Heightened Cardiovascular Risk in Hypertension Associated With Renin‐Independent Aldosteronism Versus Renin‐Dependent Aldosteronism: A Collaborative Study

Background While both renin‐dependent and renin‐independent aldosterone secretion contribute to aldosteronism, their relative associations with cardiovascular disease (CVD) risk has not been investigated. Methods and Results A total of 2909 participants from the FOS (Framingham Offspring Study) with baseline, serum aldosterone concentration, and plasma renin concentration who attended the sixth examination cycle and were followed up until 2014 and who were free of CVD were included. We further recruited 2612 hypertensive participants from the CONPASS (Chongqing Primary Aldosteronism Study). Captopril challenge test was performed to confirm renin‐dependent or ‐independent aldosteronism in CONPASS. Among 1433 hypertensive subjects of FOS, when compared with those with serum aldosterone concentration <10 ng dL −1 (normal aldosterone), participants who had serum aldosterone concentration ≥10 ng dL −1 and plasma renin concentration ≤15 mIU L −1 (identified as renin‐independent aldosteronism) showed a higher risk of CVD (hazard ratio, 1.40 [95% CI, 1.08–1.82]), while those who had serum aldosterone concentration ≥10 ng dL −1 and plasma renin concentration >15 mIU L −1 (identified as renin‐dependent aldosteronism) showed an unchanged CVD risk. In CONPASS, renin‐independent aldosteronism carried a significantly higher risk of CVD than normal aldosterone (odds ratio, 2.57 [95% CI, 1.13–5.86]), while the CVD risk remained unchanged in renin‐dependent aldosteronism. Elevation of the urinary potassium‐to‐sodium excretion ratio, reflective of mineralocorticoid receptor activity, was only observed in participants with renin‐independent aldosteronism. Conclusions Among patients with hypertension, renin‐independent aldosteronism is more closely associated with CVD risk than renin‐dependent aldosteronism.

Genetic Predictors of Salt Sensitivity of Blood Pressure: The Additive Impact of 2 Hits in the Same Biological Pathway

Salt sensitivity of blood pressure is associated with increased cardiovascular morbidity and mortality. A diplotype in the β2AR gene (rs1042713, rs1042714) and single nucleotide polymorphisms in ESR2 (rs10144225), SGK1 (rs2758151), and AGT (rs2493134) genes are all independently associated with salt sensitivity of blood pressure and all but AGT are associated with increased aldosterone levels and/or activity. We sought to determine whether individuals who carried a double hit risk phenotype—a risk allele associated with increased aldosterone secretion (either β2AR or ESR2 ) and a risk allele associated with amplification of aldosterone’s effects ( SGK1 ) would result in more significant SSBP compared with individuals homozygous for a single risk allele. Data were obtained from the Hypertension Pathotypes cohort where individuals completed 7 days of restricted sodium and liberal sodium diets. We defined 3 genetic combinations: β2AR/SGK, ESR2/SGK , and AGT/SGK. Multivariate regression analyses found a significantly higher salt sensitivity of blood pressure as the number of risk allele pairs increased in both the β2AR/SGK (β=5.46; P <0.001) and ESR2/SGK ( β =4.87; P 0.01). In addition, the number of risk allele pairs was associated with serum aldosterone levels for β2AR/SGK and ESR2/SGK . On the other hand, there was no association between the number of risk allele pairs with salt sensitivity of blood pressure nor aldosterone levels in the AGT/SGK combination. In conclusion, genetic combinations of β2AR/SGK1 and ESR2 / SGK1 are associated with greater salt sensitivity of blood pressure and plasma aldosterone concentrations. Hypertensive combination risk homozygotes may be candidates for mineralocorticoid receptor antagonist therapy—gene-driven, personalized medicine.

Repeated stimulation of the HPA axis alters white blood cell count without increasing oxidative stress or inflammatory cytokines in fasting elephant seal pups

ABSTRACT The hypothalamic–pituitary–adrenal (HPA) axis controls the release of glucocorticoids, which regulate immune and inflammatory function by modulating cytokines, white blood cells and oxidative stress via glucocorticoid receptor (GR) signaling. Although the response to HPA activation is well characterized in many species, little is known about the impacts of HPA activation during extreme physiological conditions. Hence, we challenged 18 simultaneously fasting and developing elephant seal pups with daily intramuscular injections of adrenocorticotropin (ACTH), a GR antagonist (RU486), or a combination of the two (ACTH+RU486) for 4 days. We collected blood at baseline, 2 h and 4 days after the beginning of treatment. ACTH and ACTH+RU486 elevated serum aldosterone and cortisol at 2 h, with effects diminishing at 4 days. RU486 alone induced a compensatory increase in aldosterone, but not cortisol, at 4 days. ACTH decreased neutrophils at 2 h, while decreasing lymphocytes and increasing the neutrophil:lymphocyte ratio at 4 days. These effects were abolished by RU486. Despite alterations in white blood cells, there was no effect of ACTH or RU486 on transforming growth factor-β or interleukin-6 levels; however, both cytokines decreased with the 4 day fasting progression. Similarly, ACTH did not impact protein oxidation, lipid peroxidation or antioxidant enzymes, but plasma isoprostanes and catalase activity decreased while glutathione peroxidase increased with fasting progression. These data demonstrate differential acute (2 h) and chronic (4 days) modulatory effects of HPA activation on white blood cells and that the chronic effect is mediated, at least in part, by GR. These results also underscore elephant seals' extraordinary resistance to oxidative stress derived from repeated HPA activation.

Reversible dysregulation of renal circadian rhythm in lupus nephritis

Background We have found disruption of expression of major transcriptional regulators of circadian rhythm in the kidneys of several mouse models of lupus nephritis. Here we define the consequence of this disturbance with respect to circadian gene expression and renal homeostatic function in a mouse model of lupus nephritis. Methods Molecular profiling of kidneys from 47 young and 41 nephritic female NZB/W F1 mice was performed at 4 hourly intervals over a 24 h period. Disruption of major circadian transcriptional regulators was confirmed by qPCR. Molecular data was normalized and analyzed for rhythmicity using RAIN analysis. Serum aldosterone and glucose and urine sodium and potassium were measured at 4 hourly intervals in pre-nephritic and nephritic mice and blood pressure was measured every 4 h. Analyses were repeated after induction of complete remission of nephritis using combination cyclophosphamide and costimulatory blockade. Results We show a profound alteration of renal circadian rhythms in mice with lupus nephritis affecting multiple renal pathways. Using Cosinor analysis we identified consequent alterations of renal homeostasis and metabolism as well as blood pressure dipper status. This circadian dysregulation was partially reversed by remission induction therapy. Conclusions Our studies indicate the role of inflammation in causing the circadian disruption and suggest that screening for loss of normal blood pressure dipping should be incorporated into LN management. The data also suggest a potential role for circadian agonists in the treatment of lupus nephritis.

Aldosterone and Renin Concentration Abnormally Elevated in a Cohort of Normotensive Pregnant Women

During pregnancy the renin-angiotensin-aldosterone system (RAAS) undergo major changes to preserve normal blood pressure (BP), placenta blood flow and ensure a good pregnancy outcome. Abnormal aldosterone-renin metabolism is a risk factor for arterial hypertension and cardiovascular risk, but its association to pathological conditions in pregnancy remains unknown. Hence, clinical and subclinical novel biomarkers associated to these pathological conditions are encouraged to be identified. Aim: To study a cohort of normotensive pregnant women according to their serum aldosterone and plasma renin levels and assay their small extracellular vesicles (sEV) and a specific protein-cargo (LCN2, AT1R). Methods: A cohort of 54 normotensive pregnant women at term gestation. We determined the BP, serum aldosterone and plasma renin concentration. In a subgroup, we isolated their plasma sEVs and semi-quantify two EV-proteins (AT1R, LCN2). Results: We set a normal range of aldosterone and renin based in the interquartile range. We identified 5/54(9%) pregnant women with elevated aldosterone and low renin levels, and 5/54(9%) other pregnant women with low aldosterone and elevated renin levels. No differences were found in sEV-LCN2 nor sEV-AT1R. Conclusion: We found 18% normotensive pregnant women having either high aldosterone or high renin levels, suggesting a subclinical status similar to a primary aldosteronism or a hyperreninemia. Both would evolve to pathological conditions in presence a second challenge affecting the maternal vascular physiology or the BP. sEVs and its specific cargo are encouraged to be further studied in order to clarify its role as potential biomarkers of RAAS alterations in pregnant women.

Spiral Steroids During Pregnancy - It’s All About Potassium

This presentation has two parts. The 1st section describes processes during pregnancy with unknown, underlying biochemistry. The 2nd section shows the role of spiral steroids (SS) in these processes. 1] Fetal nutrition is provided through the placenta. Plasma electrolytes are 145 mM Na+ and 3-5 mM K+. Fetal K+ requirements reach a maximum during the 3rd trimester and must be pumped into cells against the plasma- intracellular gradient. 2] During the 3rd trimester, aldosterone is present in fetal plasma but the signal for endothelial sodium channel (ENaC) synthesis is blocked, leading to fetal Na+ wasting. The mechanism is unknown. 3] After parturition, infants are fed by nursing. Human milk contains 100 mM K+ and 10 mM Na+. Newborn infants are Na+ wasting, despite normal levels of aldosterone. Na+ wasting ends during the 2nd week post-partum without change in serum aldosterone levels. Infant physiology changes from K+ saving to Na+ saving by an unknown mechanism.4] Pre-eclampsia syndrome (proteinuria and hypertension during the 2nd half of pregnancy) affects 3-5 % of pregnant women. These symptoms usually resolve after parturition. 5] Women who have had pre-eclampsia have long-term, excess risk of cardiac and renal disorders. In 2018, we discovered Ionotropin, a SS. SS are phosphocholine esters of steroids with a lactone E-ring, similar to that of spironolactone. SS compounds function as aldosterone antagonists and regulate the NaK-ATPase. SS are involved in each of the 5 steps.1] SS are present in high levels in cord serum and were probably present in fetal plasma throughout gestation. SS stimulate the NaK-ATPase to pump K+ into cells against the gradient, just as does spironolactone.2] SS interfere with aldosterone signaling, just as does amiloride. This leads to increased fetal Na+ wasting, which becomes amniotic fluid.3] SS disappear from the infant circulation during the 1st week after parturition and decrease to adult levels during the 2nd week post-partum. Simultaneously, Na+ wasting ends and growth resumes.4] Women with pre-eclampsia have excess precursors for SS. These would be converted to SS in the fetal-placental unit and, during the 3rd trimester, diffuse into the maternal circulation and could cause pre-eclampsia.5] Ouabain, a plant toxin with a lactone E ring, causes renal and cardiac disorders in rat models. In women with pre-eclampsia, persistent excess SS may cause long-term damage. During gestation, the fetus requires K+ for growth. Our theory is, if (when) a fetus has inadequate K+ (hypokalemia), [a] the mother is signaled to produce SS precursors, [b] the feto-placental unit converts the precursors to SS, [c] fetal SS increase K+ transfer into tissues, and [d] excess SS transfuse back into the maternal circulation and damage maternal organs. We propose that pre-eclampsia is a side effect of fetal efforts to increase supply of K+. There are many possible origins of fetal hypokalemia.

Adrenoleukodystrophy and Secondary Hyperaldosteronism; A Clinical Demonstration of the Zona Glomerulosa Persistence

Adrenoleukodystrophy (ALD) is a peroxisomal disorder which leads to the accumulation of very long-chain fatty acids in all tissues. Age at onset of symptoms vary depending on the phenotype severity. It can present with progressive symptoms of neurological defects and/or primary adrenal insufficiency. We report a case of 31 yo man diagnosed in childhood with ALD and treated with hydrocortisone and fludrocortisone who eventually developed resistant hypertension due to secondary hyperaldosteronism. He was diagnosed with ALD at 9-year-old and have received an allogenic hematopoietic cell graft 4 years later. After transplantation, he developed a bronchiolitis obliterans which was treated with high dose of glucocorticoids for 3 years. In 2014, at first evaluation with our team, he was on hydrocortisone 10mg/m2 and fludrocortisone 0.05 mg daily. Fludrocortisone was started at 14 yo for a clinical suspicion of mineralocorticoids deficiency. At that time, the patient was normokaliemic (3.8 mmol\L), his aldosterone was, 2 days apart, 245pmol/L lying down and 68 pmol/L (N 138 - 413) sitting, his renin activity was 0.11 ng/L/s (N 0.14 - 0.31) and no orthostatic hypotension was documented. In July 2015, high blood pressure (BP) was noticed, and fludrocortisone was decreased at 0.05 mg every other day. However, his BP continued to increase progressively, thereby fludrocortisone was discontinued in June 2018. Thereafter, amlodipine 10 mg daily, hydrochlorothiazide 12.5 mg daily and terazosin 2 mg daily were progressively introduced. Even with those three anti-hypertensive drugs his BP wasn’t controlled (190/100 mmHg) and he also developed persistent hypokalemia (3.0 - 3.3 mmol/L). Furthermore, significant aortic atheromatosis was described on abdominal computed tomography. In that context, his serum aldosterone/renin ratio was measured. The aldosterone was 632 pmol/L (N &lt; 350) and the renin mass was 93.4 ng/L (N 3 - 16). An assessment of renal arteries was done by doppler ultrasonography, which was compatible with a hemodynamically significant right renal artery stenotic lesion. The patient had never smoke, had no diabetes (HbA1c 5.1%) or dyslipidemia (LDL 2.02 mmol/L). Based on the diagnosis of secondary aldosteronism, spironolactone was introduced in June 2020. Spironolactone was titrated to 37.5 mg daily and BP significantly improved with values around 136/75 and potassium return in normal range (3.8 mmol/L). This interesting case illustrates 1) the persistence of a functioning zona glomerulosa in some patient with ALD and the possible development of secondary hyperaldosteronism in response to renovascular disorder and 2) the particularly high burden of atherosclerosis in this young patient, without classic risk factor, raises questions on the effect of the metabolic defect of ALD itself on the development of atheromatosis.

Persistent Hyperkalemia Post-Adrenalectomy for Aldosterone-Producing Adenoma

Background:Post-operative hypoaldosteronism due to chronic suppression of the renin-aldosterone axis of the contralateral gland can be complicated with hyperkalemia. We describe a case of persistent hyperkalemia post adrenalectomy for aldosterone-producing adenoma. Clinical Case: A 47-year-old male was first diagnosed with hypertension in 2011. He was investigated for secondary hypertension after hospital admission in 2019 for hypertensive urgency and symptomatic hypokalemia (potassium, K 1.9–2.3 mmol/L, n = 3.5–5.0). Subsequent laboratory investigation revealed elevated serum aldosterone (3565 pmol/L, n &lt; 103) with an aldosterone renin ratio of 115 (n &lt; 35). A confirmatory test with saline loading showed an unsuppressed serum aldosterone level of 1840 pmol/L. Adrenal CT reported a 4.1-cm, heterogeneous left adrenal lesion. A diagnosis of primary aldosteronism was made, and he underwent laparoscopic left adrenalectomy in July 2020. Histopathology examination was consistent with adrenal cortical adenoma. Both potassium supplementation and spironolactone were stopped immediately postoperatively. Two weeks later, he developed symptomatic hyperkalemia (K 6.0 mmol/L), requiring hospital admission, and started on potassium binder. Throughout clinic follow-ups, potassium remained high (K 5.4–6.1 mmol/L), despite low potassium diet and potassium binder. His case was co-managed with the nephrology team and given a trial of frusemide and sodium bicarbonate to normalize his potassium. However, after 4 months, he remained hyperkalemic. Repeated serum aldosterone was not elevated (&lt;103 pmol/L). He was then started on fludrocortisone and finally managed to achieve serum potassium normalisation (K 4.1–4.5 mmol/L). Conclusion: This case highlights the importance of monitoring potassium levels in all patients after adrenalectomy, particularly those with clinical risk factors. Retrospective studies by Park et al and Fischer et al reported that a long duration of hypertension, impaired preoperative renal function, older age, and large adenoma size represent risks for developing hyperkalemia postoperatively, whereas the use of mineralocorticoid receptor antagonists preoperatively does not prevent hyperkalemia. Treatment includes a low potassium diet, a high sodium diet, adequate hydration, potassium binder, frusemide, and fludrocortisone. In some cases, hyperkalemia may be prolonged, necessitating long-term fludrocortisone therapy, up to 11–46 months². References: 1. Park KS, Kim JH, Ku EJ, et al. Clinical risk factors of postoperative hyperkalemia after adrenalectomy in patients with aldosterone-producing adenoma. Eur J Endocrinol. 2015 Jun;172(6):725–31. 2. Fischer E, Hanslik G, Pallauf A, et al. Prolonged zona glomerulosa insufficiency causing hyperkalemia in primary aldosteronism after adrenalectomy. J Clin Endocrinol Metab. 2012 Nov;97(11):3965–73.

Aldosterone Is Positively Associated With Circulating FGF23 Levels in Chronic Kidney Disease Across Four Species, and May Drive FGF23 Secretion Directly

BackgroundChronic kidney disease (CKD) is accompanied by increases in circulating fibroblast growth factor 23 (FGF23) and aldosterone levels. Here, we tested the hypothesis that aldosterone may be one of the driving forces behind increased FGF23 secretion in CKD.MethodsUsing data from a prospective study in humans, a retrospective study in dogs and cats, and an experimental study in 5/6-nephrectomized mice, we analyzed the relationship between circulating FGF23 and serum aldosterone levels in CKD across four species. To assess the effects of acute inhibition of aldosterone signaling on circulating FGF23, we acutely treated mice with established CKD with the mineralocorticoid receptor blocker canrenone (50 mg/kg iv/sc), and measured intact FGF23 before and 24 h as well as 72 h after start of administration of the drug.ResultsWe found a tight positive association between circulating intact FGF23 and serum aldosterone in human, canine, and feline CKD patients, as well as in experimental murine CKD (humans: rS = 0.57, p = 0.0368; dogs: rS = 0.66, p = 0.0019; cats: rS = 0.75, p = 0.0003; mice: rS = 0.49, p = 0.0004). Injection of canrenone in mice with established CKD did not lead to changes in FGF23 levels within 24 h, but reduced FGF23 in all mice at 72 h.ConclusionAldosterone may drive enhanced FGF23 secretion in CKD, possibly explaining the tight positive association between circulating intact FGF23 and aldosterone in human, canine, and feline CKD patients as well as in experimental CKD models.