Disorders of bilirubin and lipid metabolism:models and targets of intervention

The increasing prevalence of metabolic disorders as well as increased knowledge about the role of nuclear receptors (NRs) in a plethora of metabolic pathways has led to a surge in the development of drugs targeting these NRs. This thesis aimed to improve our understanding of disorders of bilirubin and lipid metabolism and to find new targets of intervention. Unconjugated hyperbilirubinemia is caused by high amounts of unconjugated bilirubin and this can accumulate in the brain causing damage, which even can lead to death when left untreated. In recent years, a relationship between (mildly) unconjugated hyperbilirubinemia and a beneficial (i.e. anti-atherogenic) lipid profile has been demonstrated. However, this relationship is not yet fully understood and a better understanding of underlying mechanisms will contribute to knowledge about the risk of developing cardiovascular disease. We investigated the relation between bilirubin and lipid metabolism in an animal model for unconjugated hyperbilirubinemia, the Gunn rat. In our studies we demonstrated that activation of two NRs reduced cholesterol levels but did not lower bilirubin levels, and is therefore not a potential therapeutic strategy for unconjugated hyperbilirubinemia. Peroxisomes are cell organelles involved in metabolism of compounds including cholesterol and fatty acids. The function of many peroxisomal proteins has not been fully elucidated. In this thesis we investigated the metabolic function of the peroxisomal protein PXMP4 under different experimental conditions in a mouse model. The function of PXMP4 is redundant under the tested conditions and is likely compensated for by other peroxisomal proteins

Clinical Profile of Eprosartan: A Different Angiotensin II Receptor Blocker

Rationale. The goal of antihypertensive treatment is to reduce risk of cardiovascular morbidity and mortality. Apart from blood pressure lowering per se, also reducing the activities of the renin-angiotensin system and sympathetic nervous system appears to be important. Angiotensin II receptor blocker drugs (ARBs) have provided a useful class of anti-hypertensive drugs. Eprosartan is a relatively new ARB which is chemically distinct (non-biphenyl, non-tetrazole) from all other ARBs (biphenyl tetrazoles). An analysis has been made on available experimental and clinical data on eprosartan which not only is an effective and well tolerated antihypertensive agent, but also lowers the activities of the renin-angiotensin system and sympathetic nervous system. Experimental and pharmacokinetic studies on eprosartan have shown differences with the other ARBs. The distinct properties of this non-biphenyl, non-tetrazole ARB might be relevant in the effort to reduce cardiovascular risk, also beyond its blood pressure lowering capacity

Evidence and Consequences of the Central Role of the Kidneys in the Pathophysiology of Sympathetic Hyperactivity

Chronic elevation of the sympathetic nervous system has been identified as a major contributor to the complex pathophysiology of hypertension, states of volume overload – such as heart failure – and progressive kidney disease. It is also a strong determinant for clinical outcome. This review focuses on the central role of the kidneys in the pathogenesis of sympathetic hyperactivity. As a consequence, renal denervation may be an attractive option to treat sympathetic hyperactivity. The review will also focus on first results and the still remaining questions of this new treatment option

Adrenaline and hypertension

The questions we hoped to answer by the studies described in this thesis, were: 1 Does adrenaline, when infused intravenously in normotensive subjects leading to plasma levels in the high physiological range, cause a sustained and protracted rise in blood pressure, which outlasts the duration of the increments in circulating adrenaline? And if so, does this effect on blood pressure occurs at rest or during periods of activation of the sympathetic nervous system? In view of the data of Vincent et al (43), we hypothesized that the latter would be the case. 2 If the questions under number 1 are positively answered, does intravenous administered noradrenaline have the same effect? When the effect of adrenaline is indeed mediated through prejunctional B,-adrenoceptors, we hypothesized that this would not be the case. 3 Do the pressor responses to standardized sympathetic nervous system stimulation by cold pressor and isometric exercise testing before, during and 18 hours after cessation of infusions of adrenaline, noradrenaline or dextrose 5% differ? Again we hypothesized that infusion of adrenaline but not noradrenaline would lead to an amplification of the blood pressure responses. 4 Are the changes in plasma concentrations of adrenaline and noradrenaline during the infusions of adrenaline and noradrenaline also detectable in alterations in the amounts of catecholamines and their metabolites excreted in the urine? 5 Do the infusions of catechOiamines, which lead to alterations in plasma concentrations within the physiological range, have any effect on urinary sodium excretion or on plasma levels of several hormones, potassium or glucose? 6 What is the effect of non-selective and B,-selective B-blockade on the adrenaline mediated facilitation of noradrenaline release and the adrenaline induced enhancement of reflex sympathetic nervous system activity

Letter on 'European dermatology forum S1-guideline on the diagnosis and treatment of sclerosing diseases of the skin, Part 2: Scleromyxedema, scleredema and nephrogenic systemic fibrosis'

We read with interest the guidelines recently published on sclerosing diseases of the skin (Part 2: Scleromyxedema, scleredema and nephrogenic systemic fibrosis)[1, 2]. However, we are concerned that the guideline recommendations proposed for prevention of nephrogenic systemic fibrosis (NSF) are potentially dangerous. Although we recognise the challenges in constructing comprehensive guidelines, we are concerned that this may be because the guidelines have not involved a multidisciplinary team

Testing the (legal) waters: interpreting the political representation of a river with rights in New Zealand : “let’s talk to the river, instead of talking about the river”

In 2017, after protracted litigation between Māori iwi (tribe) and the Crown, the Whanganui River in Aotearoa/New Zealand was granted the status of a ‘legal person’. The river is described as an indivisible and living whole, so-called Te Awa Tupua. As a legal person, it includes all physical and metaphysical elements and has the right to flourish in order to maintain its health and wellbeing. Its interests are represented by two appointed ‘human faces’ and other actors including a strategy group. Potentially fraught with problems of misrepresentation, as well as a host of philosophical issues on speaking on behalf of an arguably “voiceless” and vulnerable actor, communicative problems arise how to actually politically represent a natural-cultural entity in practice. While the postcolonial context is unique and carries along dimensions of justice to the Māori, the development may also be understood against an ecocentric background. This includes the worldwide movement of earth jurisprudence, which advocates for giving rights and political agency to nature. We investigate by which epistemic and ontological claims the agency, and thereby the interests of the river are planned to be realised in the deliberative arena and inform policy. This thesis offers a qualitative, phenomenological study of how the different views on politically representing the river are juxtaposed, and how they are practically and communicatively manifested. In New Zealand we conducted eight semi-structured interviews with a selection of the appointed representative actors and the people who either appointed or advise them. A thematic analysis shows how the representative actors put an emphasis on a holistic view on, and a personal connection to the river, which both serve as a preferred moral relation in order to represent. Moreover, the concept of ‘legal personhood’ gives further standing to the river, but brings about different connotations. The findings are theoretically deepened using (political) representation theory, which shows (1) a pre-political relation based on a ‘communicative ethic’, internalising the river’s interests and (2) a political representative practice making both the river’s interests and the relations to it present by a deliberative process. This is aimed to result in a sustainable, reciprocal relationship with the river. To conclude, this study offers an empirical exploration on how the recognition of the rights of nature are implemented and given meaning to, and shows the importance of discursive plurality and ethical relations on top of the legal aspect to bring about an ecocentric paradigm shift

Controversy on the CONVINCE study findings: the PRO take

The CONVINCE study, recently published in the New England Journal of Medicine, reveals a groundbreaking 23% reduction in the relative risk of all-cause mortality among end-stage kidney patients undergoing high convective volume hemodiafiltration. This significant finding challenges the conventional use of high-flux hemodialysis and offers hope for improving outcomes in chronic kidney disease patients. While some controversies surround the study's findings, including concerns about generalizability and the causes of death, it is essential to acknowledge the study's design and its main outcomes. The CONVINCE study, part of the HORIZON 2020 project, enrolled 1360 patients and demonstrated the superiority of hemodiafiltration in reducing all-cause mortality overall, as well as in specific patient subgroups (elderly, short vintage, non-diabetic, and those without cardiac issues). Interestingly, it was shown that hemodiafiltration had a protective effect against infection, including COVID-19. Future research will address sustainability, dose scaling effects, identification of subgroups especially likely to benefit and cost-effectiveness. However, for now, the findings strongly support a broader adoption of hemodiafiltration in renal replacement therapy, marking a significant advancement in the field

Why Choose High Volume Online Post-dilution Hemodiafiltration

The mortality rate of patients on maintenance dialysis remains alarmingly high, at approximately 15–20 % per year. Increasing dialyzer urea clearance has not been shown to improve survival and hence interest has shifted towards convective therapies, such as hemodiafiltration (HDF) which can remove middle molecular weight uremic toxins, which have been suggested to increase mortality in patients with end-stage kidney disease. During the last few years, four large prospective randomized controlled trials (RCTs) have been conducted in different European countries to compare survival outcomes in prevalent patients receiving conventional hemodialysis with online post-dilution HDF (OL HDF). Furthermore, a pooled individual participant data analysis from four RCTs was performed and four large meta-analyses on convective therapies have been published in the last 2 years. Taken together, these studies support the conclusion that high volume post-dilution OL HDF is associated with improved overall survival. This advantage results predominantly from a lower cardiovascular mortality, possibly due to better preservation of left ventricle mass and function. Improved intra-dialytic blood pressure stability may contribute to the beneficial effect of high volume post-dilution OL HDF on survival. The beneficial effect is not restricted to selected subgroups, such as age, comorbidity or dialysis vintage. There is no compelling evidence that high volume post-dilution OL HDF reduces mortality by improvements in traditional and non-traditional risk factors. There are still no studies or case reports published describing adverse clinical outcomes in more than 20 years of HDF clinical experience. In conclusion, most of the available data support the choice of high volume post-dilution HDF over the current dialysis techniques. However, considering that we live in the era of evidence-based medicine, the evidence supporting the superiority of high volume post-dilution OL HDF in comparison to hemodialysis is still missing: in fact, a new RCT targeting different convection volumes would be needed to definitively examine the dose–response effect shown in previous studies

Endovascular baroreflex amplification and the effect on sympathetic nerve activity in patients with resistant hypertension: A proof-of-principle study

Background: First in human studies suggest that endovascular baroreflex amplification (EVBA) lowers blood pressure (BP). To explore potential mechanisms for BP reduction, this study examines the effects of EVBA on muscle sympathetic nerve activity (MSNA) and baroreceptor sensitivity (BRS). // Methods: In a single-center sub-study of the CALM-DIEM study (Controlling And Lowering blood pressure with the MobiusHD—Defining Efficacy Markers), 14 patients with resistant hypertension were treated with EVBA. Microneurography and non-invasive continuous BP measurements were performed at baseline and three months after MobiusHD implantation. The primary outcome was change in MSNA. Secondary outcomes were change in baroreflex sensitivity (BRS), cardiovascular responses to a sympathetic stimulus, BP, heart rate (HR) and heart rate variability (HRV). // Results: The primary endpoint was obtained in 10 of 14 patients enrolled in the sub-study. MSNA burst frequency and burst incidence decreased in 6 of 10 patients: mean change -4.1 bursts/min (95% confidence interval -12.2 to 4.0) and -3.8 bursts/100 heartbeats (-15.2 to 7.7). MSNA spike frequency and spike count decreased in 8 of 10 patients: mean change -2.8 spikes/sec (-7.3 to 1.8) and -3.0 spikes/heartbeat (-6.1 to 0.1). Change in MSNA and BP were not correlated. Office BP decreased by -14/-6 mmHg (-27 to -2/-15 to 3). We observed a trend towards decreased HR (-5 bpm, -10 to 1) and increased total power HRV (623 msec2, 78 to 1168). In contrast, BRS and cardiovascular responses remained unchanged after EVBA. // Conclusions: In this proof-of-principle study, EVBA did not significantly decrease MSNA in patients with resistant hypertension. EVBA did not impair baroreflex function