Effect of eplerenone on parathyroid hormone levels in patients with primary hyperparathyroidism: results from the EPATH randomized, placebo-controlled trial.

BACKGROUND: Accumulating evidence points toward mutual interaction between parathyroid hormone (PTH) and aldosterone as potential mechanism for increasing cardiovascular risk in primary hyperparathyroidism (pHPT). METHODS: The Eplerenone on parathyroid hormone levels in patients with primary hyperparathyroidism (EPATH) trial is a single-center, randomized, double-blind, parallel-group, placebo-controlled trial. The primary aim is to evaluate the effects of the mineralocorticoid receptor antagonist eplerenone on plasma intact PTH (iPTH) concentration in patients with pHPT. Secondary end points comprised surrogate parameters of cardiovascular health [24-h ambulatory SBP and DBP and echocardiographic parameters related to systolic/diastolic function as well as to cardiac dimensions]. RESULTS: We enrolled 110 study participants with pHPT, 25-hydroxyvitamin D at least 20 ng/ml and estimated glomerular filtration rate more than 50 ml/min per 1.73 m. Patients were 1 : 1 randomly assigned to receive either 25 mg eplerenone once daily (up-titration after 4 weeks to 50 mg/day) or matching placebo for a treatment period of 8 weeks.The study was completed by 97 participants [mean (SD) age: 67.5 ±â€Š9.5 years; 78.4% women). The mean treatment effect (95% confidence interval) for iPTH was 1.0 (0.9-1.1; P = 0.777) pg/ml. Mean 24-h ambulatory SBP and DBP decreased significantly [mean change (95% confidence interval) -6.3 (-9.4 to -3.3) and -3.7 (-5.7 to -1.7) mmHg, respectively; P < 0.001]. No differences were seen in any further secondary outcomes or frequency of adverse events. CONCLUSION: In pHPT, treatment with eplerenone compared with placebo had no effect on circulating iPTH levels. Eplerenone treatment was well tolerated and safe and followed by significant decrease of ambulatory blood pressure.

Increased Hepato-Splanchnic Vasoconstriction in Diabetics during Regular Hemodialysis.

BACKGROUND AND OBJECTIVES: Ultrafiltration (UF) of excess fluid activates numerous compensatory mechanisms during hemodialysis (HD). The increase of both total peripheral and splanchnic vascular resistance is considered essential in maintaining hemodynamic stability. The aim of this study was to evaluate the extent of UF-induced changes in hepato-splanchnic blood flow and resistance in a group of maintenance HD patients during regular dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Hepato-splanchnic flow resistance index (RI) and hepato-splanchnic perfusion index (QI) were measured in 12 chronic HD patients using a modified, non-invasive Indocyaningreen (ICG) dilution method. During a midweek dialysis session we determined RI, QI, ICG disappearance rate (kICG), plasma volume (Vp), hematocrit (Hct), mean arterial blood pressure (MAP) and heart rate (HR) at four times in hourly intervals (t1 to t4). Dialysis settings were standardized and all patient studies were done in duplicate. RESULTS: In the whole study group mean UF volume was 1.86 ± 0.46 L, Vp dropped from 3.65 ± 0.77L at t1 to 3.40 ± 0.78L at t4, and all patients remained hemodynamically stable. In all patients RI significantly increased from 12.40 ± 4.21 mmHg∙s∙m2/mL at t1 to 14.94 ± 6.36 mmHg∙s∙m2/mL at t4 while QI significantly decreased from 0.61 ± 0.22 at t1 to 0.52 ± 0.20 L/min/m2 at t4, indicating active vasoconstriction. In diabetic subjects, however, RI was significantly larger than in non-diabetics at all time points. QI was lower in diabetic subjects. CONCLUSIONS: In chronic HD-patients hepato-splanchnic blood flow substantially decreases during moderate UF as a result of an active splanchnic vasoconstriction. Our data indicate that diabetic HD-patients are particularly prone to splanchnic ischemia and might therefore have an increased risk for bacterial translocation, endotoxemia and systemic inflammation.

Interrelated aldosterone and parathyroid hormone mutually modify cardiovascular mortality risk.

BACKGROUND: Inappropriate aldosterone and parathyroid hormone (PTH) secretion is associated with increased cardiovascular risk. Accumulating evidence suggests bidirectional interplay between aldosterone and PTH. METHODS: We evaluated the cross-sectional relationship between plasma aldosterone concentration (PAC), aldosterone to renin ratio (ARR) and PTH and subsequently tested whether the interaction between PAC and PTH modified the risk of cardiovascular death. PAC [78.0 (48.0-123.0) pg/mL], ARR [6.4 (2.9-12.9) pg/mL/pg/mL] and PTH concentration [median: 29.0 (22.0-40.0) pg/mL] were measured in 3074 patients (mean age: 62.5 ± 10.6 years; 30.3% women) referred to coronary angiography in a tertiary care center in Southwest Germany. RESULTS: Using multiple linear regression analysis, PAC and ARR emerged as an independent predictor of higher PTH concentrations (ß=0.12 and 0.21, P<0.001 for both) irrespective of intake of antihypertensive treatment, 25(OH)D, kidney function, serum calcium, phosphate, magnesium, cortisol, NT-pro-BNP, soluble α-klotho and FGF-23 concentration. After a median follow-up of 9.9 years, 512 (16.7%) participants had died due to fatal cardiovascular events. Multivariate Cox proportional hazard analysis revealed that both PAC and PTH were independently associated with cardiovascular mortality, with a potential synergistic interaction (P=0.028). PAC and PTH are exclusively associated with cardiovascular death in subjects with PTH and PAC concentrations above the median, respectively (PAC: HR per log SD: 1.14; 95% CI 1.02-1.29; P=0.026; PTH: HR per log SD: 1.18; 95% CI 1.02-1.37; P=0.031). CONCLUSIONS: Higher PAC and ARR were independently associated with PTH. PAC was independently related to incident cardiovascular mortality exclusively in patients with elevated PTH and vice versa.

Prevalence of detectable venous pressure drops expected with venous needle dislodgement.

Venous needle dislodgement (VND) is a potentially fatal complication during hemodialysis (HD) treatment and the venous pressure monitor is the most widely used device for its detection. VND can only be detected by the venous sensor if the resulting pressure drop exceeds the difference between the actual venous pressure and the lower alarm limit. In clinical practice, the lower alarm limit is usually set 30-40 mmHg below the actual venous pressure to avoid a disproportionate high number of nuisance alarms. The aim of this study was to quantify the number of fistulas and grafts in a group of HD patients where venous pressure monitoring can be expected to detect VND. We determined intra-access pressures in 99 chronic HD patients. Sixty-five (65.7%) had a fistula and 34 (34.3%) had a prosthetic graft as a vascular access. Mean intra-access pressure (Pa ) in fistulas was 32.6 ± 23.5 mmHg, whereas in grafts mean Pa was 60.9 ± 19.5 mmHg. Nineteen (29.2%) of the fistulas and 32 (94.1%) of the grafts exhibited an intra-access pressure above 40 mmHg. Therefore, in our study nearly all grafts but only 29% of fistulas would fulfill the requirement for venous pressure monitoring to detect VND.

Clinical application of interventional renal sympathetic denervation: recommendations of the Austrian Society of Hypertension 2012.

Increased activity of the sympathetic nervous system plays a major role in the pathophysiology of primary arterial hypertension. Interventional renal sympathetic denervation (RSD) is a novel percutaneous treatment, decreasing sympathetic activity and consecutively blood pressure by ablating sympathetic nervous fibers located in the adventitia of the renal arteries. The procedure has been tested in several clinical trials in patients with resistant hypertension (defined as systolic office blood pressure > 160 mmHg-in diabetic patients > 150 mmHg-treated with ³ 3 antihypertensive drugs) and caused a meaningful blood pressure reduction, lasting for at least 3 years. So far, no major adverse events have been identified; however, data on the long-term consequences are lacking. The present position paper of the Austrian Society of Hypertension is aiming to assist in choosing possible indications for RSD in clinical routine, based on the available evidence in 2012.

Effect of eplerenone on parathyroid hormone levels in patients with primary hyperparathyroidism: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Increasing evidence suggests the bidirectional interplay between parathyroid hormone and aldosterone as an important mechanism behind the increased risk of cardiovascular damage and bone disease observed in primary hyperparathyroidism. Our primary object is to assess the efficacy of the mineralocorticoid receptor-blocker eplerenone to reduce parathyroid hormone secretion in patients with parathyroid hormone excess. METHODS/DESIGN: Overall, 110 adult male and female patients with primary hyperparathyroidism will be randomly assigned to eplerenone (25 mg once daily for 4 weeks and 4 weeks with 50 mg once daily after dose titration] or placebo, over eight weeks. Each participant will undergo detailed clinical assessment, including anthropometric evaluation, 24-h ambulatory arterial blood pressure monitoring, echocardiography, kidney function and detailed laboratory determination of biomarkers of bone metabolism and cardiovascular disease.The study comprises the following exploratory endpoints: mean change from baseline to week eight in (1) parathyroid hormone(1-84) as the primary endpoint and (2) 24-h systolic and diastolic ambulatory blood pressure levels, NT-pro-BNP, biomarkers of bone metabolism, 24-h urinary protein/albumin excretion and echocardiographic parameters reflecting systolic and diastolic function as well as cardiac dimensions, as secondary endpoints. DISCUSSION: In view of the reciprocal interaction between aldosterone and parathyroid hormone and the potentially ensuing target organ damage, the EPATH trial is designed to determine whether eplerenone, compared to placebo, will effectively impact on parathyroid hormone secretion and improve cardiovascular, renal and bone health in patients with primary hyperparathyroidism. TRIAL REGISTRATION: ISRCTN33941607.

Aldosterone and parathyroid hormone: a precarious couple for cardiovascular disease.

Animal and human studies support a clinically relevant interaction between aldosterone and parathyroid hormone (PTH) levels and suggest an impact of the interaction on cardiovascular (CV) health. This review focuses on mechanisms behind the bidirectional interactions between aldosterone and PTH and their potential impact on the CV system. There is evidence that PTH increases the secretion of aldosterone from the adrenals directly as well as indirectly by activating the renin-angiotensin system. Upregulation of aldosterone synthesis might contribute to the higher risk of arterial hypertension and of CV damage in patients with primary hyperparathyroidism. Furthermore, parathyroidectomy is followed by decreased blood pressure levels and reduced CV morbidity as well as lower renin and aldosterone levels. In chronic heart failure, the aldosterone activity is inappropriately elevated, causing salt retention; it has been argued that the resulting calcium wasting causes secondary hyperparathyroidism. The ensuing intracellular calcium overload and oxidative stress, caused by PTH and amplified by the relative aldosterone excess, may increase the risk of CV events. In the setting of primary aldosteronism, renal and faecal calcium loss triggers increased PTH secretion which in turn aggravates aldosterone secretion and CV damage. This sequence explains why adrenalectomy and blockade of the mineralocorticoid receptor tend to decrease PTH levels in patients with primary aldosteronism. In view of the reciprocal interaction between aldosterone and PTH and the potentially ensuing CV damage, studies are urgently needed to evaluate diagnostic and therapeutic strategies addressing the interaction between the two hormones.

Aspergillus oryzae peritonitis in CAPD: case report and review of the literature.

Fungal peritonitis is a rare, but serious, complication of continuous ambulatory peritoneal dialysis (CAPD). We report a case of peritonitis caused by Aspergillus oryzae in a man on CAPD therapy who was treated successfully with amphotericin B and caspofungin, followed by itraconazole and removal of the peritoneal catheter. A oryzae was identified by using sequence analysis of the ribosomal DNA genes. Of 10 reported cases since 2003, the mortality rate was 30%. Removal of the CAPD catheter and systemic antimycotic therapy are essential to achieve clinical cure in patients with fungal CAPD-related peritonitis.

Vitamin E attenuates oxidative stress induced by intravenous iron in patients on hemodialysis.

Intravenous iron application to anemic patients on hemodialysis leads to an "oversaturation" of transferrin. As a result, non-transferrin-bound, redox-active iron might induce lipid peroxidation. To test the hypothesis that vitamin E attenuates lipid peroxidation in patients receiving 100 mg of iron(III) hydroxide sucrose complex intravenously during a hemodialysis session, 22 patients were investigated in a randomized cross-over design, either with or without a single oral dose of 1200 IU of all-rac-alpha-tocopheryl acetate taken 6 h before the hemodialysis session. Blood was drawn before and 30, 60, 90, 135, and 180 min after the start of the iron infusion, and areas under the curve (AUC0-180 min) of ratios of plasma malondialdehyde (MDA) to cholesterol and plasma total peroxides to cholesterol (two markers of lipid peroxidation) were determined as the outcome variables. At baseline of the session without vitamin E supplementation, plasma alpha-tocopherol concentrations (27.6 +/- 1.8 micromol/L) and ratios of alpha-tocopherol to cholesterol (5.88 +/- 1.09 mmol/mol) were normal, plasma MDA concentrations were above normal (1.20 +/- 0.28 micromol/ L), and bleomycin-detectable iron (BDI), indicating the presence of redox-active iron, was not detectable. Upon iron infusion, BDI and MDA concentrations increased significantly (P < 0.001). BDI concentrations explained the increase over baseline in MDA concentrations (MDA = 1.29 +/- 0.075 x BDI). Vitamin E supplementation, leading to a 68% increase in plasma alpha-tocopherol concentrations, significantly reduced the AUC0-180 min of MDA to cholesterol (P = 0.004) and peroxides to cholesterol (P = 0.002). These data demonstrate that a single oral dose of vitamin E attenuates lipid peroxidation in patients on hemodialysis receiving intravenous iron. Given that intravenous iron is applied repeatedly to patients on hemodialysis, this therapeutic approach may protect against oxidative stress-related degenerative disease in the long term.