GUEST EDITORIAL
Secondary Hypertension: Beginnings and Transitions .it is well to recognize that the extra pressure is a necessity–as purely a mechanical affair as in any great irrigation system with old encrusted mains and weedy channels.Get it out of your heads, if possible, that the high pressure is the primary feature, and particularly the feature to treat.1,2 –Sir William Osler
A
lthough the concept of essential hypertension was not formulated by Osler, it has been recognized for more than 100 years that hypertension is a frequent companion to aging.2 In the National Health and Nutrition Examination Survey 2011 to 2012, 29.1% of US adults aged 18 and older were diagnosed with hypertension. The prevalence increased with age from 7.3% in those aged 18 to 39 to 65.0% of participants 60 years and older, with health care costs totaling $73.4 billion in 2009.3,4 Worldwide hypertension remains a similarly pressing public health emergency, afflicting approximately 22% of the world’s adult population in 2014.5 Fortunately, the recognition that essential hypertension is neither necessary nor desirable has evolved during this period, but the mechanisms of disease for a given individual often remain undefined. Within this common disorder exists a small fraction of hypertensive individuals for whom the possibility of an identifiable—or secondary—etiology exists.6 The prevalence of secondary hypertension among individuals with high blood pressure is not well defined but is often stated around 5% to 10%.7,8 This proportion grows substantially in individuals with resistant hypertension, generally defined as uncontrolled hypertension despite 3 appropriately selected and dosed medications including a diuretic.9 In such patients, primary hyperaldosteronism alone may contribute to approximately 20% of cases.10 In addition to truly resistant hypertension, other features warranting screening for secondary etiologies include onset of hypertension before the age of 30, worsening of previously well-controlled pressure, notable electrolyte abnormalities, intolerance of renin-angiotensin-aldosterone system antagonists, and signs or symptoms of associated co-morbid conditions (eg, thyrotoxicosis, Cushing’s syndrome, etc.).11 With an etiology in hand, physicians frequently entice patients with the potential for cure or at least marked improvement on directed therapy. In that regard, success has been variable, with many patients diagnosed with a secondary etiology having persistent hypertension despite etiology-targeted therapy. This speaks to the complexity of hypertension and the absence of a solitary pathway to high blood pressure. Although the utility of definitive diagnosis to the individual patient is still beneficial, the true public health value of understanding secondary etiologies is the light it shines on those encrusted pipes of essential hypertension. The unraveling of mechanisms and therapy for sec-
ondary etiologies of hypertension increases our understanding of the complex physiology that may contribute to age-associated increases in blood pressure. In this issue of Advances in Chronic Kidney Disease, selected clinically relevant etiologies of secondary hypertension and an examination of intriguing mechanisms are addressed by leading experts in the field. The regulation of sodium balance is fundamental to the Guytonian model of blood pressure regulation. This is borne out by the recognition that most monogenic etiologies of hypertension—Liddle’s syndrome for example—involve abnormal sodium transport in the kidney. Dr Ray and colleagues explore the mechanisms of hypertension and volume expansion in nephrotic syndrome, with attention to the growing appreciation for the tubular signals responsible for mediating sodium transport in the distal nephron. The primacy of sodium balance in secondary forms of hypertension is expanded further by the review of mineralocorticoid and apparent mineralocorticoid excess syndromes by Dr Ardhanari and colleagues. Hyperaldosteronism is a leading cause of secondary and resistant hypertension that deserves frequent consideration, and discoveries of the past several years have begun to unravel the genomics of aldosterone-producing adenomas. The optimal approach to therapy of primary hyperaldosteronism is then examined by Dr Steichen and colleagues. A common yet difficult diagnosis to evaluate accurately, hyperaldosteronism can be effectively managed both medically and surgically. The authors discuss indications for and outcomes of each approach and provide practical clinical pearls to guide management decisions in the setting of often ambiguous laboratory data. Medical therapy may also have particular relevance to patients lacking a diagnosis of primary hyperaldosteronism, given the growing recognition of elevated aldosterone levels in essential hypertension and the efficacy of mineralocorticoid antagonists in treating resistant disease. Dr Carey explores the growing understanding of the role of the intrarenal renin-angiotensin system (RAS) in hypertension. He details the role of the intrarenal RAS in generation and maintenance of hypertension, mechanisms of action, and novel intrarenal RAS pathways of potential clinical significance in the treatment of hypertension. These pathways are increasingly recognized to be of importance in RAS-mediated blood pressure control and in mechanisms of hypertension associated with obesity.
Financial Disclosure: The authors declare that they have no relevant financial interests. Ó 2015 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2015.03.001
Advances in Chronic Kidney Disease, Vol 22, No 3 (May), 2015: pp 177-178
177
178
Sperati and Whaley-Connell
This role for obesity in secondary and resistant hypertension is taken up by Dr Rao and colleagues. An epidemic itself, obesity has far-reaching implications for metabolic pathways and cardiovascular health, the seeds of which are often planted in childhood. The high prevalence of obesity in young individuals has altered the demographics of secondary hypertension in individuals younger than 30 years, with obesity now a major etiology of hypertension in this age group. The pathophysiology of obesity-related hypertension and the role of the RAS are highlighted, as are therapeutic strategies based on an understanding of these principles. One characteristic of obesity-associated hypertension is activation of the sympathetic nervous system. From systemic autonomic changes in obesity to catecholamine overproduction of pheochromocytoma, catecholamine excess is a well-recognized hypertensive mechanism. Less commonly discussed, however, is the entity of pseudopheochromocytoma. Drs Garcha and Cohen provide an update on this entity and discuss the roles of antihypertensive agents, psychoactive medications, and psychotherapy in the management of pseudopheochromocytoma and paroxysmal hypertension. Drs Kwon and Lerman provide an update on the current status of atherosclerotic renal artery stenosis in light of recent clinical trials that have dampened enthusiasm for percutaneous revascularization of stenotic lesions. Nevertheless, most hypertension specialists can describe patients who have derived remarkable benefit from revascularization, highlighting the need for improved identification of appropriate candidates for intervention. Mechanisms of RAS activation, oxidative stress, inflammation, and fibrosis remain central to the pathogenesis of hypertension and CKD in this disorder. The authors integrate these mechanisms with the development of novel imaging techniques that may eventually permit identification of appropriate candidates for percutaneous revascularization. Drs Hamlyn and Manunta then nicely integrate many of the preceding concepts—namely sodium, RAS, mineralocorticoids, and the sympathetic nervous system—with endogenous cardiotonic steroids in the pathogenesis of hypertension in ESRD. These long recognized but difficult to study hormones are implicated in organ fibrosis, vascular stiffness, and consequent hypertension, and they hold clues to novel antihypertensive agents, the “lag phenomenon” of blood pressure response in dialysis patients, and potentially myopathy in CKD. Lastly, in recognition that we are often our own worst enemy, Drs Kassel and Odum elegantly review pharmacologic etiologies of hypertension and describe best management practice. In an era of both prescribed and over-the-counter polypharmacy, the use of medicinal agents has become an important but often difficult to address pathway in the development of secondary hypertension.
The realm of secondary hypertension is exciting and illustrative. The study of secondary hypertension promises to usher in a new era of understanding and therapeutics for potentially billions of people with high blood pressure. As medicine, in general, transitions away from primary and secondary classifications of disease, the beginning of mechanism-based descriptions for the categorization of hypertensive patients has begun to take shape. C. John Sperati, MD, MHS Division of Nephrology Department of Medicine Johns Hopkins University School of Medicine Baltimore, MD Adam Whaley-Connell, DO, MSPH, MEd Division of Nephrology and Hypertension Department of Medicine University of Missouri-Columbia School of Medicine Harry S. Truman Memorial Veterans Hospital Columbia, MO REFERENCES 1. Osler W. An address on high blood pressure: its associations, advantages, and disadvantages: Delivered at the Glasgow Southern Medical Society. Br Med J. 1912;2:1173-1177. 2. Kotchen TA. Historical trends and milestones in hypertension research: a model of the process of translational research. Hypertension. 2011;58:522-538. 3. Nwankwo T, Yoon SS, Burt V, Gu Q. Hypertension among adults in the United States: national health and nutrition examination survey, 2011-2012. NCHS Data Brief. 2013;12(133):1-8. 4. Cohen JD. Hypertension epidemiology and economic burden: refining risk assessment to lower costs. Manag Care. 2009;18:51-58. 5. Global Status Report on Noncommunicable Diseases. In: Mendis SG, ed. Geneva: World Health Organization; 2011. 6. Vongpatanasin W. Resistant hypertension: a review of diagnosis and management. JAMA. 2014;311:2216-2224. 7. Anderson GH, Blakeman N, Streeten DH. The effect of age on prevalence of secondary forms of hypertension in 4429 consecutively referred patients. J Hypertens. 1994;12:609-615. 8. Omura M, Saito J, Yamaguchi K, Kakuta Y, Nishikawa T. Prospective study on the prevalence of secondary hypertension among hypertensive patients visiting a general outpatient clinic in Japan. Hypertens Res. 2004;27:193-202. 9. White WB, Turner JR, Sica DA, et al. Detection, evaluation, and treatment of severe and resistant hypertension. Proceedings from an American Society of Hypertension Interactive Forum held in Bethesda, MD, USA, October 10, 2013. J Am Soc Hypertens. 2014;8(10):743-757. 10. Epstein M, Calhoun DA. The role of aldosterone in resistant hypertension: Implications for pathogenesis and therapy. Curr Hypertens Rep. 2007;9:98-105. 11. Rimoldi SF, Scherrer U, Messerli FH. Secondary arterial hypertension: when, who, and how to screen? Eur Heart J. 2014;35(19): 1245-1254.
Secondary Hypertension: Beginnings and Transitions .it is well to recognize that the extra pressure is a necessity–as purely a mechanical affair as in any great irrigation system with old encrusted mains and weedy channels.Get it out of your heads, if possible, that the high pressure is the primary feature, and particularly the feature to treat.1,2 –Sir William Osler
A
lthough the concept of essential hypertension was not formulated by Osler, it has been recognized for more than 100 years that hypertension is a frequent companion to aging.2 In the National Health and Nutrition Examination Survey 2011 to 2012, 29.1% of US adults aged 18 and older were diagnosed with hypertension. The prevalence increased with age from 7.3% in those aged 18 to 39 to 65.0% of participants 60 years and older, with health care costs totaling $73.4 billion in 2009.3,4 Worldwide hypertension remains a similarly pressing public health emergency, afflicting approximately 22% of the world’s adult population in 2014.5 Fortunately, the recognition that essential hypertension is neither necessary nor desirable has evolved during this period, but the mechanisms of disease for a given individual often remain undefined. Within this common disorder exists a small fraction of hypertensive individuals for whom the possibility of an identifiable—or secondary—etiology exists.6 The prevalence of secondary hypertension among individuals with high blood pressure is not well defined but is often stated around 5% to 10%.7,8 This proportion grows substantially in individuals with resistant hypertension, generally defined as uncontrolled hypertension despite 3 appropriately selected and dosed medications including a diuretic.9 In such patients, primary hyperaldosteronism alone may contribute to approximately 20% of cases.10 In addition to truly resistant hypertension, other features warranting screening for secondary etiologies include onset of hypertension before the age of 30, worsening of previously well-controlled pressure, notable electrolyte abnormalities, intolerance of renin-angiotensin-aldosterone system antagonists, and signs or symptoms of associated co-morbid conditions (eg, thyrotoxicosis, Cushing’s syndrome, etc.).11 With an etiology in hand, physicians frequently entice patients with the potential for cure or at least marked improvement on directed therapy. In that regard, success has been variable, with many patients diagnosed with a secondary etiology having persistent hypertension despite etiology-targeted therapy. This speaks to the complexity of hypertension and the absence of a solitary pathway to high blood pressure. Although the utility of definitive diagnosis to the individual patient is still beneficial, the true public health value of understanding secondary etiologies is the light it shines on those encrusted pipes of essential hypertension. The unraveling of mechanisms and therapy for sec-
ondary etiologies of hypertension increases our understanding of the complex physiology that may contribute to age-associated increases in blood pressure. In this issue of Advances in Chronic Kidney Disease, selected clinically relevant etiologies of secondary hypertension and an examination of intriguing mechanisms are addressed by leading experts in the field. The regulation of sodium balance is fundamental to the Guytonian model of blood pressure regulation. This is borne out by the recognition that most monogenic etiologies of hypertension—Liddle’s syndrome for example—involve abnormal sodium transport in the kidney. Dr Ray and colleagues explore the mechanisms of hypertension and volume expansion in nephrotic syndrome, with attention to the growing appreciation for the tubular signals responsible for mediating sodium transport in the distal nephron. The primacy of sodium balance in secondary forms of hypertension is expanded further by the review of mineralocorticoid and apparent mineralocorticoid excess syndromes by Dr Ardhanari and colleagues. Hyperaldosteronism is a leading cause of secondary and resistant hypertension that deserves frequent consideration, and discoveries of the past several years have begun to unravel the genomics of aldosterone-producing adenomas. The optimal approach to therapy of primary hyperaldosteronism is then examined by Dr Steichen and colleagues. A common yet difficult diagnosis to evaluate accurately, hyperaldosteronism can be effectively managed both medically and surgically. The authors discuss indications for and outcomes of each approach and provide practical clinical pearls to guide management decisions in the setting of often ambiguous laboratory data. Medical therapy may also have particular relevance to patients lacking a diagnosis of primary hyperaldosteronism, given the growing recognition of elevated aldosterone levels in essential hypertension and the efficacy of mineralocorticoid antagonists in treating resistant disease. Dr Carey explores the growing understanding of the role of the intrarenal renin-angiotensin system (RAS) in hypertension. He details the role of the intrarenal RAS in generation and maintenance of hypertension, mechanisms of action, and novel intrarenal RAS pathways of potential clinical significance in the treatment of hypertension. These pathways are increasingly recognized to be of importance in RAS-mediated blood pressure control and in mechanisms of hypertension associated with obesity.
Financial Disclosure: The authors declare that they have no relevant financial interests. Ó 2015 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2015.03.001
Advances in Chronic Kidney Disease, Vol 22, No 3 (May), 2015: pp 177-178
177
178
Sperati and Whaley-Connell
This role for obesity in secondary and resistant hypertension is taken up by Dr Rao and colleagues. An epidemic itself, obesity has far-reaching implications for metabolic pathways and cardiovascular health, the seeds of which are often planted in childhood. The high prevalence of obesity in young individuals has altered the demographics of secondary hypertension in individuals younger than 30 years, with obesity now a major etiology of hypertension in this age group. The pathophysiology of obesity-related hypertension and the role of the RAS are highlighted, as are therapeutic strategies based on an understanding of these principles. One characteristic of obesity-associated hypertension is activation of the sympathetic nervous system. From systemic autonomic changes in obesity to catecholamine overproduction of pheochromocytoma, catecholamine excess is a well-recognized hypertensive mechanism. Less commonly discussed, however, is the entity of pseudopheochromocytoma. Drs Garcha and Cohen provide an update on this entity and discuss the roles of antihypertensive agents, psychoactive medications, and psychotherapy in the management of pseudopheochromocytoma and paroxysmal hypertension. Drs Kwon and Lerman provide an update on the current status of atherosclerotic renal artery stenosis in light of recent clinical trials that have dampened enthusiasm for percutaneous revascularization of stenotic lesions. Nevertheless, most hypertension specialists can describe patients who have derived remarkable benefit from revascularization, highlighting the need for improved identification of appropriate candidates for intervention. Mechanisms of RAS activation, oxidative stress, inflammation, and fibrosis remain central to the pathogenesis of hypertension and CKD in this disorder. The authors integrate these mechanisms with the development of novel imaging techniques that may eventually permit identification of appropriate candidates for percutaneous revascularization. Drs Hamlyn and Manunta then nicely integrate many of the preceding concepts—namely sodium, RAS, mineralocorticoids, and the sympathetic nervous system—with endogenous cardiotonic steroids in the pathogenesis of hypertension in ESRD. These long recognized but difficult to study hormones are implicated in organ fibrosis, vascular stiffness, and consequent hypertension, and they hold clues to novel antihypertensive agents, the “lag phenomenon” of blood pressure response in dialysis patients, and potentially myopathy in CKD. Lastly, in recognition that we are often our own worst enemy, Drs Kassel and Odum elegantly review pharmacologic etiologies of hypertension and describe best management practice. In an era of both prescribed and over-the-counter polypharmacy, the use of medicinal agents has become an important but often difficult to address pathway in the development of secondary hypertension.
The realm of secondary hypertension is exciting and illustrative. The study of secondary hypertension promises to usher in a new era of understanding and therapeutics for potentially billions of people with high blood pressure. As medicine, in general, transitions away from primary and secondary classifications of disease, the beginning of mechanism-based descriptions for the categorization of hypertensive patients has begun to take shape. C. John Sperati, MD, MHS Division of Nephrology Department of Medicine Johns Hopkins University School of Medicine Baltimore, MD Adam Whaley-Connell, DO, MSPH, MEd Division of Nephrology and Hypertension Department of Medicine University of Missouri-Columbia School of Medicine Harry S. Truman Memorial Veterans Hospital Columbia, MO REFERENCES 1. Osler W. An address on high blood pressure: its associations, advantages, and disadvantages: Delivered at the Glasgow Southern Medical Society. Br Med J. 1912;2:1173-1177. 2. Kotchen TA. Historical trends and milestones in hypertension research: a model of the process of translational research. Hypertension. 2011;58:522-538. 3. Nwankwo T, Yoon SS, Burt V, Gu Q. Hypertension among adults in the United States: national health and nutrition examination survey, 2011-2012. NCHS Data Brief. 2013;12(133):1-8. 4. Cohen JD. Hypertension epidemiology and economic burden: refining risk assessment to lower costs. Manag Care. 2009;18:51-58. 5. Global Status Report on Noncommunicable Diseases. In: Mendis SG, ed. Geneva: World Health Organization; 2011. 6. Vongpatanasin W. Resistant hypertension: a review of diagnosis and management. JAMA. 2014;311:2216-2224. 7. Anderson GH, Blakeman N, Streeten DH. The effect of age on prevalence of secondary forms of hypertension in 4429 consecutively referred patients. J Hypertens. 1994;12:609-615. 8. Omura M, Saito J, Yamaguchi K, Kakuta Y, Nishikawa T. Prospective study on the prevalence of secondary hypertension among hypertensive patients visiting a general outpatient clinic in Japan. Hypertens Res. 2004;27:193-202. 9. White WB, Turner JR, Sica DA, et al. Detection, evaluation, and treatment of severe and resistant hypertension. Proceedings from an American Society of Hypertension Interactive Forum held in Bethesda, MD, USA, October 10, 2013. J Am Soc Hypertens. 2014;8(10):743-757. 10. Epstein M, Calhoun DA. The role of aldosterone in resistant hypertension: Implications for pathogenesis and therapy. Curr Hypertens Rep. 2007;9:98-105. 11. Rimoldi SF, Scherrer U, Messerli FH. Secondary arterial hypertension: when, who, and how to screen? Eur Heart J. 2014;35(19): 1245-1254.
