Biomarkers to Guide Medical Therapy in Primary Aldosteronism.

Primary aldosteronism (PA) is an endocrinopathy characterized by dysregulated aldosterone production that occurs despite suppression of renin and angiotensin II, and that is non-suppressible by volume and sodium loading. The effectiveness of surgical adrenalectomy for patients with lateralizing PA is characterized by the attenuation of excess aldosterone production leading to blood pressure reduction, correction of hypokalemia, and increases in renin-biomarkers that collectively indicate a reversal of PA pathophysiology and restoration of normal physiology. Even though the vast majority of patients with PA will ultimately be treated medically rather than surgically, there is a lack of guidance on how to optimize medical therapy and on key metrics of success. Herein, we review the evidence justifying approaches to medical management of PA and biomarkers that reflect endocrine principles of restoring normal physiology. We review the current arsenal of medical therapies, including dietary sodium restriction, steroidal and nonsteroidal mineralocorticoid receptor antagonists, epithelial sodium channel inhibitors, and aldosterone synthase inhibitors. It is crucial that clinicians recognize that multimodal medical treatment for PA can be highly effective at reducing the risk for adverse cardiovascular and kidney outcomes when titrated with intention. The key biomarkers reflective of optimized medical therapy are unsurprisingly similar to the physiologic expectations following surgical adrenalectomy: control of blood pressure with the fewest number of antihypertensive agents, normalization of serum potassium without supplementation, and a rise in renin. Pragmatic approaches to achieve these objectives while mitigating adverse effects are reviewed.

Primary Aldosteronism in Chronic Kidney Disease: Blood Pressure Control and Kidney and Cardiovascular Outcomes After Surgical Versus Medical Management.

BACKGROUND: Diagnosis and treatment of primary aldosteronism (PA) in chronic kidney disease (CKD) may be deferred due to limited evidence supporting safety and efficacy of treatment. Our goal was to assess clinical outcomes in patients with PA and CKD who received surgical or medical management. METHODS: We conducted a multicenter, retrospective cohort study of patients with PA and CKD who underwent adrenal vein sampling from 2009-2019. We characterized clinical outcomes and evaluated differences by surgical versus medical management. Primary outcomes were systolic blood pressure and number of antihypertensive medications. Secondary outcomes were diastolic blood pressure, serum potassium, estimated glomerular filtration rate (eGFR), and kidney and cardiovascular events. Analyses were adjusted for age, sex, race, cardiovascular disease, diabetes, and eGFR. RESULTS: Of 239 participants with PA and CKD, 158 (66%) underwent adrenalectomy, and 81 (34%) were treated medically. Mean age was 57±10 years, 67% were female, mean eGFR was 45±12 mL/min per 1.73 m2, and 49% were on potassium supplementation. At 5 years, mean blood pressure decreased from 149±22/85±14 to 131±28/78±16 mm Hg and mean number of antihypertensive medications decreased from 4.0±1.5 to 2.4±1.4. Adrenalectomy, compared to medical management, was associated with similar systolic blood pressure (-0.90 mm Hg [95% CI, -6.99 to 5.07]) but fewer medications (1.7 [95% CI, -2.24 to -1.10]), and no difference in potassium levels or kidney or cardiovascular outcomes. CONCLUSIONS: Patients with PA and CKD are likely to benefit from either surgical adrenalectomy or medical management. Detection and treatment of PA may help to reduce blood pressure and medication burden in patients with CKD.

Evolution of the Primary Aldosteronism Syndrome: Updating the Approach.

CONTEXT: New approaches are needed to address the evolution of the primary aldosteronism syndrome and to increase its recognition. Herein, we review evidence indicating that primary aldosteronism is a prevalent syndrome that is mostly unrecognized, and present a pragmatic and pathophysiology-based approach to improve diagnosis and treatment. METHODS: Evidence was gathered from published guidelines and studies identified from PubMed by searching for primary aldosteronism, aldosterone, renin, and hypertension. This evidence was supplemented by the authors' personal knowledge, research experience, and clinical encounters in primary aldosteronism. INTERPRETATION OF EVIDENCE: Renin-independent aldosterone production is a prevalent phenotype that is diagnosed as primary aldosteronism when severe in magnitude, but is largely unrecognized when milder in severity. Renin-independent aldosterone production can be detected in normotensive and hypertensive individuals, and the magnitude of this biochemical phenotype parallels the magnitude of blood pressure elevation, the risk for incident hypertension and cardiovascular disease, and the likelihood and magnitude of blood pressure reduction with mineralocorticoid receptor antagonist therapy. Expansion of the indications to screen for primary aldosteronism, combined with the use of a pathophysiology-based approach that emphasizes inappropriate aldosterone production in the context of renin suppression, will substantially increase the diagnostic and therapeutic yields for primary aldosteronism. CONCLUSIONS: The landscape of primary aldosteronism has evolved to recognize that it is a prevalent syndrome of renin-independent aldosterone production that contributes to the pathogenesis of hypertension and cardiovascular disease. Expanding screening indications and simplifying the diagnostic approach will enable implementation of targeted treatment for primary aldosteronism.

Low Bone Density and Bisphosphonate Use and the Risk of Kidney Stones.

BACKGROUND AND OBJECTIVES: Previous studies have demonstrated lower bone density in patients with kidney stones, but no longitudinal studies have evaluated kidney stone risk in individuals with low bone density. Small studies with short follow-up reported reduced 24-hour urine calcium excretion with bisphosphonate use. We examined history of low bone density and bisphosphonate use and the risk of incident kidney stone as well as the association with 24-hour calcium excretion. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a prospective analysis of 96,092 women in the Nurses' Health Study II. We used Cox proportional hazards models to adjust for age, body mass index, thiazide use, fluid intake, supplemental calcium use, and dietary factors. We also conducted a cross-sectional analysis of 2294 participants using multivariable linear regression to compare 24-hour urinary calcium excretion between participants with and without a history of low bone density, and among 458 participants with low bone density, with and without bisphosphonate use. RESULTS: We identified 2564 incident stones during 1,179,860 person-years of follow-up. The multivariable adjusted relative risk for an incident kidney stone for participants with history of low bone density compared with participants without was 1.39 (95% confidence interval [95% CI], 1.20 to 1.62). Among participants with low bone density, the multivariable adjusted relative risk for an incident kidney stone for bisphosphonate users was 0.68 (95% CI, 0.48 to 0.98). In the cross-sectional analysis of 24-hour urine calcium excretion, the multivariable adjusted mean difference in 24-hour calcium was 10 mg/d (95% CI, 1 to 19) higher for participants with history of low bone density. However, among participants with history of low bone density, there was no association between bisphosphonate use and 24-hour calcium with multivariable adjusted mean difference in 24-hour calcium of -2 mg/d (95% CI, -25 to 20). CONCLUSIONS: Low bone density is an independent risk factor for incident kidney stone and is associated with higher 24-hour urine calcium excretion. Among participants with low bone density, bisphosphonate use was associated with lower risk of incident kidney stone but was not independently associated with 24-hour urine calcium excretion.

Human interventions to characterize novel relationships between the renin-angiotensin-aldosterone system and parathyroid hormone.

Observational studies in primary hyperaldosteronism suggest a positive relationship between aldosterone and parathyroid hormone (PTH); however, interventions to better characterize the physiological relationship between the renin-angiotensin-aldosterone system (RAAS) and PTH are needed. We evaluated the effect of individual RAAS components on PTH using 4 interventions in humans without primary hyperaldosteronism. PTH was measured before and after study (1) low-dose angiotensin II (Ang II) infusion (1 ng/kg per minute) and captopril administration (25 mg×1); study (2) high-dose Ang II infusion (3 ng/kg per minute); study (3) blinded crossover randomization to aldosterone infusion (0.7 µg/kg per hour) and vehicle; and study (4) blinded randomization to spironolactone (50 mg/daily) or placebo for 6 weeks. Infusion of Ang II at 1 ng/kg per minute acutely increased aldosterone (+148%) and PTH (+10.3%), whereas Ang II at 3 ng/kg per minute induced larger incremental changes in aldosterone (+241%) and PTH (+36%; P<0.01). Captopril acutely decreased aldosterone (-12%) and PTH (-9.7%; P<0.01). In contrast, aldosterone infusion robustly raised serum aldosterone (+892%) without modifying PTH. However, spironolactone therapy during 6 weeks modestly lowered PTH when compared with placebo (P<0.05). In vitro studies revealed the presence of Ang II type I and mineralocorticoid receptor mRNA and protein expression in normal and adenomatous human parathyroid tissues. We observed novel pleiotropic relationships between RAAS components and the regulation of PTH in individuals without primary hyperaldosteronism: the acute modulation of PTH by the RAAS seems to be mediated by Ang II, whereas the long-term influence of the RAAS on PTH may involve aldosterone. Future studies to evaluate the impact of RAAS inhibitors in treating PTH-mediated disorders are warranted.

Evaluating hormonal mechanisms of vitamin D receptor agonist therapy in diabetic kidney disease: the VALIDATE-D study.

BACKGROUND: Insufficient vitamin D status and increased renin-angiotensin system (RAS) activity have been associated with renal-vascular disease and nephropathy in diabetes. Accumulating evidence indicates that vitamin D receptor (VDR) activation lowers unfavorable RAS activity; however, more human intervention studies evaluating whether this mechanism could influence diabetic kidney disease are needed. We previously reported that both vitamin D levels and genetic variation at the VDR predict human RAS activity, and that vitamin D therapy can lower RAS activity in non-diabetics. The VALIDATE-D study is a randomized, placebo-controlled, intervention study designed to extend these findings by evaluating whether direct VDR activation in diabetes lowers circulating and local renal-vascular tissue RAS activity (Aims 1 and 2) in a manner similar to the action of ACE inhibitors (Aim 3). METHODS/DESIGN: Forty subjects with type 2 diabetes, microalbuminuria, and without chronic kidney disease will be recruited to undergo detailed assessment of the RAS before and after randomization to calcitriol 0.75 mcg/day or placebo. Primary analyses will evaluate whether calcitriol therapy reduces circulating and renal-vascular tissue-RAS activity in comparison to placebo. All subjects will thereafter be treated with lisinopril and followed for 3.5 months to evaluate whether combination therapy (calcitriol + lisinopril vs. placebo + lisinopril) additively or synergistically improves renal-vascular function, and lowers proteinuria. DISCUSSION: The VALIDATE-D study is the first human intervention study to evaluate whether direct VDR activation can lower the human RAS in diabetes, compared to the effect of an ACE inhibitor, and whether this mechanism can translate to clinically relevant endpoints for diabetic kidney disease. The outcomes of VALIDATE-D will have major implications for the recommendation of vitamin D supplementation for the primary prevention of kidney complications in diabetes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01635062.

Vitamin D and vascular disease: the current and future status of vitamin D therapy in hypertension and kidney disease.

Over the past decade, vitamin D has generated considerable interest as potentially having important effects on the vasculature and the kidney. Animal and human data indicate that vitamin D suppresses the activity of the renin-angiotensin system and improves endothelial function. Observational studies in humans suggest that low 25-hydroxyvitamin D (25[OH]D) levels are associated with a higher risk of hypertension. However, findings from randomized trials of vitamin D supplementation (with cholecalciferol or ergocalciferol) to lower blood pressure are inconsistent, possibly stemming from variability in study population, sample size, vitamin D dose, and duration. Supplementation with activated vitamin D (i.e., 1,25-dihydroxyvitamin D or analogues) in patients with chronic kidney disease reduces urine albumin excretion, an important biomarker for future decline in renal function. These studies are reviewed, with special emphasis on recent findings. Definitive studies are warranted to elucidate the effects of vitamin D supplementation on mechanisms of hypertension and kidney disease.

The independent association between 25-hydroxyvitamin D and adiponectin and its relation with BMI in two large cohorts: the NHS and the HPFS.

Low 25-hydroxyvitamin D (25(OH)D) and adiponectin levels are both associated with obesity and cardiovascular disease. Cross-sectional studies have suggested that 25(OH)D concentrations are positively associated with adiponectin, and that this relation may strengthen with increasing BMI. However, these studies had small samples sizes and did not account for many known confounders of adiponectin levels. We evaluated whether 25(OH)D was independently associated with circulating adiponectin in two large populations, and whether BMI modified this relationship. Cross-sectional analyses were performed on 1,206 women from the Nurses' Health Study I (NHS) and 439 men from the Health Professionals Follow-Up Study. Multivariable linear regression was used to analyze the independent association between 25(OH)D and adiponectin after controlling for potential confounders. Effect modification by BMI was examined by creating interaction terms between vitamin D and BMI. 25(OH)D concentrations were positively associated with circulating adiponectin in univariate analyses, and also independently associated with adiponectin after multivariable adjustments in both populations (women: ß = 0.06, P < 0.001; men: ß = 0.07, P < 0.05). BMI did not significantly modify the relation between 25(OH)D and adiponectin in either population. Higher 25(OH)D concentrations were independently associated with higher adiponectin concentrations in large populations of women and men. Since lower levels of 25(OH)D and adiponectin are associated with higher cardio-metabolic risk, assessing the effect of vitamin D supplementation on adiponectin levels is warranted.

The influence of body mass index and renin-angiotensin-aldosterone system activity on the relationship between 25-hydroxyvitamin D and adiponectin in Caucasian men.

OBJECTIVE: Previous studies have suggested that circulating adiponectin concentrations are associated positively with vitamin D and negatively with body mass index (BMI) but have not accounted for the influence of the renin-angiotensin-aldosterone system (RAAS) in this relationship. This is particularly relevant because increased RAAS activity is associated with obesity and is known to lower adiponectin levels. We evaluated the association between adiponectin and 25-hydroxyvitamin D (25(OH)D) after controlling RAAS activity with dietary sodium equilibration and also evaluated whether this relationship was influenced by BMI. DESIGN: Cross-sectional study of 115 hypertensive Caucasian men from the Hypertensive Pathotype Consortium. METHODS: To manipulate RAAS activity, all subjects underwent 1 week of high dietary sodium (HS) diet to suppress RAAS and 1 week of low dietary sodium (LS) diet to stimulate RAAS. Linear regression was used to evaluate the association between adiponectin and 25(OH)D, and the effect of BMI on this relationship, in each dietary condition. RESULTS: Adiponectin was higher on HS, where circulating RAAS activity was low, when compared with LS (HS=2.9 versus LS=2.4 µg/ml, P<0.0001). 25(OH)D levels were positively associated with adiponectin, and BMI was a statistically significant effect modifier of the relationship between 25(OH)D and adiponectin on both diets (P interaction <0.01 between BMI and 25(OH)D). CONCLUSIONS: Higher 25(OH)D concentrations were independently associated with higher adiponectin levels, particularly when BMI was high. Dietary sodium balance and circulating RAAS activity did not appear to affect this relationship. Future studies should explore whether vitamin D supplementation increases adiponectin levels in obesity.

Angiotensin receptor blockade with candesartan attenuates atherosclerosis, plaque disruption, and macrophage accumulation within the plaque in a rabbit model.

BACKGROUND: Little is known about whether direct angiotensin receptor blockade can reduce atherosclerosis and plaque disruption. This study evaluated the effect of angiotensin receptor blockade on both the development of atherosclerosis and the disruption of plaque in a modified Constantinides animal model. METHODS AND RESULTS: Twenty-eight New Zealand White rabbits underwent aortic balloon injury followed by a 1% cholesterol diet for 8 weeks. Thirteen rabbits received candesartan at 0.5 mg x kg(-1) x d(-1) beginning 2 days before aortic balloon injury and continued for the total 8 weeks of the cholesterol diet. The rabbits were then pharmacologically triggered and humanely killed, and their aortas were analyzed. The degree of atherosclerosis was determined by intima-media ratio of the infrarenal portion of the aorta. The frequency of intra-aortic thrombosis, a measure of plaque disruption, and the percentages of macrophage area and collagen-staining area of the plaque were determined. Candesartan-treated rabbits had less atherosclerosis (intima-media infrarenal aorta ratio of 1.18+/-0.08 versus 1.57+/-0.08 [mean+/-SEM] for the placebo group, P<0.001); fewer thrombi (3 of 13 versus 11 of 15; P<0.05); lower percentage area of macrophages to total plaque (18.8+/-2.7% versus 27+/-2.5%, P<0.05); and higher collagen to total plaque area (45+/-3% versus 35+/-2%, P<0.01). CONCLUSIONS: These results demonstrate that angiotensin receptor blockade attenuates the degree of atherosclerosis and reduces both plaque disruption and macrophage accumulation while increasing collagen deposition in the aortas of this animal model.