The ViKTORIES trial: A randomized, double-blind, placebo-controlled trial of vitamin K supplementation to improve vascular health in kidney transplant recipients.

Premature cardiovascular disease and death with a functioning graft are leading causes of death and graft loss, respectively, in kidney transplant recipients (KTRs). Vascular stiffness and calcification are markers of cardiovascular disease that are prevalent in KTR and associated with subclinical vitamin K deficiency. We performed a single-center, phase II, parallel-group, randomized, double-blind, placebo-controlled trial (ISRCTN22012044) to test whether vitamin K supplementation reduced vascular stiffness (MRI-based aortic distensibility) or calcification (coronary artery calcium score on computed tomography) in KTR over 1 year of treatment. The primary outcome was between-group difference in vascular stiffness (ascending aortic distensibility). KTRs were recruited between September 2017 and June 2018, and randomized 1:1 to vitamin K (menadiol diphosphate 5 mg; n = 45) or placebo (n = 45) thrice weekly. Baseline demographics, clinical history, and immunosuppression regimens were similar between groups. There was no impact of vitamin K on vascular stiffness (treatment effect -0.23 [95% CI -0.75 to 0.29] × 10-3  mmHg-1 ; p = .377), vascular calcification (treatment effect -141 [95% CI - 320 to 38] units; p = .124), nor any other outcome measure. In this heterogeneous cohort of prevalent KTR, vitamin K supplementation did not reduce vascular stiffness or calcification over 1 year. Improving vascular health in KTR is likely to require a multifaceted approach.

Vitamin K Supplementation to Improve Vascular Stiffness in CKD: The K4Kidneys Randomized Controlled Trial.

BACKGROUND: Vascular calcification, a risk factor for cardiovascular disease, is common among patients with CKD and is an independent contributor to increased vascular stiffness and vascular risk in this patient group. Vitamin K is a cofactor for proteins involved in prevention of vascular calcification. Whether or not vitamin K supplementation could improve arterial stiffness in patients with CKD is unknown. METHODS: To determine if vitamin K supplementation might improve arterial stiffness in patients in CKD, we conducted a parallel-group, double-blind, randomized trial in participants aged 18 or older with CKD stage 3b or 4 (eGFR 15-45 ml/min per 1.73 m2). We randomly assigned participants to receive 400 µg oral vitamin K2 or matching placebo once daily for a year. The primary outcome was the adjusted between-group difference in carotid-femoral pulse wave velocity at 12 months. Secondary outcomes included augmentation index, abdominal aortic calcification, BP, physical function, and blood markers of mineral metabolism and vascular health. We also updated a recently published meta-analysis of trials to include the findings of this study. RESULTS: We included 159 randomized participants in the modified intention-to-treat analysis, with 80 allocated to receive vitamin K and 79 to receive placebo. Mean age was 66 years, 62 (39%) were female, and 87 (55%) had CKD stage 4. We found no differences in pulse wave velocity at 12 months, augmentation index at 12 months, BP, B-type natriuretic peptide, or physical function. The updated meta-analysis showed no effect of vitamin K supplementation on vascular stiffness or vascular calcification measures. CONCLUSIONS: Vitamin K2 supplementation did not improve vascular stiffness or other measures of vascular health in this trial involving individuals with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Vitamin K therapy to improve vascular health in patients with chronic kidney disease, ISRCTN21444964 (www.isrctn.com).

Analysis and modelling of cholesterol and high-density lipoprotein cholesterol changes across the range of C-reactive protein levels in clinical practice as an aid to better understanding of inflammation-lipid interactions.

OBJECTIVES: Raised total cholesterol (TC) and reduced high-density lipoprotein (HDL) cholesterol levels are established cardiovascular disease (CVD) risk factors. However, in autoimmune conditions the lipid-CVD association appears paradoxical, with inflammation as a potential confounding factor. We therefore sought to model the relationship between systemic inflammatory illness and lipid levels using C-reactive protein (CRP) as the prototypical marker of inflammation. Our hypothesis was that there would be an inverse association between raised CRP levels and both TC and HDL-cholesterol levels. METHODS: Results from samples analysed simultaneously for CRP and lipids in a 6-month period were collected retrospectively from a large city hospital laboratory database that collates results from both primary and secondary care. The relationships between CRP and lipids were determined using graphical techniques and empirical, non-parametric, best fit models. RESULTS: A total of 11 437 blood samples was included. We identified a significant (p<0.001) biphasic relationship between TC and CRP: TC increased within the healthy CRP range of less than 5 mg/l, but decreased with CRP levels above 10 mg/l. The two effects approximately cancelled each other out in the intermediate CRP range of 5-10 mg/l. There was an inverse relationship between HDL-cholesterol and CRP. CONCLUSIONS: Lipid levels change significantly during inflammatory illness in a population with both acute and chronic conditions. These results provide a strong epidemiological basis for the better understanding of lipid changes in inflammatory conditions and with anti-inflammatory therapies.

Starvation ketoacidosis and refeeding syndrome.

Starvation ketoacidosis (SKA) is a rarer cause of ketoacidosis. Most patients will only have a mild acidosis, but if exacerbated by stress can result in a severe acidosis. We describe a 66-year-old man admitted with reduced consciousness and found to have a severe metabolic acidosis with raised anion gap. His body mass index (BMI) was noted to be within the healthy range at 23 kg/m2; however, it was last documented 1 year previously at 28 kg/m2 with no clear timeframe of weight loss. While his acidosis improved with intravenous fluids, he subsequently developed severe electrolyte imbalance consistent with refeeding during his admission. Awareness of SKA as a cause for high anion gap metabolic acidosis is important and knowledge of management including intravenous fluids, thiamine, dietetic input and electrolyte replacement is vital.

Diagnosing unsuspected hypopituitarism in adults from suggestive thyroid function test results.

BACKGROUND: The typical pattern of thyroid function tests (TFTs) associated with hypopituitarism consists of subnormal free T4 (fT4) or total T4 and normal or marginally elevated thyroid-stimulating hormone (TSH). A previous study calculated an incidence of hypopituitarism of 3.2 cases/100,000/year by following up abnormal TFTs. The aim of this study was to verify the incidence of unsuspected hypopituitarism diagnosed by reflective testing on such samples in a Scottish population. METHODS: Prospective audit of TFT results over 15 months. Individuals with suitable results (fT4 < 9 pmol/L, TSH < 10 mU/L) were identified by the laboratory information system at the Biochemistry Department, Glasgow Royal Infirmary, serving a population of 200,000. fT4 (repeat analysis following assay recalibration), total T3, testosterone (males), luteinizing hormone, follicle-stimulating hormone, prolactin and cortisol were analysed on appropriate samples. RESULTS: Three hundred and eleven suitable results from 266 adult individuals were identified from a total of 73,650 TFT results, leading to the diagnosis of 10 new cases (age range 28-90 years) of hypopituitarism (approximately 4 cases/100,000/year). Nine patients now attend endocrine clinics. Pituitary imaging was abnormal in five cases (2 large pituitary tumours, one macroadenoma, 2 empty sellae), normal in three cases and two patients were not scanned. CONCLUSIONS: A significant number of cases of unsuspected hypopituitarism can be diagnosed by reflective testing on appropriate samples. fT4 should be an integral part of frontline TFTs as TSH alone cannot assist in the identification of possible hypopituitarism. Laboratories are in an excellent position to assist in early identification of hypopituitarism, which may lead to improved outcomes in such patients.

Simvastatin inhibits lymphocyte function in normal subjects and patients with cardiovascular disease.

HMG-CoA reductase inhibitors (statins) block the mevalonate pathway, preventing biosynthesis of cholesterol and isoprenoids. We investigated the effect of simvastatin on lymphocytes from normal human subjects and cardiovascular disease patients in order to provide a model for the in vivo actions of statins. Thirteen healthy volunteers were treated with 40 mg per day of simvastatin following which mean total cholesterol was reduced by 23% (S.D.+/- 11.7%) and mean LDL-cholesterol by 36% (S.D.+/- 16.3%). Lymphocyte lipid raft levels, represented by Lyn and Fyn, were also reduced by simvastatin. Treatment with simvastatin did not alter ex vivo T-lymphocyte proliferation. However, the in vitro addition of 1 microM simvastatin reduced T-lymphocyte proliferation by 39% (S.D.+/- 18.1%) and a combination of prenyl transferase inhibitors reduced proliferation by 19% (S.D.+/- 22.7%). We also assessed the cytotoxicity of natural killer (NK) cells-a T-lymphocyte subset. NK cell cytotoxicity ex vivo was reduced by 30% (S.D.+/- 33.6%) following oral simvastatin treatment and by 56% (S.D.+/- 24.68%) after the in vitro addition of 1 microM simvastatin. Significant ex vivo reductions in T-cell proliferation and NK cell cytotoxicity were observed in patients with cardiovascular disease on treatment with statins. NK cells have been implicated in the pathogenesis of atherosclerosis, so the effect of statin therapy on NK cell cytotoxicity may contribute to the benefits of statins in cardiovascular disease.

Resistance to thyroid hormone--an incidental finding.

A 16-year-old female with mild hirsutism was noted to have a small, smooth, non-tender goitre. A resting peripheral tremor, but no other symptoms or signs of thyroid dysfunction were present. Her only medication was the contraceptive pill. There was no family history of thyroid disease. Investigation showed elevated free thyroxine (28 pmol/l) and total triiodothyronine (3.4 nmol/l) with non-suppressed thyroid stimulating hormone (1.4 mU/l). Radioiodine uptake scan of the thyroid showed bilateral increased tracer uptake, suggestive of Graves' disease, however thyroid peroxidase and antithyroid stimulating hormone (TSH) receptor antibody testing was negative and sex hormone binding globulin concentration was normal. Laboratory analyses excluded assay artefact or abnormal circulating thyroid hormone binding proteins. Genetic analysis identified a thyroid hormone receptor gene mutation (T277I), making a diagnosis of resistance to thyroid hormone (RTH). RTH is a disorder characterised by elevated thyroid hormones, failure to suppress pituitary TSH secretion and variable refractoriness to hormone action in peripheral tissues.

Use of cetrorelix in the investigation of testosterone excess in a postmenopausal woman.

A 65-year-old woman presented to the endocrine clinic with increasing facial hirsutism over the past 6 months. She was noted to have excess hair on forearms, back and abdomen, along with some frontal balding. There were no abnormalities of the external genitalia, blood pressure was satisfactory and weight was stable. Biochemistry confirmed elevated testosterone (4.1 nmol/l). No abnormalities were seen on CT of abdomen and pelvis, nor by transvaginal ultrasound of the ovaries. Six months after her initial clinic visit, testosterone had increased to 6.0 nmol/l, rising to 7.3 nmol/l a few months later. Testosterone failed to suppress to low-dose dexamethasone suggesting excessive adrenal production was unlikely. Urine steroid profiling revealed no abnormality of adrenal steroid metabolites. Testosterone suppression was achieved with a rapidly-acting luteinizing-hormone-releasing hormone antagonist (cetrorelix), suggesting an ovarian source of excess production. Histology following bilateral salpingo-oophorectomy revealed a benign 6 mm diameter Leydig cell tumour in the right ovary.