Renal Hypertension – Causes, Symptoms, Diagnosis, Treatment

High blood pressure affects 75 million adults in the United States[rx] and accounts for 8.6% of all primary care visits.[rx] Renovascular hypertension is one of the most common causes of secondary hypertension and often leads to resistant hypertension. It is defined as systemic hypertension that manifests secondary to the compromised blood supply to the kidneys, usually due to an occlusive lesion in the main renal artery.

Causes of Renal Hypertension

The cause of renovascular hypertension is consistent with any narrowing/blockage of blood supply to the renal organ (renal artery stenosis). As a consequence of this action the renal organs release hormones that indicate to the body to maintain a higher amount of sodium and water, which in turn causes blood pressure to rise. Factors that may contribute are: diabetes, high cholesterol and advanced age,^[rx] also of importance is that a unilateral condition is sufficient to cause renovascular hypertension.^[rx]

It is important to realize that any condition that compromises blood flow to the kidneys can contribute to renovascular hypertension.[rx] The most common causes of renovascular hypertension include:

• Renal artery stenosis (RAS), mostly secondary to atherosclerosis
• Fibromuscular dysplasia (FMD)
• Arteritides such as Takayasu’s, Antiphospholipid Antibody (APLA) or Mid aortic syndrome[rx][rx]
• Extrinsic compression of a renal artery
• Renal artery dissection or infarction[rx]
• Radiation fibrosis
• Obstruction from aortic endovascular grafts[rx]

The underlying mechanism in renovascular hypertension involves decreased perfusion to the kidney and activation of the Renin-Angiotensin-Aldosterone (RAAS) pathway. This was first explained by Goldblatt et al. in the 1930s. His model studied the effect of decreased blood supply to the kidneys in dogs and found that ischemic kidneys contribute to persistent hypertension. He also proposed the presence of a substance that “may affect a pressor action like that of a hormone.” This hormone he was referring to was ‘renin,’ which is secreted by juxtaglomerular cells of the kidney. Renin secretion by the kidneys is stimulated by three main pathways,

• 1) renal baroreceptors that sense decrease perfusion to the kidney,
• 2) low sodium chloride levels detected by the macula densa and
• 3) beta-adrenergic stimulation. Prolonged ischemia also increases the number of renin expressing cells in the kidney in a process called ‘JG recruitment.’[rx] When renin is secreted into the blood, it acts on angiotensinogen (produced by the liver). Renin cleaves angiotensinogen to angiotensin I, which is then converted to angiotensin II by angiotensin-converting enzyme (ACE) that is primarily found in the vascular endothelium of lungs and kidney. Angiotensin II raises blood pressure by multiple mechanisms, which include:
• Vasoconstriction, mostly in the heart, kidney, and vascular smooth muscle[rx]
• Sympathetic nervous stimulation causing a presynaptic release of norepinephrine
• Stimulates secretion of aldosterone by the adrenal cortex, which in turn causes sodium and water retention, thereby raising blood pressure.
• It also causes the increased synthesis of collagen type I and III in fibroblasts, leading to thickening of the vascular wall and myocardium, and fibrosis
• It has been shown to have a growth effect on renal cells, which has been implicated in the development of glomerulosclerosis and tubulointerstitial fibrosis

Though atherosclerotic renal artery stenosis (ARAS) and FMD are the two most common conditions causing this cascade, any pathology leading to decreased blood flow to the kidneys can essentially trigger this and lead to high blood pressure.

Symptoms Of Renal Hypertension 

The main symptoms of renovascular hypertension are rapidly increasing blood pressure of 180/120 or higher and signs of organ damage. Usually, the damage happens to the kidneys or the eyes.

Other symptoms depend on how the rise in blood pressure affects your organs. A common symptom is bleeding and swelling in the tiny blood vessels in the retina. The retina is the layer of nerves that line the back of the eye. It senses light and sends signals to the brain through the optic nerve, which can also be affected by renovascular hypertension. When the eye is involved, can renovascular hypertension cause changes in vision.

Other symptoms of malignant hypertension include

• Pheochromocytoma – Sweating, increased frequency or force of heartbeats, headache, anxiety
• Cushing’s syndrome – Weight gain, weakness, abnormal growth of body hair or loss of menstrual periods (in women), purple striations (lines) on the skin of the abdomen
• Thyroid problems – Fatigue (tiredness), weight gain or weight loss, intolerance to heat or cold
• Conn’s syndrome or primary aldosteronism – Weakness due to low levels of potassium in the body
• Obstructive sleep apnea – excessive fatigue or sleepiness during daytime, snoring, pauses in breathing during sleep
• High blood pressure at a young age
• High blood pressure that suddenly gets worse or is hard to control
• Kidneys that are not working well (this can start suddenly)
• Narrowing of other arteries in the body, such as to the legs, the brain, the eyes and elsewhere
• Sudden buildup of fluid in the air sacs of the lungs (pulmonary edema)
• High blood pressure (early age)
• Kidney dysfunction
• Narrowing of arteries elsewhere in the body
• Pulmonary edema
• Change in mental status, such as anxiety, confusion, decreased alertness, decreased ability to concentrate, fatigue, restlessness, sleepiness, or stupor
• Chest pain (feeling of crushing or pressure)
• Cough
• Headache
• Nausea or vomiting
• Numbness of the arms, legs, face, or other areas
• Reduced urine output
• Seizure
• Shortness of breath
• Weakness of the arms, legs, face, or other areas
• Blurred vision
• Chest pain (angina)
• Difficulty breathing
• Dizziness
• Numbness in the arms, legs, and face
• Severe headache
• Shortness of breath

In rare cases, renovascular hypertension can cause brain swelling, which leads to a dangerous condition called hypertensive encephalopathy. Symptoms include:

• Changes in mental status
• Coma
• Confusion
• Drowsiness
• Headache that continues to get worse
• Nausea and vomiting
• Seizures

Diagnosis of Renal Hypertension

History and Physical

Salient points in history that suggest the presence of renovascular hypertension include:

• Resistant hypertension –  Uncontrolled blood pressure necessitating the use of 2 or 3 antihypertensive agents of different classes, one of which is a diuretic
• Trial of multiple medications to control blood pressure
• History of multiple hospital admissions for hypertensive crisis
• Elevation in creatinine of more than 30% after starting an angiotensin-converting enzyme (ACE) inhibitor (ACEI)
• Patients with renal artery stenosis secondary to atherosclerosis are usually older and might have the presence of other atherosclerotic diseases such as carotid artery stenosis, peripheral artery stenosis or coronary artery disease
• A premenopausal female (15-50 years) with hypertension is most likely to have FMD[rx]
• Long term history of smoking
• Patients with systemic vasculitis can develop vasculitis of renal arteries and present with renovascular hypertension
• Recurrent episodes of flash pulmonary edema and/or unexplained congestive heart failure
• Unexplained Azotemia
• Elevation in serum creatinine on starting ACE-I, which occurs due to interference with autoregulation and post glomerular arterial tone
• Unexplained hypokalemia and metabolic alkalosis
• Unilateral small or atrophic kidney.

Physical examination may reveal an abdominal bruit, indicating the presence of renal artery stenosis.

Lab Test

Patients with renovascular hypertension often undergo an extensive evaluation to find a cause for uncontrolled hypertension.

Laboratory tests

• Urine analysis – to check for proteinuria, hematuria, and casts. The presence of proteinuria indicates the presence of renal parenchymal disorder, whereas the presence of hematuria or RBC casts indicates the presence of glomerulonephritis.
• Blood urea nitrogen and serum creatinine – to assess baseline kidney function.
• Basal metabolic profile: to assess for electrolyte disturbances and acid-base balance.
• Complement levels and autoimmune profile – in suspected cases of autoimmune diseases affecting the renal vasculature.
• Plasma free metanephrines or 24-hour urinary fractionated metanephrines and normetanephrine to rule out pheochromocytoma
• Plasma renin-aldosterone ratio to rule out hyperaldosteronism
• 24 hr urinary free cortisol or low dose dexamethasone suppression test to rule out Cushing’s syndrome

Imaging

• Catheter angiography  – There are multiple imaging modalities available to evaluate renovascular hypertension. Since the most common cause of renovascular hypertension is renal artery stenosis, renal arteriography remains the gold standard diagnostic test.[rx] However, catheter angiography is invasive, costly, time-consuming, and can lead to complications such as renal artery dissection or cholesterol embolization. Other imaging tests that can be done to evaluate the renal vessels include duplex ultrasonography, computed tomography with angiography (CTA), and magnetic resonance angiography (MRA). The type of imaging test used often depends on the suspicion for high-grade lesions, and the need for intervention.[rx]
• Duplex ultrasonography – is the initial imaging test of choice to evaluate the renal arteries. It is relatively cheap, non-invasive, and does not involve the administration of contrast or exposure to radiation. A duplex scan has been shown to have an excellent correlation with contrast-enhanced angiography.[rx] Though there are several criteria to assess the presence of renal artery stenosis, the most important sign is peak systolic velocity (PSV). A PSV higher than 180 cm/s suggests the presence of stenosis of greater than 60%.[rx]
• Ultrasonography – can also measure the resistive index (RI), which is calculated as ((PSV-End diastolic velocity)/PSV)). A value of more than 0.7 indicates the presence of pathological resistance to flow, and studies have shown that a value >0.8 predicts poor response to revascularization treatments.[rx] The most significant setbacks for duplex ultrasonography are its reduced sensitivity in obese patients, hindrance by overlying bowel gas and operator dependence.
• CT angiography – involves the administration of intravenous contrast and acquiring detailed images of blood vessels or tissues by moving the beam in a helical manner across the area being studied. In a study by Wittenberg et al, the sensitivity and specificity for hemodynamically significant RAS (>50%) by CTA was found to be 96% and 99%. CTA also has a comparable negative predictive value to MRA in ruling out renal artery stenosis.[rx] It can also diagnose extrinsic compression of renal arteries, FMD, arterial dissection, and help in evaluating surrounding structures. However, CTA can only provide an anatomical assessment of the lesion and is not able to evaluate the degree of obstruction to renal blood flow. Exposure to radiation, allergy to contrast, and acute kidney injury are other downfalls of CTA.
• MRA  – uses a powerful magnetic field, pulses of radio waves, and intravenous gadolinium to evaluate the renal blood vessels and surrounding structures. Several studies have shown the sensitivity and specificity of MRA to be around 97% and 92%[rx] in diagnosing renal artery. MRA does not involve radiation, and gadolinium contrast is less likely to cause an allergic reaction as compared to the iodine contrast used in CTA. However, MRA has been shown to overestimate the grade of stenosis and is often affected by motion artifacts or opacification of renal veins, leading to difficulty visualizing the renal arteries.[15] Also, gadolinium has been shown to induce a rare, progressively fatal disease called nephrogenic systemic fibrosis (NSF).  NSF can affect the skin, joints, and multiple organs leading to progressive, irreversible fibrosis and eventual death. This occurs due to a transmetalation reaction that displaces gadolinium ion from its chelate, resulting in the deposition of gadolinium in the skin and soft tissues. The 1-year incidence of NSF has been reported to be around 4.6%[rx] and almost all cases occurred in patients with a glomerular filtration rate < 30 mL/min/1.73 m.
• Nuclear medicine ACE-Inhibitor (ACE-I) renography – is another non-invasive, relatively safe imaging method that uses radioactive material, a special camera, and a computer to evaluate for renovascular hypertension. It involves the administration of an ACE-I to determine if the cause of hypertension is due to the narrowing of the renal arteries. The sensitivity and specificity of this test have shown to be variable, with values between 74% – 94% for sensitivity and 59% – 95% for specificity.[rx] It is a time-consuming procedure, and there is a risk of radiation exposure and irritation or pain from the injection of the radiotracer. The sensitivity of ultrasound has shown to be higher than captopril renography[rx] which makes it a better choice for an initial diagnostic test.
• Magnetic resonance angiogram, or MRA – Images from this test show blood flow and organ function without using x-rays. Contrast medium may be injected into a vein in your arm to better see the structure of your arteries. You remain awake, although a muscle relaxer may be used, if necessary. You lie still on a table that slides into a tunnel-shaped device. There is no radiation exposure with this study. Claustrophobia can be an issue with MRAs as the tube is quite narrow.
• Catheter angiogram – A special kind of x-ray in which a catheter, or a thin, flexible tube, is threaded through your large arteries into your renal artery. This often is from a small slit in the groin. The patient is usually awake, although a muscle relaxer may be given to lessen anxiety during the procedure. A contrast medium, or a colored dye, is injected through the catheter, so the renal artery shows up more clearly on the x-ray. The benefits of this study are that it is more accurate than the other tests and if a significant narrowing is seen, it can be dilated with a balloon (angioplasty) or stented (a tube-like cage that keeps the vessels open) at the same time. A catheter angiogram is an invasive procedure so this is usually reserved for patients who have a positive result of one of the other tests and plans are made to dilate the blood vessel.

Catheter arteriography – is the gold standard test to evaluate for renovascular hypertension and provides the best temporal and spatial resolution. Catheter angiography has the added advantage of measuring translesional pressure gradients to assess the hemodynamic significance of anatomically severe lesions.[rx] It is most useful in:

• Patients with a disparity between imaging modalities
• Patients with a high index of suspicion and negative imaging findings
• Patients anticipated having an intervention

It can also evaluate anatomical abnormalities of the kidney, renal arteries, aorta, and can be followed by endovascular intervention for the treatment of significant lesions. Also, the surrounding tissues and bones can be removed or subtracted from the final image revealing only the arterial framework. This method is known as digital subtraction angiography (DSA). However, the radiation doses are higher than CTA, and because it is an invasive procedure, there are risks of complications such as arterial dissection, tear, rupture, or thromboembolic phenomenon.[rx]

Treatment of Renal Hypertension

The management of renovascular hypertension aims to treat the underlying cause. Several options are available, which include pharmacological and invasive therapy.

Pharmacological therapy entails the use of antihypertensive medications to control blood pressure. The American College of Cardiology and the American Heart Association (ACC/AHA) advocates pharmacological therapy as the first-line treatment for renal artery stenosis.[rx] Since RAAS is the most prominent pathway contributing to hypertension in these disorders,

• ACEI and angiotensin receptor blockers (ARBs) form the cornerstone of managing renovascular hypertension (Class 1a indication). Often more than one medication will be needed to control the blood pressure.
• Calcium channel blockers, thiazides, beta-blockers, and hydralazine have been shown to be effective to control blood pressure in patients with RAS.[rx] Direct renin inhibitors such as aliskiren have been studied as monotherapy or in combination with ACEIs/ARBs to treat hypertension. Though it has been shown to be effective for the treatment of hypertension[rx][rx][rx][rx][rx] there is not enough data to prove its efficacy in treating renovascular hypertension.
• ACEIs and ARBs inhibit the action of angiotensin II, thereby causing vasodilation and promote sodium and water excretion. However, these medications are contraindicated in patients with a single functioning kidney or bilateral lesions as they can cause efferent arteriolar vasodilatation leading to interruption in autoregulation and thereby decreasing glomerular filtration. While these medications are effective in controlling blood pressure, they can also lead to worsening renal function.
• Percutaneous angioplasty is the treatment of choice for renovascular hypertension due to FMD and for patients with atherosclerotic renal artery stenosis that is not controlled with medications.[rx] The ACC/AHA guidelines recommend revascularization for renal artery disease in the following scenarios:[rx]
• Patients with hemodynamically significant RAS and recurrent, unexplained congestive heart failure or sudden, unexplained pulmonary edema (class Ia)
• Hemodynamically significant RAS and accelerated hypertension, resistant hypertension, malignant hypertension or hypertension with an unexplained unilateral small kidney, and hypertension with intolerance to medication (Class IIa)
• Patients with bilateral RAS and progressive chronic kidney disease or a RAS to a solitary functioning kidney (Class IIa)
• Patients with hemodynamically significant RAS and unstable angina (class IIa)
• Asymptomatic bilateral or solitary viable kidney with hemodynamically significant RAS (Class IIb)
• Patients with RAS and chronic renal insufficiency with unilateral RAS (class IIb)
• In addition to angioplasty, renal stent placement is indicated for patients with ostial atherosclerotic lesions (Class I).
• Patients with FMD and renovascular hypertension are also treated with percutaneous intervention with or without a stent.[rx] Multiple studies have shown a decrease in baseline blood pressure after intervention for FMD.[rx][rx] However, there remains an ongoing debate about the benefit of revascularization when compared to medical management in patients with atherosclerotic renal artery stenosis (ARAS). Several studies have failed to show a significant decrease in blood pressure or the number of antihypertensive agents between angioplasty and medical treatment groups.

A meta-analysis of 7 trials by Zhu et al. revealed that medical management is as effective as percutaneous revascularization in the treatment of RAS.[rx] Three recent trials ASTRAL, CORAL, and STAR found no difference between stenting and medical therapy in patients with atherosclerotic renal artery stenosis.[rx] [rx][rx] Thus it can be established that revascularization does not reverse renal damage or decrease blood pressure in patients with atherosclerotic renal artery stenosis.

In the case of recurrent renal artery stenosis or blood pressure not controlled with medication and or/angioplasty, renal bypass surgery may be an option. In this procedure, the surgeon uses a vein or synthetic tube to connect the kidney to the aorta, to create an alternate route for blood to flow around the blocked artery into the kidney. This is a complex procedure and rarely used. The ACC/AHA guidelines recommend surgery for RAS in[rx]

• Patients with RAS secondary to FMD, especially those with complex disease and/or those having microaneurysms
• Patients with atherosclerotic RAS involving multiple vessels or involvement of early primary branch of the main renal artery
• Patients with atherosclerotic RAS who require pararenal aortic reconstructions (such as with aortic aneurysms or severe aortoiliac obstruction).

Several studies have also evaluated the role of unilateral nephrectomy in patients with renovascular hypertension and have shown improvement in blood pressure control, renal function, and decrease in the use of anti-hypertensives.[rx][rx] However, this is an invasive procedure with inherent risks and long term consequences of such a procedure are unclear.

Surgery

• In terms of treatment for renovascular hypertension surgical revascularization versus medical therapy for atherosclerosis, it is not clear if one option is better than the other according to a 2014 Cochrane review; balloon angioplasty did show a small improvement in blood pressure .^[rx]
• Surgery can include percutaneous surgical revascularization, and also nephrectomy or autotransplantation, and the individual may be given beta-adrenergic blockers.^[rx] Early therapeutic intervention is important if ischemic nephropathy is to be prevented. Inpatient care is necessary for the management of hypertensive urgencies, quick intervention is required to prevent further damage to the kidneys.^[rx]

References