular filtration rate (GFR) and such resultantCKD is called as ischemic nephropathy.[7,10] Atherosclerosisaffecting the renal artery, mostly at its origin accounts for85% of cases. Fibromuscular dysplasia (FMD) which is a noninflammatory,non-atherosclerotic disorder affecting youngladies is the second most common cause of RVHTN.[11,12]

Table 1: Clinical features of renal artery stenosis due toatherosclerosis and fibromuscular dysplasia
Select Considerations for Secondary Hypertension
ARAS: Atherosclerotic renal artery stenosis, FMD: Fibromuscular dysplasia

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Nair and Joseph Secondary hypertension

Clinical characteristics of these two pathologies are detailedin Table 1.

Clinical Clues to RVHTN[10,11]
  • Late-onset severe hypertension - more than 180/120 bloodpressure after the age of 55 years.
  • Episodes of flash pulmonary edema with normal ventricularfunction.
  • Unexplained acute kidney injury (AKI) within 1-2 weeks ofstarting ACEI or ARB.
  • Asymmetric kidney size with more than 1.5 cm difference.
  • Severe hypertension with features of diffuse atherosclerosis,especially in >50 years.
  • Presence of unilateral systolic-diastolic bruit.

Establishing the Diagnosis of RVHTN

Detailed diagnostic testing is advocated only in those patientswith high clinical suspicion and those who have high likelihoodof benefiting from the procedure. Compelling indications forextensive evaluation include as follows:
  • A short duration of accelerated hypertension
  • Failure or intolerance to optimal medical therapy
  • Progressive renal failure in the absence of another etiologyfor CKD
  • High clinical suspicion of FMD in young hypertensives.
  • Recurrent flash pulmonary edema.[11,12]

The gold standard for diagnosing renal artery stenosis is renalarteriography. However, a variety of less invasive tests is availablefor initial evaluation. They are renal artery duplex ultrasonography(RADUS), CT angiography, and MR angiography. The choiceof the test depends on patient factors and institutional expertise.Testing for RVHTN is associated with potential risks, particularlyin patients with impaired renal function who are at risk forcontrast-induced nephropathy and nephrogenic systemic fibrosisassociated with gadolinium exposure during MR angiogram.Invasive testing is done if the screening tests are inconclusive withhighly suggestive clinical setting.

RADUS is an important diagnostic test in assessing RAS. Itis relatively easier non-invasive test which can be repeated andit provides functional assessment of the renal arteries along withcertain anatomical information.

Peak systolic velocity 180 cm/s and/or a relative velocity above3.5 as compared to the adjacent aortic flow are useful. This has asensitivity and specificity of 90 and 96%, respectively, in lesionshaving more than 60% stenosis determined angiographically.As with many diagnostic procedures, a positive test is moreinformative than a negative test. Disadvantages of Dopplerstudy of renal arteries in diagnosing RVHTN are its operatordependence, failure to identify accessory, distal branch stenosis,and inability to predict outcome after revascularization.[13]

Spiral CT scan with CT angiography is highly accurate foratherosclerotic RAS but less useful for FMD.

 
Magnetic Resonance Angiography

It provides excellent vascular images of RAS, especiallygadolinium contrast-enhanced images. The risk of nephrogenicsystemic fibrosis is avoided by technical improvements in MRAlike breath-hold MRA with paramagnetic less nephrotoxiccontrast material.

Invasive imaging

Intra-arterial angiography is the gold standard for diagnosingRAS . More than 70% stenosis in angiography, restingtranslesional mean pressure gradient of more than 10 mmHg,and renal fractional flow reserve ≤0.8 are features to suggest ahemodynamically significant stenosis. However, most centers donot proceed directly to arteriography due to the risk of contrastnephropathy and cholesterol embolization. If there is hugesuspicion of RVHTN both clinically and by way of screeningtests like Doppler, CTA, or MRA, one can proceed with invasivearteriography. This is particularly useful in young FMD patientswhere non-invasive tests might miss the lesion.[14,15]

Carbon dioxide angiography - CO2 is useful as an alternativecontrast agent either alone or in combination with smallerdoses of iodinated contrast. It is the only known contrast agentwhich is non-nephrotoxic. CO2 is also of help in people withhypersensitivity to iodine-containing contrast medium. It isworth mentioning here that though CO2 is regarded as a usefulcontrast agent, it should not be used in coronary, cerebral, andthoracic imaging due to its potential neurotoxicity. Lack offamiliarity restricts its use in day-to-day practice.[15]

In patients without renal failure Doppler study, CTangiography and MR angiography are safe and useful tests beforeproceeding with intrarenal arteriography. However, in patientswith renal failure, both invasive and non-invasive tests usingcontrast agents carry risk of nephrotoxicity. In patients withGFR < 30 ml/mt, CT angiogram is preferred over MR angiogramdue to higher risk of gadolinium-induced nephrogenic systemicfibrosis.

Treatment of Unilateral Renal Artery Stenosis - Three
Options are Available[16-20]
  1. Medical management - Medical management should beessentially offered to all patients. Addition of ACE inhibitorsand ARBs has markedly improved blood pressure control. Ifadequate blood pressure control is not achieved, diuretics,long-acting calcium channel blockers, beta-blockers, etc.,may be added as in primary hypertension. Progressivestenosis resulting in long-term ischemic changes in thekidneys and resultant renal failure is potential concerns withmedical management.
  2. Revascularization by percutaneous transluminal renalangioplasty with stenting is advised in patients whohave a high likelihood of benefiting from the procedureand in patients who fail to tolerate or achieve optimalblood pressure control with medical management. Thisincludes patients who have a short duration of refractoryhypertension, young ladies on multiple drugs in whom thechances of FMD are high and in those with refractory heartfailure with resistant hypertension and repeated occurrenceof flash pulmonary edema. Observational outcome studiesof atherosclerotic renal artery stenosis from 14 series of trialscomprising 678 patients showed hypertension cure definedas BP < 140/90 with no antihypertensive medications wereseen in 12%. In 73% BP level improved with lesser number ofdrugs and in 41%, the renal function also improved. Properselection of patient who is best suited for this treatment isimportant rather than performing angioplasty in all innocentincidental lesions.
  3. Surgical treatment - Splenorenal and hepatorenal bypasssurgeries are less commonly performed in selected categoryof patients with complex anatomical lesions and with severeaortoiliac occlusive disease.

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Treatment of Bilateral Renal Artery Stenosis

All management options discussed with unilateral renal arterystenosis are applicable in the case of bilateral disease also.Additional concerns here are high chances of chronic ischemicnephropathy, progressive renal failure, and hemodynamicallymediated AKI while on ARB or ACE inhibitors.

Endocrine Hypertension

Primary hyperaldosteronism[21-23]

It is the most common but often underdiagnosed cause ofhypertension due to an endocrinopathy. Among patients withresistant hypertension, the prevalence is around 11-20%. Itmay be caused by bilateral adrenal hyperplasia (65% of cases),aldosterone-producing adenoma (30%), or rarely secretoryadrenal carcinoma or inherited endocrinopathies. Other thanfeatures of resistant hypertension, patients can present withepisodic paralysis secondary to hypokalemia and alkalosis.

Screening for hyperaldosteronism is recommended for thefollowing groups:
  1. Sustained BP >150/100 on three different occasions,resistant hypertension despite three drugs, or controlledhypertension on four or more drugs.
  2. Hypertension with spontaneous or diuretic-inducedhypokalemia.
  3. Hypertension with adrenal incidentaloma.
  4. Hypertension with OSA.
  5. Hypertension and a family history of early-onset hypertensionor cerebrovascular accident at a young age of < 40 years.
  6. All hypertensive first-degree relatives of patients with PA.

Measurement of the ratio of plasma aldosteroneconcentration (PAC) to plasma renin activity (PRA) is thescreening test of choice. Although at present, there are no firmrecommendations for aldosterone to renin ratio cutoffs, due tovariability of assays, a PAC/PRA >20 in combination with a PAC>15 ng/dl or 416 pmol/L is considered as a positive screeningtest result. Many factors such as GFR, diet, drugs, potassiumlevel, and menstruationetc affect the value and hence should beappropriately addressed before screening.

 
How to Confirm?

The hallmark of primary aldosteronism is non-suppressiblealdosterone secretion with non-stimulable renin secretion.Therefore, aldosterone suppression tests with fludrocortisone,saline suppression test, and oral salt loading are suggested. Sincetheir tests are cumbersome, time consuming, and with risksattached, radiological methods are preferred. CT and MRI areused to differentiate between a unilateral and bilateral adenoma.Adrenal vein renin sampling is theoretically useful but difficult toput in practice.

Treatment

Medical management is best with aldosterone antagonistssuch as eplerenone, spironolactone, or amiloride. Additionalantihypertensives like ARBs are most often needed. Surgicalremoval and ethanol embolization are done for unilateraladenomas. If no discrete nodules are identified in the CT scanwith negative adrenal vein renin lateralization, it is advisable todo follow-up under medical management.

Sleep Apnea Syndrome

Sleep apnea syndrome has emerged as an independent riskfactor for hypertension irrespective of the associated metabolicfactors such as diabetes, dyslipidemia, and obesity. Around 50%of patients with OSA are estimated to be having hypertension.Although OSA has been linked to high risk for cardiovasculardisease, stroke, pulmonary hypertension, and arrhythmias,the association with hypertension is very much obvious in alllongitudinal and cross-sectional studies. The observed risk factorsare male sex, ethnicity, and high apnea-hypopnea index (morethan 30/h). Increased sympathetic nervous system activity andabnormal vascular functional and structural changes resultingfrom oxidant stress are supposed to be contributory factors forhypertension. Sleep study is diagnostic. Weight reduction andcontinuous positive airway pressure are beneficial in most of thepatients and surgical intervention is rarely needed.[24,25]

Conclusion

Secondary hypertension being rare often goes underdiagnosed.0It is not cost effective to evaluate extensively every hypertensiveperson for a secondary cause. Young hypertensives, those whodevelop early target organ damage and patients on multipledrugs, should be screened for a treatable cause, in these patientsif investigations are carefully selected, it is an extremely fruitfulexercise because in a good proportion of patients, hypertensioncan either be cured or at least better controlled. The commoncauses of secondary hypertension are renal parenchymaldiseases, renovascular diseases, primary hyperaldosteronism,and sleep-disordered breathing. Among patients with resistanthypertension, investigations such as urine analysis, renalfunction tests, electrolytes, sonogram for kidneys, duplexDoppler ultrasound for renal artery stenosis, PAC/PRA ratio,and sleep study can be done serially to rule out a secondarycause. Drug-induced hypertension should always be addressedin young ladies on oral contraceptives pills and in chronicobstructive pulmonary disease patients on long-term steroids.Rarer causes include pheochromocytoma, Cushing's syndrome,and coarctation of aorta which should be excluded in appropriateclinical settings. With the background of fast-growing economy,unhealthy lifestyle practices, and progressive urbanization, wehave a growing epidemic of obesity and metabolic syndrome andtherefore of OSA. More studies should be directed to identifyhypertension in relation to OSA and sleep-disordered breathing.

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