Effect of cinacalcet cessation in renal transplant recipients with persistent hyperparathyroidism

Background. Persistent hyperparathyroidism after renal transplantation affects bone and allografts. Cinacalcet, a calcimimetic, reduces serum calcium and PTH in renal transplant recipients with persistent hyperparathyroidism. Here, we address the question whether this effect of cinacalcet persists after withdrawal. Methods. Therefore, cinacalcet was stopped after 12 months treatment in 10 stable renal transplant patients. Serum calcium, phosphate, PTH, creatinine and cystatin C were monitored for 3 months. Results. Serum calcium, normalized in nine patients before cessation of cinacalcet (2.32 ± 0.05mmol/l, mean ± SEM), increased after 3 months of discontinuation by 0.17 ± 0.04mmol/l, P < 0.05, but remained within the normal range in eight patients. Compared with the time point of cessation, PTH remained unchanged or decreased further after 3 months without therapy in six patients. Measurements of cystatin C suggested an improvement of the glomerular filtration rate after cessation in 9 out of 10 patients (1.55 ± 0.09 vs 1.33 ± 0.12 mg/l, P < 0.01). Conclusion. First, a beneficial effect of cinacalcet beyond the duration of a 12-month therapy appears to be present in some patients and second, the previously suspected influence of cinacalcet therapy on renal function is reversible. Thus, it is reasonable to consider a trial of cinacalcet cessation to identify these patients. The optimal time point for such a discontinuation is unknown. The present observations are preliminary. They clearly require a prospective randomized trial for definitive confirmatio

The calcimimetic cinacalcet normalizes serum calcium in renal transplant patients with persistent hyperparathyroidism

Background. Treatment of persistent hyperparathyroidism in renal transplant patients resistant to calcium and vitamin D sterols is limited and often requires parathyroidectomy. Given the potential hazards linked to surgery, an alternative approach to manage excess parathyroid hormone (PTH) secretion is needed. Calcimimetics inhibit PTH secretion by modulating the calcium-sensing receptor in the parathyroid. Lowering of the serum calcium concentration with the calcimimetic cinacalcet has previously been demonstrated in patients with primary hyperparathyroidism or with secondary hyperparathyroidism on dialysis. Here we present the first clinical observations of a calcimimetic in patients with persistent hyperparathyroidism. Methods. A 30 mg dose of cinacalcet was prescribed once daily for 3 months to seven female and seven male stable renal transplant patients, aged 23-65 years, 7 months to 14 years after transplantation, with a serum creatinine ranging from 89 to 229 µmol/l and persistent hyperparathyroidism. Concomitant medication included cyclosporin and low-dose prednisone in all patients. Results. On cinacalcet, serum calcium decreased and normalized in all but two patients (baseline 2.72±0.03 mmol/l; 1 month 2.42±0.04 mmol/l, P<0.001), whereas serum PTH and phosphate levels did not change significantly. A slight reduction in renal function, as assessed by serum creatinine concentration, was observed at months 2 and 3 (P<0.05). An immunoglobulin-deficient patient developed colitis after 1 week of treatment and cinacalcet was withdrawn. No patient stopped cinacalcet because of other presumed side effects. Conclusion. Calcimimetics are a promising therapy in renal transplant patients with persistent hyperparathyroidism. Prospective controlled studies must now be designed focusing on functionally relevant musculo-skeletal end-points and allowing the exclusion of negative effects on long-term renal and general outcome of such patient

PTH and 1.25 vitamin D response to a low-calcium diet is associated with bone mineral density in renal stone formers

Background. Renal calcium stones and hypercalciuria are associated with a reduced bone mineral density (BMD). Therefore, the effect of changes in calcium homeostasis is of interest for both stones and bones. We hypothesized that the response of calciuria, parathyroid hormone (PTH) and 1.25 vitamin D to changes in dietary calcium might be related to BMD. Methods. A single-centre prospective interventional study of 94 hyper- and non-hypercalciuric calcium stone formers consecutively retrieved from our stone clinic. The patients were investigated on a free-choice diet, a low-calcium diet, while fasting and after an oral calcium load. Patient groups were defined according to lumbar BMD (z-score) obtained by dual X-ray absorptiometry (group 1: z-score 0.5, n = 28). The effect of the dietary interventions on calciuria, 1.25 vitamin D and PTH in relation to BMD was measured. Results. An inverse relationship between BMD and calciuria was observed on all four calcium intakes (P = 0.009). On a free-choice diet, 1.25 vitamin D and PTH levels were identical in the three patient groups. However, the relative responses of 1.25 vitamin D and PTH to the low-calcium diet were opposite in the three groups with the highest increase of 1.25 vitamin D in group 1 and the lowest in group 3, whereas PTH increase was most pronounced in group 3 and least in group 1. Conclusion. Calcium stone formers with a low lumbar BMD exhibit a blunted response of PTH release and an apparently overshooting production of 1.25 vitamin D following a low-calcium die

Androgens Tend to Be Higher, but What about Altered Progesterone Metabolites in Boys and Girls with Autism?

BACKGROUND Evidence exists that steroid hormones are altered in individuals with autism, especially androgens. Despite lower prevalence in girls than boys, evidence of potential alterations in progesterone metabolites is sparse, so the aim of this study was to elucidate different progesterone metabolites in affected children with autism versus healthy controls. MATERIAL AND METHODS Circadian urine samples from 48 boys and 16 girls with autism spectrum disorders and a matched case-control group were analysed for progesterone metabolites by gas chromatography-mass spectrometry and normalised for creatinine excretion. RESULTS In boys with autism, the majority of progesterone metabolites were reduced, such as progesterone, 6a-OH-3a5b-TH-progesterone, or 20a-DH-progesterone (p &lt; 0.01 for all). In girls with autism, a similar pattern of reduction in progesterone metabolites was detected; however, potentially due to the relatively small sample, this pattern was only detectable on the level of a trend. DISCUSSION As stated, androgen levels are higher in boys and girls with autism, but evidence for progesterone metabolites is much sparser. The pattern of a decrease in progesterone metabolites suggests the existence of an altered routing of steroid metabolites, probably in combination with a dysregulation of the HPAG axis. As, recently, increased CYP17A1 activity has been suggested, the stronger routing towards androgens is further implied in line with our findings of lower progesterone concentrations in boys and girls with autism than healthy controls

Postpartal recurrent non-ST elevation myocardial infarction in essential thrombocythaemia: case report and review of the literature

Normal pregnancy corresponds to a procoagulant state. Acute myocardial infarction during pregnancy is rare, yet considering the low non-pregnant risk score of childbearing women it is still surprisingly frequent. We report a case of postpartum recurrent non-ST elevation myocardial infarction in a 40-year-old caucasian woman with essential thrombocythaemia in the presence of a positive JAK-2 mutation and an elevated anti-cardiolipin IgM antibody titer. In the majority of cases of myocardial infarction in pregnancy or in the peripartal period, atherosclerosis, a thrombus or coronary artery dissection is observed. The combination of essential thrombocythaemia and elevated anti-cardiolipin IgM antibody titer in the presence of several cardiovascular risk factors seems to be causative in our case. In conclusion, with the continuing trend of childbearing at older ages, rare or unlikely conditions leading to severe events such as myocardial infarction must be considered in pregnant women

Gain-of-function haplotype in the epithelial calcium channel TRPV6 is a risk factor for renal calcium stone formation

The rate-limiting step of dietary calcium absorption in the intestine requires the brush border calcium entry channel TRPV6. The TRPV6 gene was completely sequenced in 170 renal calcium stone patients. The frequency of an ancestral TRPV6 haplotype consisting of three non-synonymous polymorphisms (C157R, M378V, M681T) was significantly higher (P = 0.039) in calcium stone formers (8.4%; derived = 502, ancestral = 46) compared to non-stone-forming individuals (5.4%; derived = 645, ancestral = 37). Mineral metabolism was investigated on four different calcium regimens: (i) free-choice diet, (ii) low calcium diet, (iii) fasting and (iv) after a 1 g oral calcium load. When patients homozygous for the derived haplotype were compared with heterozygous patients, no differences were found with respect to the plasma concentrations of 1,25-vitamin D, PTH and calcium, and the urinary excretion of calcium. In one stone-forming patient, the ancestral haplotype was found to be homozygous. This patient had absorptive hypercalciuria. We therefore expressed the ancestral protein (157R+378V+681T) in Xenopus oocytes and found a significantly enhanced calcium permeability when tested by a 45Ca2+ uptake assay (7.11 ± 1.93 versus 3.61 ± 1.01 pmol/min/oocyte for ancestral versus derived haplotype, P < 0.01). These results suggest that the ancestral gain-of-function haplotype in TRPV6 plays a role in calcium stone formation in certain forms of absorptive hypercalciuri

The relative myocardial blood volume differentiates between hypertensive heart disease and athlete's heart in humans

Aims The adaptation of the myocardial microcirculation in humans to pathologic and physiologic stress has not been examined in vivo so far. We sought to test whether the relative blood volume (rBV) measured by myocardial contrast echocardiography (MCE) can differentiate between left ventricular (LV) hypertrophy (LVH) in hypertensive heart disease and athlete's heart. Methods and results Four groups were investigated: hypertensive patients with LVH (n=15), semi-professional triathletes with LVH (n=15), professional football players (n=15), and sedentary control individuals without cardiovascular disease (n=15). MCE was performed at rest and during adenosine-induced hyperaemia. The rBV (mL mL−1), its exchange frequency (β, min−1), and myocardial blood flow (mL min−1 g−1) were derived from steady state and refill sequences of ultrasound contrast agent. Hypertensive patients had lower rBV (0.093±0.013 mL mL−1) than triathletes (0.141±0.012 mL mL−1, P<0.001), football players (0.129±0.014 mL mL−1, P<0.001), and sedentary individuals (0.126±0.018 mL mL−1, P<0.001). Conversely, the exchange frequency (β) was significantly higher in hypertensive patients (11.3±3.8 min−1) than in triathletes (7.4±1.8 min−1), football players (7.7±2.3 min−1), and sedentary individuals (9.0±2.5 min−1). An rBV below 0.114 mL mL−1 distinguished hypertensive patients and triathletes with a sensitivity of 93% and a specificity of 100%. Conclusion Pathologic and physiologic LVH were differentiated non-invasively and accurately by rBV, a measure of vascularisation assessed by MC

Electrical carotid baroreceptor stimulation

Summary: The Barostim neoTM system is a novel implantable device that activates the carotid baroreflex. It decreases the sympathetic activity and inhibits the renin system, which results in reduced blood pressure and heart rate. In patients with resistant hypertension, electrically activation of the baroreflex leads to an average decrease in systolic blood pressure of 38, 36, 40 and 53mmHg at 1, 2, 3 and 4 years, respectively. Additionally, cardiac remodelling with reduced left ventricular mass and posterior wall thickness has been observed in long-term studies. In a limited number of patients with heart failure, baroreflex activation therapy leads to a decrease in muscle sympathetic nerve activity and to improved quality of life and functional capacities. The implantation procedure is safe and associated with risks comparable with those of other active implantable devices. Barostim neo is currently available in several European countries