Efferent Fibers ( Figure 22-1 )

Signals from the central nervous system (amygdala, ventrolateral nucleus of the hypothalamus, cortex, pons) and chemo- and baroreceptors are integrated in the medulla oblongata (solitary tract nucleus and rostral ventral medulla oblongata) from where sympathetic nerve fibers course within the spinal cord to the intermediolateral nucleus (Th10-L2). In the intermediolateral nucleus, signals are relayed to presynaptic fibers that exit the spinal cord and terminate at postsynaptic fibers in the celiac, superior, and inferior mesenteric ganglion. Postsynaptic fibers (located predominantly within the adventitia of the renal arteries) supply the tubuloepithelial cells, granular cells of the juxtaglomerular apparatus, and arteriolar smooth muscle cells. Norepinephrine and neuropeptide Y are released ( Figure 22-2 ). Norepinephrine binds to both alpha-1b receptors and beta-receptors (located in the adluminal membrane of the tubuloepithelial cells ) causing stimulation and inhibition of the sodium/potassium ATPase, respectively, with an overall neutral effect. However, neuropeptide Y enhances the stimulatory effect of norepinephrine. The net effect is a stimulation of the sodium/potassium ATPase causing sodium and water retention and a blood pressure increase. At the granular cells of the juxtaglomerular apparatus, norepinephrine binds to beta-1 receptors, causing G-protein-coupled activation of adenyl cyclase, generating cyclic AMP that stimulates renin release ( Figure 22-3 ). Renin causes activation of the renin angiotensin system, generating angiotensin II and aldosterone and causing vasoconstriction and sodium and water retention, respectively, with subsequent blood pressure increase. Hormones of the angiotensin-aldosterone system also cause vascular remodeling and changes in cardiac architecture such as left ventricular hypertrophy and fibrosis. At arteriolar smooth muscle cells, norepinephrine binds to alpha-1a receptors and (via G-protein-coupled mechanism) activates phospholipase C, releasing inositol trisphosphate and diacylglycerol ( Figure 22-4 ). Inositol trisphosphate stimulates calcium release from the sarcoplasmic reticulum that binds to the contractile apparatus, triggering smooth muscle contraction and vasoconstriction.

Illustration of the anatomy of the efferent renal sympathetic nervous system (for description, see text). JGA, Juxtaglomerular apparatus; NTS, solitary tract nucleus; RVLM, rostroventrolateral medulla; VLN, ventrolateral nucleus of the hypothalamus.

Illustration of the efferent sympathetic fiber endings at the adluminal membrane of the tubuloepithelial cells on a cellular/molecular level (please refer to text for description). Not illustrated: the inhibitory effect of norepinephrine on the beta-receptor. ADP, Adenosine diphosphate; ATP, adenosine trisphosphate; K +, potassium; Na +, sodium; NE, norepinephrine; NY, neuropeptide Y; P, phosphate.

Illustration of the efferent sympathetic nerve fiber endings at the juxtaglomerular apparatus on a cellular/molecular level (please refer to text for description). AC, Adenylcyclase; ATP, adenosine trisphosphate; cAMP, cyclic adenosine monophosphate; G, G-protein; NE, norepinephrine.

Illustration of the efferent sympathetic nerve fiber ending at the renal arterioles on a cellular/molecular level (see text for description).

Ca ^{2 +} , Calcium; DAG, diacylglycerol; G, G-protein; IP3, inositol trisphosphate; NE, norepinephrine; PL, phospholipid; PLC, phospholipase C.

Afferent Fibers

Renal afferent nerve fiber endings are most abundant within the renal pelvis. Mechano- and chemoreceptors stimulate the renal afferent nervous system. Mechanoreceptors provide feedback on hydrostatic pressure within the renal pelvis, arteries, and veins. Chemoreceptors are a gauge for the renal interstitial milieu and are activated by mediators released during renal parenchymal ischemia. Signals are relayed from the kidney via afferent sympathetic fibers with nuclei located in the dorsal root ganglia to the ipsilateral posterior gray column (lamina I-III). The neurotransmitters are substance P– and calcitonin gene–related peptide. Signals are then further transmitted from the spinal cord to central nervous system autonomic centers (paraventricular nucleus of the hypothalamus and solitary tract nucleus in the brainstem) and to the contralateral kidney. Autonomic center stimulation, in turn, increases the overall sympathetic tone causing vasoconstriction, fluid retention, and, consequently, blood pressure increase. Stimulation of the contralateral kidney alters the sodium and water balance (renorenal reflex). The impact of renal afferent sympathetic nervous stimulation on blood pressure has been shown in animal studies that target activation or inhibition of afferent fibers. Renal injury in rats by toxin injection or ischemia results in activation of the afferent sympathetic fibers causing an increase in overall sympathetic nervous system activity and blood pressure that can be attenuated or prevented by prior dorsal rhizotomy (transection of the dorsal roots—the equivalent to interruption of the afferent sympathetic pathway). Likewise, a blood pressure reduction has been shown in renal insufficiency rat models after dorsal rhizotomy. In this model, the hypertensive response after near total nephrectomy is less pronounced if these animals have first undergone dorsal (Th10-L2) rhizotomy.

Percutaneous Renal Sympathetic Denervation

The aforementioned physiological and clinical observations underlining the importance of the renal sympathetic nervous system in blood pressure control and the convenient location of the sympathetic nerve fibers (predominantly in the renal artery adventitia and perivascular space) led to the concept and evaluation of catheter-based renal sympathetic denervation by radiofrequency application. The efficacy and safety were first assessed in pigs. Renal denervation using the Symplicity Flex Renal Denervation System (Medtronic Inc., Minneapolis, Minnesota) ( Figure 22-5 ) was accompanied by histological evidence of neuronal injury in the perivascular space of the renal artery, as well as a reduction in sympathetic axons in the renal cortex (by tyrosine hydroxylase staining) and a 90% reduction in renal norepinephrine concentration (unpublished report by Medtronic). Optical coherence tomography (OCT) examination of the renal artery after renal denervation in a pig demonstrated endothelial denudation, transmural tissue coagulation followed by tissue fibrosis, and re-endothelialization and renal nerve necrosis 10 days after ablation. Six months after ablation, histology demonstrated necrotic nerve fibers and fibrosis involving 10% to 25% of the media and adventitia without stenosis.

Image illustrating the Symplicity Flex Renal Denervation System (Medtronic Inc., St. Paul, Minn.). The generator and the Symplicity catheter are shown.

In Symplicity-1, 45 patients with severe resistant hypertension underwent radiofrequency renal sympathetic denervation. A significant 27/17 mm Hg 1-year office blood pressure reduction was observed. An increase in antihypertensive therapy occurred in four patients; however, a significant and pronounced blood pressure reduction remained after excluding these patients from analysis. In addition, blood pressure medications were reduced in nine patients due to improved blood pressure control. Thirteen percent of patients were considered nonresponders (defined as systolic blood pressure reduction of <10 mm Hg). Ambulatory blood pressure reductions were less pronounced (11 mm Hg systolic) than office blood pressures, a common theme in all subsequent studies examining renal denervation.

Renal and total body norepinephrine spillover decreased after renal denervation (n = 10), supporting the notion that renal denervation reduces renal and overall sympathetic nervous system activity. A reduction in overall sympathetic tone assessed by muscle sympathetic nerve activity has been demonstrated in one patient from Symplicity HTN-1 and subsequently in a separate study. One guide catheter–induced renal artery dissection requiring stenting and one femoral artery pseudoaneurysm were reported.

In a registry including Symplicity HTN-1 patients and others, office blood pressure reductions were durable, 33/14 mm Hg at 24 months and 32/14 mm Hg at 36 months (n = 87), regardless of age, diabetic status, or baseline renal function. Furthermore, the responder rate increased over time from 70% at 1 month to 93% at 36 months. One de novo renal artery stenosis possibly related to renal denervation requiring stenting, one renal artery stenosis at a site remote from the treatment site (with some degree of preexistent stenosis) requiring stenting, and two hemodynamically insignificant mild renal artery stenoses were reported throughout the 36-month follow-up.

In Symplicity HTN-2 (n = 106), patients with severe resistant hypertension were randomized to renal sympathetic denervation (in addition to conventional medical therapy) or conventional medical therapy alone. There was a significant 32/12 mm Hg office blood pressure reduction in the denervation group versus none in the control group at 6 months with a responder rate of 84% (vs. 35% in the control group). The ambulatory pressure (11/7 mm Hg) was, once again, less pronounced than the office blood pressure reduction after renal denervation; however, it remained significant (vs. no change in the control group). There were no major adverse events. No changes in renal function or urine albumin to creatinine ratios were seen in either group. Forty-six patients from the control group crossed over to renal denervation and experienced a significant 24/8 mm Hg blood pressure reduction 6 months after cross-over. In addition, a lasting 33/14 mm Hg reduction in office blood pressure has been demonstrated in those 40 patients of the initial group who underwent 36-month follow-up.

Renal denervation has more recently been studied in a small number (n = 20) of patients with milder forms of resistant hypertension (systolic office blood pressure 140 to 160 mm Hg) with significant 13/5 mm Hg office and 11/4 mm Hg ambulatory blood pressure reductions at 6 months. Similar findings were reported subsequently in 54 patients with mild resistant hypertension with 13/7 mm Hg and 14/7 mm Hg office and ambulatory blood pressure reductions at 6 months. Therefore, it appears that hypertension severity predicts the magnitude of response.

Limitations

All limitations that accompany unblinded studies without a control group including selection and observer bias, placebo effect, and Hawthorne effect apply to Symplicity HTN-1, and the same limitations, with the exception of selection bias, apply to Symplicity HTN-2. In addition, given inclusion of patients into the study based on systolic office blood pressure and comparison of follow-up blood pressure with the blood pressure used for inclusion, regression to the mean may lead to overestimation of the treatment effect. Though it does not eliminate regression to the mean, comparison of ambulatory blood pressures before and after treatment attenuates (but does not completely eliminate) the consequences of this statistical phenomenon. It is, therefore, not surprising that ambulatory blood pressure effects are invariably lower than office blood pressure effects unless measures are taken to prevent regression to the mean.

Any injury to the renal artery as it occurs with radiofrequency or ultrasound energy application may, in addition to the intraprocedural risk of renal artery dissection or thrombus formation with or without embolization, lead to renal artery stenosis. In this context, pulmonary vein stenosis has been reported after radiofrequency application for the purpose of pulmonary vein isolation in patients with atrial fibrillation. However, the radiofrequency energy used for renal denervation (e.g., 8 W with the Symplicity Renal Denervation System) is lower than for pulmonary vein isolation (up to 30 W). In studies with imaging follow-up, renal artery stenosis has been a rare event. For example, at the 36-month follow-up of Symplicity HTN-1 and registry patients, only one of 153 patients was found to have a renal artery stenosis potentially related to renal denervation requiring stenting. Nevertheless, renal artery stenoses have been reported not only with radiofrequency but also with ultrasound energy application. It is noteworthy that imaging follow-up in many studies is limited and the exact incidence of renal artery stenoses at long-term follow-up remains to be determined.

Renal denervation has not led to meaningful blood pressure responses in approximately 15% of patients, for unclear reasons. Possibilities include incomplete denervation due to technical limitations, procedural shortcomings, or the presence of hypertension not driven by sympathetic overactivity. In this context, it would be desirable to measure renal and/or overall sympathetic nerve activity routinely prior to, during, and after renal denervation; however, this is cumbersome and not without risks (norepinephrine spillover measurements require invasive measurements). Moreover, it is also not clear whether such measurements would help predict clinical success. Discrepant regional sympathetic activity may further complicate matters. For example in some hypertensive patients, renal norepinephrine spillover is normal whereas muscle sympathetic nerve activity is increased. To date, the only known independent predictors of response are baseline blood pressure (more pronounced response in patients with higher baseline blood pressures ) and baseline baroreceptor sensitivity (more pronounced blood pressure reduction the lower the baseline baroreceptor activity). In an effort to establish methods to gauge sympathetic nerve activity during denervation, Chinushi et al. have studied blood pressure, heart rate, heart rate variability, and plasma catecholamines during transcatheter electrical nerve stimulation in dogs. Autonomic nerve stimulation of the nondenervated renal artery was accompanied by a pronounced increase in heart rate, blood pressure, and catecholamine levels, whereas these parameters increased only minimally after stimulation of the denervated artery. Similar techniques and methods, provided they can safely be performed, may have merit by providing feedback regarding procedural and, perhaps, clinical success.

The possibility of renal sympathetic re-innervation has been raised as it occurs in some animal models. Moreover, sympathetic cardiac re-innervation has been described in humans after heart transplantation. In this context, histologic examination of transplanted kidneys suggests re-innervation ; however, it does not appear to be of functional relevance. The durability of blood pressure reductions in HTN-1 and -2 (described above) does not suggest relevant sympathetic re-innervation, at least up to 36 months.

Symplicity HTN-3

The above-mentioned potential shortcomings of Symplicity 1 and 2 and of a number of other uncontrolled studies demonstrating a blood pressure reduction have led to the performance of the Symplicity HTN-3. In this trial, maximum efforts were made to minimize the possibility that a blood pressure difference between the treatment and control group might be driven by placebo and Hawthorne effect by randomly assigning patients with resistant hypertension to renal denervation or a sham procedure (renal angiography without denervation) in a 2:1 fashion with blinding of investigators and patients at follow-up. The design also eliminated a potential operator and patient bias. A total of 535 patients were enrolled. Renal denervation with the Symplicity Flex Renal Denervation System (Medtronic Inc.) was performed in those assigned to renal denervation (in 364 patients) and renal artery angiography in the control group. Endpoints were safety (composite of death from any cause, end-stage renal disease, embolic event resulting in end-organ damage, vascular complications, hypertensive crisis within 30 days, or renal artery stenosis within 6 months) and efficacy (change in systolic office blood pressure at 6 months with a superiority margin of 5 mm Hg). The study demonstrated an excellent safety profile. There was no significant difference in the composite safety endpoint at 6 months (4% in the renal denervation group vs. 5.8% in the sham group). There was also no significant difference in the number of major adverse events (1.4% in the denervation group vs. 0.6% in the sham group). However, although the systolic office blood pressure decreased in both groups (by 14 mm Hg in the denervation group vs. 11.7 in the sham group), there was no significant difference between the groups (2.39 mm Hg). Likewise, there was no significant difference in ambulatory blood pressure reduction between the groups (reduction of 6.8 mm Hg in the denervation group vs. 4.8 mm Hg in the sham group). The reason for the discrepant findings between the first two Symplicity trials and a number of other studies demonstrating a favorable blood pressure response and Symplicity HTN-3 remains unclear. It is possible that effects of previous trials were artificial and driven by above described limitations, particularly regression to the mean, also referred to as “big day bias” (by which the blood pressure that was used to enter the trial was also used as the baseline), placebo/Hawthorne effect, and observer bias. However, several aspects deserve consideration.

First, there is sound physiological evidence supporting a reduction in renal and overall sympathetic nervous system activity after renal denervation both from animal and human experience, described in detail previously. This suggests the possibility of technical limitations in the trial. It is, for example, conceivable that the procedural technique did not lead to the desired interruption of the renal sympathetic nervous fibers. In this context, it has been pointed out that the mean number of ablations (3.9 per artery) was smaller than is common practice. However, the number of ablations was no different in Symplicity HTN-1 (4 per artery) and it has yet to be shown that the number of ablations corresponds to efficacy. Furthermore, operator experience was limited as reflected by the number of procedures per operator. Only one denervation was performed by 31% of operators and all procedures (364) were performed by 111 operators (average number of procedures: 3.3). It is, therefore, possible that limited experience may have affected the efficacy. Yet there was no difference in efficacy between those operators who performed ≥5 and those who performed <5 procedures. Further, there was no difference in efficacy when results after first were compared with later denervations.

Second, patient selection may have influenced the results. It is possible that patient characteristics differed between patients enrolled in Symplicity HTN-3 and prior studies. To this effect, subgroup analyses have been performed and demonstrated a more pronounced office blood pressure reduction with a significant difference compared with the sham group in patients who were not of African-American descent, patients younger than 65 years, and those with a GFR ≥60 mL/min/173 m ² . In this context, in the population in which renal denervation was studied and taking a smaller treatment effect than predicted into account, Symplicity HTN-3 may have been underpowered to demonstrate a significant difference in blood pressure reductions between the treatment and control groups. It should be noted, however, that the ambulatory blood pressure monitoring did not confirm a significant effect in the above subgroups.

Until further data are available, aforementioned aspects remain speculations.

Case Selection

For the first few cases, for those who do not have prior experience with renal artery intervention, definition of the anatomy may be helpful for appropriate case selection. It may be prudent to select cases with no or only mild abdominal aortic tortuosity and/or atherosclerosis. Prior computed tomographic (CT) or magnetic resonance angiography (MRA) outline the abdominal aortic anatomy and illustrate potential challenges due to tortuosity or pronounced atherosclerosis. Some imaging software programs may allow determination of the optimal fluoroscopy angle to visualize the ostium and takeoff of the renal artery. Of note, MRA using gadolinium is contraindicated in patients with a glomerular filtration rate of <30 mL/min. However, the use of special imaging techniques may allow adequate visualization of the aorta and renal arteries without the use of contrast. Nevertheless, noninvasive imaging does not replace an abdominal aortography, as all current methods, Duplex ultrasound, and CT or MRI may not adequately identify accessory renal arteries. Hence, generally, abdominal aortography should be part of most renal denervation procedures.

Patient Selection

Patient selection can be performed with a simple algorithm ( Figure 22-6 ). The first question that must be answered is: Does the patient have severe resistant hypertension? In pivotal trials, severe resistant hypertension was defined as a blood pressure of ≥160 mm Hg (or ≥150 mm Hg in the presence of diabetes mellitus). Milder forms of resistant hypertension appear to benefit from renal denervation but the magnitude of blood pressure reduction is generally lower. Key elements of accurate office blood pressure measurement have been well described in the attached reference. If it is measured accurately and the patient meets these criteria, the next step is to rule out white coat hypertension (normal blood pressures except when the patient is in a medical environment). This can be done with ambulatory blood pressure measurement or, if unavailable, by periodic home blood pressure measurements, provided the patient’s device is well calibrated. To eliminate the possibility of medical noncompliance, one might consider administration of all antihypertensive medications under the physician’s or nurse’s supervision prior to ambulatory blood pressure device hook-up to assure at least compliance with morning medications. If there are serious doubts, one could ask the patient to return for supervised evening medication administration (though this may pose logistical challenges) while the patient is wearing the monitor. Other techniques to enhance surveillance of medical compliance may be pill counts or measurement of antihypertensive medication blood levels but this has proven unreliable or costly in our experience. The next question is: Are there medications or illicit drugs that may cause a blood pressure increase, and, if so, can these be replaced by alternative medications? Table 22-1 provides a list of the more common medications and illicit drugs that one needs to consider. When it is determined by ambulatory blood pressure measurement that the patient indeed has resistant hypertension, and after all medications or illicit drugs that may cause a high blood pressure are eliminated, the next step is an assessment for secondary hypertension. A list of the most common causes is outlined in Table 22-2 . Many can be eliminated by history, physical exam (including measurement of blood pressure in both upper and lower extremities to rule out aortic coarctation and subclavian artery stenosis), and standard laboratory tests that would be recommended in any patient with hypertension (including serum electrolytes [calcium included], creatinine, uric acid, complete blood count, urinalysis including check for microalbuminuria, and analysis of the urinary sediment). Screening for endocrine causes of secondary hypertension requires a set of laboratory tests that can easily be performed in most practices. A comprehensive discussion of endocrine hypertension is beyond the scope of this chapter, but a practical approach (and that pursued in our practice) may be the following: The patient is instructed to take 1 mg of dexamethasone orally at 11 pm and to come to the office the following morning when plasma renin, aldosterone, cortisol, and thyroid-stimulating hormone (TSH) levels are measured (at 8 am ). In addition, 24-hour collection for urinary catecholamines and metanephrines is started. If urinary metanephrines pose a logistical challenge, alternatively, plasma metanephrines can be measured, recognizing a higher rate of false positive results than with urinary metanephrines. The upper limit of normal for renin/aldosterone ratio is 20 to 30 and the aldosterone level is typically above >15 ng/dL with an undetectable renin concentration in primary hyperaldosteronism. The above ratio takes into account that plasma renin activity is measured in ng/mL/hr and plasma aldosterone concentration in measured in ng/dL. However, the upper normal ratio may vary if other units or assays are used as outlined in the attached reference. In healthy individuals, the 8 am cortisol level should be less than 1.8 mcg/dL. This cutoff provides a sensitivity of >95% and a specificity of 80%. The urinary catecholamines should be less than twice the upper limit of normal. In the presence of a pheochromocytoma, typically the urinary metanephrine levels are significantly elevated (several-fold higher than the upper reference limit). There are a few important aspects when considering endocrine secondary hypertension:

• 1.
  

  Hyperaldosteronism. The estimated prevalence of primary hyperaldosteronism in patients with hypertension and resistant hypertension is 5% to 12% and 23% to 26%, respectively. This estimate was lower (0.05% to 2%) when hypokalemia was considered to be an essential component of hyperaldosteronism. It is now recognized that most patients with primary hyperaldosteronism are, in fact, normokalemic. Nevertheless, lab clues may include hypokalemia and a slightly increased sodium concentration. Plasma renin and aldosterone levels are measured while the patient has been sitting for at least 5 minutes, in the morning, and after at least 2 hours of upright posture (standing, walking, or sitting). Postural maneuvers are not necessary. It is essential that the patient is normokalemic at the time of measurement because hypokalemia suppresses aldosterone secretion (potentially leading to false negative results) and, under optimal circumstances, liberal salt intake should be encouraged. Though a number of medications may interfere with test accuracy, for practical purposes, all antihypertensive medications may be continued with the exception of aldosterone inhibitors (spironolactone or eplerenone) and direct renin inhibitors (e.g., aliskiren). Aldosterone inhibitors should be discontinued 6 weeks prior to measurement. Further, chewing tobacco and licorice may affect test accuracy and must be discontinued before testing. It is best to keep in mind that most commonly used antihypertensive agents (including angiotensin conversion enzyme inhibitors, angiotensin receptor blockers, diuretics, and dihydropyridine calcium channel blockers) have a tendency to cause false negative results by virtue of primarily increasing the renin level. Therefore, if these agents are continued, a markedly positive test result and/or a renin level above the upper limit of detection are accompanied by a high likelihood of primary aldosteronism. Treatment with beta-blockers or central alpha-2 agonists (e.g., clonidine and methyldopa) may lower the plasma renin activity but it also lowers plasma aldosterone concentrations typically leaving the renin:aldosterone ratio unchanged; however, false positive test results have been reported (related to a more pronounced reduction in renin levels compared with aldosterone concentration). Depending on whether renin activity or concentration is measured, false positive and false negative results, respectively, have been reported. Hence with regard to the aforementioned antihypertensives, if test results are not diagnostic, discontinuation of these medications and temporary replacement with alternative antihypertensive medications that do not interfere with testing (e.g., verapamil, hydralazine, prazosin, doxazosin, terazosin) followed by test repetition can be considered. When an abnormal renin:aldosterone level is encountered, collaboration with an endocrinologist for the purpose of confirmatory tests (oral or intravenous salt loading or fludrocortisone stimulation test) will facilitate further management. When screening and confirmatory tests are positive, most would proceed with imaging (CT with protocol focusing on the adrenal gland) and adrenal vein sampling, with adrenal gland removal in case of lateralization (particularly if this corresponds with an adrenal mass). An argument can also be made to proceed with unilateral removal of the adrenal gland in young patients (<40 years) who are found to have an unequivocal adrenal mass without prior adrenal vein sampling as an incidental adrenal mass (incidentaloma) is uncommon in this age category. However, it is important to keep in mind that CT scanning alone to localize an adrenal adenoma can be misleading as misidentification is not uncommon. Adrenal vein sampling can be technically challenging but the success rate has been reported as high as 74% to 96%. The sensitivity of adrenal vein sampling for the detection of a unilateral adrenal adenoma is 95% and 100%, respectively, and superior to CT imaging. Adrenal vein sampling is important because it helps to determine whether a patient has “surgical disease” (adrenal adenoma [35%] or unilateral primary adrenal hyperplasia [2%]) with a potential cure after unilateral adrenalectomy or idiopathic hyperaldosteronism (60%) or glucocorticoid remediable hyperaldosteronism (<3%), both of which are treated medically. Adrenal aldosterone-producing carcinomas (<1%) and ectopic aldosterone-producing carcinomas (<0.1%) are so rare that they will not be discussed here.

  
  

  What if the patient has hypertension and hypokalemia and very low renin and aldosterone concentrations? Under these circumstances, conditions that mimic hyperaldosteronism but do not cause aldosterone excess should be considered. These include exogenous administration of substances such glucocorticoids or licorice ingestion, conditions that lead to an excess of substances with mineralocorticoid activity other than aldosterone (11-beta hydroxylase deficiency, deoxycorticosterone-producing tumors, glucocorticoid-producing tumors, congenital adrenal hyperplasia), or Liddle syndrome, caused by a sodium channel defect in the tubuloepithelial cells leading to sodium retention and potassium wasting.

  
  
• 2.
  

  Glucocorticoid excess. Though the most convenient screening test, especially in patients with a low clinical suspicion, is the overnight dexamethasone suppression test, alternative tests (midnight salivary cortisol [should be measured twice] and urinary free cortisol [should be measured twice]), particularly in patients with a higher degree of suspicion, are reasonable. Potential pitfalls are medications that interact with the cytochrome P450 enzyme thereby interfering with cortisol metabolism causing false positive or negative results. If feasible, these should be discontinued prior to testing. In patients with renal failure, dexamethasone suppression test should be preferred over urinary free cortisol. In patients with suspected cyclic Cushing syndrome, urinary free cortisol or midnight salivary cortisol are preferred over dexamethasone suppression test. In those without renal insufficiency, if urinary free cortisol is chosen as the screening test, high performance liquid chromatography has a better performance than immunoassays and the upper normal is 40 to 50 mcg/24 hours with a greater than four times upper limit of normal highly suggestive of Cushing syndrome. If the screening test is abnormal it is best to collaborate with an endocrinologist for confirmatory testing and determination if the underlying problem is a pituitary adenoma (68%) or ectopic ACTH syndrome (usually the consequence of small cell lung cancer [12%], adrenal adenoma [10%], or adrenal carcinoma [8%]). Other tumors (ectopic corticotropin-releasing hormone [CRH] secreting tumors or micronodular hyperplasia) are rare, <2%. Under most circumstances the next steps would be brain MRI, CRH stimulation test, ACTH level determination, and high-dose 48-hour dexamethasone suppression test.

  
  
• 3.
  

  Pheochromocytoma. Though pheochromocytomas are rare even in patients with resistant hypertension, screening in resistant hypertension is recommended, as the consequences of a missed tumor are serious and appropriate treatment may offer a potential cure. The use of plasma metanephrines for screening is more convenient than urinary collection; however, it is important to recognize that the specificity is limited with a false positive rate of 15% to 25% depending on age. Therefore, given the rarity of this tumor, the chance that an elevated plasma metanephrine result is, in fact, related to a pheochromocytoma in a patient with a low clinical suspicion is very low. Hence, urine metanephrine collection (specificity >90% ) may be a better screening test in patients with low clinical suspicion. Importantly, provided high power liquid chromatography or mass spectrometry methods are used, most medications, including antihypertensives, can be continued with the exception of tricyclic antidepressants and flexeril. Measurement during major stress (e.g., critical illness, postsurgery, during drug withdrawal) is not recommended, due to a high false positive rate. It probably does not matter whether the patient is supine or upright when the blood sample is obtained.

  
  
• 4.
  

  Hyperparathyroidism, hyperthyroidism. These conditions can easily be ruled out by including a TSH level and calcium level in the routine laboratory investigations.

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