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Hypertension and chloride transporters and clinically mimic loop diuretic iatrogenic hyperventilation, pregnancy, nicotine, salicylate and thiazide diuretic use, respectively. These diagnoses should intoxication, subarachnoid hemorrhage), hypoxemia, and be considered only after urine diuretic screening. pulmonary disease with stimulation of thoracic stretch recep- tors (pneumonia, acute respiratory distress syndrome, pulmo- nary embolism). e The most common causes of metabolic alkalosis are Acute hypocapnia leads to a rapid increase in arterial pH. associated with low urine chloride and chloride deple- However, immediate compensatory diffusion of hydrogen ions tion (vomiting, nasogastric suction, and diuretic use). from intracellular stores, and subsequent reduction in serum ¢ Metabolic alkalosis from mineralocorticoid excess pre- bicarbonate through regeneration of CO,, limits the magni- sents with hypertension, hypokalemia, euvolemia, and tude of alkalosis. The typical arterial blood gas in this setting an elevated urine chloride. demonstrates a decrease in Pco,, an increase in pH, and a e Patients with metabolic alkalosis, volume overload, and slight decrease in bicarbonate. Over 2 to 3 days, bicarbonate a low urine chloride usually have low effective arterial levels decrease further as compensatory kidney excretion of

and chloride transporters and clinically mimic loop diuretic iatrogenic hyperventilation, pregnancy, nicotine, salicylate and thiazide diuretic use, respectively. These diagnoses should intoxication, subarachnoid hemorrhage), hypoxemia, and be considered only after urine diuretic screening. pulmonary disease with stimulation of thoracic stretch recep- tors (pneumonia, acute respiratory distress syndrome, pulmo- nary embolism). e The most common causes of metabolic alkalosis are Acute hypocapnia leads to a rapid increase in arterial pH. associated with low urine chloride and chloride deple- However, immediate compensatory diffusion of hydrogen ions tion (vomiting, nasogastric suction, and diuretic use). from intracellular stores, and subsequent reduction in serum ¢ Metabolic alkalosis from mineralocorticoid excess pre- bicarbonate through regeneration of CO,, limits the magni- sents with hypertension, hypokalemia, euvolemia, and tude of alkalosis. The typical arterial blood gas in this setting an elevated urine chloride. demonstrates a decrease in Pco,, an increase in pH, and a e Patients with metabolic alkalosis, volume overload, and slight decrease in bicarbonate. Over 2 to 3 days, bicarbonate a low urine chloride usually have low effective arterial levels decrease further as compensatory kidney excretion of blood volume from cirrhosis or heart failure. bicarbonate reaches a new steady state (see Table 8). Respiratory alkalosis may cause increased cellular lactic acid production. Increases in negatively charged albumin may cause a mildly increased anion gap and decreased ionized Respiratory Acidosis calcium (from enhanced albumin binding). Finally, severe Respiratory acidosis is characterized by retention of arterial hypophosphatemia can occur due to a shift of phosphate from CO,. The most common causes are impaired arterial-alveolar extracellular to intracellular fluid. gas exchange (pneumonia, pulmonary edema, interstitial lung Clinical presentation includes underlying tachypnea and diseases), airway obstruction (COPD, status asthmaticus, neurologic findings such as lightheadedness, numbness and upper airway obstruction), disordered regulation of ventila- paresthesia, cramps, confusion, and, rarely, seizures. An tion (central or obstructive sleep apnea), or inadequate venti- important consideration is salicylate intoxication, which in lation (musculoskeletal disease, neuromuscular disorders). its early phases presents as respiratory alkalosis and an With acute respiratory acidosis, excess CO, is initially increased anion gap metabolic acidosis with mental status buffered by water, leading to formation of hydrogen ions and changes. bicarbonate. Thus, the acute arterial blood gas reveals Treatment is directed at correction of the primary disor- increased Pco,, decreased pH, and a slight increase in bicarbo- der. Treatment of salicylate intoxication includes forced diure- nate. Over 3 to 5 days, compensatory increases in renal acid sis, urine alkalization, or hemodialysis. For anxiety-induced or excretion (with bicarbonate reabsorption) reach a new steady psychogenic hyperventilation, increasing inspired Pco, by state (see Table 7). closed bag rebreathing may be effective. In rare circumstances Clinical manifestations of respiratory acidosis are com- of severe alkalemia (pH >7.55) with hemodynamic instability, plicated by frequently associated hypoxemia. Symptoms are arrhythmias, or altered mental status, strategies to reduce predominantly neurologic, including headache, anxiety, bicarbonate include acetazolamide or controlled mechanical blurred vision, and tremor. Severe acidosis can cause confu- hypoventilation. sion, somnolence, or seizures. Chronic respiratory acidosis may have milder neurologic effects such as memory loss, inattentiveness, or irritability. Cardiovascular manifesta- e Respiratory alkalosis is associated with a decrease in Pco,,

blood volume from cirrhosis or heart failure. bicarbonate reaches a new steady state (see Table 8). Respiratory alkalosis may cause increased cellular lactic acid production. Increases in negatively charged albumin may cause a mildly increased anion gap and decreased ionized Respiratory Acidosis calcium (from enhanced albumin binding). Finally, severe Respiratory acidosis is characterized by retention of arterial hypophosphatemia can occur due to a shift of phosphate from CO,. The most common causes are impaired arterial-alveolar extracellular to intracellular fluid. gas exchange (pneumonia, pulmonary edema, interstitial lung Clinical presentation includes underlying tachypnea and diseases), airway obstruction (COPD, status asthmaticus, neurologic findings such as lightheadedness, numbness and upper airway obstruction), disordered regulation of ventila- paresthesia, cramps, confusion, and, rarely, seizures. An tion (central or obstructive sleep apnea), or inadequate venti- important consideration is salicylate intoxication, which in lation (musculoskeletal disease, neuromuscular disorders). its early phases presents as respiratory alkalosis and an With acute respiratory acidosis, excess CO, is initially increased anion gap metabolic acidosis with mental status buffered by water, leading to formation of hydrogen ions and changes. bicarbonate. Thus, the acute arterial blood gas reveals Treatment is directed at correction of the primary disor- increased Pco,, decreased pH, and a slight increase in bicarbo- der. Treatment of salicylate intoxication includes forced diure- nate. Over 3 to 5 days, compensatory increases in renal acid sis, urine alkalization, or hemodialysis. For anxiety-induced or excretion (with bicarbonate reabsorption) reach a new steady psychogenic hyperventilation, increasing inspired Pco, by state (see Table 7). closed bag rebreathing may be effective. In rare circumstances Clinical manifestations of respiratory acidosis are com- of severe alkalemia (pH >7.55) with hemodynamic instability, plicated by frequently associated hypoxemia. Symptoms are arrhythmias, or altered mental status, strategies to reduce predominantly neurologic, including headache, anxiety, bicarbonate include acetazolamide or controlled mechanical blurred vision, and tremor. Severe acidosis can cause confu- hypoventilation. sion, somnolence, or seizures. Chronic respiratory acidosis may have milder neurologic effects such as memory loss, inattentiveness, or irritability. Cardiovascular manifesta- e Respiratory alkalosis is associated with a decrease in Pco,, tions include vasodilation and tachycardia that may evolve an increase in pH, and a slight decrease in bicarbonate.

blood volume from cirrhosis or heart failure. bicarbonate reaches a new steady state (see Table 8). Respiratory alkalosis may cause increased cellular lactic acid production. Increases in negatively charged albumin may cause a mildly increased anion gap and decreased ionized Respiratory Acidosis calcium (from enhanced albumin binding). Finally, severe Respiratory acidosis is characterized by retention of arterial hypophosphatemia can occur due to a shift of phosphate from CO,. The most common causes are impaired arterial-alveolar extracellular to intracellular fluid. gas exchange (pneumonia, pulmonary edema, interstitial lung Clinical presentation includes underlying tachypnea and diseases), airway obstruction (COPD, status asthmaticus, neurologic findings such as lightheadedness, numbness and upper airway obstruction), disordered regulation of ventila- paresthesia, cramps, confusion, and, rarely, seizures. An tion (central or obstructive sleep apnea), or inadequate venti- important consideration is salicylate intoxication, which in lation (musculoskeletal disease, neuromuscular disorders). its early phases presents as respiratory alkalosis and an With acute respiratory acidosis, excess CO, is initially increased anion gap metabolic acidosis with mental status buffered by water, leading to formation of hydrogen ions and changes. bicarbonate. Thus, the acute arterial blood gas reveals Treatment is directed at correction of the primary disor- increased Pco,, decreased pH, and a slight increase in bicarbo- der. Treatment of salicylate intoxication includes forced diure- nate. Over 3 to 5 days, compensatory increases in renal acid sis, urine alkalization, or hemodialysis. For anxiety-induced or excretion (with bicarbonate reabsorption) reach a new steady psychogenic hyperventilation, increasing inspired Pco, by state (see Table 7). closed bag rebreathing may be effective. In rare circumstances Clinical manifestations of respiratory acidosis are com- of severe alkalemia (pH >7.55) with hemodynamic instability, plicated by frequently associated hypoxemia. Symptoms are arrhythmias, or altered mental status, strategies to reduce predominantly neurologic, including headache, anxiety, bicarbonate include acetazolamide or controlled mechanical blurred vision, and tremor. Severe acidosis can cause confu- hypoventilation. sion, somnolence, or seizures. Chronic respiratory acidosis may have milder neurologic effects such as memory loss, inattentiveness, or irritability. Cardiovascular manifesta- e Respiratory alkalosis is associated with a decrease in Pco,, tions include vasodilation and tachycardia that may evolve an increase in pH, and a slight decrease in bicarbonate. to cardiac arrhythmias and decreased cardiac output. e Salicylate intoxication presents in its early phase as res- Treatment involves correcting the underlying mechanism piratory alkalosis and an increased anion gap metabolic if possible and may necessitate mechanical ventilation to acidosis. reduce CO, and oxygen supplementation.

to cardiac arrhythmias and decreased cardiac output. e Salicylate intoxication presents in its early phase as res- Treatment involves correcting the underlying mechanism piratory alkalosis and an increased anion gap metabolic if possible and may necessitate mechanical ventilation to acidosis. reduce CO, and oxygen supplementation. e In respiratory acidosis, arterial blood gases demonstrate Hypertension elevated Pco, (hypercapnia), decreased pH, and increased bicarbonate. Epidemiology In the United States, hypertension is second only to smoking as a risk factor for death and disability. Hypertension is also Respiratory Alkalosis one of the leading risk factors for cardiovascular death and Respiratory alkalosis is defined by a reduction in arterial Pco, disability worldwide. The prevalence of hypertension varies due to increased ventilation. The most common causes are an based on the designated cut-point, increasing from 32% to enhanced respiratory drive (sepsis, hepatic failure, anxiety, 46% when the cutoff is changed from a blood pressure (BP) 26

Hypertension 2140/90 mm Hg to 2130/80 mm Hg. Prevalence increases as Brain the population ages. Overall, persons free of hypertension at Hypertension is the most important risk factor that accounts 55 years of age still have a 90% lifetime risk for developing for 50% of transient ischemic attacks, lacunar infarction, and hypertension. Although several clinical trials revealed that other stroke subtypes. Hypertension is also associated with treatment of hypertension with medication reduces cardio- vascular neurocognitive disorder. vascular events, hypertension control to a BP <140/90 mm Hg Hypertensive emergency has serious manifestations such is achieved in only 50% of the U.S. population. as hemorrhagic stroke or subarachnoid hemorrhage from cer- ebral aneurysmal rupture. Consequences of Sustained Heart Hypertension Hypertension is a major risk factor for acute coronary syn-

2140/90 mm Hg to 2130/80 mm Hg. Prevalence increases as Brain the population ages. Overall, persons free of hypertension at Hypertension is the most important risk factor that accounts 55 years of age still have a 90% lifetime risk for developing for 50% of transient ischemic attacks, lacunar infarction, and hypertension. Although several clinical trials revealed that other stroke subtypes. Hypertension is also associated with treatment of hypertension with medication reduces cardio- vascular neurocognitive disorder. vascular events, hypertension control to a BP <140/90 mm Hg Hypertensive emergency has serious manifestations such is achieved in only 50% of the U.S. population. as hemorrhagic stroke or subarachnoid hemorrhage from cer- ebral aneurysmal rupture. Consequences of Sustained Heart Hypertension Hypertension is a major risk factor for acute coronary syn- End-Organ Injury drome, myocardial infarction, and both diastolic and systolic heart failure. Either acute (hypertensive emergency) or chronic elevation in BP may lead to end-organ damage. Kidney Injury to the renal vasculature results in arteriosclerosis and Eye atherosclerosis and, ultimately, hypertensive nephrosclerosis Chronic elevation of BP can lead to elevated arteriolar pres- and chronic kidney disease (CKD). Hypertension is a major sure, resulting in hypertensive retinopathy, which manifests as cause of CKD and end-stage kidney disease (ESKD), espe- vasoconstriction and arteriolar narrowing (arteriovenous cially in Black persons. Additionally, uncontrolled hyperten- nicking or copper wiring on funduscopic examination), sion can increase the rate of CKD progression in patients endothelial damage, and retinal hemorrhage (flame hemor- with other underlying CKD causes, such as diabetic kidney rhages) (Figure 12). Optic neuropathy may result from ischemia disease. to the nerve fiber secondary to fibrinoid necrosis of vessels, Hypertensive emergency can cause acute kidney injury manifesting as cotton wool spots or optic disc pallor. (AKI), with arteriolar proliferation (onion skinning), fibrinoid Hypertensive emergency can lead to papilledema, result- necrosis, and features of thrombotic microangiopathy. ing from leakage, ischemia, and fibrinoid necrosis of arterioles supplying the optic disc, causing optic nerve hemorrhage and Clinical Impact swelling. Loss of visual acuity and blindness can occur. Hypertension is one of the most significant but modifiable

End-Organ Injury drome, myocardial infarction, and both diastolic and systolic heart failure. Either acute (hypertensive emergency) or chronic elevation in BP may lead to end-organ damage. Kidney Injury to the renal vasculature results in arteriosclerosis and Eye atherosclerosis and, ultimately, hypertensive nephrosclerosis Chronic elevation of BP can lead to elevated arteriolar pres- and chronic kidney disease (CKD). Hypertension is a major sure, resulting in hypertensive retinopathy, which manifests as cause of CKD and end-stage kidney disease (ESKD), espe- vasoconstriction and arteriolar narrowing (arteriovenous cially in Black persons. Additionally, uncontrolled hyperten- nicking or copper wiring on funduscopic examination), sion can increase the rate of CKD progression in patients endothelial damage, and retinal hemorrhage (flame hemor- with other underlying CKD causes, such as diabetic kidney rhages) (Figure 12). Optic neuropathy may result from ischemia disease. to the nerve fiber secondary to fibrinoid necrosis of vessels, Hypertensive emergency can cause acute kidney injury manifesting as cotton wool spots or optic disc pallor. (AKI), with arteriolar proliferation (onion skinning), fibrinoid Hypertensive emergency can lead to papilledema, result- necrosis, and features of thrombotic microangiopathy. ing from leakage, ischemia, and fibrinoid necrosis of arterioles supplying the optic disc, causing optic nerve hemorrhage and Clinical Impact swelling. Loss of visual acuity and blindness can occur. Hypertension is one of the most significant but modifiable Medium to Large Blood Vessels risk factors for cardiovascular disease, stroke, ESKD, and

End-Organ Injury drome, myocardial infarction, and both diastolic and systolic heart failure. Either acute (hypertensive emergency) or chronic elevation in BP may lead to end-organ damage. Kidney Injury to the renal vasculature results in arteriosclerosis and Eye atherosclerosis and, ultimately, hypertensive nephrosclerosis Chronic elevation of BP can lead to elevated arteriolar pres- and chronic kidney disease (CKD). Hypertension is a major sure, resulting in hypertensive retinopathy, which manifests as cause of CKD and end-stage kidney disease (ESKD), espe- vasoconstriction and arteriolar narrowing (arteriovenous cially in Black persons. Additionally, uncontrolled hyperten- nicking or copper wiring on funduscopic examination), sion can increase the rate of CKD progression in patients endothelial damage, and retinal hemorrhage (flame hemor- with other underlying CKD causes, such as diabetic kidney rhages) (Figure 12). Optic neuropathy may result from ischemia disease. to the nerve fiber secondary to fibrinoid necrosis of vessels, Hypertensive emergency can cause acute kidney injury manifesting as cotton wool spots or optic disc pallor. (AKI), with arteriolar proliferation (onion skinning), fibrinoid Hypertensive emergency can lead to papilledema, result- necrosis, and features of thrombotic microangiopathy. ing from leakage, ischemia, and fibrinoid necrosis of arterioles supplying the optic disc, causing optic nerve hemorrhage and Clinical Impact swelling. Loss of visual acuity and blindness can occur. Hypertension is one of the most significant but modifiable Medium to Large Blood Vessels risk factors for cardiovascular disease, stroke, ESKD, and Long-standing hypertension can damage the vascular overall mortality. Systolic is more important than diastolic BP

End-Organ Injury drome, myocardial infarction, and both diastolic and systolic heart failure. Either acute (hypertensive emergency) or chronic elevation in BP may lead to end-organ damage. Kidney Injury to the renal vasculature results in arteriosclerosis and Eye atherosclerosis and, ultimately, hypertensive nephrosclerosis Chronic elevation of BP can lead to elevated arteriolar pres- and chronic kidney disease (CKD). Hypertension is a major sure, resulting in hypertensive retinopathy, which manifests as cause of CKD and end-stage kidney disease (ESKD), espe- vasoconstriction and arteriolar narrowing (arteriovenous cially in Black persons. Additionally, uncontrolled hyperten- nicking or copper wiring on funduscopic examination), sion can increase the rate of CKD progression in patients endothelial damage, and retinal hemorrhage (flame hemor- with other underlying CKD causes, such as diabetic kidney rhages) (Figure 12). Optic neuropathy may result from ischemia disease. to the nerve fiber secondary to fibrinoid necrosis of vessels, Hypertensive emergency can cause acute kidney injury manifesting as cotton wool spots or optic disc pallor. (AKI), with arteriolar proliferation (onion skinning), fibrinoid Hypertensive emergency can lead to papilledema, result- necrosis, and features of thrombotic microangiopathy. ing from leakage, ischemia, and fibrinoid necrosis of arterioles supplying the optic disc, causing optic nerve hemorrhage and Clinical Impact swelling. Loss of visual acuity and blindness can occur. Hypertension is one of the most significant but modifiable Medium to Large Blood Vessels risk factors for cardiovascular disease, stroke, ESKD, and Long-standing hypertension can damage the vascular overall mortality. Systolic is more important than diastolic BP endothelium and, combined with elevated cholesterol and as an independent risk factor for coronary events, heart fail-

Medium to Large Blood Vessels risk factors for cardiovascular disease, stroke, ESKD, and Long-standing hypertension can damage the vascular overall mortality. Systolic is more important than diastolic BP endothelium and, combined with elevated cholesterol and as an independent risk factor for coronary events, heart fail- especially in the presence of diabetes mellitus, lead to periph- ure, stroke, and ESKD. Data suggest that BP-related cardio- eral vascular disease, including aortic aneurysm. vascular disease, kidney disease, and risk for vascular death Hypertensive emergency may cause aortic aneurysmal are evident before development of hypertension per se; risk rupture or aortic wall dissection. increases progressively throughout ranges of BP that were previously recognized as normal and are now referred to as “elevated blood pressure.” Therefore, a large proportion of the U.S. population has BP below the traditional threshold for pharmacologic treatment but high enough to signify future risk. e Either acute (hypertensive emergency) or chronic eleva- tion of blood pressure can lead to significant injury in multiple organs, including the eyes, blood vessels, brain, heart, and kidneys.

e Either acute (hypertensive emergency) or chronic eleva- tion of blood pressure can lead to significant injury in multiple organs, including the eyes, blood vessels, brain, heart, and kidneys. Blood Pressure Measurement Proper Technique The calculated average of repeat BP measurements using FIGURE 12. Changes of arteriosclerosis characterized by arteriovenous proper technique is necessary for clinical management. nicking, defined as disappearance of a short segment of the venule where it is crossed by the arteriole (arrow) and 90-degree angle crossing of the arterioles and Smoking, caffeinated beverages, or exercise within 30 minutes venules. before measurements should be avoided. A properly calibrated 27

Hypertension and validated instrument should be employed. BP should be 60 minutes. Normal BP by ABPM includes a 24-hour average measured in both arms during the first visit, and the arm with BP <115/75 mm Hg, daytime average BP <120/80 mm Hg, and the higher value should be used to measure BP during subse- nighttime average BP <100/65 mm Hg. ABPM provides valua- quent visits. The patient should be seated, not talking, in a ble information supplementary to office BP in the evaluation chair for >3 to 5 minutes, with the back supported, feet on the of conditions, including the following: floor, legs uncrossed, and the arm bared and supported on a ¢ Suspected white coat hypertension (BP measures higher flat surface at the level of the right atrium. The cuff size should in the office) be chosen to ensure that the bladder encircles >80% of the e Suspected masked hypertension (BP measures lower in the upper arm. Using a cuff that is too small will result in an arti- office) ficially elevated reading, and using a cuff that is too large will e Suspected episodic hypertension result in an artificially lower reading. At least two measure- ments should be taken and averaged, approximately 2 minutes e Apparent treatment-resistant hypertension apart; the process should be repeated if the initial measure- e Hypotensive symptoms with antihypertensive medication ments differ by >5 mm Hg. treatment

and validated instrument should be employed. BP should be 60 minutes. Normal BP by ABPM includes a 24-hour average measured in both arms during the first visit, and the arm with BP <115/75 mm Hg, daytime average BP <120/80 mm Hg, and the higher value should be used to measure BP during subse- nighttime average BP <100/65 mm Hg. ABPM provides valua- quent visits. The patient should be seated, not talking, in a ble information supplementary to office BP in the evaluation chair for >3 to 5 minutes, with the back supported, feet on the of conditions, including the following: floor, legs uncrossed, and the arm bared and supported on a ¢ Suspected white coat hypertension (BP measures higher flat surface at the level of the right atrium. The cuff size should in the office) be chosen to ensure that the bladder encircles >80% of the e Suspected masked hypertension (BP measures lower in the upper arm. Using a cuff that is too small will result in an arti- office) ficially elevated reading, and using a cuff that is too large will e Suspected episodic hypertension result in an artificially lower reading. At least two measure- ments should be taken and averaged, approximately 2 minutes e Apparent treatment-resistant hypertension apart; the process should be repeated if the initial measure- e Hypotensive symptoms with antihypertensive medication ments differ by >5 mm Hg. treatment e Autonomic dysfunction Auscultatory Blood Pressure Monitoring ¢ Possible nondipping (<10% nocturnal decrease in BP, The sphygmomanometer bladder is placed on the bare arm which is associated with increased risk for cardiovascular over the pulsation of the brachial artery, with the edge of the events) lower cuff approximately 2 to 3 cm above the antecubital fossa. A stethoscope is placed over the brachial artery in the antecu- Home Blood Pressure Monitoring bital fossa. The cuff is inflated >30 mm Hg above the point at Home BP monitoring refers to the measurement of BP at home which the palpated brachial pulse disappears (estimated sys- by the patient, often by using an electronic BP device, and is tolic BP), then deflated at a rate of 2 mm Hg per second. an alternative for the measurement of out-of-office BP when Systolic BP is recorded at the point at which the first sound is ABPM is not available or tolerable by the patient. Observational heard (onset of the first Korotkoff sound), and diastolic BP is data show that average home systolic and diastolic BP meas- recorded at the point the sound disappears (disappearance of urements are more predictive of cardiovascular death than all Korotkoff sounds). office readings, but less predictive than ABPM average read- ings. The advantage of home BP monitoring over ABPM is that Automated Blood Pressure Monitoring home monitoring is more readily available, less expensive, and Fully automated devices using the oscillometric method may less time consuming. In addition, home BP monitoring reduce human error and may be preferred for use in clinical encourages patient adherence to lifestyle modifications and practice. These devices can take multiple readings without the antihypertensive medications. However, unlike ABPM, which presence of an observer and may provide more accurate BP provides information regarding continuous BP measurements measurements than auscultation. Proper calibration is essen- during awake, asleep, and exertion periods, home BP meas- tial for accuracy. BP measured with automated devices versus urements can only be taken during awake hours and when the the auscultatory method has been shown to be closer to awake patient is at rest. out-of-office BP levels measured with ambulatory BP moni- To ensure the most accurate BP measurements at home, toring and may have a stronger association with subclinical upper arm cuffs are preferred over newer devices that meas- cardiovascular disease. ure BP more distally, such as at the wrist, given that systolic BP The American Heart Association recommends the use of is higher and diastolic lower in distal arteries. Finger meas- a validated, automated office BP device as the preferred urements are generally not accurate. In addition, patients approach for evaluating office BP. Three separate automated should be educated on the proper measurement technique, measurements, optimally taken when the patient is unat- frequency and timing of measurements, and avoidance of tended, should be averaged to obtain the final BP reading. self-adjustment of antihypertensive medications based on home BP. BP readings and times of measurement should be Out-of-Office Blood Pressure Monitoring recorded, and a running list brought to office visits for assis- Ambulatory Blood Pressure Monitoring tance with management. The device should be brought to the Ambulatory BP monitoring (ABPM) using an electronic BP office initially and periodically to validate accuracy of read- measuring device is the gold standard for the assessment of BP ings. Hypertension is defined as home BP monitoring meas- out of the office and is a better predictor of cardiovascular urements that average 2130/80 mm Hg. outcomes, including left ventricular hypertrophy and cardiac death, compared with office-based measurements. The device Other Blood Pressure Monitoring Approaches can be worn continuously for periods of 24 hours or longer With increased access to technology and interest in telehealth, and is programmed to measure and record BP every 15 to new approaches for measurement of BP outside of the office

e Autonomic dysfunction Auscultatory Blood Pressure Monitoring ¢ Possible nondipping (<10% nocturnal decrease in BP, The sphygmomanometer bladder is placed on the bare arm which is associated with increased risk for cardiovascular over the pulsation of the brachial artery, with the edge of the events) lower cuff approximately 2 to 3 cm above the antecubital fossa. A stethoscope is placed over the brachial artery in the antecu- Home Blood Pressure Monitoring bital fossa. The cuff is inflated >30 mm Hg above the point at Home BP monitoring refers to the measurement of BP at home which the palpated brachial pulse disappears (estimated sys- by the patient, often by using an electronic BP device, and is tolic BP), then deflated at a rate of 2 mm Hg per second. an alternative for the measurement of out-of-office BP when Systolic BP is recorded at the point at which the first sound is ABPM is not available or tolerable by the patient. Observational heard (onset of the first Korotkoff sound), and diastolic BP is data show that average home systolic and diastolic BP meas- recorded at the point the sound disappears (disappearance of urements are more predictive of cardiovascular death than all Korotkoff sounds). office readings, but less predictive than ABPM average read- ings. The advantage of home BP monitoring over ABPM is that Automated Blood Pressure Monitoring home monitoring is more readily available, less expensive, and Fully automated devices using the oscillometric method may less time consuming. In addition, home BP monitoring reduce human error and may be preferred for use in clinical encourages patient adherence to lifestyle modifications and practice. These devices can take multiple readings without the antihypertensive medications. However, unlike ABPM, which presence of an observer and may provide more accurate BP provides information regarding continuous BP measurements measurements than auscultation. Proper calibration is essen- during awake, asleep, and exertion periods, home BP meas- tial for accuracy. BP measured with automated devices versus urements can only be taken during awake hours and when the the auscultatory method has been shown to be closer to awake patient is at rest. out-of-office BP levels measured with ambulatory BP moni- To ensure the most accurate BP measurements at home, toring and may have a stronger association with subclinical upper arm cuffs are preferred over newer devices that meas- cardiovascular disease. ure BP more distally, such as at the wrist, given that systolic BP The American Heart Association recommends the use of is higher and diastolic lower in distal arteries. Finger meas- a validated, automated office BP device as the preferred urements are generally not accurate. In addition, patients approach for evaluating office BP. Three separate automated should be educated on the proper measurement technique, measurements, optimally taken when the patient is unat- frequency and timing of measurements, and avoidance of tended, should be averaged to obtain the final BP reading. self-adjustment of antihypertensive medications based on home BP. BP readings and times of measurement should be Out-of-Office Blood Pressure Monitoring recorded, and a running list brought to office visits for assis- Ambulatory Blood Pressure Monitoring tance with management. The device should be brought to the Ambulatory BP monitoring (ABPM) using an electronic BP office initially and periodically to validate accuracy of read- measuring device is the gold standard for the assessment of BP ings. Hypertension is defined as home BP monitoring meas- out of the office and is a better predictor of cardiovascular urements that average 2130/80 mm Hg. outcomes, including left ventricular hypertrophy and cardiac death, compared with office-based measurements. The device Other Blood Pressure Monitoring Approaches can be worn continuously for periods of 24 hours or longer With increased access to technology and interest in telehealth, and is programmed to measure and record BP every 15 to new approaches for measurement of BP outside of the office 28

Hypertension TABLE 12. Definitions of Blood Pressure for Adults Definitions? Office-Based Readings 24-Hour Ambulatory Self-Recorded Readings | (mm Hg)? Readings (mm Hg)? (mm Hg)? | Normal <120/80 <115/75 <120/80 | Elevated Blood Pressure 120-129/<80 - - Hypertension, Stage 1 130-139/80-89 2125/75 2130/80 Hypertension, Stage 2 2140/90 2130/80 2135/85 | White Coat Hypertension >130/80 <125/75 <130/80 | Masked Hypertension <130/80 2125/75 2130/80 Based on Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, | and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71:e127-e248. [PMID: 29146535] doi:10.1016/j.jacc.2017.11.006 ’The corresponding thresholds of 24-hour ambulatory and self-recorded home blood pressure readings are provided as a guide and should be interpreted with caution, given | that they are based on European, Australian, and Asian populations, with few available data in U.S. populations.

Based on Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, | and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71:e127-e248. [PMID: 29146535] doi:10.1016/j.jacc.2017.11.006 ’The corresponding thresholds of 24-hour ambulatory and self-recorded home blood pressure readings are provided as a guide and should be interpreted with caution, given | that they are based on European, Australian, and Asian populations, with few available data in U.S. populations. include pharmacist-measured BP, BP kiosks (self-contained <130/85 mm Hg and without cardiovascular risk factors stations for measuring BP in otherwise public areas, such as should be rescreened every 3 to 5 years. Those aged supermarkets or airports), and wearable devices, which can >40 years and persons at increased risk for hypertension raise patient awareness and possibly improve adherence. (e.g., those who have BP of 130-139/85-89 mm Hg, are over- However, given the potential lack of device calibration and weight, or are Black) should be screened annually. The ACC/ validation, more studies are needed before these measures can AHA recommends that adults with an elevated BP be substituted for ABPM and home BP measurements in (120-129/<80 mm Hg) or stage 1 hypertension (130-139/ practice. 80-89 mm Hg) who are not yet on therapy have their BP repeated within 3 to 6 months. A diagnosis of hypertension (BP =130/80 mm Hg) should e Ambulatory blood pressure monitoring is a better pre- be based on an average of two or more elevated systolic and/or dictor of cardiovascular outcomes, including left ven- diastolic BP measurements obtained on two or more occa- tricular hypertrophy and cardiac death, compared with sions. Out-of-office ABPM or home BP monitoring of BP office-based blood pressure measurements. measurements is recommended to confirm hypertension. ¢ Normal blood pressure by ambulatory blood pressure Compared with a single measurement, multiple measure- measurement includes a 24-hour average blood pres- ments over time have better positive predictive values for sure <115/75 mm Hg, daytime average blood pressure hypertension diagnosis. Evidence regarding the prevalence of <120/80 mm Hg, and nighttime average BP <100/65 mm white coat hypertension supports confirming elevated BP with Hg. 24-hour ABPM or home BP monitoring before initiating

include pharmacist-measured BP, BP kiosks (self-contained <130/85 mm Hg and without cardiovascular risk factors stations for measuring BP in otherwise public areas, such as should be rescreened every 3 to 5 years. Those aged supermarkets or airports), and wearable devices, which can >40 years and persons at increased risk for hypertension raise patient awareness and possibly improve adherence. (e.g., those who have BP of 130-139/85-89 mm Hg, are over- However, given the potential lack of device calibration and weight, or are Black) should be screened annually. The ACC/ validation, more studies are needed before these measures can AHA recommends that adults with an elevated BP be substituted for ABPM and home BP measurements in (120-129/<80 mm Hg) or stage 1 hypertension (130-139/ practice. 80-89 mm Hg) who are not yet on therapy have their BP repeated within 3 to 6 months. A diagnosis of hypertension (BP =130/80 mm Hg) should e Ambulatory blood pressure monitoring is a better pre- be based on an average of two or more elevated systolic and/or dictor of cardiovascular outcomes, including left ven- diastolic BP measurements obtained on two or more occa- tricular hypertrophy and cardiac death, compared with sions. Out-of-office ABPM or home BP monitoring of BP office-based blood pressure measurements. measurements is recommended to confirm hypertension. ¢ Normal blood pressure by ambulatory blood pressure Compared with a single measurement, multiple measure- measurement includes a 24-hour average blood pres- ments over time have better positive predictive values for sure <115/75 mm Hg, daytime average blood pressure hypertension diagnosis. Evidence regarding the prevalence of <120/80 mm Hg, and nighttime average BP <100/65 mm white coat hypertension supports confirming elevated BP with Hg. 24-hour ABPM or home BP monitoring before initiating e Home blood pressure monitoring is an acceptable alter- treatment.

include pharmacist-measured BP, BP kiosks (self-contained <130/85 mm Hg and without cardiovascular risk factors stations for measuring BP in otherwise public areas, such as should be rescreened every 3 to 5 years. Those aged supermarkets or airports), and wearable devices, which can >40 years and persons at increased risk for hypertension raise patient awareness and possibly improve adherence. (e.g., those who have BP of 130-139/85-89 mm Hg, are over- However, given the potential lack of device calibration and weight, or are Black) should be screened annually. The ACC/ validation, more studies are needed before these measures can AHA recommends that adults with an elevated BP be substituted for ABPM and home BP measurements in (120-129/<80 mm Hg) or stage 1 hypertension (130-139/ practice. 80-89 mm Hg) who are not yet on therapy have their BP repeated within 3 to 6 months. A diagnosis of hypertension (BP =130/80 mm Hg) should e Ambulatory blood pressure monitoring is a better pre- be based on an average of two or more elevated systolic and/or dictor of cardiovascular outcomes, including left ven- diastolic BP measurements obtained on two or more occa- tricular hypertrophy and cardiac death, compared with sions. Out-of-office ABPM or home BP monitoring of BP office-based blood pressure measurements. measurements is recommended to confirm hypertension. ¢ Normal blood pressure by ambulatory blood pressure Compared with a single measurement, multiple measure- measurement includes a 24-hour average blood pres- ments over time have better positive predictive values for sure <115/75 mm Hg, daytime average blood pressure hypertension diagnosis. Evidence regarding the prevalence of <120/80 mm Hg, and nighttime average BP <100/65 mm white coat hypertension supports confirming elevated BP with Hg. 24-hour ABPM or home BP monitoring before initiating e Home blood pressure monitoring is an acceptable alter- treatment. native if ambulatory blood pressure monitoring is not available or tolerable by the patient. e The U.S. Preventive Services Task Force recommends screening for hypertension in adults >18 years of age to identify those at increased risk for cardiovascular dis- Definitions ease from hypertension and to begin early interventions The 2017 American College of Cardiology (ACC)/American to decrease this risk. Heart Association (AHA) BP guideline provides BP defini- e The American College of Cardiology/American Heart tions and recommendations. Hypertension is defined as BP Association guideline recommends that patients with 2130/80 mm Hg. Additional definitions of BP are listed in elevated blood pressure or stage 1 hypertension who Table 12. are not yet on therapy have repeat BP assessment in 3 to 6 months.

native if ambulatory blood pressure monitoring is not available or tolerable by the patient. e The U.S. Preventive Services Task Force recommends screening for hypertension in adults >18 years of age to identify those at increased risk for cardiovascular dis- Definitions ease from hypertension and to begin early interventions The 2017 American College of Cardiology (ACC)/American to decrease this risk. Heart Association (AHA) BP guideline provides BP defini- e The American College of Cardiology/American Heart tions and recommendations. Hypertension is defined as BP Association guideline recommends that patients with 2130/80 mm Hg. Additional definitions of BP are listed in elevated blood pressure or stage 1 hypertension who Table 12. are not yet on therapy have repeat BP assessment in 3 to 6 months. Screening and Diagnosis e A diagnosis of hypertension should be based on an average of two or more elevated systolic and/or diastolic The U.S. Preventive Services Task Force (USPSTF) recom- blood pressure measurements obtained on two or more mends screening for hypertension in adults 218 years of age occasions; obtaining measurements outside of the clini- to identify those at increased risk for cardiovascular disease cal setting for diagnostic confirmation is recommended from hypertension and to begin early interventions to before starting treatment. decrease this risk. Adults aged 18 to 39 years with a BP

Screening and Diagnosis e A diagnosis of hypertension should be based on an average of two or more elevated systolic and/or diastolic The U.S. Preventive Services Task Force (USPSTF) recom- blood pressure measurements obtained on two or more mends screening for hypertension in adults 218 years of age occasions; obtaining measurements outside of the clini- to identify those at increased risk for cardiovascular disease cal setting for diagnostic confirmation is recommended from hypertension and to begin early interventions to before starting treatment. decrease this risk. Adults aged 18 to 39 years with a BP 29

Hypertension Evaluation of the Patient with changes (to assess end-organ damage); or gross hematuria (which may suggest underlying kidney disease). Behavioral and Newly Diagnosed Hypertension psychosocial contributors to hypertension, including a seden- Initial evaluation of a patient with newly diagnosed hyperten- tary routine, illicit drug use, excessive alcohol, tobacco smok- sion includes a complete history, physical examination, and ing, and high dietary sodium intake should also be explored. screening laboratory studies to address the following: A complete list of prescription and nonprescription medi- e Establish whether a familial pattern of hypertension is cations, including complementary and alternative medica- present. tions (herbal supplements) and illicit drugs, is of utmost importance because many medications can result in reversible e Rule out secondary, potentially reversible, causes. BP elevations (Table 13). If the patient is taking any drugs that e Identify and eliminate modifiable factors that can elevate BP. may result in BP elevation, the drug should be discontinued e Assess for the presence of other cardiovascular risk factors. and BP remeasured in 1 month. e Assess for end-organ damage. Physical Examination e Identify potential barriers to lifestyle modification for Physical examination should focus on the following: lowering BP. e Measure BP accurately in both arms. History e Measure body weight and calculate BMI to ascertain car-

e Establish whether a familial pattern of hypertension is cations, including complementary and alternative medica- present. tions (herbal supplements) and illicit drugs, is of utmost importance because many medications can result in reversible e Rule out secondary, potentially reversible, causes. BP elevations (Table 13). If the patient is taking any drugs that e Identify and eliminate modifiable factors that can elevate BP. may result in BP elevation, the drug should be discontinued e Assess for the presence of other cardiovascular risk factors. and BP remeasured in 1 month. e Assess for end-organ damage. Physical Examination e Identify potential barriers to lifestyle modification for Physical examination should focus on the following: lowering BP. e Measure BP accurately in both arms. History e Measure body weight and calculate BMI to ascertain car- A complete history should be elicited to identify a personal diovascular risk.

e Establish whether a familial pattern of hypertension is cations, including complementary and alternative medica- present. tions (herbal supplements) and illicit drugs, is of utmost importance because many medications can result in reversible e Rule out secondary, potentially reversible, causes. BP elevations (Table 13). If the patient is taking any drugs that e Identify and eliminate modifiable factors that can elevate BP. may result in BP elevation, the drug should be discontinued e Assess for the presence of other cardiovascular risk factors. and BP remeasured in 1 month. e Assess for end-organ damage. Physical Examination e Identify potential barriers to lifestyle modification for Physical examination should focus on the following: lowering BP. e Measure BP accurately in both arms. History e Measure body weight and calculate BMI to ascertain car- A complete history should be elicited to identify a personal diovascular risk. history of the following: stroke or myocardial infarction, thy- e Recognize target organ damage: eye examination (retinop- roid disease, kidney disease, obstructive sleep apnea, and athy or papilledema); volume status (elevated jugular ve- additional cardiovascular risk factors. Family history should nous pressure or lower extremity edema suggesting heart be explored for a genetic pattern of hypertension and prema- failure or CKD); peripheral vascular examination (unequal ture cardiovascular disease. pulses, carotid or abdominal bruits suggesting vascular A complete review of the systems is warranted, especially disease); cardiac examination (laterally displaced point of to elicit the presence of episodic palpitations, headaches, or maximal impulse, left ventricular enlargement, or S, gallop sweating (which may suggest pheochromocytoma); visual suggestive of left ventricular hypertrophy or fibrosis).

history of the following: stroke or myocardial infarction, thy- e Recognize target organ damage: eye examination (retinop- roid disease, kidney disease, obstructive sleep apnea, and athy or papilledema); volume status (elevated jugular ve- additional cardiovascular risk factors. Family history should nous pressure or lower extremity edema suggesting heart be explored for a genetic pattern of hypertension and prema- failure or CKD); peripheral vascular examination (unequal ture cardiovascular disease. pulses, carotid or abdominal bruits suggesting vascular A complete review of the systems is warranted, especially disease); cardiac examination (laterally displaced point of to elicit the presence of episodic palpitations, headaches, or maximal impulse, left ventricular enlargement, or S, gallop sweating (which may suggest pheochromocytoma); visual suggestive of left ventricular hypertrophy or fibrosis). TABLE 13. Drugs That Can Raise Blood Pressure Drug/Drug Class Potential Mechanisms Prescription Drugs Antidepressants: monoamine oxidase inhibitors; selective serotonin Adrenergic stimulation reuptake inhibitors; serotonin-norepinephrine reuptake inhibitors Calcineurin inhibitors: cyclosporine A; tacrolimus Vasoconstriction; sympathetic excitation; sodium retention Contraceptives: estrogens; progesterones Sodium retention; increased renin-angiotensin system activity Glucocorticoids Sodium retention; weight gain Erythropoietin-stimulating agents Vasoconstriction NSAIDs Sodium retention | Sympathomimetics (methylphenidate) Adrenergic stimulation Vascular endothelial growth factor antagonists Endothelial dysfunction; vasoconstriction | Nonprescription Drugs Anabolic steroids Sodium retention Caffeine Adrenergic stimulation

Vascular endothelial growth factor antagonists Endothelial dysfunction; vasoconstriction | Nonprescription Drugs Anabolic steroids Sodium retention Caffeine Adrenergic stimulation Ethanol Adrenergic stimulation Glycyrrhizic acid (in some licorice, cough drops, chewing tobacco) Mineralocorticoid activity; sodium retention Herbal supplements: ephedra; 1,3-dimethylamine; synephrine; Sympathomimetic N-methylamine; Citrus aurantium; Caulophyllum thalictroides Illicit drugs: amphetamines; cocaine; Sympathomimetic 3,4-methylenedioxymethamphetamine (ecstasy) NSAIDs Sodium retention | Sympathomimetic nonprescription drugs: decongestants (phenylephrine, Sympathomimetic pseudoephedrine); appetite suppressants; vigilance enhancers 30

Hypertension e Identify abnormalities that suggest potential secondary presence of left ventricular hypertrophy would neces- causes from pheochromocytoma, renovascular hyperten- sitate treatment with antihypertensive medication, even sion, hyperthyroidism, or Cushing syndrome. in the absence of elevated home BP. Echocardiography should also be done to confirm left ventricular hypertro- Testing phy suggested by ECG or abnormal cardiac examination. Initial testing is performed to identify common secondary More extensive diagnostic testing can be pursued if the causes, assess for other cardiovascular risk factors, and detect history, physical examination, or initial testing raises suspicion end-organ damage. for secondary causes (Table 14). e Baseline ECG to assess for left ventricular hypertro- phy (end-organ damage) or previous silent myocardial ¢ Initial evaluation of patients with newly diagnosed infarction. hypertension includes a complete history, physical e Blood laboratory studies: complete blood count, serum cre- examination, and screening laboratory studies to assess atinine, estimated glomerular filtration rate (eGFR), serum for a familial pattern, secondary causes, other cardio- sodium, potassium, calcium, bicarbonate, fasting glucose, vascular risk factors, end-organ damage, and modifiable lipid panel, thyroid-stimulating hormone. lifestyle factors. ® Urinalysis with microscopic examination; in addition, e Baseline ECG is appropriate for all patients with newly urine albumin-creatinine ratio in patients with diabetes diagnosed hypertension. and in those with a high clinical suspicion for underlying e Baseline echocardiography is not routinely recommended, HVC CKD, such as a positive family history or presence of other but should be done if examination or ECG suggest cardiac end-organ damage (left ventricular hypertrophy on ECG). hypertrophy or to evaluate the need for therapy in patients e Echocardiography is not routinely recommended but may with white coat hypertension. be helpful in suspected white coat hypertension in which

e Identify abnormalities that suggest potential secondary presence of left ventricular hypertrophy would neces- causes from pheochromocytoma, renovascular hyperten- sitate treatment with antihypertensive medication, even sion, hyperthyroidism, or Cushing syndrome. in the absence of elevated home BP. Echocardiography should also be done to confirm left ventricular hypertro- Testing phy suggested by ECG or abnormal cardiac examination. Initial testing is performed to identify common secondary More extensive diagnostic testing can be pursued if the causes, assess for other cardiovascular risk factors, and detect history, physical examination, or initial testing raises suspicion end-organ damage. for secondary causes (Table 14). e Baseline ECG to assess for left ventricular hypertro- phy (end-organ damage) or previous silent myocardial ¢ Initial evaluation of patients with newly diagnosed infarction. hypertension includes a complete history, physical e Blood laboratory studies: complete blood count, serum cre- examination, and screening laboratory studies to assess atinine, estimated glomerular filtration rate (eGFR), serum for a familial pattern, secondary causes, other cardio- sodium, potassium, calcium, bicarbonate, fasting glucose, vascular risk factors, end-organ damage, and modifiable lipid panel, thyroid-stimulating hormone. lifestyle factors. ® Urinalysis with microscopic examination; in addition, e Baseline ECG is appropriate for all patients with newly urine albumin-creatinine ratio in patients with diabetes diagnosed hypertension. and in those with a high clinical suspicion for underlying e Baseline echocardiography is not routinely recommended, HVC CKD, such as a positive family history or presence of other but should be done if examination or ECG suggest cardiac end-organ damage (left ventricular hypertrophy on ECG). hypertrophy or to evaluate the need for therapy in patients e Echocardiography is not routinely recommended but may with white coat hypertension. be helpful in suspected white coat hypertension in which TABLE 14. Secondary Causes of Hypertension and Diagnostic Testing

e Identify abnormalities that suggest potential secondary presence of left ventricular hypertrophy would neces- causes from pheochromocytoma, renovascular hyperten- sitate treatment with antihypertensive medication, even sion, hyperthyroidism, or Cushing syndrome. in the absence of elevated home BP. Echocardiography should also be done to confirm left ventricular hypertro- Testing phy suggested by ECG or abnormal cardiac examination. Initial testing is performed to identify common secondary More extensive diagnostic testing can be pursued if the causes, assess for other cardiovascular risk factors, and detect history, physical examination, or initial testing raises suspicion end-organ damage. for secondary causes (Table 14). e Baseline ECG to assess for left ventricular hypertro- phy (end-organ damage) or previous silent myocardial ¢ Initial evaluation of patients with newly diagnosed infarction. hypertension includes a complete history, physical e Blood laboratory studies: complete blood count, serum cre- examination, and screening laboratory studies to assess atinine, estimated glomerular filtration rate (eGFR), serum for a familial pattern, secondary causes, other cardio- sodium, potassium, calcium, bicarbonate, fasting glucose, vascular risk factors, end-organ damage, and modifiable lipid panel, thyroid-stimulating hormone. lifestyle factors. ® Urinalysis with microscopic examination; in addition, e Baseline ECG is appropriate for all patients with newly urine albumin-creatinine ratio in patients with diabetes diagnosed hypertension. and in those with a high clinical suspicion for underlying e Baseline echocardiography is not routinely recommended, HVC CKD, such as a positive family history or presence of other but should be done if examination or ECG suggest cardiac end-organ damage (left ventricular hypertrophy on ECG). hypertrophy or to evaluate the need for therapy in patients e Echocardiography is not routinely recommended but may with white coat hypertension. be helpful in suspected white coat hypertension in which TABLE 14. Secondary Causes of Hypertension and Diagnostic Testing | Underlying Cause Diagnostic Testing

e Identify abnormalities that suggest potential secondary presence of left ventricular hypertrophy would neces- causes from pheochromocytoma, renovascular hyperten- sitate treatment with antihypertensive medication, even sion, hyperthyroidism, or Cushing syndrome. in the absence of elevated home BP. Echocardiography should also be done to confirm left ventricular hypertro- Testing phy suggested by ECG or abnormal cardiac examination. Initial testing is performed to identify common secondary More extensive diagnostic testing can be pursued if the causes, assess for other cardiovascular risk factors, and detect history, physical examination, or initial testing raises suspicion end-organ damage. for secondary causes (Table 14). e Baseline ECG to assess for left ventricular hypertro- phy (end-organ damage) or previous silent myocardial ¢ Initial evaluation of patients with newly diagnosed infarction. hypertension includes a complete history, physical e Blood laboratory studies: complete blood count, serum cre- examination, and screening laboratory studies to assess atinine, estimated glomerular filtration rate (eGFR), serum for a familial pattern, secondary causes, other cardio- sodium, potassium, calcium, bicarbonate, fasting glucose, vascular risk factors, end-organ damage, and modifiable lipid panel, thyroid-stimulating hormone. lifestyle factors. ® Urinalysis with microscopic examination; in addition, e Baseline ECG is appropriate for all patients with newly urine albumin-creatinine ratio in patients with diabetes diagnosed hypertension. and in those with a high clinical suspicion for underlying e Baseline echocardiography is not routinely recommended, HVC CKD, such as a positive family history or presence of other but should be done if examination or ECG suggest cardiac end-organ damage (left ventricular hypertrophy on ECG). hypertrophy or to evaluate the need for therapy in patients e Echocardiography is not routinely recommended but may with white coat hypertension. be helpful in suspected white coat hypertension in which TABLE 14. Secondary Causes of Hypertension and Diagnostic Testing | Underlying Cause Diagnostic Testing Kidney disease Serum creatinine; estimated glomerular filtration rate; urinalysis with microscopic examination; urine albumin-creatinine ratio; kidney ultrasonography

Kidney disease Serum creatinine; estimated glomerular filtration rate; urinalysis with microscopic examination; urine albumin-creatinine ratio; kidney ultrasonography Renovascular disease Renal duplex Doppler ultrasonography; CT or MR angiography; renal artery angiography Obstructive sleep apnea Polysomnography | Pheochromocytoma Plasma fractionated metanephrines; 24-hour urine metanephrines and catecholamines Hypo- or hyperthyroidism Thyroid-stimulating hormone; free thyroxine Primary hyperparathyroidism Intact parathyroid hormone; serum calcium and phosphorus Gordon syndrome (pseudohypoaldosteronism type I!) Clinical diagnosis; family history; aldosterone and renin levels; electrolytes Aortic coarctation Blood pressure measurements in arms and legs; CT or MR angiography; transthoracic echocardiography Conditions Associated with Hypokalemia Diagnostic Testing High aldosterone conditions: Serum sodium and potassium concentrations; plasma aldosterone concentration/plasma renin activity ratio; saline suppression test; Primary hyperaldosteronism: adrenal adenoma (rarely CT imaging; adrenal vein sampling; genetic testing carcinoma or ectopic); bilateral adrenal hyperplasia Familial hyperaldosteronism type | (glucocorticoid-remediable aldosteronism; >50% normokalemic), type Il, or type Ill Secondary hyperaldosteronism: renal artery stenosis; renin- secreting tumor

High aldosterone conditions: Serum sodium and potassium concentrations; plasma aldosterone concentration/plasma renin activity ratio; saline suppression test; Primary hyperaldosteronism: adrenal adenoma (rarely CT imaging; adrenal vein sampling; genetic testing carcinoma or ectopic); bilateral adrenal hyperplasia Familial hyperaldosteronism type | (glucocorticoid-remediable aldosteronism; >50% normokalemic), type Il, or type Ill Secondary hyperaldosteronism: renal artery stenosis; renin- secreting tumor Cushing syndrome Dexamethasone suppression test; 24-hour urine cortisol excretion; salivary cortisol Congenital adrenal hyperplasia Clinical diagnosis Apparent mineralocorticoid excess Clinical diagnosis; aldosterone and renin levels; electrolytes Liddle syndrome Clinical diagnosis; family history; aldosterone and renin levels; electrolytes 31

Hypertension normotensive clinic populations. A 3-month trial of lifestyle modifications should be considered in suspected cases. ¢ Resistant hypertension is defined as BP that remains Antihypertensive treatment should be initiated if daytime above goal despite the concurrent use of three antihy- ABPM or home BP is still >130/80 mm Hg. pertensive agents of different classes, or BP at goal but requiring four or more medications; one of the medica- tions must be a diuretic. e Masked hypertension is associated with an increased risk for sustained hypertension and cardiovascular e Management of resistant hypertension includes con- disease; after a 3-month trial of lifestyle modifica- firming accurate out-of-office BP measurement, tions, antihypertensive medication should be initiated addressing behaviors that contribute to high BP, avoid- if daytime ambulatory or home blood pressure is still ing drugs that exacerbate hypertension, reducing die- 2130/80 mm Hg. tary sodium, and ensuring appropriate diuretic dose and frequency. Resistant Hypertension Resistant hypertension is defined as BP that remains above Secondary Hypertension goal despite concurrent use of three antihypertensive agents of In about 10% of adults with hypertension, a specific and reme- different classes, or BP at goal but requiring four or more diable cause can be identified. Diagnostic testing for secondary medications. One of these medications must be a diuretic. A causes of hypertension can be pursued if'a high clinical suspi- prevalence of 2% to 10% is reported in the general population cion exists following history, physical examination, and initial

Resistant Hypertension Resistant hypertension is defined as BP that remains above Secondary Hypertension goal despite concurrent use of three antihypertensive agents of In about 10% of adults with hypertension, a specific and reme- different classes, or BP at goal but requiring four or more diable cause can be identified. Diagnostic testing for secondary medications. One of these medications must be a diuretic. A causes of hypertension can be pursued if'a high clinical suspi- prevalence of 2% to 10% is reported in the general population cion exists following history, physical examination, and initial but can be as high as 40% in patients with CKD. Other risk laboratory testing (see Table 14). Factors that raise pretest factors include older age, male sex, Black race, diabetes, and probability for secondary hypertension include hypertension higher BMI. onset at <30 years of age; abrupt-onset or worsening BP if Before the diagnosis is made, a systematic approach previously well controlled; drug resistance; clinical features to BP control should include ensuring accuracy of BP indicating a secondary process; presence of target organ dam- readings, confirming adherence to antihypertensive age disproportionate to hypertension duration or severity; medications, optimizing medication selection and dos- diastolic hypertension onset in those >65 years of age; and ing, and addressing potential secondary and reversible unprovoked or excessive hypokalemia. causes of hypertension. The importance of out-of-office BP measurements (home or ABPM) as a part of evaluation Kidney Disease to rule out white coat hypertension and to confirm resist- Pathophysiology and Epidemiology ance is increasingly recognized. Behaviors that could lead Hypertension develops in the setting of both AKI and CKD. to high BP, including excessive sodium consumption, Underlying parenchymal kidney disease is an important cause should be reviewed, and use of recreational drugs and of hypertension, and up to 85% of patients with CKD have high prescription or nonprescription medications (such as BP. Hypertension prevalence increases with GFR decline. complementary and alternative medications) that may Additionally, chronic uncontrolled hypertension is a leading exacerbate hypertension should be excluded. Adherence cause of CKD and progression to ESKD. BP elevation in glo- to antihypertensive medications, including correct fre- merular disease is primarily attributed to fluid overload, as quency and dosage, should be confirmed, and potential evidenced by suppression of the RAS and increased release of reasons for nonadherence, such as medication side atrial natriuretic peptide. In acute vascular diseases affecting effects, should be addressed. the kidney (vasculitis or scleroderma renal crisis), elevated BP The cornerstone of management includes a low sodium is thought to result from ischemia-induced activation of the diet and treatment with an appropriate diuretic with atten- RAS. Endothelial injury, increased sympathetic tone, and tion to dose and frequency (see Diuretics). Patients should impaired nitric oxide synthesis are also implicated. be treated with a combination of medications from different classes: a RAS agent (either an ACE inhibitor, an ARB, or a Clinical Manifestations direct renin inhibitor), a calcium channel blocker, a diu- Underlying kidney disease is suggested by an elevated serum retic, and possibly a B-blocker. Trials support the efficacy of creatinine concentration and/or an abnormal urinalysis or adding a low-dose aldosterone receptor antagonist (spirono- albuminuria. Patients can present with edema, but its absence lactone or eplerenone) for treatment of resistant hyperten- does not exclude kidney disease as hypertension etiology. sion. If additional agents are needed for BP control or the patient is intolerant of the aforementioned agents, then Diagnosis vasodilators (hydralazine or minoxidil), «-blockers (doxa- Initial evaluation of hypertension in all patients includes zosin, prazosin), or central sympathetic agonists (clonidine) assessment of serum creatinine and eGFR, urinalysis with can be added. microscopic examination to exclude hematuria and/or

but can be as high as 40% in patients with CKD. Other risk laboratory testing (see Table 14). Factors that raise pretest factors include older age, male sex, Black race, diabetes, and probability for secondary hypertension include hypertension higher BMI. onset at <30 years of age; abrupt-onset or worsening BP if Before the diagnosis is made, a systematic approach previously well controlled; drug resistance; clinical features to BP control should include ensuring accuracy of BP indicating a secondary process; presence of target organ dam- readings, confirming adherence to antihypertensive age disproportionate to hypertension duration or severity; medications, optimizing medication selection and dos- diastolic hypertension onset in those >65 years of age; and ing, and addressing potential secondary and reversible unprovoked or excessive hypokalemia. causes of hypertension. The importance of out-of-office BP measurements (home or ABPM) as a part of evaluation Kidney Disease to rule out white coat hypertension and to confirm resist- Pathophysiology and Epidemiology ance is increasingly recognized. Behaviors that could lead Hypertension develops in the setting of both AKI and CKD. to high BP, including excessive sodium consumption, Underlying parenchymal kidney disease is an important cause should be reviewed, and use of recreational drugs and of hypertension, and up to 85% of patients with CKD have high prescription or nonprescription medications (such as BP. Hypertension prevalence increases with GFR decline. complementary and alternative medications) that may Additionally, chronic uncontrolled hypertension is a leading exacerbate hypertension should be excluded. Adherence cause of CKD and progression to ESKD. BP elevation in glo- to antihypertensive medications, including correct fre- merular disease is primarily attributed to fluid overload, as quency and dosage, should be confirmed, and potential evidenced by suppression of the RAS and increased release of reasons for nonadherence, such as medication side atrial natriuretic peptide. In acute vascular diseases affecting effects, should be addressed. the kidney (vasculitis or scleroderma renal crisis), elevated BP The cornerstone of management includes a low sodium is thought to result from ischemia-induced activation of the diet and treatment with an appropriate diuretic with atten- RAS. Endothelial injury, increased sympathetic tone, and tion to dose and frequency (see Diuretics). Patients should impaired nitric oxide synthesis are also implicated. be treated with a combination of medications from different classes: a RAS agent (either an ACE inhibitor, an ARB, or a Clinical Manifestations direct renin inhibitor), a calcium channel blocker, a diu- Underlying kidney disease is suggested by an elevated serum retic, and possibly a B-blocker. Trials support the efficacy of creatinine concentration and/or an abnormal urinalysis or adding a low-dose aldosterone receptor antagonist (spirono- albuminuria. Patients can present with edema, but its absence lactone or eplerenone) for treatment of resistant hyperten- does not exclude kidney disease as hypertension etiology. sion. If additional agents are needed for BP control or the patient is intolerant of the aforementioned agents, then Diagnosis vasodilators (hydralazine or minoxidil), «-blockers (doxa- Initial evaluation of hypertension in all patients includes zosin, prazosin), or central sympathetic agonists (clonidine) assessment of serum creatinine and eGFR, urinalysis with can be added. microscopic examination to exclude hematuria and/or 36

Hypertension proteinuria, and urine albumin-creatinine ratio in those with There are two types of renovascular disease: (1) athero- diabetes or family history of kidney disease. Abnormalities in sclerotic renovascular disease, which usually occurs in patients any of these tests can signify underlying kidney disease. In >45 years of age, especially in those with diffuse atherosclero- those with a normal serum creatinine but a high suspicion for sis but can also be isolated to the kidney; and (2) fibromuscu- certain kidney diseases, such as a positive family history of lar dysplasia, a nonatherosclerotic disorder that usually affects autosomal dominant polycystic kidney disease, kidney ultra- the mid and distal portions of the renal artery and usually sonography can be undertaken. occurs in young persons, particularly women.

proteinuria, and urine albumin-creatinine ratio in those with There are two types of renovascular disease: (1) athero- diabetes or family history of kidney disease. Abnormalities in sclerotic renovascular disease, which usually occurs in patients any of these tests can signify underlying kidney disease. In >45 years of age, especially in those with diffuse atherosclero- those with a normal serum creatinine but a high suspicion for sis but can also be isolated to the kidney; and (2) fibromuscu- certain kidney diseases, such as a positive family history of lar dysplasia, a nonatherosclerotic disorder that usually affects autosomal dominant polycystic kidney disease, kidney ultra- the mid and distal portions of the renal artery and usually sonography can be undertaken. occurs in young persons, particularly women. Management Clinical Manifestations The 2017 ACC/AHA BP guideline recommends a BP target of Patients with atherosclerotic renovascular disease often have <130/80 mm Hg for patients with hypertension and CKD. An other manifestations of atherosclerosis, including the presence ACE inhibitor or an ARB is a preferred drug for treatment of of coronary artery, cerebrovascular, or peripheral vascular hypertension for patients with stage G3 CKD or higher or for disease. Bruits may be auscultated, especially a systolic- those with stage G1 or G2 CKD with severe albuminuria diastolic abdominal bruit that lateralizes to one side. Clinical (albumin-creatinine ratio >300 mg/g). suspicion should be high in patients who present with onset of Kidney function and serum potassium should be reas- severe hypertension after age 55 years; recurrent flash pulmo- sessed 2 to 3 weeks after initiation of an ACE inhibitor or ARB. nary edema; refractory heart failure; AKI after initiation of an An increase in serum creatinine of 25% to 30% is acceptable, ACE inhibitor/ARB; or AKI after control of BP to target. but the dose may need to be lowered or medication discontin- Asymmetry in kidney sizes of >1.5 cm on imaging or the pres- ued if more severe decline in kidney function is observed; in ence of a unilateral small kidney <9 cm also increases the such cases, bilateral renovascular disease should also be likelihood. considered. Abrupt onset of hypertension at an age <35 years suggests Given that sodium retention and volume overload are fibromuscular dysplasia. major contributory factors in the hypertension of CKD, dietary sodium restriction to <2000 mg/d and addition of a diuretic Diagnosis are both essential for control of BP, especially in advanced Routine testing for renovascular disease may not change man- CKD. The following factors addressing appropriate dose and agement because recent data suggest that medical therapy may dosing interval for diuretics should be considered: be as beneficial as invasive procedures, especially for those

Management Clinical Manifestations The 2017 ACC/AHA BP guideline recommends a BP target of Patients with atherosclerotic renovascular disease often have <130/80 mm Hg for patients with hypertension and CKD. An other manifestations of atherosclerosis, including the presence ACE inhibitor or an ARB is a preferred drug for treatment of of coronary artery, cerebrovascular, or peripheral vascular hypertension for patients with stage G3 CKD or higher or for disease. Bruits may be auscultated, especially a systolic- those with stage G1 or G2 CKD with severe albuminuria diastolic abdominal bruit that lateralizes to one side. Clinical (albumin-creatinine ratio >300 mg/g). suspicion should be high in patients who present with onset of Kidney function and serum potassium should be reas- severe hypertension after age 55 years; recurrent flash pulmo- sessed 2 to 3 weeks after initiation of an ACE inhibitor or ARB. nary edema; refractory heart failure; AKI after initiation of an An increase in serum creatinine of 25% to 30% is acceptable, ACE inhibitor/ARB; or AKI after control of BP to target. but the dose may need to be lowered or medication discontin- Asymmetry in kidney sizes of >1.5 cm on imaging or the pres- ued if more severe decline in kidney function is observed; in ence of a unilateral small kidney <9 cm also increases the such cases, bilateral renovascular disease should also be likelihood. considered. Abrupt onset of hypertension at an age <35 years suggests Given that sodium retention and volume overload are fibromuscular dysplasia. major contributory factors in the hypertension of CKD, dietary sodium restriction to <2000 mg/d and addition of a diuretic Diagnosis are both essential for control of BP, especially in advanced Routine testing for renovascular disease may not change man- CKD. The following factors addressing appropriate dose and agement because recent data suggest that medical therapy may dosing interval for diuretics should be considered: be as beneficial as invasive procedures, especially for those e Higher doses of diuretics are required in patients with with atherosclerotic renovascular disease. However, in young

Management Clinical Manifestations The 2017 ACC/AHA BP guideline recommends a BP target of Patients with atherosclerotic renovascular disease often have <130/80 mm Hg for patients with hypertension and CKD. An other manifestations of atherosclerosis, including the presence ACE inhibitor or an ARB is a preferred drug for treatment of of coronary artery, cerebrovascular, or peripheral vascular hypertension for patients with stage G3 CKD or higher or for disease. Bruits may be auscultated, especially a systolic- those with stage G1 or G2 CKD with severe albuminuria diastolic abdominal bruit that lateralizes to one side. Clinical (albumin-creatinine ratio >300 mg/g). suspicion should be high in patients who present with onset of Kidney function and serum potassium should be reas- severe hypertension after age 55 years; recurrent flash pulmo- sessed 2 to 3 weeks after initiation of an ACE inhibitor or ARB. nary edema; refractory heart failure; AKI after initiation of an An increase in serum creatinine of 25% to 30% is acceptable, ACE inhibitor/ARB; or AKI after control of BP to target. but the dose may need to be lowered or medication discontin- Asymmetry in kidney sizes of >1.5 cm on imaging or the pres- ued if more severe decline in kidney function is observed; in ence of a unilateral small kidney <9 cm also increases the such cases, bilateral renovascular disease should also be likelihood. considered. Abrupt onset of hypertension at an age <35 years suggests Given that sodium retention and volume overload are fibromuscular dysplasia. major contributory factors in the hypertension of CKD, dietary sodium restriction to <2000 mg/d and addition of a diuretic Diagnosis are both essential for control of BP, especially in advanced Routine testing for renovascular disease may not change man- CKD. The following factors addressing appropriate dose and agement because recent data suggest that medical therapy may dosing interval for diuretics should be considered: be as beneficial as invasive procedures, especially for those e Higher doses of diuretics are required in patients with with atherosclerotic renovascular disease. However, in young CKD due to decreased GFR. patients with resistant hypertension and a high clinical suspi- cion for fibromuscular dysplasia, renal artery imaging may be e Thiazide diuretics may be less effective if the eGFR is <30 mL/ considered. Plasma renin activity, captopril renal scintigraphy, min/1.73 m?; although there are no head-to-head trials, it and selective renal vein renin measurements are no longer seems preferable to use chlorthalidone instead of hydrochlo- recommended given the availability of more sensitive and rothiazide in patients with CKD because of a longer half-life. specific imaging tests. e For an eGFR <20 to 30 mL/min/1.73 m?, a loop diuretic Renal duplex Doppler ultrasonography is a reasonable can be used effectively, with a more frequent dosing inter- imaging modality if performed by experienced sonographers. val (e.g., furosemide should be dosed at least two to three MR and CT angiography have higher diagnostic utility but are times daily). potentially harmful in patients with severe CKD given the risk e The combination of a thiazide and a loop diuretic can be for contrast-associated nephropathy and gadolinium-induced used to augment diuresis, with careful monitoring. nephrogenic systemic fibrosis. A stenosis >75% in one or both

CKD due to decreased GFR. patients with resistant hypertension and a high clinical suspi- cion for fibromuscular dysplasia, renal artery imaging may be e Thiazide diuretics may be less effective if the eGFR is <30 mL/ considered. Plasma renin activity, captopril renal scintigraphy, min/1.73 m?; although there are no head-to-head trials, it and selective renal vein renin measurements are no longer seems preferable to use chlorthalidone instead of hydrochlo- recommended given the availability of more sensitive and rothiazide in patients with CKD because of a longer half-life. specific imaging tests. e For an eGFR <20 to 30 mL/min/1.73 m?, a loop diuretic Renal duplex Doppler ultrasonography is a reasonable can be used effectively, with a more frequent dosing inter- imaging modality if performed by experienced sonographers. val (e.g., furosemide should be dosed at least two to three MR and CT angiography have higher diagnostic utility but are times daily). potentially harmful in patients with severe CKD given the risk e The combination of a thiazide and a loop diuretic can be for contrast-associated nephropathy and gadolinium-induced used to augment diuresis, with careful monitoring. nephrogenic systemic fibrosis. A stenosis >75% in one or both e Volume overload refractory to medical management in renal arteries or >50% with post-stenotic dilatation suggests those with stage G5 CKD (eGFR <15 mL/min/1.73 m2) may the diagnosis. Renal intra-arterial angiography is the gold

CKD due to decreased GFR. patients with resistant hypertension and a high clinical suspi- cion for fibromuscular dysplasia, renal artery imaging may be e Thiazide diuretics may be less effective if the eGFR is <30 mL/ considered. Plasma renin activity, captopril renal scintigraphy, min/1.73 m?; although there are no head-to-head trials, it and selective renal vein renin measurements are no longer seems preferable to use chlorthalidone instead of hydrochlo- recommended given the availability of more sensitive and rothiazide in patients with CKD because of a longer half-life. specific imaging tests. e For an eGFR <20 to 30 mL/min/1.73 m?, a loop diuretic Renal duplex Doppler ultrasonography is a reasonable can be used effectively, with a more frequent dosing inter- imaging modality if performed by experienced sonographers. val (e.g., furosemide should be dosed at least two to three MR and CT angiography have higher diagnostic utility but are times daily). potentially harmful in patients with severe CKD given the risk e The combination of a thiazide and a loop diuretic can be for contrast-associated nephropathy and gadolinium-induced used to augment diuresis, with careful monitoring. nephrogenic systemic fibrosis. A stenosis >75% in one or both e Volume overload refractory to medical management in renal arteries or >50% with post-stenotic dilatation suggests those with stage G5 CKD (eGFR <15 mL/min/1.73 m2) may the diagnosis. Renal intra-arterial angiography is the gold necessitate dialysis. standard and can be considered if other noninvasive tests are negative, clinical suspicion is high, and an invasive procedure is contemplated. It is not recommended as a routine test Renovascular Hypertension because of adverse risks, such as contrast-associated nephrop- Pathophysiology and Epidemiology athy and cholesterol emboli. Prevalence of renovascular hypertension is higher in White than in Black populations. Pathogenesis involves renal hypop- Management erfusion as a result of renal artery stenosis, with subsequent Three large randomized trials (STAR, ASTRAL, and CORAL) release of renin and angiotensin resulting in systemic vasocon- failed to show that renal artery angioplasty confers addi- striction, sodium retention, and hypertension. Disease can be tional benefit above optimal medical therapy in patients unilateral or bilateral. Parenchymal kidney damage with loss with atherosclerotic renovascular disease and stable kidney of kidney function can occur. function. Medical therapy includes treatment of underlying

necessitate dialysis. standard and can be considered if other noninvasive tests are negative, clinical suspicion is high, and an invasive procedure is contemplated. It is not recommended as a routine test Renovascular Hypertension because of adverse risks, such as contrast-associated nephrop- Pathophysiology and Epidemiology athy and cholesterol emboli. Prevalence of renovascular hypertension is higher in White than in Black populations. Pathogenesis involves renal hypop- Management erfusion as a result of renal artery stenosis, with subsequent Three large randomized trials (STAR, ASTRAL, and CORAL) release of renin and angiotensin resulting in systemic vasocon- failed to show that renal artery angioplasty confers addi- striction, sodium retention, and hypertension. Disease can be tional benefit above optimal medical therapy in patients unilateral or bilateral. Parenchymal kidney damage with loss with atherosclerotic renovascular disease and stable kidney of kidney function can occur. function. Medical therapy includes treatment of underlying 37

Hypertension cardiovascular risk factors (such as hypercholesterolemia) and artery stenosis and renin-secreting tumors generate both high an ACE inhibitor or ARB. Patients who may benefit from per- PRA and PAC, with subsequent lowering of the PAC/PRA ratio, cutaneous angioplasty and stenting or surgical intervention to usually <10. See MKSAP 19 Endocrinology and Metabolism include those with the following: a short hypertension dura- for more information. tion; atherosclerotic renovascular disease refractory to optimal medical therapy; severe hypertension or recurrent acute flash Pheochromocytomas pulmonary edema; AKI following treatment with an ACE Pheochromocytomas are rare catecholamine-secreting neo- inhibitor or ARB; or progressive impaired kidney function plasms of the adrenal medulla or sympathetic ganglia that thought to result from bilateral renovascular disease or unilat- occur in <0.2% of patients with hypertension. Presence of the eral stenosis affecting a solitary functioning kidney. Patients following characteristics raises clinical suspicion and may with advanced CKD or with proteinuria >1000 mg/24 h are prompt testing: resistant hypertension; hypertension onset less likely to benefit from revascularization. that is new or at a young age; paroxysmal hypertension; epi- Nephrologists or hypertension specialists should be sodic tachycardia, headaches, and sweating; history of familial involved in the care of patients with hemodynamically signifi- syndromes; adrenal adenoma found incidentally on imaging cant renovascular disease, as BP is often difficult to control, with or without hypertension; or pressor response during the criteria for intervention are complex, and the risk for AKI invasive procedures or anesthesia. Diagnostic tests include is increased compared with the typical hypertensive patient plasma fractionated metanephrines and 24-hour urine population. metanephrines and catecholamines. Positive test results In young persons with fibromuscular dysplasia, studies should be followed by imaging to locate the tumor. Definitive suggest that angioplasty alone may improve BP and even cure treatment is surgical resection. See MKSAP 19 Endocrinology hypertension. and Metabolism for details.

cardiovascular risk factors (such as hypercholesterolemia) and artery stenosis and renin-secreting tumors generate both high an ACE inhibitor or ARB. Patients who may benefit from per- PRA and PAC, with subsequent lowering of the PAC/PRA ratio, cutaneous angioplasty and stenting or surgical intervention to usually <10. See MKSAP 19 Endocrinology and Metabolism include those with the following: a short hypertension dura- for more information. tion; atherosclerotic renovascular disease refractory to optimal medical therapy; severe hypertension or recurrent acute flash Pheochromocytomas pulmonary edema; AKI following treatment with an ACE Pheochromocytomas are rare catecholamine-secreting neo- inhibitor or ARB; or progressive impaired kidney function plasms of the adrenal medulla or sympathetic ganglia that thought to result from bilateral renovascular disease or unilat- occur in <0.2% of patients with hypertension. Presence of the eral stenosis affecting a solitary functioning kidney. Patients following characteristics raises clinical suspicion and may with advanced CKD or with proteinuria >1000 mg/24 h are prompt testing: resistant hypertension; hypertension onset less likely to benefit from revascularization. that is new or at a young age; paroxysmal hypertension; epi- Nephrologists or hypertension specialists should be sodic tachycardia, headaches, and sweating; history of familial involved in the care of patients with hemodynamically signifi- syndromes; adrenal adenoma found incidentally on imaging cant renovascular disease, as BP is often difficult to control, with or without hypertension; or pressor response during the criteria for intervention are complex, and the risk for AKI invasive procedures or anesthesia. Diagnostic tests include is increased compared with the typical hypertensive patient plasma fractionated metanephrines and 24-hour urine population. metanephrines and catecholamines. Positive test results In young persons with fibromuscular dysplasia, studies should be followed by imaging to locate the tumor. Definitive suggest that angioplasty alone may improve BP and even cure treatment is surgical resection. See MKSAP 19 Endocrinology hypertension. and Metabolism for details. Primary Hyperaldosteronism Primary hyperaldosteronism, in which aldosterone produc- e The 2017 American College of Cardiology/American tion cannot be suppressed with sodium loading, is the most Heart Association blood pressure (BP) guideline recom- common cause of secondary hypertension in middle-aged mends a target BP of <130/80 mm Hg in patients with

Primary Hyperaldosteronism Primary hyperaldosteronism, in which aldosterone produc- e The 2017 American College of Cardiology/American tion cannot be suppressed with sodium loading, is the most Heart Association blood pressure (BP) guideline recom- common cause of secondary hypertension in middle-aged mends a target BP of <130/80 mm Hg in patients with adults and an important cause of resistant hypertension (See hypertension and chronic kidney disease.

Primary Hyperaldosteronism Primary hyperaldosteronism, in which aldosterone produc- e The 2017 American College of Cardiology/American tion cannot be suppressed with sodium loading, is the most Heart Association blood pressure (BP) guideline recom- common cause of secondary hypertension in middle-aged mends a target BP of <130/80 mm Hg in patients with adults and an important cause of resistant hypertension (See hypertension and chronic kidney disease. MKSAP 19 Endocrinology and Metabolism). A triad of resistant e An ACE inhibitor or an angiotensin receptor blocker is hypertension, metabolic alkalosis, and hypokalemia (includ- a preferred drug for treatment of hypertension for ing in patients treated with low-dose thiazide diuretics) should patients with stage G3 chronic kidney disease (CKD) raise suspicion (see Table 14). Screening is recommended if any or higher and for those with stage G1 or G2 CKD with of the following are present: resistant hypertension, hypoka- albumin-creatinine ratio >300 mg/g; treatment also lemia (spontaneous or substantial, if diuretic induced), inci- includes dietary sodium restriction to <2000 mg/d and dentally discovered adrenal mass, family history of early-onset addition of a diuretic as needed to control intravascular hypertension, moderately severe hypertension (>160/100 mm volume. Hg), or stroke at age <40 years. It is common for patients with ¢ Medical therapy for renovascular disease, including primary aldosteronism to have normal potassium; a high treatment of underlying cardiovascular risk factors and index of suspicion is required. Higher cardiovascular morbid- use of an ACE inhibitor or angiotensin receptor blocker, ity and mortality are noted in patients with primary hyperal- may be as beneficial as invasive procedures. dosteronism compared with primary hypertension and e Primary hyperaldosteronism is the most common cause similar BP control. of secondary hypertension in middle-aged adults and Calculation of plasma aldosterone concentration (PAC)/ an important cause of resistant hypertension; the plasma renin activity (PRA) ratio is used for screening, with a plasma aldosterone concentration/plasma renin activity very high ratio of PAC/PRA suggestive of the diagnosis. ratio is used for screening. After the diagnosis is confirmed, a dedicated adrenal CT should be performed to determine whether the hyperaldoster- onism is caused by diffuse hyperplasia, as seen in two thirds of patients and managed by an aldosterone-receptor antagonist Hypertensive Urgency such as spironolactone, versus an aldosterone-producing ade- Hypertensive urgency is defined as severely elevated BP—often noma amendable to surgical resection. a systolic BP =>180 mm Hg and/or diastolic BP >110 mm Hg— PAC and PRA are usually suppressed in other disorders without obvious signs or symptoms of acute or impending with hypokalemia and hypertension, including Cushing syn- target organ damage or dysfunction. Patients are often asymp- drome, syndrome of apparent mineralocorticoid excess, famil- tomatic or present with a mild headache. The most important ial hyperaldosteronism type I (glucocorticoid-remediable aspect of initial management is a focused history and physical aldosteronism), and Liddle syndrome (see Table 14). Renal examination to exclude the presence of acute end-organ

MKSAP 19 Endocrinology and Metabolism). A triad of resistant e An ACE inhibitor or an angiotensin receptor blocker is hypertension, metabolic alkalosis, and hypokalemia (includ- a preferred drug for treatment of hypertension for ing in patients treated with low-dose thiazide diuretics) should patients with stage G3 chronic kidney disease (CKD) raise suspicion (see Table 14). Screening is recommended if any or higher and for those with stage G1 or G2 CKD with of the following are present: resistant hypertension, hypoka- albumin-creatinine ratio >300 mg/g; treatment also lemia (spontaneous or substantial, if diuretic induced), inci- includes dietary sodium restriction to <2000 mg/d and dentally discovered adrenal mass, family history of early-onset addition of a diuretic as needed to control intravascular hypertension, moderately severe hypertension (>160/100 mm volume. Hg), or stroke at age <40 years. It is common for patients with ¢ Medical therapy for renovascular disease, including primary aldosteronism to have normal potassium; a high treatment of underlying cardiovascular risk factors and index of suspicion is required. Higher cardiovascular morbid- use of an ACE inhibitor or angiotensin receptor blocker, ity and mortality are noted in patients with primary hyperal- may be as beneficial as invasive procedures. dosteronism compared with primary hypertension and e Primary hyperaldosteronism is the most common cause similar BP control. of secondary hypertension in middle-aged adults and Calculation of plasma aldosterone concentration (PAC)/ an important cause of resistant hypertension; the plasma renin activity (PRA) ratio is used for screening, with a plasma aldosterone concentration/plasma renin activity very high ratio of PAC/PRA suggestive of the diagnosis. ratio is used for screening. After the diagnosis is confirmed, a dedicated adrenal CT should be performed to determine whether the hyperaldoster- onism is caused by diffuse hyperplasia, as seen in two thirds of patients and managed by an aldosterone-receptor antagonist Hypertensive Urgency such as spironolactone, versus an aldosterone-producing ade- Hypertensive urgency is defined as severely elevated BP—often noma amendable to surgical resection. a systolic BP =>180 mm Hg and/or diastolic BP >110 mm Hg— PAC and PRA are usually suppressed in other disorders without obvious signs or symptoms of acute or impending with hypokalemia and hypertension, including Cushing syn- target organ damage or dysfunction. Patients are often asymp- drome, syndrome of apparent mineralocorticoid excess, famil- tomatic or present with a mild headache. The most important ial hyperaldosteronism type I (glucocorticoid-remediable aspect of initial management is a focused history and physical aldosteronism), and Liddle syndrome (see Table 14). Renal examination to exclude the presence of acute end-organ 38

Hypertension damage, which would raise concern for hypertensive emer- Hypertensive Emergency gency. Referral to an emergency department may be required Hypertensive emergency refers to elevated BP significantly above for further diagnostic testing. the normal range causing acute organ damage or dysfunction, Management includes the assessment of imminent risk of such as ischemic or hemorrhagic stroke, encephalopathy, AKI, cardiovascular events from severe hypertension versus risk of acute myocardial infarction, aortic dissection, or acute heart fail- adverse sequelae from rapid BP reduction, which include AKI, ure. These effects often occur at BP >180/110 mm Hg, but there is myocardial infarction, or stroke resulting from decreased no specific BP threshold above which the syndrome is defined. organ perfusion and limited time for autoregulation. There are Hypertensive emergency should be treated by rapidly scant data to determine how quickly the BP should be low- lowering the BP, usually using intravenous short-acting agents ered. Generally, systolic BP may be lowered in patients with in the ICU setting (Table 17 and Table 18). The 2017 ACC/AHA imminent risk of target organ damage but without acute organ BP guideline recommends that for adults with acute organ injury (see Hypertensive Emergency) by no more than 25% injury (such as aortic dissection, severe preeclampsia or within the first hour, then to <160/100 mm Hg within the next eclampsia, or pheochromocytoma), systolic BP should be 2 to 6 hours, then cautiously to target during the following 24 reduced to <140 mm Hg during the first hour and to <120 mm to 48 hours. Choice of antihypertensive medication should be Hg in aortic dissection. See MKSAP 19 Neurology for further tailored to the specific patient. If there is concern for imminent discussion of the treatment of hypertension associated with end-organ damage, faster-acting antihypertensive agents, ischemic stroke and intracerebral hemorrhage. such as oral clonidine, can be given to lower BP. Several hours of observation in the ambulatory setting may be required to ensure that the patient remains asymptomatic and that BP is e Hypertensive urgency is defined as severely elevated decreasing before discharge. In patients in whom hypertensive blood pressure (BP)—often a systolic BP >180 mm Hg urgency developed because of medication nonadherence, and/or diastolic BP >110 mm Hg-in a patient without antihypertensive medications can be resumed slowly in a step- obvious signs or symptoms of acute or impending target wise fashion, with care not to drop the BP precipitously. Close organ damage or dysfunction. follow-up is necessary, and further management can include (Continued) home monitoring of BP.

damage, which would raise concern for hypertensive emer- Hypertensive Emergency gency. Referral to an emergency department may be required Hypertensive emergency refers to elevated BP significantly above for further diagnostic testing. the normal range causing acute organ damage or dysfunction, Management includes the assessment of imminent risk of such as ischemic or hemorrhagic stroke, encephalopathy, AKI, cardiovascular events from severe hypertension versus risk of acute myocardial infarction, aortic dissection, or acute heart fail- adverse sequelae from rapid BP reduction, which include AKI, ure. These effects often occur at BP >180/110 mm Hg, but there is myocardial infarction, or stroke resulting from decreased no specific BP threshold above which the syndrome is defined. organ perfusion and limited time for autoregulation. There are Hypertensive emergency should be treated by rapidly scant data to determine how quickly the BP should be low- lowering the BP, usually using intravenous short-acting agents ered. Generally, systolic BP may be lowered in patients with in the ICU setting (Table 17 and Table 18). The 2017 ACC/AHA imminent risk of target organ damage but without acute organ BP guideline recommends that for adults with acute organ injury (see Hypertensive Emergency) by no more than 25% injury (such as aortic dissection, severe preeclampsia or within the first hour, then to <160/100 mm Hg within the next eclampsia, or pheochromocytoma), systolic BP should be 2 to 6 hours, then cautiously to target during the following 24 reduced to <140 mm Hg during the first hour and to <120 mm to 48 hours. Choice of antihypertensive medication should be Hg in aortic dissection. See MKSAP 19 Neurology for further tailored to the specific patient. If there is concern for imminent discussion of the treatment of hypertension associated with end-organ damage, faster-acting antihypertensive agents, ischemic stroke and intracerebral hemorrhage. such as oral clonidine, can be given to lower BP. Several hours of observation in the ambulatory setting may be required to ensure that the patient remains asymptomatic and that BP is e Hypertensive urgency is defined as severely elevated decreasing before discharge. In patients in whom hypertensive blood pressure (BP)—often a systolic BP >180 mm Hg urgency developed because of medication nonadherence, and/or diastolic BP >110 mm Hg-in a patient without antihypertensive medications can be resumed slowly in a step- obvious signs or symptoms of acute or impending target wise fashion, with care not to drop the BP precipitously. Close organ damage or dysfunction. follow-up is necessary, and further management can include (Continued) home monitoring of BP. TABLE 17. Intravenous Antihypertensive Drugs for Treatment of Hypertensive Emergencies

damage, which would raise concern for hypertensive emer- Hypertensive Emergency gency. Referral to an emergency department may be required Hypertensive emergency refers to elevated BP significantly above for further diagnostic testing. the normal range causing acute organ damage or dysfunction, Management includes the assessment of imminent risk of such as ischemic or hemorrhagic stroke, encephalopathy, AKI, cardiovascular events from severe hypertension versus risk of acute myocardial infarction, aortic dissection, or acute heart fail- adverse sequelae from rapid BP reduction, which include AKI, ure. These effects often occur at BP >180/110 mm Hg, but there is myocardial infarction, or stroke resulting from decreased no specific BP threshold above which the syndrome is defined. organ perfusion and limited time for autoregulation. There are Hypertensive emergency should be treated by rapidly scant data to determine how quickly the BP should be low- lowering the BP, usually using intravenous short-acting agents ered. Generally, systolic BP may be lowered in patients with in the ICU setting (Table 17 and Table 18). The 2017 ACC/AHA imminent risk of target organ damage but without acute organ BP guideline recommends that for adults with acute organ injury (see Hypertensive Emergency) by no more than 25% injury (such as aortic dissection, severe preeclampsia or within the first hour, then to <160/100 mm Hg within the next eclampsia, or pheochromocytoma), systolic BP should be 2 to 6 hours, then cautiously to target during the following 24 reduced to <140 mm Hg during the first hour and to <120 mm to 48 hours. Choice of antihypertensive medication should be Hg in aortic dissection. See MKSAP 19 Neurology for further tailored to the specific patient. If there is concern for imminent discussion of the treatment of hypertension associated with end-organ damage, faster-acting antihypertensive agents, ischemic stroke and intracerebral hemorrhage. such as oral clonidine, can be given to lower BP. Several hours of observation in the ambulatory setting may be required to ensure that the patient remains asymptomatic and that BP is e Hypertensive urgency is defined as severely elevated decreasing before discharge. In patients in whom hypertensive blood pressure (BP)—often a systolic BP >180 mm Hg urgency developed because of medication nonadherence, and/or diastolic BP >110 mm Hg-in a patient without antihypertensive medications can be resumed slowly in a step- obvious signs or symptoms of acute or impending target wise fashion, with care not to drop the BP precipitously. Close organ damage or dysfunction. follow-up is necessary, and further management can include (Continued) home monitoring of BP. TABLE 17. Intravenous Antihypertensive Drugs for Treatment of Hypertensive Emergencies | Class Examples Comments

damage, which would raise concern for hypertensive emer- Hypertensive Emergency gency. Referral to an emergency department may be required Hypertensive emergency refers to elevated BP significantly above for further diagnostic testing. the normal range causing acute organ damage or dysfunction, Management includes the assessment of imminent risk of such as ischemic or hemorrhagic stroke, encephalopathy, AKI, cardiovascular events from severe hypertension versus risk of acute myocardial infarction, aortic dissection, or acute heart fail- adverse sequelae from rapid BP reduction, which include AKI, ure. These effects often occur at BP >180/110 mm Hg, but there is myocardial infarction, or stroke resulting from decreased no specific BP threshold above which the syndrome is defined. organ perfusion and limited time for autoregulation. There are Hypertensive emergency should be treated by rapidly scant data to determine how quickly the BP should be low- lowering the BP, usually using intravenous short-acting agents ered. Generally, systolic BP may be lowered in patients with in the ICU setting (Table 17 and Table 18). The 2017 ACC/AHA imminent risk of target organ damage but without acute organ BP guideline recommends that for adults with acute organ injury (see Hypertensive Emergency) by no more than 25% injury (such as aortic dissection, severe preeclampsia or within the first hour, then to <160/100 mm Hg within the next eclampsia, or pheochromocytoma), systolic BP should be 2 to 6 hours, then cautiously to target during the following 24 reduced to <140 mm Hg during the first hour and to <120 mm to 48 hours. Choice of antihypertensive medication should be Hg in aortic dissection. See MKSAP 19 Neurology for further tailored to the specific patient. If there is concern for imminent discussion of the treatment of hypertension associated with end-organ damage, faster-acting antihypertensive agents, ischemic stroke and intracerebral hemorrhage. such as oral clonidine, can be given to lower BP. Several hours of observation in the ambulatory setting may be required to ensure that the patient remains asymptomatic and that BP is e Hypertensive urgency is defined as severely elevated decreasing before discharge. In patients in whom hypertensive blood pressure (BP)—often a systolic BP >180 mm Hg urgency developed because of medication nonadherence, and/or diastolic BP >110 mm Hg-in a patient without antihypertensive medications can be resumed slowly in a step- obvious signs or symptoms of acute or impending target wise fashion, with care not to drop the BP precipitously. Close organ damage or dysfunction. follow-up is necessary, and further management can include (Continued) home monitoring of BP. TABLE 17. Intravenous Antihypertensive Drugs for Treatment of Hypertensive Emergencies | Class Examples Comments Dihydropyridine calcium channel Nicardipine Nicardipine: Contraindicated in patients with severe aortic stenosis. block re Rie cant 4 : : , stenosis, oS Clevidipine Clevidipine: Contraindicated in patients with severe aortic ,

Dihydropyridine calcium channel Nicardipine Nicardipine: Contraindicated in patients with severe aortic stenosis. block re Rie cant 4 : : , stenosis, oS Clevidipine Clevidipine: Contraindicated in patients with severe aortic , soy allergy, egg allergy, hyperlipidemia, lipoid nephrosis, acute | pancreatitis. Vasodilator-nitric oxide dependent Sodium nitroprusside Sodium nitroprusside: Intra-arterial blood pressure monitoring recommended. Tachyphylaxis common with prolonged use. Irreversible cyanide toxicity possible with prolonged use. | Nitroglycerin Nitroglycerin: Use only for patients with acute coronary syndrome or acute pulmonary edema. Avoid in patients with right ventricular infarction and those taking PDE-5 inhibitors. Vasodilator-direct Hydralazine Not first-line drug because of unpredictable response and long duration of action. Adrenergic blocker-B, selective Esmolol Contraindicated with concurrent B-blocker therapy, bradycardia, pulmonary edema, severe HF.

Vasodilator-direct Hydralazine Not first-line drug because of unpredictable response and long duration of action. Adrenergic blocker-B, selective Esmolol Contraindicated with concurrent B-blocker therapy, bradycardia, pulmonary edema, severe HF. Adrenergic blocker-combined a, Labetalol Useful in hyperadrenergic syndromes. Contraindicated in patients | and nonselective B-blocker with asthma, COPD, heart block. May worsen heart failure. Adrenergic blocker-nonselective Phentolamine Useful in patients with pheochromocytoma, cocaine toxicity, | a-blocker amphetamine overdose, clonidine withdrawal. | Dopamine,-agonist Fenoldopam Contraindicated in patients with glaucoma or increased intracerebral pressure. ACE inhibitor Enalapril Useful in situations associated with high plasma renin activity (scleroderma renal crisis). Contraindicated in pregnancy, acute MI, bilateral renal artery stenosis. HF = heart failure; Ml = myocardial infarction; PDE = phosphodiesterase. Data from Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71:e127-e248. [PMID: 29146535] doi:10.1016/j.jacc.2017.11.006 39

Hypertension TABLE 18. Intravenous Antihypertensive Drugs for Treatment of Hypertensive Emergencies with Selected Comorbidities | Comorbidity Preferred Drugs? Comments | Acute aortic dissection Esmolol, labetalol Rapid systolic BP lowering to <120 mm Hg. B-Blockade should precede vasodilator (such as with nicardipine or nitroprusside) administration. Acute pulmonary edema Nitroglycerin, nitroprusside, clevidipine B-Blockers contraindicated. Acute coronary syndromes Esmolol, labetalol, nicardipine, nitroglycerin Esmolol and nitroglycerin are first-line drugs. Acute kidney injury Clevidipine, fenoldopam, nicardipine - Eclampsia or preeclampsia Hydralazine, labetalol, nicardipine ACE inhibitors, ARBs, renin inhibitors, nitroprusside contraindicated. ARB = angiotensin receptor blocker; BP = blood pressure. See Table 17 for specific drug contraindications. Data from Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71:e127-e248. [PMID: 29146535] doi:10.1016/j.jacc.2017.11.006

Data from Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71:e127-e248. [PMID: 29146535] doi:10.1016/j.jacc.2017.11.006 patients with diabetes, a thiazide diuretic or CCB is recom- mended as initial therapy. e For adults with a hypertensive emergency and acute The American Diabetes Association (ADA) recommends organ injury, systolic blood pressure should be reduced that patients with diabetes and hypertension with a 10-year to <140 mm Hg during the first hour and to <120 mm Hg atherosclerotic cardiovascular disease (ASCVD) event risk <15% in aortic dissection. should be treated to a BP goal of 140/90 mm Hg; a lower target of <130/80 mm Hg is appropriate for individuals with existing ASCVD or 10-year ASCVD event risk 215%, ifthis can be achieved Specific Populations safely. The ADA also recommends an ACE inhibitor or ARB, at Women the maximum tolerated dose indicated for BP treatment, as first- Hypertension prevalence is lower in women <50 years of age line treatment for hypertension in patients with diabetes and compared with men, but prevalence increases with older age coronary artery disease or a urine albumin-creatinine ratio and eventually becomes similar in both sexes. Women, par- >300 mg/g; such treatment should also be considered if the ticularly if premenopausal, are at a lower risk than men for urine albumin-creatinine ratio is >30 mg/g to 300 mg/g. hypertension complications, such as coronary artery disease, stroke, and left ventricular hypertrophy. Clinical trials suggest Black Patients that women derive similar relative benefits from antihyper- Physicians are increasingly aware of the limitations in making tensive treatment as men, and recommendations for BP targets management decisions based upon skin color and that labeling and agents are the same. patients as Black or not Black may be overly simplistic and inap- Women of childbearing age who anticipate pregnancy propriate. Unfortunately, in the absence of more precise genetic should not be prescribed RAS agents (ACE inhibitors, ARBs, or markers that help to explain difference in epidemiology and direct renin inhibitors) because of the risk for urogenital response to therapy among differing patient populations, many developmental abnormalities; these agents are contraindi- experts and guidelines continue to use race-based terminology. cated in pregnant women. Instead, transition to methyldopa, Although hypertension is more prevalent in Black patients nifedipine, and/or labetalol during pregnancy are reasonable and correlates with a higher risk for cardiovascular and kidney choices. See The Kidney in Pregnancy for more information. outcomes, current recommendations for target BP are similar in Oral contraceptives may be associated with modest Black patients to those in other racial groups. The difference in increases in BP, which usually resolve with discontinuation; management is with regard to the agent used. In general, ACE women prescribed these medications should be monitored. inhibitors are less efficacious in lowering BP in Black patients Hormone replacement therapy consists of much lower estro- than are CCBs. Additionally, a landmark trial (ALLHAT) revealed gen doses and is not associated with elevated BP. that in Black patients, a thiazide diuretic was more effective in improving cardiovascular outcomes compared with an ACE Patients with Diabetes Mellitus inhibitor, and there was a higher risk of stroke with use of an ACE The 2017 ACC/AHA BP guideline recommends a BP goal of inhibitor as initial therapy compared with a CCB. Therefore, in <130/80 mm Hg for patients with diabetes. First-line therapy the absence of CKD or heart failure, initial antihypertensive treat- in non-Black patients with diabetes includes a thiazide diu- ment should include a thiazide diuretic or CCB in Black patients. retic, CCB, ACE inhibitor, or ARB; ACE inhibitors or ARBs are If CKD is present, initial or add-on therapy should include an ACE reasonable choices in the presence of albuminuria. In Black inhibitor or ARB, especially in those with proteinuria, as

patients with diabetes, a thiazide diuretic or CCB is recom- mended as initial therapy. e For adults with a hypertensive emergency and acute The American Diabetes Association (ADA) recommends organ injury, systolic blood pressure should be reduced that patients with diabetes and hypertension with a 10-year to <140 mm Hg during the first hour and to <120 mm Hg atherosclerotic cardiovascular disease (ASCVD) event risk <15% in aortic dissection. should be treated to a BP goal of 140/90 mm Hg; a lower target of <130/80 mm Hg is appropriate for individuals with existing ASCVD or 10-year ASCVD event risk 215%, ifthis can be achieved Specific Populations safely. The ADA also recommends an ACE inhibitor or ARB, at Women the maximum tolerated dose indicated for BP treatment, as first- Hypertension prevalence is lower in women <50 years of age line treatment for hypertension in patients with diabetes and compared with men, but prevalence increases with older age coronary artery disease or a urine albumin-creatinine ratio and eventually becomes similar in both sexes. Women, par- >300 mg/g; such treatment should also be considered if the ticularly if premenopausal, are at a lower risk than men for urine albumin-creatinine ratio is >30 mg/g to 300 mg/g. hypertension complications, such as coronary artery disease, stroke, and left ventricular hypertrophy. Clinical trials suggest Black Patients that women derive similar relative benefits from antihyper- Physicians are increasingly aware of the limitations in making tensive treatment as men, and recommendations for BP targets management decisions based upon skin color and that labeling and agents are the same. patients as Black or not Black may be overly simplistic and inap- Women of childbearing age who anticipate pregnancy propriate. Unfortunately, in the absence of more precise genetic should not be prescribed RAS agents (ACE inhibitors, ARBs, or markers that help to explain difference in epidemiology and direct renin inhibitors) because of the risk for urogenital response to therapy among differing patient populations, many developmental abnormalities; these agents are contraindi- experts and guidelines continue to use race-based terminology. cated in pregnant women. Instead, transition to methyldopa, Although hypertension is more prevalent in Black patients nifedipine, and/or labetalol during pregnancy are reasonable and correlates with a higher risk for cardiovascular and kidney choices. See The Kidney in Pregnancy for more information. outcomes, current recommendations for target BP are similar in Oral contraceptives may be associated with modest Black patients to those in other racial groups. The difference in increases in BP, which usually resolve with discontinuation; management is with regard to the agent used. In general, ACE women prescribed these medications should be monitored. inhibitors are less efficacious in lowering BP in Black patients Hormone replacement therapy consists of much lower estro- than are CCBs. Additionally, a landmark trial (ALLHAT) revealed gen doses and is not associated with elevated BP. that in Black patients, a thiazide diuretic was more effective in improving cardiovascular outcomes compared with an ACE Patients with Diabetes Mellitus inhibitor, and there was a higher risk of stroke with use of an ACE The 2017 ACC/AHA BP guideline recommends a BP goal of inhibitor as initial therapy compared with a CCB. Therefore, in <130/80 mm Hg for patients with diabetes. First-line therapy the absence of CKD or heart failure, initial antihypertensive treat- in non-Black patients with diabetes includes a thiazide diu- ment should include a thiazide diuretic or CCB in Black patients. retic, CCB, ACE inhibitor, or ARB; ACE inhibitors or ARBs are If CKD is present, initial or add-on therapy should include an ACE reasonable choices in the presence of albuminuria. In Black inhibitor or ARB, especially in those with proteinuria, as 40

Chronic Tubulointerstitial Nephritis illustrated by the AASK study. Choice of antihypertensive medi- cation in patients with heart failure should be guideline directed. e In the absence of chronic kidney disease or heart fail- ure, initial antihypertensive treatment for Black patients Older Patients with or without diabetes mellitus includes a thiazide Prevalence of hypertension increases with age and is as high as diuretic or calcium channel blocker. 60% to 80% in patients >65 years of age. A wide pulse pressure and isolated systolic hypertension (>160 mm Hg with diastolic e The 2017 American College of Cardiology/American <90 mm Hg) are common. Heart Association blood pressure (BP) guideline recom- According to the 2017 ACC/AHA BP guideline, the target mends a target systolic BP goal of <130 mm Hg for systolic BP goal for noninstitutionalized, ambulatory community- community-dwelling patients who are >65 years of age, dwelling patients who are 265 years of age is <130 mm Hg. In whereas the American College of Physicians and those with a high burden of comorbidity and limited life American Academy of Family Physicians recommend expectancy, clinical judgement, patient preference, and an a target systolic BP goal of <150 mm Hg in patients assessment of risk-benefit ratio should be considered. 260 years of age.

those with a high burden of comorbidity and limited life American Academy of Family Physicians recommend expectancy, clinical judgement, patient preference, and an a target systolic BP goal of <150 mm Hg in patients assessment of risk-benefit ratio should be considered. 260 years of age. On the other hand, a 2017 guideline from the American College of Physicians and American Academy of Family Physicians (http: //annals.org/aim/article/2598413/pharmacologic- treatment-hypertension-adultsaged-60-years-older-higher- Chronic Tubulointerstitial versus) addressed the treatment of hypertension in patients 260 years of age, including three recommendations: Nephritis e Initiate treatment in patients >60 years of age with a Epidemiology and systolic BP persistently >150 mm Hg to achieve a target Pathophysiology systolic BP <150 mm Hg to reduce the risk for mortality, Tubulointerstitial nephritis (TIN) is characterized by damage to stroke, and cardiac events. the renal tubules and interstitium. TIN can be acute or chronic. ¢ Consider initiating or intensifying pharmacologic treat- Acute interstitial nephritis is commonly due to allergic drug ment in patients 260 years of age with a history of stroke reactions or infection and can cause acute kidney injury within or transient ischemic attack to achieve a target systolic BP days to weeks. It is characterized by inflammation and edema <140 mm Hg to reduce the risk for recurrent stroke. of the renal interstitium and tubules, which generally improves ¢ Consider initiating or intensifying pharmacologic treat- after the offending drug is discontinued or the underlying dis- ment in some patients 260 years of age at high cardiovas- ease is treated (see Acute Kidney Injury). Chronic TIN (CTIN) cular risk, based on individualized assessment, to achieve causes a slow decline in kidney function over months and years a target systolic BP <140 mm Hg to reduce the risk for and is characterized by interstitial scarring, fibrosis, and tubu- stroke or cardiac events. lar atrophy. Acute interstitial nephritis can progress to CTIN

On the other hand, a 2017 guideline from the American College of Physicians and American Academy of Family Physicians (http: //annals.org/aim/article/2598413/pharmacologic- treatment-hypertension-adultsaged-60-years-older-higher- Chronic Tubulointerstitial versus) addressed the treatment of hypertension in patients 260 years of age, including three recommendations: Nephritis e Initiate treatment in patients >60 years of age with a Epidemiology and systolic BP persistently >150 mm Hg to achieve a target Pathophysiology systolic BP <150 mm Hg to reduce the risk for mortality, Tubulointerstitial nephritis (TIN) is characterized by damage to stroke, and cardiac events. the renal tubules and interstitium. TIN can be acute or chronic. ¢ Consider initiating or intensifying pharmacologic treat- Acute interstitial nephritis is commonly due to allergic drug ment in patients 260 years of age with a history of stroke reactions or infection and can cause acute kidney injury within or transient ischemic attack to achieve a target systolic BP days to weeks. It is characterized by inflammation and edema <140 mm Hg to reduce the risk for recurrent stroke. of the renal interstitium and tubules, which generally improves ¢ Consider initiating or intensifying pharmacologic treat- after the offending drug is discontinued or the underlying dis- ment in some patients 260 years of age at high cardiovas- ease is treated (see Acute Kidney Injury). Chronic TIN (CTIN) cular risk, based on individualized assessment, to achieve causes a slow decline in kidney function over months and years a target systolic BP <140 mm Hg to reduce the risk for and is characterized by interstitial scarring, fibrosis, and tubu- stroke or cardiac events. lar atrophy. Acute interstitial nephritis can progress to CTIN Non-Black older patients without CKD can be treated with a over time. CTIN can also develop in the setting of chronic

On the other hand, a 2017 guideline from the American College of Physicians and American Academy of Family Physicians (http: //annals.org/aim/article/2598413/pharmacologic- treatment-hypertension-adultsaged-60-years-older-higher- Chronic Tubulointerstitial versus) addressed the treatment of hypertension in patients 260 years of age, including three recommendations: Nephritis e Initiate treatment in patients >60 years of age with a Epidemiology and systolic BP persistently >150 mm Hg to achieve a target Pathophysiology systolic BP <150 mm Hg to reduce the risk for mortality, Tubulointerstitial nephritis (TIN) is characterized by damage to stroke, and cardiac events. the renal tubules and interstitium. TIN can be acute or chronic. ¢ Consider initiating or intensifying pharmacologic treat- Acute interstitial nephritis is commonly due to allergic drug ment in patients 260 years of age with a history of stroke reactions or infection and can cause acute kidney injury within or transient ischemic attack to achieve a target systolic BP days to weeks. It is characterized by inflammation and edema <140 mm Hg to reduce the risk for recurrent stroke. of the renal interstitium and tubules, which generally improves ¢ Consider initiating or intensifying pharmacologic treat- after the offending drug is discontinued or the underlying dis- ment in some patients 260 years of age at high cardiovas- ease is treated (see Acute Kidney Injury). Chronic TIN (CTIN) cular risk, based on individualized assessment, to achieve causes a slow decline in kidney function over months and years a target systolic BP <140 mm Hg to reduce the risk for and is characterized by interstitial scarring, fibrosis, and tubu- stroke or cardiac events. lar atrophy. Acute interstitial nephritis can progress to CTIN Non-Black older patients without CKD can be treated with a over time. CTIN can also develop in the setting of chronic thiazide diuretic, CCB, or ACE inhibitor or ARB, similar to patients primary glomerular disease, vascular diseases, and ischemia

On the other hand, a 2017 guideline from the American College of Physicians and American Academy of Family Physicians (http: //annals.org/aim/article/2598413/pharmacologic- treatment-hypertension-adultsaged-60-years-older-higher- Chronic Tubulointerstitial versus) addressed the treatment of hypertension in patients 260 years of age, including three recommendations: Nephritis e Initiate treatment in patients >60 years of age with a Epidemiology and systolic BP persistently >150 mm Hg to achieve a target Pathophysiology systolic BP <150 mm Hg to reduce the risk for mortality, Tubulointerstitial nephritis (TIN) is characterized by damage to stroke, and cardiac events. the renal tubules and interstitium. TIN can be acute or chronic. ¢ Consider initiating or intensifying pharmacologic treat- Acute interstitial nephritis is commonly due to allergic drug ment in patients 260 years of age with a history of stroke reactions or infection and can cause acute kidney injury within or transient ischemic attack to achieve a target systolic BP days to weeks. It is characterized by inflammation and edema <140 mm Hg to reduce the risk for recurrent stroke. of the renal interstitium and tubules, which generally improves ¢ Consider initiating or intensifying pharmacologic treat- after the offending drug is discontinued or the underlying dis- ment in some patients 260 years of age at high cardiovas- ease is treated (see Acute Kidney Injury). Chronic TIN (CTIN) cular risk, based on individualized assessment, to achieve causes a slow decline in kidney function over months and years a target systolic BP <140 mm Hg to reduce the risk for and is characterized by interstitial scarring, fibrosis, and tubu- stroke or cardiac events. lar atrophy. Acute interstitial nephritis can progress to CTIN Non-Black older patients without CKD can be treated with a over time. CTIN can also develop in the setting of chronic thiazide diuretic, CCB, or ACE inhibitor or ARB, similar to patients primary glomerular disease, vascular diseases, and ischemia <65 years of age. Antihypertensive medications should be initi- secondary to atherosclerosis and hypertension.

Non-Black older patients without CKD can be treated with a over time. CTIN can also develop in the setting of chronic thiazide diuretic, CCB, or ACE inhibitor or ARB, similar to patients primary glomerular disease, vascular diseases, and ischemia <65 years of age. Antihypertensive medications should be initi- secondary to atherosclerosis and hypertension. ated at lower doses with close monitoring of BP and adverse events, given that older individuals are more prone to drug-drug interactions, hyponatremia from thiazide diuretics, and ortho- Diagnosis and Evaluation static hypotension when treated with diuretics, vasodilators, CTIN is often asymptomatic until severe loss of kidney func- o-blockers, and central-acting drugs (such as clonidine). tion occurs. Patients frequently present with only an elevated serum creatinine, although they may have symptoms such as polyuria and nocturia due to renal concentrating defects. ¢ Women of childbearing age who anticipate pregnancy A careful history with a review of medications and symp- should not be prescribed renin-angiotensin system toms suggesting nonpharmacologic triggers should be per- agents because of the risk for urogenital developmental formed to determine the cause of CTIN (Table 19 and Table 20). abnormalities. A thorough physical examination infrequently provides clues ¢ In the absence of chronic kidney disease, first-line to the diagnosis. Patients may be hypertensive. Urinalysis may therapy for hypertension in non-Black patients with be normal or demonstrate pyuria and/or proteinuria diabetes mellitus is similar to treatment of patients <1500 mg/24 h. Nonalbumin proteinuria will require a random

¢ In the absence of chronic kidney disease, first-line to the diagnosis. Patients may be hypertensive. Urinalysis may therapy for hypertension in non-Black patients with be normal or demonstrate pyuria and/or proteinuria diabetes mellitus is similar to treatment of patients <1500 mg/24 h. Nonalbumin proteinuria will require a random without diabetes: a thiazide diuretic, calcium channel (spot) total protein-creatinine ratio determination. See Table 21 blocker, ACE inhibitor, or angiotensin receptor blocker. for other laboratory manifestations of CTIN. Kidney ultra- sound typically reveals small kidneys if disease is advanced. (Continued) Kidney biopsy may establish a definitive diagnosis. 41

Chronic Tubulointerstitial Nephritis TABLE 19. Pharmacologic Causes of TABLE 20. Nonpharmacologic Causes of Chronic Tubulointerstitial Nephritis Tubulointerstitial Nephritis Analgesics Immunologic Diseases Analgesic nephropathy (e.g., aspirin, caffeine, acetaminophen, Sarcoidosis NSAIDs [including COX-2 inhibitors]), or NSAID combinations) Sjdgren syndrome Antibiotics | Systemic lupus erythematosus Penicillins (e.g., amoxicillin, methicillin, oxacillin) | IgG4-related disease | Cephalosporins (e.g., cefazolin, cephalexin, cefoxitin) Tubulointerstitial nephritis with uveitis (TINU) Fluoroquinolones (e.g., ciprofloxacin, levofloxacin) Vasculitis Sulfonamides (e.g., trimethoprim-sulfamethoxazole) | Toxic Causes Macrolides (e.g., azithromycin, clarithromycin) Aristolochic acid (Balkan) nephropathy (urologic evaluation is | Rifampin indicated due to increased risk for transitional cell [urothelial] carcinoma) Calcineurin Inhibitors Heavy metal nephropathy (e.g., lead, cadmium, mercury, Cyclosporine _ arsenic, bismuth, chromium, copper, gold, iron, uranium) Tacrolimus Chronic interstitial nephritis in agricultural communities Antineoplastics | Hereditary Tubulointerstitial Nephritis

Analgesic nephropathy (e.g., aspirin, caffeine, acetaminophen, Sarcoidosis NSAIDs [including COX-2 inhibitors]), or NSAID combinations) Sjdgren syndrome Antibiotics | Systemic lupus erythematosus Penicillins (e.g., amoxicillin, methicillin, oxacillin) | IgG4-related disease | Cephalosporins (e.g., cefazolin, cephalexin, cefoxitin) Tubulointerstitial nephritis with uveitis (TINU) Fluoroquinolones (e.g., ciprofloxacin, levofloxacin) Vasculitis Sulfonamides (e.g., trimethoprim-sulfamethoxazole) | Toxic Causes Macrolides (e.g., azithromycin, clarithromycin) Aristolochic acid (Balkan) nephropathy (urologic evaluation is | Rifampin indicated due to increased risk for transitional cell [urothelial] carcinoma) Calcineurin Inhibitors Heavy metal nephropathy (e.g., lead, cadmium, mercury, Cyclosporine _ arsenic, bismuth, chromium, copper, gold, iron, uranium) Tacrolimus Chronic interstitial nephritis in agricultural communities Antineoplastics | Hereditary Tubulointerstitial Nephritis | Immune checkpoint inhibitors (e.g., atezolizumab, ipilimumab) Medullary cystic kidney disease | Tyrosine kinase inhibitors (e.g., sorafenib, sunitinib) Mitochondrial disorders lfosfamide Nephronophthisis Pemetrexed | Infection-Related Causes Lenalidomide _ Viruses (notably, BK polyoma virus after kidney transplantation, HIV) Vemurafenib Fungal infections Nitrosoureas (e.g., streptozotocin, semustine) | Parasitic infections Gastrointestinal Therapeutics Spirochetes Proton pump inhibitors (e.g., omeprazole, pantoprazole) Chronic pyelonephritis Hp blockers (e.g., ranitidine) Bacterial infections (e.g., brucellosis, tuberculosis) | 5-Aminosalicylates (e.g., mesalazine, sulfasalazine) Malignancy-Related Causes | Sodium phosphate (can cause phosphate nephropathy) Leukemia Drugs of Abuse Lymphoma | Synthetic cannabinoids Malignancy-associated monoclonal gammopathies (e.g., | Anabolic androgenic steroids multiple myeloma, plasmacytoma)

| Immune checkpoint inhibitors (e.g., atezolizumab, ipilimumab) Medullary cystic kidney disease | Tyrosine kinase inhibitors (e.g., sorafenib, sunitinib) Mitochondrial disorders lfosfamide Nephronophthisis Pemetrexed | Infection-Related Causes Lenalidomide _ Viruses (notably, BK polyoma virus after kidney transplantation, HIV) Vemurafenib Fungal infections Nitrosoureas (e.g., streptozotocin, semustine) | Parasitic infections Gastrointestinal Therapeutics Spirochetes Proton pump inhibitors (e.g., omeprazole, pantoprazole) Chronic pyelonephritis Hp blockers (e.g., ranitidine) Bacterial infections (e.g., brucellosis, tuberculosis) | 5-Aminosalicylates (e.g., mesalazine, sulfasalazine) Malignancy-Related Causes | Sodium phosphate (can cause phosphate nephropathy) Leukemia Drugs of Abuse Lymphoma | Synthetic cannabinoids Malignancy-associated monoclonal gammopathies (e.g., | Anabolic androgenic steroids multiple myeloma, plasmacytoma) Toluene Metabolic Disorders | Cocaine Oxalate nephropathy Other Uric acid nephropathy Antiretrovirals (e.g., abacavir, indinavir, tenofovir) Nephrocalcinosis Allopurinol Hypokalemic nephropathy Diuretics (e.g., thiazide, loop, potassium sparing) Urinary Tract Obstruction

Other Uric acid nephropathy Antiretrovirals (e.g., abacavir, indinavir, tenofovir) Nephrocalcinosis Allopurinol Hypokalemic nephropathy Diuretics (e.g., thiazide, loop, potassium sparing) Urinary Tract Obstruction Lithium Obstructive uropathy Antiepileptic drugs (e.g., carbamazepine, phenytoin, Nephrolithiasis phenobarbital) Reflux disease Antihypertensives (e.g., ACE inhibitors, angiotensin receptor blockers, calcium channel blockers) Prolonged exposure to any medication that can cause acute interstitial nephritis 42

Chronic Tubulointerstitial Nephritis TABLE 21. Laboratory Manifestations of Chronic Systemic Lupus Erythematosus Tubulointerstitial Nephritis TIN may occur in systemic lupus erythematosus and is often | Abnormality? Causes associated with concurrent glomerular disease, but can also be the only manifestation of lupus nephritis. The severity of TIN Decline in GFR Obstruction of tubules; damage to microvasculature; interstitial fibrosis is a useful predictor of progressive kidney disease. and sclerosis of glomeruli

| Abnormality? Causes associated with concurrent glomerular disease, but can also be the only manifestation of lupus nephritis. The severity of TIN Decline in GFR Obstruction of tubules; damage to microvasculature; interstitial fibrosis is a useful predictor of progressive kidney disease. and sclerosis of glomeruli Proximal tubular Incomplete absorption and kidney IgG4-Related Disease _ damage (Fanconi wasting of glucose, phosphate, uric TIN is the most common renal manifestation of systemic syndrome) acid, bicarbonate, and amino acids IgG4-related disease and is characterized by abundant IgG4- Normal anion gap Proximal and distal RTA; decreased positive plasma cell interstitial infiltrates. Other features may metabolic acidosis ammonia production include hypocomplementemia, peripheral eosinophilia, and Polyuria and Decreased concentrating and diluting || renal masses. See MKSAP 19 Rheumatology for more | isosthenuria ability | information. Proteinuria Decreased tubular protein reabsorption (usually <1500 mg/24 h) Infections | Hyperkalemia Defect in potassium secretion (type 4 [hyperkalemic] distal RTA) Certain infections are associated with acute interstitial nephri-

Proximal tubular Incomplete absorption and kidney IgG4-Related Disease _ damage (Fanconi wasting of glucose, phosphate, uric TIN is the most common renal manifestation of systemic syndrome) acid, bicarbonate, and amino acids IgG4-related disease and is characterized by abundant IgG4- Normal anion gap Proximal and distal RTA; decreased positive plasma cell interstitial infiltrates. Other features may metabolic acidosis ammonia production include hypocomplementemia, peripheral eosinophilia, and Polyuria and Decreased concentrating and diluting || renal masses. See MKSAP 19 Rheumatology for more | isosthenuria ability | information. Proteinuria Decreased tubular protein reabsorption (usually <1500 mg/24 h) Infections | Hyperkalemia Defect in potassium secretion (type 4 [hyperkalemic] distal RTA) Certain infections are associated with acute interstitial nephri- Hypokalemia Defect in potassium reabsorption | tis and can contribute to CTIN. Etiologies include bacterial (type 1 [hypokalemic] distal RTA) | (such as brucellosis and tuberculosis), viral, fungal, and para- | Anemia Injury to erythropoietin-producing sitic infections. cells in the kidney | In immunosuppressed patients with kidney transplants, GFR = glomerular filtration rate; RTA = renal tubular acidosis. BK polyoma virus causes an interstitial nephritis that is diffi- The degree of these abnormalities depends on the extent and location of injury. cult to distinguish by biopsy from acute cellular rejection. Urine and serum BK polyoma virus polymerase chain reaction titers and a specific BK stain (SV40) help determine etiology. The most effective intervention is reduction of immunosup- pressive therapy. ¢ Chronic tubulointerstitial nephritis is characterized by Chronic pyelonephritis resulting from chronic infections interstitial scarring, fibrosis, and tubular atrophy and results or vesicoureteral reflux may cause CTIN. Patients may present in a slow decline in kidney function over months and years. with fever, chills, dysuria, flank or back pain, and hyperten- e Features of chronic tubulointerstitial nephritis include sion. Persistent chronic pyelonephritis can progress to polyuria and nocturia due to renal concentrating localized xanthogranulomatous pyelonephritis, which is defects; hypertension; and a urinalysis that is normal or characterized by a destructive mass that invades the renal demonstrates pyuria and/or proteinuria <1500 mg/24 h. parenchyma. e Some clinical features of chronic tubulointerstitial nephri- tis may reflect tubular dysfunction, including glucosuria Malignancy and other features of Fanconi syndrome, normal anion gap Lymphoma and acute leukemia can infiltrate the kidney, metabolic acidosis, hypokalemia, or hyperkalemia. causing TIN. Presenting features include proteinuria, sterile pyuria, and enlarged kidneys. Plasma cell dyscrasias such as multiple myeloma can cause TIN in the form of myeloma cast Causes nephropathy, Fanconi syndrome, or interstitial light chain See Table 19 and Table 20 for the pharmacologic and nonphar- deposition. macologic causes of TIN.

Hypokalemia Defect in potassium reabsorption | tis and can contribute to CTIN. Etiologies include bacterial (type 1 [hypokalemic] distal RTA) | (such as brucellosis and tuberculosis), viral, fungal, and para- | Anemia Injury to erythropoietin-producing sitic infections. cells in the kidney | In immunosuppressed patients with kidney transplants, GFR = glomerular filtration rate; RTA = renal tubular acidosis. BK polyoma virus causes an interstitial nephritis that is diffi- The degree of these abnormalities depends on the extent and location of injury. cult to distinguish by biopsy from acute cellular rejection. Urine and serum BK polyoma virus polymerase chain reaction titers and a specific BK stain (SV40) help determine etiology. The most effective intervention is reduction of immunosup- pressive therapy. ¢ Chronic tubulointerstitial nephritis is characterized by Chronic pyelonephritis resulting from chronic infections interstitial scarring, fibrosis, and tubular atrophy and results or vesicoureteral reflux may cause CTIN. Patients may present in a slow decline in kidney function over months and years. with fever, chills, dysuria, flank or back pain, and hyperten- e Features of chronic tubulointerstitial nephritis include sion. Persistent chronic pyelonephritis can progress to polyuria and nocturia due to renal concentrating localized xanthogranulomatous pyelonephritis, which is defects; hypertension; and a urinalysis that is normal or characterized by a destructive mass that invades the renal demonstrates pyuria and/or proteinuria <1500 mg/24 h. parenchyma. e Some clinical features of chronic tubulointerstitial nephri- tis may reflect tubular dysfunction, including glucosuria Malignancy and other features of Fanconi syndrome, normal anion gap Lymphoma and acute leukemia can infiltrate the kidney, metabolic acidosis, hypokalemia, or hyperkalemia. causing TIN. Presenting features include proteinuria, sterile pyuria, and enlarged kidneys. Plasma cell dyscrasias such as multiple myeloma can cause TIN in the form of myeloma cast Causes nephropathy, Fanconi syndrome, or interstitial light chain See Table 19 and Table 20 for the pharmacologic and nonphar- deposition. macologic causes of TIN. Medications Immunologic Diseases Medication-induced acute interstitial nephritis (Table 19) may Sjogren Syndrome evolve to CTIN due to protracted exposure to an offending Kidney involvement in Sjogren syndrome may include inter- agent. The most common associated drug classes include anti- stitial nephritis, distal (type 1) renal tubular acidosis (RTA), and biotics, NSAIDs, and proton pump inhibitors. glomerulonephritis. Nephrolithiasis, nephrocalcinosis, and progressive kidney disease may also occur. Analgesics Sarcoidosis Analgesic nephropathy was first described in patients taking Kidney involvement in sarcoidosis is not uncommon and can combinations of phenacetin (banned since 1983) with aspirin, manifest as nephrocalcinosis from hypercalcemia and hyper- caffeine, acetaminophen, or NSAIDs. It can also occur with the calciuria, obstructive uropathy, and TIN with granuloma for- individual drugs. When severe, analgesic nephropathy is asso- mation. Kidney recovery is often incomplete. ciated with renal papillary necrosis, manifesting as gross

Medications Immunologic Diseases Medication-induced acute interstitial nephritis (Table 19) may Sjogren Syndrome evolve to CTIN due to protracted exposure to an offending Kidney involvement in Sjogren syndrome may include inter- agent. The most common associated drug classes include anti- stitial nephritis, distal (type 1) renal tubular acidosis (RTA), and biotics, NSAIDs, and proton pump inhibitors. glomerulonephritis. Nephrolithiasis, nephrocalcinosis, and progressive kidney disease may also occur. Analgesics Sarcoidosis Analgesic nephropathy was first described in patients taking Kidney involvement in sarcoidosis is not uncommon and can combinations of phenacetin (banned since 1983) with aspirin, manifest as nephrocalcinosis from hypercalcemia and hyper- caffeine, acetaminophen, or NSAIDs. It can also occur with the calciuria, obstructive uropathy, and TIN with granuloma for- individual drugs. When severe, analgesic nephropathy is asso- mation. Kidney recovery is often incomplete. ciated with renal papillary necrosis, manifesting as gross 43