ADVANCE ARTICLE: JCEM
THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
Renin Phenotypes Characterize Vascular Disease, Autonomous Aldosteronism, and Mineralocorticoid Receptor Activity
Gregory L. Hundemer, Rene Baudrand, Jenifer M. Brown, Gary Curhan, Gordon H. Williams, Anand Vaidya The Journal of Clinical Endocrinology & Metabolism Endocrine Society Submitted: December 06, 2016 Accepted: February 14, 2017 First Online: February 17, 2017
Advance Articles are PDF versions of manuscripts that have been peer reviewed and accepted but not yet copyedited. The manuscripts are published online as soon as possible after acceptance and before the copyedited, typeset articles are published. They are posted "as is" (i.e., as submitted by the authors at the modification stage), and do not reflect editorial changes. No corrections/changes to the PDF manuscripts are accepted. Accordingly, there likely will be differences between the Advance Article manuscripts and the final, typeset articles. The manuscripts remain listed on the Advance Article page until the final, typeset articles are posted. At that point, the manuscripts are removed from the Advance Article page.
DISCLAIMER: These manuscripts are provided "as is" without warranty of any kind, either express or particular purpose, or non-infringement. Changes will be made to these manuscripts before publication. Review and/or use or reliance on these materials is at the discretion and risk of the reader/user. In no event shall the Endocrine Society be liable for damages of any kind arising references to, products or publications do not imply endorsement of that product or publication.
The Journal of Clinical Endocrinology & Metabolism; Copyright 2017
DOI: 10.1210/jc.2016-3867
Autonomous aldosteronism and renin stimulation
Renin Phenotypes Characterize Vascular Disease, Autonomous Aldosteronism, and Mineralocorticoid Receptor Activity Gregory L. Hundemer1, Rene Baudrand2, Jenifer M. Brown3, Gary Curhan1, Gordon H. Williams3, Anand Vaidya3 Division of Renal Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
LE
1
2 Program for Adrenal Disorders and Endocrine Hypertension, Department of Endocrinology, Pontificia Universidad Catolica de Chile School of Medicine, Santiago, Chile 3
T IC
Received 06 December 2016. Accepted 14 February 2017.
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Context: Mild cases of autonomous aldosterone secretion may go unrecognized using current diagnostic criteria for primary aldosteronism (PA). Objective: To investigate whether the inability to stimulate renin serves as a biomarker for unrecognized autonomous aldosterone secretion and mineralocorticoid receptor (MR) activation. Participants: 663 normotensive and mildly hypertensive participants, who were confirmed to not have PA using current guideline criteria and were on no antihypertensive medications. Design: Participants had their maximally stimulated plasma renin activity (PRA) measured while standing upright after sodium restriction. Tertiles of maximally stimulated PRA were hypothesized to reflect the degree of MR activation: lowest PRA tertile= “Inappropriate/Excess MR Activity”; middle PRA tertile = “Intermediate MR Activity”; highest PRA tertile= “Physiologic MR Activity”. All participants underwent detailed biochemical and vascular characterizations under conditions of liberalized sodium intake and associations with stimulated PRA phenotypes were performed. Results: Participants with lower stimulated PRA had greater autonomous aldosterone secretion (higher aldosterone-to-renin ratio [P = 0.002], higher urine aldosterone excretion rate [P = 0.003]), higher systolic blood pressure [P = 0.004], lower renal plasma flow [P = 0.04]), and a non-significant trend toward lower serum potassium and higher urine potassium excretion which became significant after stratification by hypertension status. Conclusions: In participants without clinical PA, the inability to stimulate renin was associated with greater autonomous aldosterone secretion, impaired vascular function, and suggestive trends in potassium handling that indicate an extensive spectrum of unrecognized autonomous aldosterone secretion and MR activation. In individuals without primary aldosteronism, the inability to stimulate renin is associated with unrecognized autonomous aldosterone secretion and excessive mineralocorticoid receptor activation.
A
ADVANCE ARTICLE: Endocrine ADVANCE ARTICLE: JCEM Reviews
THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
Center for Adrenal Disorders, Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
Introduction: Primary aldosteronism (PA) is regarded as a form of autonomous aldosterone secretion that is independent of renin and angiotensin II and results in a syndrome of inappropriate and excessive mineralocorticoid receptor (MR) activation. The current screening and diagnostic recommendations for detecting PA (1) focus on diagnosing the more severe and overt instances of renin-independent aldosteronism, usually attributable to an aldosterone-producing adenoma or bilateral adrenal hyperplasia. However, milder forms of autonomous aldosterone secretion have 1
The Journal of Clinical Endocrinology & Metabolism; Copyright 2017
DOI: 10.1210/jc.2016-3867
T IC
R
A
E
C
N
Materials and Methods:
Study Population and Study Protocol
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A
Participants for the current cross-sectional analyses were from the Hypertensive Pathotype (HyperPATH) cohort, which has been described in detail previously. (14,15) Briefly, normotensive and stage I hypertensive subjects were recruited to participate in the HyperPATH study protocol. Normotensives were defined by blood pressure (BP) 12 mcg/24h with urine sodium excretion >200 mmol/24h OR urine aldosterone excretion rate >10 mcg/24h with urine sodium excretion >200 mmol/24h and an aldosterone-to-renin ratio (ARR) >30 ng/dL per ng/mL/h. The resultant study population was 663 participants for the current analysis. A random subset of this population (N=440) had RPF measured. Some of the data presented herein have been published previously from the HyperPATH cohort; however, the current analyses are original and have not been reported previously.
Statistical Analysis
Our analytic approach was to assess whether hypothesized stimulated renin and MR activation phenotypes corresponded to the expected degrees of autonomous aldosterone secretion, vascular function, and MR activity (Figure 1). Participants were categorized based on their sodium
3
The Journal of Clinical Endocrinology & Metabolism; Copyright 2017
DOI: 10.1210/jc.2016-3867
T IC
Autonomous Aldosterone Secretion RAAS phenotypes (PRA, serum aldosterone, ARR, and urine aldosterone excretion rate) were compared across categories of stimulated PRA using multivariate linear regression analyses in order to assess for differences in autonomous aldosterone secretion. This allowed for testing of our hypothesis that participants with lower stimulated PRA and higher MR activity would have greater autonomous aldosterone secretion.
E
A
R
Vascular Phenotypes BP and RPF were compared across categories of stimulated PRA using multivariate linear regression analyses in order to assess for differences in vascular function. We also measured the salt sensitivity of BP and RPF (calculated as the values on the liberal sodium diet minus the values on the restricted sodium diet) as these have been shown to associate with aldosterone excess in prior studies. (19-21) These measures allowed for testing of our hypothesis that participants with lower stimulated PRA and greater MR activity would have the most impaired vascular function.
D V
A
N
C
MR Activity (Potassium Regulation) Serum potassium concentration and urine potassium excretion were compared across categories of stimulated PRA using multivariate linear regression analyses. These measures allowed for testing of our hypothesis that participants with lower stimulated PRA had correspondingly greater MR activity as demonstrated by lower serum potassium concentration and higher urine potassium excretion. Age, (22-24) sex, (23,25,26) race, (27,28) and diabetes (29,30) are all potential confounders of the associations with RAAS, BP, and RPF. Additionally, recent studies have shown that visceral adiposity increases RAAS activity via extra-adrenal aldosterone synthesis by adipocytes. (31-34) Accordingly, age, sex, race, diabetes status, and body mass index (BMI), along with the 24h urine sodium excretion, were included in all of our regression models. Additionally, stratified analyses based on hypertension status were performed for RPF and potassium regulation. A P-value
THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
Renin Phenotypes Characterize Vascular Disease, Autonomous Aldosteronism, and Mineralocorticoid Receptor Activity
Gregory L. Hundemer, Rene Baudrand, Jenifer M. Brown, Gary Curhan, Gordon H. Williams, Anand Vaidya The Journal of Clinical Endocrinology & Metabolism Endocrine Society Submitted: December 06, 2016 Accepted: February 14, 2017 First Online: February 17, 2017
Advance Articles are PDF versions of manuscripts that have been peer reviewed and accepted but not yet copyedited. The manuscripts are published online as soon as possible after acceptance and before the copyedited, typeset articles are published. They are posted "as is" (i.e., as submitted by the authors at the modification stage), and do not reflect editorial changes. No corrections/changes to the PDF manuscripts are accepted. Accordingly, there likely will be differences between the Advance Article manuscripts and the final, typeset articles. The manuscripts remain listed on the Advance Article page until the final, typeset articles are posted. At that point, the manuscripts are removed from the Advance Article page.
DISCLAIMER: These manuscripts are provided "as is" without warranty of any kind, either express or particular purpose, or non-infringement. Changes will be made to these manuscripts before publication. Review and/or use or reliance on these materials is at the discretion and risk of the reader/user. In no event shall the Endocrine Society be liable for damages of any kind arising references to, products or publications do not imply endorsement of that product or publication.
The Journal of Clinical Endocrinology & Metabolism; Copyright 2017
DOI: 10.1210/jc.2016-3867
Autonomous aldosteronism and renin stimulation
Renin Phenotypes Characterize Vascular Disease, Autonomous Aldosteronism, and Mineralocorticoid Receptor Activity Gregory L. Hundemer1, Rene Baudrand2, Jenifer M. Brown3, Gary Curhan1, Gordon H. Williams3, Anand Vaidya3 Division of Renal Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
LE
1
2 Program for Adrenal Disorders and Endocrine Hypertension, Department of Endocrinology, Pontificia Universidad Catolica de Chile School of Medicine, Santiago, Chile 3
T IC
Received 06 December 2016. Accepted 14 February 2017.
D V
A
N
C
E
A
R
Context: Mild cases of autonomous aldosterone secretion may go unrecognized using current diagnostic criteria for primary aldosteronism (PA). Objective: To investigate whether the inability to stimulate renin serves as a biomarker for unrecognized autonomous aldosterone secretion and mineralocorticoid receptor (MR) activation. Participants: 663 normotensive and mildly hypertensive participants, who were confirmed to not have PA using current guideline criteria and were on no antihypertensive medications. Design: Participants had their maximally stimulated plasma renin activity (PRA) measured while standing upright after sodium restriction. Tertiles of maximally stimulated PRA were hypothesized to reflect the degree of MR activation: lowest PRA tertile= “Inappropriate/Excess MR Activity”; middle PRA tertile = “Intermediate MR Activity”; highest PRA tertile= “Physiologic MR Activity”. All participants underwent detailed biochemical and vascular characterizations under conditions of liberalized sodium intake and associations with stimulated PRA phenotypes were performed. Results: Participants with lower stimulated PRA had greater autonomous aldosterone secretion (higher aldosterone-to-renin ratio [P = 0.002], higher urine aldosterone excretion rate [P = 0.003]), higher systolic blood pressure [P = 0.004], lower renal plasma flow [P = 0.04]), and a non-significant trend toward lower serum potassium and higher urine potassium excretion which became significant after stratification by hypertension status. Conclusions: In participants without clinical PA, the inability to stimulate renin was associated with greater autonomous aldosterone secretion, impaired vascular function, and suggestive trends in potassium handling that indicate an extensive spectrum of unrecognized autonomous aldosterone secretion and MR activation. In individuals without primary aldosteronism, the inability to stimulate renin is associated with unrecognized autonomous aldosterone secretion and excessive mineralocorticoid receptor activation.
A
ADVANCE ARTICLE: Endocrine ADVANCE ARTICLE: JCEM Reviews
THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
Center for Adrenal Disorders, Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
Introduction: Primary aldosteronism (PA) is regarded as a form of autonomous aldosterone secretion that is independent of renin and angiotensin II and results in a syndrome of inappropriate and excessive mineralocorticoid receptor (MR) activation. The current screening and diagnostic recommendations for detecting PA (1) focus on diagnosing the more severe and overt instances of renin-independent aldosteronism, usually attributable to an aldosterone-producing adenoma or bilateral adrenal hyperplasia. However, milder forms of autonomous aldosterone secretion have 1
The Journal of Clinical Endocrinology & Metabolism; Copyright 2017
DOI: 10.1210/jc.2016-3867
T IC
R
A
E
C
N
Materials and Methods:
Study Population and Study Protocol
D V
A
Participants for the current cross-sectional analyses were from the Hypertensive Pathotype (HyperPATH) cohort, which has been described in detail previously. (14,15) Briefly, normotensive and stage I hypertensive subjects were recruited to participate in the HyperPATH study protocol. Normotensives were defined by blood pressure (BP) 12 mcg/24h with urine sodium excretion >200 mmol/24h OR urine aldosterone excretion rate >10 mcg/24h with urine sodium excretion >200 mmol/24h and an aldosterone-to-renin ratio (ARR) >30 ng/dL per ng/mL/h. The resultant study population was 663 participants for the current analysis. A random subset of this population (N=440) had RPF measured. Some of the data presented herein have been published previously from the HyperPATH cohort; however, the current analyses are original and have not been reported previously.
Statistical Analysis
Our analytic approach was to assess whether hypothesized stimulated renin and MR activation phenotypes corresponded to the expected degrees of autonomous aldosterone secretion, vascular function, and MR activity (Figure 1). Participants were categorized based on their sodium
3
The Journal of Clinical Endocrinology & Metabolism; Copyright 2017
DOI: 10.1210/jc.2016-3867
T IC
Autonomous Aldosterone Secretion RAAS phenotypes (PRA, serum aldosterone, ARR, and urine aldosterone excretion rate) were compared across categories of stimulated PRA using multivariate linear regression analyses in order to assess for differences in autonomous aldosterone secretion. This allowed for testing of our hypothesis that participants with lower stimulated PRA and higher MR activity would have greater autonomous aldosterone secretion.
E
A
R
Vascular Phenotypes BP and RPF were compared across categories of stimulated PRA using multivariate linear regression analyses in order to assess for differences in vascular function. We also measured the salt sensitivity of BP and RPF (calculated as the values on the liberal sodium diet minus the values on the restricted sodium diet) as these have been shown to associate with aldosterone excess in prior studies. (19-21) These measures allowed for testing of our hypothesis that participants with lower stimulated PRA and greater MR activity would have the most impaired vascular function.
D V
A
N
C
MR Activity (Potassium Regulation) Serum potassium concentration and urine potassium excretion were compared across categories of stimulated PRA using multivariate linear regression analyses. These measures allowed for testing of our hypothesis that participants with lower stimulated PRA had correspondingly greater MR activity as demonstrated by lower serum potassium concentration and higher urine potassium excretion. Age, (22-24) sex, (23,25,26) race, (27,28) and diabetes (29,30) are all potential confounders of the associations with RAAS, BP, and RPF. Additionally, recent studies have shown that visceral adiposity increases RAAS activity via extra-adrenal aldosterone synthesis by adipocytes. (31-34) Accordingly, age, sex, race, diabetes status, and body mass index (BMI), along with the 24h urine sodium excretion, were included in all of our regression models. Additionally, stratified analyses based on hypertension status were performed for RPF and potassium regulation. A P-value
