Chronic kidney disease is defined by a GFR < 60 mL/min or abnormal findings in urinalysis and/or kidney morphology for 3 months.1 As CKD advances, AH increases progressively, affecting 90% of stage 5 patients.2

All patients with AH should have plasma creatinine measured, their GFR calculated and urinalysis performed to screen for CKD.3 (GR: I; LE: A). Additional investigation includes renal US for all.3 Other exams (albuminuria, CT, MRI) can be necessary. Kidney biopsy is indisputably indicated in the presence of rapid decline in glomerular filtration or proteinuria > 3.5 g/g of urine creatinine.4 Arterial hypertension accelerates the progression of CKD5 and BP reduction attenuates CKD course.6 The treatment goals and most indicated medications for BP control in patients with CKD are described in Chapter 8. For CKD patients on dialysis, BP reduction decreases mortality,7 and loop DIUs are indicated in the presence of residual renal function, as well as ultrafiltration, in selected cases.8

Renovascular hypertension (RVAH) is secondary to partial or total, uni- or bilateral stenosis of the renal artery or of one of its branches, triggered and maintained by renal tissue ischemia. The RVAH prevalence is 5% of hypertensive patients.9 Its major cause is atherosclerosis (90%), followed by renal artery fibromuscular dysplasia,10 Takayasu's arteritis being the less frequent.9 Regardless of its cause, it is an important determinant of CV morbidity and mortality.10

The diagnosis and assessment of the extent of involvement with TOD are essential for the choice of treatment. A cost-effective investigation requires proper selection of candidates, and anatomical and functional assessment of the stenosis, in addition to methods to correct the anatomical and functional defect.11 Charts 2 and 3 12^-14 list the main steps.

The indication for the therapeutic option should consider the etiology and clinical conditions associated with renal artery stenosis, such as AH, ischemic nephropathy and accelerated CVD. Evidence of benefit of the percutaneous or surgical mechanical treatment is restricted to situations, such as progressive renal function loss, APE and difficulty to control BP, that cause irreversible TOD.15 Regarding patients with RVAH due to fibromuscular dysplasia, 82-100% of them have BP control, and 10%, restenosis.11 (GR: IIa; LE: B). Regarding atherosclerotic RVAH without complications, three randomized studies have shown no benefit of stent implantation as compared to optimized clinical treatment in BP control, kidney disease progression, and occurrence of clinical events and mortality.16^-18 For patients with atherosclerotic renal artery stenosis and controlled BP with clinical treatment, without heart complications and stable kidney function for 6-12 months, the mechanical intervention is not recommended, clinical treatment being the first option. (GR: II; LE: B).

Figure 1 shows a flowchart for the assessment of patients suspected of having renal artery stenosis.

Figure 1

Obstructive sleep apnea-hypopnea syndrome is characterized by recurring upper airway obstructions during sleep, causing reductions in intrathoracic pressure, intermittent hypoxia and sleep fragmentation.19 There is evidence that OSAHS is related to the development of AH regardless of obesity.20^,21 The prevalence of OSAHS in patients with AH is 30-56%,22^,23 reaching 64-83% in those with resistant AH (RAH).24^,25 OSAHS contributes to TOD26 and acceleration of atherosclerosis in hypertensives.27

The risk factors for OSAHS are age, male sex, obesity and MS. The Berlin questionnaire28 can be used to screen for OSAHS,23 but does not seem useful in patients with RAH.29 Changes in the physiological BP decrease during nocturnal sleep can indicate the presence of OSAHS.30 Polysomnography or home respiratory polygraphy confirms the diagnosis with the finding of at least five episodes of apnea and/or hypopnea per hour of sleep (apnea-hypopnea index - AHI), and an AHI ≥15 events/hour seems to have a higher impact on AH.31

The treatment of choice for moderate or severe OSAHS is the use of continuous positive airway pressure (CPAP) during sleep.31 Meta-analyses have shown a small effect of CPAP in reducing BP, but they have limitations because they included studies on individuals with normal BP and controlled hypertensives.32^-34 Most randomized studies35^-38 on patients with OSAHS and RAH have shown more significant reductions in BP than those of patients with non-resistant AH. Body weight loss in combination with CPAP has resulted in greater BP reduction than each isolated intervention in obese individuals with OSAHS.39 Mandibular advancement with mobile orthodontic devices for mild to moderate OSAHS can also reduce BP,34 but further studies are necessary.34 Although several antihypertensive classes have been tested,40 there is no definitive conclusion about the best drug for hypertensives with OSAHS.40^,41

Primary hyperaldosteronism (PHA) is a clinical condition characterized by excessive, inappropriate and autonomous production of aldosterone42 (Aldo), caused by bilateral adrenal hyperplasia or unilateral Aldo producing adenoma (APA), and, more rarely, unilateral adrenal hyperplasia, adrenal carcinoma or genetic origin (monogenic or chimeric gene). The prevalence of PHA in hypertensives is 3-22%, being higher in stage 3 and/or resistant hypertensives.43

Primary hyperaldosteronism is suspected when AH is associated with: spontaneous or DIU-induced hypokalemia; adrenal incidentaloma; RAH; family history of AH or CbVD before the age of 40 years; and MS. The prevalence of hypokalemia in PHA is 9-37%.43

Figure 2 shows the flowchart for screening, diagnostic confirmation and treatment of PHA.

Figure 2

Laboratory tests do not require suspension of antihypertensive agents, except for spironolactone for 4-6 weeks.43 Suppressed plasma renin activity (PRA) and Aldo > 15 ng/dL, with an Aldo/PRA ratio > 30, indicate the diagnosis of PHA. Confirmatory testing is recommended when Aldo > 15 ng/dL and < 25 ng/dL, with an Aldo/PRA ratio > 30 and < 100. The furosemide and captopril tests have higher diagnostic accuracy than the saline infusion test.44 In the furosemide upright test, the patient should remain lying down for at least 30 minutes, then receive 40 mg of furosemide (IV), and renin should be measured after 2 hours of walking. The test is positive if PRA < 2 ng/mL/h. In the captopril challenge test, 50 mg of captopril are administered orally after the patient remained seated or in the upright position for at least 1 hour. Renin and Aldo should be measured at the times 0, 60 and 120 minutes. The test is positive if there is no drop > 30% in plasma Aldo or if it remains > 12 ng/dL. In the saline infusion test, 2 liters of 0.9% saline are administered (IV) in 4 hours. The Aldo measurement will be ≥ 5 ng/dL.

For APA or hyperplasia to be detected, thin-sliced CT or MRI of the adrenal glands is indicated.43 Catheterization of the adrenal veins is indicated when, on CT, the adrenal glands are normal, have bilateral abnormalities (thickening or micronodules) or a unilateral lesion in patients > 40 years.44 The dexamethasone suppression test is indicated to investigate PHA suppressible with glucocorticoid in patients with PHA and AH beginning before the age of 40 years.44

Laparoscopic surgery is indicated in APA,43 preferably with previous treatment with spironolactone up to 3-4 weeks.45 Clinical treatment of hyperplasia requires spironolactone, 50-300 mg/day, if well tolerated.45 Cure of AH with surgery is observed in 35-60% of the patients.42^,45

Pheochromocytomas (PHEO) are tumors of chromaffin cells of the sympathetic adrenomedullary axis that produce catecholamines.46 Of PHEOs, 10% to 15% are extraadrenal (paragangliomas), 10% are bilateral, and 10% are malignant.47 Familial forms have the dominant autosomal trait or are part of syndromes with known gene mutations.47

Presence of persistent or paroxysmal AH (50%), paroxysmal headache, excessive sweating and palpitations (classic triad)46 is indicative of the disease, and concomitance of the classic triad with HC has sensitivity of 89% and specificity of 67% for the PHEO diagnosis.46

Laboratory diagnosis is based on the measurement of catecholamines and their metabolites in blood and urine. Free plasma metanephrine has the highest sensitivity and specificity,48 but because of its higher cost, urine metanephrine isolated or associated with plasma catecholamines is indicated in cases of high likelihood.48 The measurement of urine vanillylmandelic acid has good specificity, but the lowest sensitivity of all methods, being indicated only when the other tests are not available.48 If the diagnosis is not certain, clonidine suppression test is indicated in hypertensives, and glucagon stimulation test, in individuals with normal BP levels.47

The imaging tests to locate adrenal tumors are CT and MRI, with sensitivity of 89% and 98%, respectively.49 The MRI is superior to identify paragangliomas. MIBG whole body scan is useful in extraadrenal, bilateral PHEOs, and metastases and relapses.50 Octreoscan, bone scan and positron-emission CT can be indicated when the localizing exams cited are negative or when investigating malignancy.51

The preferential treatment is surgery, whose preoperative preparation should include alpha1-blockers (doxazosin or prazosin) and appropriate hydration for at least 2 weeks before surgery.52 The chronic pharmacological treatment includes alpha1-blockers, BBs (only after beginning alpha1-blockers, in the presence of symptomatic tachycardia), CCBs, ACEIs and central action agonists.52 The paroxysmal HC of PHEO is a HE, and should be treated with SNP or injectable phentolamine and volume replacement, if necessary.46

Total and early removal of the neoplasm usually determines total remission of symptoms and cure of AH.47^,49 For malignant PHEOs with unresectable metastases, the following are indicated: chemotherapy, embolization, radiotherapy, and, if possible, ablation with MIBG-131.47 Clinical, biochemical and radiological follow-up of the patients is essential to detect recurrences or metastases, in the malignant form, and other tumor in familial syndromes.

Chart 4 shows the medicines and licit and illicit drugs related to AH development or worsening.