Effect of high-dose mineralocorticoid receptor antagonist eplerenone on urinary albumin excretion in patients with type 2 diabetes and high cardiovascular risk: Data from the MIRAD trial.

AIM: As mineralocorticoid receptor antagonists (MRAs) may possess renoprotective effects in type 2 diabetes (T2D), it was decided to investigate the impact of high-dose MRA on prespecified secondary endpoints-namely, change in urinary albumin-creatinine ratio (UACR) and 24-h ambulatory blood pressure-in the MIRAD trial. METHODS: This was a double-blind clinical trial in which T2D patients at high risk of or with established cardiovascular disease (CVD) were randomized to either high-dose (100-200 mg) eplerenone or a dose-matched placebo as an add-on to background antihypertensive treatment for 26 weeks. Safety was evaluated by the incidence of hyperkalaemia and kidney-related adverse events. RESULTS: A total of 140 patients were enrolled (70 in each group). Baseline UACR was 17 mg/g (geometric mean; 95% CI: 13-22); this decreased by 34% in the eplerenone group compared with the placebo group at week 26 (95% CI: -51% to -12%; P = 0.005). There was no significant decrease in 24-h systolic blood pressure (SBP) due to treatment (-3 mmHg; 95% CI: -6 to 1; P = 0.150). However, the observed change in 24-h SBP correlated with the relative change in UACR in the eplerenone group (r = 0.568, P < 0.001). Mean baseline (± SD) estimated glomerular filtration rate (eGFR) was 85 (± 18.6) mL/min/1.73 m2, and 12 (± 9%) had an eGFR of 41-59 mL/min/1.73 m2. No significant differences in the incidence of mild hyperkalaemia (≥ 5.5 mmol/L; eplerenone vs placebo: 6 vs 2, respectively; P = 0.276) and no severe hyperkalaemia (≥ 6.0 mmol/L) were observed. CONCLUSION: The addition of high-dose eplerenone to T2D patients at high risk of CVD can markedly reduce UACR with an acceptable safety profile.

Patients with acute heart failure treated with the CARRESS-HF diuretic protocol in association with canrenoate potassium: Tolerance of high doses of canrenoate potassium.

BACKGROUND: Oral mineralocorticoid receptor antagonists have failed to prove their efficacy for decongestion and potassium homeostasis in acute heart failure. Intravenous mineralocorticoid receptor antagonists have yet to be studied. AIM: The aim of this study was to confirm the safety of high-dose potassium canrenoate in association with classic diuretics in acute heart failure. METHODS: This retrospective single-centre study included consecutive patients who were hospitalized with acute heart failure between 2013 and 2018. One hundred patients with overload treated with the standardized diuretic protocol from the CARRESS-HF trial were included. There were no exclusion criteria relating to creatinine or kalaemia at the time of admission. Two groups were constituted on the basis of potassium canrenoate posology: a low-dose group (<300mg/day) and a high-dose group (≥300mg/day); the groups were similar in terms of baseline characteristics. RESULTS: Mean daily potassium canrenoate doses were 198mg/day (range 100-280mg/day) in the low-dose group and 360mg/day (range 300-600mg/day) in the high-dose group. There was no significant difference between the high-dose and low-dose groups in terms of mortality, dialysis, renal function, hyperkalaemia, haemorrhage, sepsis or confusion. CONCLUSIONS: Potassium canrenoate at high doses can be used safely in association with standard diuretics in acute heart failure, even in patients with altered renal function. A prospective study is required to evaluate the efficacy of high-dose potassium canrenoate in preventing hypokalaemia and improving decongestion.

Congenital adrenal hyperplasia due to 11-Beta-hydroxylase deficiency in a Tunisian family.

Congenital adrenal hyperplasia refers to a group of rare genetic disorders affecting the adrenal glands. 21-hydroxylase deficiency is the most prevalent and the most studied cause while the remaining enzymatic defects are less common, accounting for less than 10% of cases. We herein described the clinical, biological and molecular characteristics and outcome of patients of the same family diagnosed with 11-Beta-hydroxylase deficiency. The disorder was revealed by peripheral precocious puberty between the age of 2-3 years in males and by the virilization of the external genitalia in females. Genetics finding a homozygous p.Gly379Val mutation in the CYP11B1 gene. All patients received hydrocortisone supplementation therapy and mineralocorticoid-receptor antagonist. The females underwent a surgical correction of the ambiguous genitalia at the neonatal age. Long term follow-up revealed metabolic syndrome, obesity and hypertension in the first two patients, an impaired final height in the two females and hypokalemia in three patients.

Systemic lupus erythematosus complicated by a Gitelman-like syndrome in an 8-year-old girl.

An 8-year-old girl with recently diagnosed Systemic Lupus Erythematosus (SLE) (class 4 lupus nephritis with autoimmune hemolytic anemia) presented to the pediatric nephrology clinic with polyuria, tiredness and cramps; laboratory investigations revealed refractory hypokalemia, hypomagnesemia, metabolic alkalosis, hypocalciuria and hyperchloriuria. There was no history of diuretic administration. These features were consistent with the Gitelman syndrome. She required large doses of potassium and magnesium supplementation along with spironolactone, for normalization of the serum potassium and magnesium levels. Immunosuppressive therapy was continued with cyclophosphamide pulses administered on a monthly basis. The doses of potassium and magnesium supplements were tapered off over the next 6 months. The clinical exome sequencing was negative for any mutations in the SLC12A3 gene. An 'acquired' form of Gitelman syndrome has been reported earlier in association with Sjogren syndrome and systemic sclerosis. Though tubular disorders such as renal tubular acidosis have been reported in association with SLE, a Gitelman-like syndrome has not been reported earlier. This case adds Gitelman-like tubulopathy to the clinical spectrum of tubular disorders complicating SLE.

Adding High-Dose Spironolactone to Tolvaptan Improves Acute Decompensated Heart Failure Due to Obstructive Hypertrophic Cardiomyopathy and Aortic Stenosis: A Case Report.

BACKGROUND In the setting of acute decompensated heart failure (ADHF), tolvaptan, a selective V2 receptor antagonist, did not alter plasma renin activity or angiotensin II level, but significantly increased plasma aldosterone by the activation of V1ₐ receptor, suggesting that a high-dose mineralocorticoid receptor antagonist (MRA) combined with a V2 receptor antagonist might be of interest, especially in ADHF patients. However, in the setting of ADHF, the short-term and long-term efficacy of a high-dose MRA combined with tolvaptan remains unclear. CASE REPORT An 86-year-old woman with a history of chronic HF with a preserved ejection fraction due to obstructive hypertrophic cardiomyopathy and severe aortic stenosis was transferred to our hospital complaining of persistent dyspnea (New York Heart Association class IV). She did not respond to standard therapy with tolvaptan (15.0 mg/day). However, the present case demonstrated that adding high-dose spironolactone (100 mg/day) to low-dose tolvaptan (15.0 mg/day) is safe and well tolerated, resulting in an increase in urine output and improvement of the symptoms or signs of ADHF in a patient who was refractory to loop diuretics and tolvaptan. CONCLUSIONS The short- and long-term efficacy of high-dose spironolactone combined with low-dose tolvaptan may be associated with an attenuation of the aldosterone level, which is increased through V1ₐ activation by vasopressin during tolvaptan administration.

Spironolactone in Acute Heart Failure Patients With Renal Dysfunction and Risk Factors for Diuretic Resistance: From the ATHENA-HF Trial.

BACKGROUND: Acute heart failure (HF) patients with renal insufficiency and risk factors for diuretic resistance may be most likely to derive incremental improvement in congestion with the addition of spironolactone. METHODS: The Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure (ATHENA-HF) trial randomized 360 acute HF patients with reduced or preserved ejection fraction to spironolactone 100 mg daily or usual care for 96 hours. The current analysis assessed the effects of study therapy within tertiles of baseline estimated glomerular filtration rate (eGFR) and subgroups at heightened risk for diuretic resistance. RESULTS: Across eGFR tertiles, there was no incremental benefit of high-dose spironolactone on any efficacy endpoint, including changes in log N-terminal pro-B-type natriuretic peptide and signs and symptoms of congestion (all P for interaction ≥ 0.06). High-dose spironolactone had no significant effect on N-terminal pro-B-type natriuretic peptide reduction regardless of blood pressure, diabetes mellitus status, and loop diuretic dose (all P for interaction ≥ 0.38). In-hospital changes in serum potassium and creatinine were similar between treatment groups for all GFR tertiles (all P for interaction ≥ 0.18). Rates of inpatient worsening HF, 30-day worsening HF, and 60-day all-cause mortality were numerically higher among patients with lower baseline eGFR, but relative effects of study treatment did not differ with renal function (all P for interaction ≥ 0.27). CONCLUSIONS: High-dose spironolactone did not improve congestion over usual care among patients with acute HF, irrespective of renal function and risk factors for diuretic resistance. In-hospital initiation or continuation of spironolactone was safe during the inpatient stay, even when administered at high doses to patients with moderate renal dysfunction.

Spironolactone to increase natriuresis in congestive heart failure with cardiorenal syndrome.

BACKGROUND: Signs and symptoms of volume overload are the most frequent reason for hospital admission in acute heart failure (AHF). Diuretics are mainstay treatment, but their optimal type and dose regimen remain unclear, especially in patients with cardiorenal syndrome. METHODS: This prospective study aimed to include 80 AHF patients with volume overload and cardiorenal syndrome. Through a 2 × 2 factorial design, patients were randomised towards (1) combinational treatment with acetazolamide and low-dose loop diuretics versus high-dose loop diuretics; and (2) open-label oral spironolactone 25 mg OD given upfront versus at discharge. Here reported are the results of the spironolactone treatment arm after complete follow-up of 34/80 patients (since the study was stopped because of slow recruitment). The primary study end-point was incident hypokalaemia (<3.5 mmol/L) or hyperkalaemia (>5.5 mmol/L). RESULTS: Serum potassium derangements were numerically less frequent in the upfront versus discharge spironolactone group, yet this result was underpowered due to incomplete study recruitment (hyperkalaemia: 6% vs. 11%; hypokalaemia: 13% vs. 28%, respectively; p-value = .270). Natriuresis after 24 h was higher in the upfront vs. discharge spironolactone group (314 ± 142 vs. 200 ± 91 mmol/L, respectively; p-value = .010). Relative change in plasma NT-proBNP level after 72 h was similar among both groups (-16 ± 29% vs. -5 ± 45%, respectively; p value = .393), with no difference in all-cause mortality (p-value = .682) or the combination of all-cause mortality and heart failure readmission (p-value = .799). DISCUSSION: Spironolactone use upfront in AHF patients at high risk for cardiorenal syndrome is safe and increases natriuresis.

Licorice-induced apparent mineralocorticoid excess compounded by excessive use of terbutaline and high water intake.

This case highlights the clinical course of a 54-year-old male patient presenting with hypertension and long-term refractory hypokalaemia. He reported long-term malaise, fatigue and physical discomfort. Diarrhoea, vomiting, over-the-counter drugs, dietary supplements and any kind of medical abuse were all denied. Physical examination was normal. Suppressed plasma renin activity along with a low aldosterone level and elevated urinary cortisone/cortisol metabolite excretion ratio raised the suspicion of apparent mineralocorticoid excess (AME). The patient started treatment with spironolactone, but serum potassium levels were persistently fluctuating and the patient was hospitalised for further evaluation. During hospitalisation, repeated medical history and diagnostic examinations revealed licorice-induced AME complicated by excessive use of terbutaline and massive water intake. Licorice discontinuation, reduction of terbutaline and normalisation of water intake led to fully normalised potassium levels. Despite careful clinical history and diagnostic work-up, hospitalisation may be necessary in selected patients with long-term hypokalaemia.

Efficacy and Safety of Spironolactone in Acute Heart Failure: The ATHENA-HF Randomized Clinical Trial.

Importance: Persistent congestion is associated with worse outcomes in acute heart failure (AHF). Mineralocorticoid receptor antagonists administered at high doses may relieve congestion, overcome diuretic resistance, and mitigate the effects of adverse neurohormonal activation in AHF. Objective: To assess the effect of high-dose spironolactone and usual care on N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels compared with usual care alone. Design, Setting, and Participants: This double-blind and placebo (or low-dose)-controlled randomized clinical trial was conducted in 22 US acute care hospitals among patients with AHF who were previously receiving no or low-dose (12.5 mg or 25 mg daily) spironolactone and had NT-proBNP levels of 1000 pg/mL or more or B-type natriuretic peptide levels of 250 pg/mL or more, regardless of ejection fraction. Interventions: High-dose spironolactone (100 mg) vs placebo or 25 mg spironolactone (usual care) daily for 96 hours. Main Outcomes and Measures: The primary end point was the change in NT-proBNP levels from baseline to 96 hours. Secondary end points included the clinical congestion score, dyspnea assessment, net urine output, and net weight change. Safety end points included hyperkalemia and changes in renal function. Results: A total of 360 patients were randomized, of whom the median age was 65 years, 129 (36%) were women, 200 (55.5%) were white, 151 (42%) were black, 8 (2%) were Hispanic or Latino, 9 (2.5%) were of other race/ethnicity, and the median left ventricular ejection fraction was 34%. Baseline median (interquartile range) NT-proBNP levels were 4601 (2697-9596) pg/mL among the group treated with high-dose spironolactone and 3753 (1968-7633) pg/mL among the group who received usual care. There was no significant difference in the log NT-proBNP reduction between the 2 groups (-0.55 [95% CI, -0.92 to -0.18] with high-dose spironolactone and -0.49 [95% CI, -0.98 to -0.14] with usual care, P = .57). None of the secondary end point or day-30 all-cause mortality or heart failure hospitalization rate differed between the 2 groups. The changes in serum potassium and estimated glomerular filtration rate at 24, 48, 72, and 96 hours. were similar between the 2 groups. Conclusions and Relevance: Adding treatment with high-dose spironolactone to usual care for patients with AHF for 96 hours was well tolerated but did not improve the primary or secondary efficacy end points. Trial Registration: clinicaltrials.gov Identifier: NCT02235077.

Effects of combined low-dose spironolactone plus vitamin E vs vitamin E monotherapy on insulin resistance, non-invasive indices of steatosis and fibrosis, and adipokine levels in non-alcoholic fatty liver disease: a randomized controlled trial.

The beneficial effects of mineralocorticoid receptor blockade by spironolactone have been shown in animal models of non-alcoholic fatty liver disease (NAFLD). The aim of the present 52-week randomized controlled trial was to compare the effects of low-dose spironolactone and vitamin E combination with those of vitamin E monotherapy on insulin resistance, non-invasive indices of hepatic steatosis and fibrosis, liver function tests, circulating adipokines and hormones in patients with histologically confirmed NAFLD. Homeostasis model of assessment of insulin resistance (HOMA-IR) and non-invasive indices of steatosis and fibrosis were calculated. Analysis was intention-to-treat. NAFLD liver fat score, an index of steatosis, decreased significantly in the combination treatment group (P = .028), but not in the vitamin E group, and the difference for group*time interaction was significant (P = .047). Alanine aminotransferase-to-platelet ratio index, an index of fibrosis, did not change. Insulin levels and HOMA-IR decreased significantly only within the combination group (P = .011 and P = .011, respectively). In conclusion, the combined low-dose spironolactone plus vitamin E regimen significantly decreased NAFLD liver fat score. Larger-scale trials are needed to clarify the effect of low-dose spironolactone on hepatic histology.

A randomized controlled study of finerenone versus placebo in Japanese patients with type 2 diabetes mellitus and diabetic nephropathy.

AIMS: Finerenone (BAY 94-8862) is a novel non-steroidal mineralocorticoid receptor antagonist. The aim of this study was to compare the efficacy and safety of seven once-daily oral doses of finerenone (1.25-20mg) and placebo in 96 patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) receiving a RAS blocker. METHODS: ARTS-DN Japan was a multicenter, randomized, double-blind, placebo-controlled, phase 2b study. RESULTS: Analysis of the urinary albumin-to-creatinine ratio (UACR) at day 90 relative to baseline indicated a nominally significant effect of finerenone. The UACR at day 90 relative to baseline for each finerenone treatment group was numerically reduced compared with placebo. No serious adverse events (AEs) or deaths were reported and no patients experienced treatment-emergent AEs resulting in discontinuation of study drug. Small mean increases in serum potassium level were observed in the finerenone treatment groups (0.025-0.167mmol/L) compared with the placebo group (-0.075mmol/L); no patients developed hyperkalemia. CONCLUSION: When given in addition to a RAS inhibitor, finerenone reduced albuminuria without adverse effects on serum potassium levels or renal function in Japanese patients with T2DM and DN.

Beneficial effects of mineralocorticoid receptor blockade in experimental non-alcoholic steatohepatitis.

BACKGROUND: Therapeutic options to treat Non-alcoholic steatohepatitis (NASH) are limited. Mineralocorticoid receptor (MR) activation could play a role in hepatic fibrogenesis and its modulation could be beneficial for NASH. AIM: To investigate whether eplerenone, a specific MR antagonist, ameliorates liver damage in experimental NASH. METHODS: C57bl6 mice were fed a choline-deficient and amino acid-defined (CDAA) diet for 22 weeks with or without eplerenone supplementation. Serum levels of aminotransferases and aldosterone were measured and hepatic steatosis, inflammation and fibrosis scored histologically. Hepatic triglyceride content (HTC) and hepatic mRNA levels of pro-inflammatory pro-fibrotic, oxidative stress-associated genes and of MR were also assessed. RESULTS: CDAA diet effectively induced fibrotic NASH, and increased the hepatic expression of pro-inflammatory, pro-fibrotic and oxidative stress-associated genes. Hepatic MR mRNA levels significantly correlated with the expression of pro-inflammatory and pro-fibrotic genes and were significantly increased in hepatic stellate cells obtained from CDAA-fed animals. Eplerenone administration was associated to a reduction in histological steatosis and attenuation of liver fibrosis development, which was associated to a significant decrease in the expression of collagen-α1, collagen type III, alpha 1 and Matrix metalloproteinase-2. CONCLUSION: The expression of MR correlates with inflammation and fibrosis development in experimental NASH. Specific MR blockade with eplerenone has hepatic anti-steatotic and anti-fibrotic effects. These data identify eplerenone as a potential novel therapy for NASH. Considering its safety and FDA-approved status, human studies are warranted.

[Diuretic therapy in acute heart failure]. / Tratamiento con diuréticos en la insuficiencia cardíaca aguda.

Diuretics are widely recommended in patients with acute heart failure (AHF). Unfortunately, despite their widespread use, limited data are available from randomized clinical trials to guide clinicians on the appropriate management of diuretic therapy. Loop diuretics are considered the first-line diuretic therapy, especially intravenous furosemide, but the best mode of administration (high-dose versus low-dose and continuous infusion versus bolus) is unclear. When diuretic resistance develops, different therapeutic strategies can be adopted, including combined diuretic therapy with thiazide diuretics and/or aldosterone antagonists. Low or "non-diuretic" doses (25-50mg QD) of aldosterone antagonists have been demonstrated to confer a survival benefit in patients with heart failure and reduced ejection fraction and consequently should be prescribed in all such patients, unless contraindicated by potassium and/or renal function values. There is less evidence on the use of aldosterone antagonists at higher or "diuretic" doses (≥ 100mg QD) but these drugs could be useful in relieving congestive symptoms in combination with furosemide. Thiazide diuretics can also be helpful as they have synergic effects with loop diuretics by inhibiting sodium reabsorption in distal parts of the nephron. The effect of diuretic therapy in AHF should be monitored with careful observation of clinical signs and symptoms of congestion. Serum electrolytes and kidney function should also be monitored during the use of intravenous diuretics.

Tratamiento con diuréticos en la insuficiencia cardíaca aguda / Diuretic therapy in acute heart failure

El tratamiento diurético es ampliamente recomendado y utilizado en pacientes con insuficiencia cardíaca aguda. A pesar de su amplio uso, existen pocas evidencias sobre el tratamiento con diuréticos en insuficiencia cardíaca que provengan de ensayos clínicos aleatorizados. Los diuréticos de asa son los más utilizados, en especial furosemida por vía intravenosa, pero todavía no está claro cuál es su mejor forma de administración, ni las dosis (altas frente a bajas), ni la vía de administración (en forma de bolo o en perfusión continua). Cuando aparece resistencia a diuréticos de asa hay diferentes estrategias de tratamiento diurético, siendo una de ellas el tratamiento diurético combinado con diuréticos tiacídicos y/o antagonistas de la aldosterona. Los antagonistas de la aldosterona en dosis bajas o no diuréticas (25-50 mg/día) han demostrado mejorar la supervivencia en pacientes con insuficiencia cardíaca y fracción de eyección deprimida, por lo que todos los pacientes deberían recibirlos, siempre que las cifras de potasio y/o la función renal lo permitan. Hay menos evidencia sobre su uso en dosis altas o diuréticas (≥ 100 mg/día), pero también podrían ser útiles para aliviar de forma precoz los síntomas congestivos en combinación con furosemida. Los diuréticos tiacídicos pueden ser también útiles utilizados de forma sinérgica con los diuréticos de asa al inhibir la reabsorción de sodio en porciones más distales de la nefrona. Durante el tratamiento diurético es importante monitorizar los signos y síntomas de congestión, así como vigilar la aparición de efectos adversos, sobre todo deterioro de la función renal y alteraciones electrolíticas (AU)

Diuretics are widely recommended in patients with acute heart failure (AHF). Unfortunately, despite their widespread use, limited data are available from randomized clinical trials to guide clinicians on the appropriate management of diuretic therapy. Loop diuretics are considered the first-line diuretic therapy, especially intravenous furosemide, but the best mode of administration (high-dose versus low-dose and continuous infusion versus bolus) is unclear. When diuretic resistance develops, different therapeutic strategies can be adopted, including combined diuretic therapy with thiazide diuretics and/or aldosterone antagonists. Low or "non-diuretic" doses (25-50 mg QD) of aldosterone antagonists have been demonstrated to confer a survival benefit in patients with heart failure and reduced ejection fraction and consequently should be prescribed in all such patients, unless contraindicated by potassium and/or renal function values. There is less evidence on the use of aldosterone antagonists at higher or "diuretic" doses (≥ 100 mg QD) but these drugs could be useful in relieving congestive symptoms in combination with furosemide. Thiazide diuretics can also be helpful as they have synergic effects with loop diuretics by inhibiting sodium reabsorption in distal parts of the nephron. The effect of diuretic therapy in AHF should be monitored with careful observation of clinical signs and symptoms of congestion. Serum electrolytes and kidney function should also be monitored during the use of intravenous diuretics (AU)

Interactions of enhanced urocortin 2 and mineralocorticoid receptor antagonism in experimental heart failure.

BACKGROUND: Mineralocorticoid receptor antagonists (MRAs) have become established therapy in heart failure (HF). Urocortin 2 (Ucn2) is a novel peptide with potential in the treatment of this disease. The present study investigated the interactions of acute administration of Ucn2 and an MRA in experimental HF. METHODS AND RESULTS: Ucn2 and an MRA (canrenoic acid [CA]) were infused for 4 hours, both singly and together, in 8 sheeps with pacing-induced HF. Ucn2, when administered as an adjunct to CA, further improved hemodynamic indices relative to that achieved by CA alone, producing additional increases in cardiac output and decreases in left atrial pressure and peripheral resistance but without eliciting a supplementary reduction in arterial pressure. Ucn2 cotreatment reversed CA-induced rises in circulating aldosterone levels, and also significantly reduced plasma renin activity, angiotensin II, and vasopressin concentrations. Although both CA and Ucn2 infusion produced a diuresis and natriuresis, responses with Ucn2 and Ucn+CA were 2- to 3-fold greater than that elicited by separate CA. Ucn2 cotherapy additionally increased urine potassium and creatinine excretion. In contrast to the rise in plasma potassium induced by CA, Ucn2 cotreatment reduced potassium concentrations. CONCLUSIONS: Ucn2 cotreatment with an MRA in HF further improved hemodynamics relative to that achieved by CA alone, while also reducing plasma renin activity, angiotensin II, aldosterone and vasopressin levels, and enhancing renal function. Importantly, Ucn2 prevented CA-induced rises in plasma potassium. These data demonstrate a favorable profile of effects with short-term adjunct Ucn2 therapy and an MRA in HF.

Quadriparesis in an adult--Gitelman syndrome.

A 24 years old soldier presented with sudden onset of weakness in all four limbs. There was no history of any antecedent respiratory infection, fever, diarrhoea or vomiting. Neurological examination of limbs revealed reduced tone and power in all limbs. Although the tendon reflexes were diminished they could be elicited in all limbs. Rest of the clinical examination was unremarkable. Serum potassium was 2.1 mmol/l, sodium 138 mmol/l, bicarbonate 35.3 mmol/l, urea 5.7 mmol/l, creatinine 69 umol/l and serum creatine kinase (CK) was 686 U/l. Power in the patient's limbs gradually improved to normal by following afternoon after potassium chloride infusion. Serum chloride was 93 mmol/l, bicarbonate 33.4 mmol/l, calcium 2.1 mmol/l, urine sodium 134 mmol/l, urine potassium 82 mmol/l, urine chloride 156 mmol/l and urine pH 6.0. Urinary calcium excretion was 2.2 mmol in 24 hours. Serum magnesium was 0.7 mmol/l. A diagnosis of Gitelman syndrome was made. He is doing well on spironolactone, potassium chloride supplementation and high sodium diet, maintaining serum potassium level between 3.5 and 4.5 mmol/l.

Central neuronal activation and pressor responses induced by circulating ANG II: role of the brain aldosterone-"ouabain" pathway.

An increase in plasma ANG II causes neuronal activation in hypothalamic nuclei and a slow pressor response, presumably by increasing sympathetic drive. We evaluated whether the activation of a neuromodulatory pathway, involving aldosterone and "ouabain," is involved in these responses. In Wistar rats, the subcutaneous infusion of ANG II at 150 and 500 ng x kg(-1) x min(-1) gradually increased blood pressure up to 60 mmHg at the highest dose. ANG II at 500 ng x kg(-1) x min(-1) increased plasma ANG II by 4-fold, plasma aldosterone by 25-fold, and hypothalamic aldosterone by 3-fold. The intracerebroventricular infusion of an aldosterone synthase (AS) inhibitor prevented the ANG II-induced increase in hypothalamic aldosterone without affecting the increase in plasma aldosterone. Neuronal activity, as assessed by Fra-like immunoreactivity, increased transiently in the subfornical organ (SFO) but progressively in the paraventricular nucleus (PVN) and supraoptic nucleus (SON). The central infusion of the AS inhibitor or a mineralocorticoid receptor blocker markedly attenuated the ANG II-induced neuronal activation in the PVN but not in the SON. Pressor responses to ANG II at 150 ng x kg(-1) x min(-1) were abolished by an intracerebroventricular infusion of the AS inhibitor. Pressor responses to ANG II at 500 ng x kg(-1) x min(-1) were attenuated by the central infusion of the AS inhibitor or the mineralocorticoid receptor blocker by 70-80% and by Digibind (to bind "ouabain") by 50%. These results suggest a novel central nervous system mechanism for the ANG II-induced slow pressor response, i.e., circulating ANG II activates the SFO, leading to the direct activation of the PVN and SON, and, in addition, via aldosterone-dependent amplifying mechanisms, causes sustained activation of the PVN and thereby hypertension.

Predictors of hyperkalemia risk following hypertension control with aldosterone blockade.

BACKGROUND: Aldosterone antagonists have proven efficacy for management of resistant hypertension and proteinuria reduction; however, they are not widely used due to risk of hyperkalemia. This study assesses the risk factors for hyperkalemia in patients with chronic kidney disease (CKD) and resistant hypertension whose blood pressure (BP) is reduced to a guideline goal. METHODS: This is a two-center study conducted in university-based hypertension clinics directed by clinical hypertension specialists. Forty-six patients with resistant hypertension and stages 2 or 3 CKD (mean estimated glomerular filtration rate (eGFR) 56.5 + or - 16.2 ml/min/1.73 m(2)) were evaluated for safety and efficacy of aldosterone blockade added to preexisting BP-lowering regimens. All patients were on three mechanistically complementary antihypertensive agents including a diuretic and a renin-angiotensin system blocker. Patients were evaluated after a median of 45 treatment days. The primary endpoint was change in systolic BP. Secondary endpoints included change in serum potassium, creatinine, eGFR, diastolic BP and tolerability. RESULTS: The mean age of the patients studied was 64.9 + or - 10.7 years, all were obese and 86% had type 2 diabetes, with 82% being African-American. Addition of aldosterone antagonism yielded a further mean reduction in systolic BP of 14.7 + or - 5.1 mm Hg (p = 0.001). Females with BMI >30 and those with a baseline systolic BP >160 mm Hg were more likely to have a greater BP reduction to aldosterone antagonism. In total, 39% of the patients had a >30% decrease in eGFR when the BP goal was achieved. The mean increase in serum potassium was 0.4 mEq/l above baseline (p = 0.001), with 17.3% manifesting hyperkalemia, i.e. serum potassium >5.5 mEq/l. Predictors of hyperkalemia included a baseline eGFR of < or = 45 ml/min/1.73 m(2) in whom serum potassium was >4.5 mEq/l on appropriately dosed diuretics. Contributing risks in this subgroup included a systolic BP reduction of >15 mm Hg associated with an eGFR fall of >30%. CONCLUSION: Aldosterone antagonism is effective and safe for achieving a BP goal among people with diabetic nephropathy when added to a triple antihypertensive regimen that includes a blocker of the renin-angiotensin system and an appropriately selected and dosed diuretic. Caution is advised when using aldosterone blockade for BP control in people with advanced stage 3 nephropathy with a serum potassium of >4.5 mEq/l for safety reasons.

Medical therapy of adrenocortical tumors.

Medical therapy is but one of a multiarm, multispecialty approach that is needed in order to successfully treat adrenocortical tumors. The role of surgery, radiation therapy, radiofrequency ablation, and the need for a team approach for the care of the patient cannot be over-emphasized. In this article current and potential future medical therapies for adrenocortical tumors are reviewed.