Adam Whaley-Connell

Narrative Review: The Emerging Clinical Implications of the Role of Aldosterone in the Metabolic Syndrome and Resistant Hypertension

Pathophysiology A new paradigm indicates that elevated levels of plasma aldosterone mediate several maladaptive changes that contribute to the pathogenesis of the metabolic syndrome, resistant hypertension, and associated cardiovascular and renal structural and functional abnormalities. Accumulating evidence indicates that adipose tissue produces aldosterone secretory factors that promote excessive adrenal aldosterone production. Elevated plasma aldosterone levels in turn promote insulin resistance, inflammation, oxidative stress, and sodium retention. These maladaptive processes contribute to the development of a hypertensive state that is relatively resistant to pharmacologic therapy. Clinical Implications Evidence is emerging that mineralocorticoid receptor blockade is useful in treating hypertensive patients who have both the metabolic syndrome and resistant hypertension. Mineralocorticoid antagonism therapy seems to have considerable clinical utility for reducing cardiovascular and renal disease associated with the metabolic syndrome, diabetes, and resistant hypertension. The prevalences of obesity, diabetes, hypertension, and cardiovascular and chronic kidney disease are increasing in the United States. Data from NHANES (National Health and Nutrition Examination Survey) III suggest that the prevalence of hypertension increases progressively with increasing body mass index from about 15% among people with a body mass index less than 25 kg/m2 to approximately 40% among those with a body mass index of 30 kg/m2 or greater (1). Obesity, insulin resistance, and hypertension commonly cluster with other risk factors for cardiovascular or chronic kidney disease to form the metabolic syndrome, which is associated with increased cardiovascular disease morbidity and mortality (15). Our understanding of the role of the reninangiotensinaldosterone system in insulin resistance through the action of aldosterone has undergone a paradigm shift in recent years. We know now that aldosterone participates in the pathogenesis of the metabolic syndrome (46). Recent evidence shows that elevated plasma aldosterone levels directly contribute to the pathogenesis of insulin resistance and endothelial dysfunction, processes that in turn contribute to maladaptive renal and cardiovascular remodeling (46). These actions of aldosterone promote the development of resistant hypertensiondefined as the need for 3 or more antihypertensive medications to control blood pressurein association with obesity and the metabolic syndrome. The Emergence of a New Paradigm for Aldosterone Aldosterone was isolated and characterized by Simpson and Tait (7) more than 50 years ago and was initially termed electrocortin. During the subsequent 4 decades, clinicians and medical investigators thought of aldosterone as acting primarily to regulate extracellular fluid volume and potassium handling. Classic agonistantagonist experiments in the toad bladder model in the 1960s (7, 8) revealed that alterations in sodiumpotassium ion flux did not occur immediately after aldosterone administration. This delay was due to aldosterones binding to cytosolic steroid receptors; translocation to the nucleus; interaction with DNA; and, finally, genomic transcription and translation of effector proteins. Investigators applied molecular biology techniques over the next several decades to understand aldosterone-mediated gene transcription and subsequent protein synthesis (8, 9). In 1992, investigators reported rapid, nongenomic effects of aldosterone that did not require signaling through the classic pathways of gene activation, transcription, and protein synthesis. These nongenomic actions included regulation of intracellular cations, cell volume, redox status, metabolic signaling, and endothelial-mediated relaxation (5, 8, 10). It is increasingly evident that these nongenomic effects, which occur independent of hemodynamic factors, are a substantial part of the mechanisms by which aldosterone contributes to the pathogenesis of the metabolic syndrome and resistant hypertension, as well as enhanced risk for cardiovascular and chronic kidney disease (915). Regulation of Aldosterone Secretion and Mineralocorticoid Receptor Activation For decades, we believed that activation of the reninangiotensin system, largely in response to intravascular volume contraction, regulated the biosynthesis of aldosterone (59). Hyperaldosteronism may occur when the relationship between salt ingestion or volume status and aldosterone secretion is perturbed (Figure 1). In fact, inappropriate aldosterone secretion occurs in diverse disease states, including the metabolic syndrome, heart failure, and chronic kidney disease, despite high salt and volume retention. Figure 1. Systemic effects of aldosterone on insulin sensitivity and hypertension. High salt intake, obesity, inactivity, and other environmental factors interact to activate the reninangiotensinaldosterone system, with subsequent inflammation and oxidative stress that drive maladaptive tissue responses. ACE = angiotensin-converting enzyme; ACTH = adrenocorticotropic hormone; Aldo = aldosterone; Ang I = angiotensin I; Ang II = angiotensin II; ASCVD = atherosclerotic cardiovascular disease; AT1 = angiotensin type 1 receptor; AT2 = angiotensin type 2 receptor; CAD = coronary artery disease; CHF = congestive heart failure; CRH = corticotropin-releasing hormone; LVH = left ventricular hypertrophy; MR = mineralocorticoid receptor; SNS = sympathetic nervous system. Mounting evidence in recent years suggests that mineralocorticoid receptors on the surface of nonepithelial cells send extracellular signals that do not require gene transcription for their action. These so-called nongenomic actions of aldosterone are involved in the pathophysiology of insulin resistance and endothelial dysfunction (Figure 1). The mineralocorticoid receptor has a high affinity for both aldosterone and 11-hydroxyglucocorticoids (4). Cells at the distal end of the nephron have relatively high levels of the enzyme 11-hydroxysteroid dehydrogenase, which prevents glucocorticoids from acting in the distal tubule and collecting duct. However, cardiovascular and metabolic tissue, such as skeletal muscle, liver, and fat, have much lower levels of this enzyme, which allows glucocorticoids to signal through the mineralocorticoid receptors (25). This signaling is particularly important in persons with the metabolic syndrome, because they have circulating glucocorticoid concentrations that are several orders of magnitude greater than their aldosterone concentrations. Mineralocorticoid receptor activation by glucocorticoids promotes inflammation, oxidative stress, fibrosis, insulin resistance, and endothelial dysfunction (5, 9, 10). Aldosterone Antagonists 17-Spirolactone steroids, or spirolactones, were developed 50 years ago to antagonize the action of aldosterone and other sodium-retaining hormones on the renal distal tubule (12). Initially, the mineralocorticoid receptor antagonist spironolactone was used widely as a potassium-sparing diuretic in volume-overload states, such as congestive heart failure, cirrhosis, and primary hyperaldosteronism (8, 12). Later, RALES (Randomized Aldactone Evaluation Study) (14) showed that mineralocorticoid receptor antagonists reduced cardiovascular events. This study demonstrated that a low dose of spironolactone improved morbidity and mortality in patients with severe heart failure. Subsequently, EPHESUS (Eplerenone Post-AMI Heart Failure Efficacy and Survival Study) (15) demonstrated that treatment with eplerenone, a selective mineralocorticoid receptor antagonist, reduced mortality after myocardial infarction. These studies refocused attention on aldosterones effects on the mineralocorticoid receptors of nonrenal cells and have allowed investigators to use both spironolactone and eplerenone as pharmacologic probes to delineate the role of aldosterone and mineralocorticoid receptor signaling in various clinical disorders. Eplerenone is a newer, selective mineralocorticoid receptor antagonist that offers the same benefits as generic spironolactone, but it is no longer actively promoted. The protective effects of mineralocorticoid receptor blockade complement the effects of reninangiotensin system blockade (6). Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists act on the angiotensin peptides and receptors, respectively, and also suppress aldosterone secretion by the adrenal glands. Although the clinical effects are not fully elucidated, the complementary actions of these 2 classes of drugs provide a potential framework for treating various disorders, including resistant hypertension, cardiovascular disease, and chronic kidney disease. The Role of Aldosterone in Resistant Hypertension Resistant hypertension is defined as hypertension that requires more than 3 drugs in full doses to adequately control pressure. It is an increasingly common condition in industrialized nations (1623) that parallels the exponential growth in global obesity and the diabetes and chronic kidney disease epidemics (4, 5). Mounting evidence suggests that an elevated aldosterone level, in association with obesity and insulin resistance, contributes not only to salt retention and volume expansion but also to the inflammation and oxidative stress that promote the development of the metabolic syndrome and resistant hypertension (Figure 1) (46). The 17% to 22% prevalence of primary aldosteronism in individuals with resistant hypertension, which is much higher than that in the general population with hypertension, suggests a relationship between elevated aldosterone levels and resistant hypertension (1923). Moreover, individuals with resistant hypertension but without primary hyperaldosteronism have higher aldosterone levels and greater intravascular volume expansion than do control participants (17). The elevated 24-hour urinary levels of both

Diabetic Kidney Disease: A Report From an ADA Consensus Conference

The incidence and prevalence of diabetes mellitus have grown significantly throughout the world, due primarily to the increase in type 2 diabetes. This overall increase in the number of people with diabetes has had a major impact on development of diabetic kidney disease (DKD), one of the most frequent complications of both types of diabetes. DKD is the leading cause of end-stage renal disease (ESRD), accounting for approximately 50% of cases in the developed world. Although incidence rates for ESRD attributable to DKD have recently stabilized, these rates continue to rise in high-risk groups such as middle-aged African Americans, Native Americans, and Hispanics. The costs of care for people with DKD are extraordinarily high. In the Medicare population alone, DKD-related expenditures among this mostly older group were nearly

Mitochondrial biogenesis in the metabolic syndrome and cardiovascular disease

25 billion in 2011. Due to the high human and societal costs, the Consensus Conference on Chronic Kidney Disease and Diabetes was convened by the American Diabetes Association in collaboration with the American Society of Nephrology and the National Kidney Foundation to appraise issues regarding patient management, highlighting current practices and new directions. Major topic areas in DKD included 1) identification and monitoring, 2) cardiovascular disease and management of dyslipidemia, 3) hypertension and use of renin-angiotensin-aldosterone system blockade and mineralocorticoid receptor blockade, 4) glycemia measurement, hypoglycemia, and drug therapies, 5) nutrition and general care in advanced-stage chronic kidney disease, 6) children and adolescents, and 7) multidisciplinary approaches and medical home models for health care delivery. This current state summary and research recommendations are designed to guide advances in care and the generation of new knowledge that will meaningfully improve life for people with DKD.

Prevalence of CKD and Comorbid Illness in Elderly Patients in the United States: Results From the Kidney Early Evaluation Program (KEEP)

The metabolic syndrome is a constellation of metabolic disorders including obesity, hypertension, and insulin resistance, components which are risk factors for the development of diabetes, hypertension, cardiovascular, and renal disease. Pathophysiological abnormalities that contribute to the development of the metabolic syndrome include impaired mitochondrial oxidative phosphorylation and mitochondrial biogenesis, dampened insulin metabolic signaling, endothelial dysfunction, and associated myocardial functional abnormalities. Recent evidence suggests that impaired myocardial mitochondrial biogenesis, fatty acid metabolism, and antioxidant defense mechanisms lead to diminished cardiac substrate flexibility, decreased cardiac energetic efficiency, and diastolic dysfunction. In addition, enhanced activation of the renin–angiotensin–aldosterone system and associated increases in oxidative stress can lead to mitochondrial apoptosis and degradation, altered bioenergetics, and accumulation of lipids in the heart. In addition to impairments in metabolic signaling and oxidative stress, genetic and environmental factors, aging, and hyperglycemia all contribute to reduced mitochondrial biogenesis and mitochondrial dysfunction. These mitochondrial abnormalities can predispose a metabolic cardiomyopathy characterized by diastolic dysfunction. Mitochondrial dysfunction and resulting lipid accumulation in skeletal muscle, liver, and pancreas also impede insulin metabolic signaling and glucose metabolism, ultimately leading to a further increase in mitochondrial dysfunction. Interventions to improve mitochondrial function have been shown to correct insulin metabolic signaling and other metabolic and cardiovascular abnormalities. This review explores mechanisms of mitochondrial dysfunction with a focus on impaired oxidative phosphorylation and mitochondrial biogenesis in the pathophysiology of metabolic heart disease.

Chronic kidney disease, prevalence of premature cardiovascular disease, and relationship to short-term mortality

BACKGROUND Elderly individuals with chronic kidney disease (CKD) have high rates of comorbid conditions, including cardiovascular disease and its risk factors, and CKD-related complications. In individuals aged > or = 65 years, we sought to describe the prevalence of CKD determined from laboratory test results in the Kidney Early Evaluation Program (KEEP; n = 27,017) and National Health and Nutrition Examination Survey (NHANES) 1999-2006 (n = 5,538) and the prevalence of diagnosed CKD determined from billing codes in the Medicare 5% sample (n = 1,236,946). In all 3 data sources, we also explored comorbid conditions and CKD-related complications. METHODS CKD was identified as decreased estimated glomerular filtration rate (<60 mL/min/1.73 m(2)) or increased albumin-creatinine ratio in KEEP and NHANES; CKD was identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes in Medicare. Investigated comorbid conditions included diabetes, hypertension, high cholesterol level, coronary artery disease, congestive heart failure, cerebrovascular disease, peripheral vascular disease, and cancer, and CKD-related complications included anemia, hypocalcemia, hyperphosphatemia, and hyperparathyroidism. RESULTS The prevalence of CKD was approximately 44% in both KEEP and NHANES participants, and the prevalence of diagnosed CKD was 7% in Medicare beneficiaries. In all 3 data sets, the prevalence of CKD or diagnosed CKD was higher in participants aged > or = 80 years and those with comorbid conditions. For KEEP and NHANES participants, the prevalence of most comorbid conditions and CKD complications increased with decreasing estimated glomerular filtration rate. For participants with CKD stages 3-5, a total of 29.2% (95% CI, 27.8-30.6) in KEEP and 19.9% (95% CI, 17.0-23.1) in NHANES had anemia, 0.7% (95% CI, 0.4-0.9) and 0.6% (95% CI, 0.3-1.3) had hypocalcemia, 5.4% (95% CI, 4.7-6.1) and 6.4% (95% CI, 5.1-8.0) had hyperphosphatemia, and 52.0% (95% CI, 50.4-53.6) and 30.0% (95% CI, 25.9-34.3) had hyperparathyroidism, respectively. CONCLUSIONS CKD is common in the elderly population and is associated with high frequencies of concomitant comorbid conditions and biochemical abnormalities. Because CKD is not commonly diagnosed, greater emphasis on physician education may be beneficial.

CKD in the United States: Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES) 1999-2004

BACKGROUND Chronic kidney disease (CKD) is recognized as an independent cardiovascular disease (CVD) risk state, particularly in the elderly, and has been defined by levels of estimated glomerular filtration rate (eGFR) and markers of kidney damage. The relationship between CKD and CVD in younger and middle-aged adults has not been fully explored. METHODS Community volunteers completed surveys regarding past medical events and underwent blood pressure and laboratory testing. Chronic kidney disease was defined as an eGFR <60 mL x min(-1) x 1.73 m(-2) or urine albumin-creatinine ratio (ACR) > or =30 mg/g. Premature CVD was defined as self-reported myocardial infarction or stroke at <55 years of age in men and <65 years of age in women. Mortality was ascertained by linkage to national data systems. RESULTS Of 31 417 participants, the mean age was 45.1 +/- 11.2 years, 75.5% were female, 36.8% African American, and 21.6% had diabetes. A total of 20.6% were found to have CKD, with the ACR and eGFR being the dominant positive screening tests in the younger and older age deciles, respectively. The prevalences of premature myocardial infarction (MI), stroke, or death, and the composite were 5.3%, 4.7%, 0.8%, 9.2%, and 2.5%, 2.2%, 0.2%, 4.2% for those with and without CKD, respectively (P < .0001 for composite). Multivariable analysis found CKD (OR 1.44, 95% CI 1.27-1.63), age (OR 1.05 [per year], 95% CI 1.04-1.06), hypertension (OR 1.61, 95% CI 1.40-1.84), diabetes (OR 2.03, 95% CI 1.79-2.29), smoking (OR 1.91, 95% CI 1.66-2.21), and less than high school education (OR 1.59, 95% CI 1.37-1.85) as the most significantly associated factors for premature CVD or death (all P < .0001). Survival analysis found those with premature MI or stroke and CKD had the poorest short-term survival over the next 3 years after screening. CONCLUSIONS Chronic kidney disease is an independent predictor of MI, stroke, and death among men and women younger than age 55 and 65 years, respectively. These data suggest the biologic changes that occur with kidney failure promote CVD at an accelerated rate that cannot be fully explained by conventional risk factors or older age. Screening for CKD by using both the ACR and eGFR can identify younger and middle-aged individuals at high risk for premature CVD and near-term death.

CKD and cardiovascular disease in screened high-risk volunteer and general populations: the Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES) 1999-2004.

BACKGROUND The prevalence of chronic kidney disease (CKD) is increasing in the United States, caused in part by older age and increasing prevalences of hypertension and type 2 diabetes. CKD is silent and undetected until advanced stages. The study of populations with earlier stages of kidney disease may improve outcomes of CKD. METHODS The Kidney Early Evaluation Program (KEEP), a National Kidney Foundation program, is a targeted community-based health-screening program enrolling individuals 18 years and older with diabetes, hypertension, or family history of kidney disease, diabetes, or hypertension. Participants who had received transplants or were on regular dialysis treatment were excluded from this analysis. The National Health and Nutrition Examination Survey (NHANES) 1999-2004 was a nationally representative cross-sectional survey; participants were interviewed in their homes and/or received standardized medical examinations in mobile examination centers. RESULTS Of the 61,675 KEEP participants, 16,689 (27.1%) were found to have CKD. In the NHANES sample of 14,632 participants, 2,734 (15.3%) had CKD. Older age, smoking, obesity, diabetes, hypertension, and cardiovascular disease were associated significantly with CKD in both KEEP and NHANES (P < 0.05 for all). Of note, the likelihood for CKD in African Americans differed between KEEP (odds ratio, 0.81; P < 0.001) and NHANES (odds ratio, 1.10; P = 0.2). CONCLUSION A greater prevalence of CKD was detected in the KEEP screening than in the NHANES data. KEEP has the limitations common to population-screening studies and conclusions for population-attributable risk may be limited. The targeted nature of the KEEP screening program and the large sample size with clinical characteristics comparable to NHANES validates KEEP as a valuable cohort to explore health associations for the CKD and at-risk-for-CKD populations in the United States.

Aldosterone: Role in the Cardiometabolic Syndrome and Resistant Hypertension

BACKGROUND Chronic kidney disease (CKD) is recognized as an independent cardiovascular disease risk state. The relationship between CKD and cardiovascular disease in volunteer and general populations has not been explored. METHODS The National Kidney Foundation Kidney Early Evaluation Program (KEEP) is a community-based health-screening program to raise kidney disease awareness and detect CKD for early disease intervention in individuals 18 years or older with diabetes, hypertension, or family history of kidney disease, diabetes, or hypertension. KEEP volunteers completed surveys and underwent blood pressure and laboratory testing. Estimated glomerular filtration rate (eGFR) was computed, and urine albumin-creatinine ratio (ACR) was measured. In KEEP, CKD was defined as eGFR less than 60 mL/min/1.73 m(2) or ACR of 30 mg/g or greater. Cardiovascular disease was defined as self-reported myocardial infarction or stroke. Data were compared with National Health and Nutrition Examination Survey (NHANES) 1999-2004 data for prevalence of cardiovascular disease risk factors and cardiovascular outcomes. RESULTS Of 69,244 KEEP participants, mean age was 53.4 +/- 15.7 years, 68.3% were women, 33.0% were African American, and 27.6% had diabetes. Of 17,061 NHANES participants, mean age was 45.1 +/- 0.27 years, 52% were women, 11.2% were African American, and 6.7% had diabetes. In KEEP, 26.8% had CKD, and in NHANES, 15.3%. ACR was the dominant positive screening test for younger age groups, and eGFR, for older age groups, for both populations. Prevalences of myocardial infarction or stroke were 16.5% in KEEP and 15.1% in NHANES (P < 0.001) and 7.8% in KEEP and 3.7% in NHANES (P < 0.001) for individuals with and without CKD, respectively. In adjusted analysis of both KEEP and NHANES data, CKD was associated with a significantly increased risk of prevalent myocardial infarction or stroke (odds ratio, 1.34; 95% confidence interval, 1.25 to 1.43; odds ratio, 1.37; 95% confidence interval, 1.10 to 1.70, respectively). In KEEP, short-term mortality was greater in individuals with CKD (1.52 versus 0.33 events/1,000 patient-years). CONCLUSIONS CKD is independently associated with myocardial infarction or stroke in participants in a voluntary screening program and a randomly selected survey population. Heightened concerns regarding risks in volunteers yielded greater cardiovascular disease prevalence in KEEP, which was associated with increased short-term mortality.

Redox Control of Renal Function and Hypertension

The prevalence of diabetes, hypertension, and cardiovascular disease (CVD) and chronic kidney disease (CKD) is increasing in concert with obesity. Insulin resistance, metabolic dyslipidemia, central obesity, albuminuria. and hypertension commonly cluster to comprise the cardiometabolic syndrome (CMS). Emerging evidence supports a shift in our understanding of the crucial role of elevated serum aldosterone in promoting insulin resistance and resistant hypertension. Aldosterone enhances tissue generation of oxygen free radicals and systemic inflammation. This increase in oxidative stress and inflammation, in turn, contributes to impaired insulin metabolic signaling, reduced endothelial-mediated vasorelaxation, and associated cardiovascular and renal structural and functional abnormalities. In this context, recent investigation indicates that hyperaldosteronism, which is often associated with obesity, contributes to impaired pancreatic beta-cell function as well as diminished skeletal muscle insulin metabolic signaling. Accumulating evidence indicates that the cardiovascular and renal abnormalities associated with insulin resistance are mediated, in part, by aldosterones nongenomic as well as genomic signaling through the mineralocorticoid receptor (MR). In the CMS, there are increased circulating levels of glucocorticoids, which can also activate MR signaling in cardiovascular, adipose, skeletal muscle, neuronal, and liver tissue. Furthermore, there is increasing evidence that fat tissue produces a lipid soluble factor that stimulates aldosterone production from the adrenal zona glomerulosa. Recently, we have learned that MR blockade improves pancreatic insulin release, insulin-mediated glucose utilization, and endothelium-dependent vasorelaxation as well as reduces the progression of CVD and CKD. In summary, aldosterone excess exerts detrimental metabolic effects that contribute to the development of the CMS and resistant hypertension as well as CVD and CKD.

Comparison of the CKD Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) Study Equations: Risk Factors for and Complications of CKD and Mortality in the Kidney Early Evaluation Program (KEEP)

Loss of redox homeostasis and formation of excessive free radicals play an important role in the pathogenesis of kidney disease and hypertension. Free radicals such as reactive oxygen species (ROS) are necessary in physiologic processes. However, loss of redox homeostasis contributes to proinflammatory and profibrotic pathways in the kidney, which in turn lead to reduced vascular compliance and proteinuria. The kidney is susceptible to the influence of various extracellular and intracellular cues, including the renin-angiotensin-aldosterone system (RAAS), hyperglycemia, lipid peroxidation, inflammatory cytokines, and growth factors. Redox control of kidney function is a dynamic process with reversible pro- and anti-free radical processes. The imbalance of redox homeostasis within the kidney is integral in hypertension and the progression of kidney disease. An emerging paradigm exists for renal redox contribution to hypertension.