Cardiovascular, renal and thyroid toxicity during angiogenesis inhibition: A translational approach

Inhibition of angiogenesis with humanized monoclonal antibodies to vascular endothelial growth factor (VEGF) or with tyrosine kinase inhibitors targeting VEGF receptors has become an established treatment for various tumor types. Contrary to expectations, angiogenesis inhibition by blocking VEGF-mediated signaling is associated with serious side effects including hypertension and renal and cardiac toxicity in a substantial proportion of patients. Fortunately, most of these side effects as discussed in this paper seem to be manageable, but likely become more problematic when survival increases. Although several hypotheses regarding the etiology of angiogenesis inhibition-related cardiovascular and renal side effects have been postulated, many of the underlying pathophysiological mechanisms remain to be elucidated. This may lead to the development of more specific angiogenesis inhibitors, better management of their side effects and may potentially provide new insights into the pathogenesis of cardiovascular disease in general

Mechanism of hypertension and proteinuria during angiogenesis inhibition: Evolving role of endothelin-1

Angiogenesis inhibition by blocking vascular endothelial growth factor (VEGF)-mediated signalling with monoclonal antibodies or tyrosine kinase inhibitors has become an established treatment of various forms of cancer. This treatment is frequently associated with the development of hypertension and proteinuria. As VEGF increases the expression and the activity of nitric oxide synthase in endothelial cells, a decrease in the bioavailability of nitric oxide has been proposed as a key mechanism leading to hypertension during angiogenesis inhibition. However, results of clinical and experimental studies exploring this possibility are conflicting. Rarefaction, that is a structural decrease of microcirculatory vessels, has been reported during antiangiogenic treatment, but evidence that it plays a role in development of hypertension is lacking. Elevated circulating and urinary levels of endothelin-1 have been observed in clinical and experimental studies with angiogenesis inhibitors. Furthermore, the observation that endothelin receptor blockers can prevent or revert the rise in blood pressure during angiogenesis inhibition and attenuate proteinuria provides strong evidence that an activated endothelin-signalling pathway is a final common mediator of angiogenesis inhibition-induced rise in blood pressure and renal toxicity

Hypertension induced by antiangiogenic therapy: Clinical and pathophysiological aspects

Angiogenesis inhibition with humanised monoclonal antibodies to vascular endothelial growth factor (VEGF) or with VEGF receptor tyrosine kinase inhibitors targeting VEGF receptors has become an established treatment for various forms of cancer. Unfortunately, inhibition of the VEGF pathway is associated with serious side effects including hypertension. The development of this hypertension is likely to be multifactorial with a major role of the endothelin system. Although initially considered as a toxic effect, the development of hypertension may predict a favourable antitumour response. As a consequence, hypertension should not be a reason for dose reduction or discontinuation of antiangiogenic therapy but should be treated with antihypertensive therapy according to existing guidelines

The effect of combining therapeutic drug monitoring of antihypertensive drugs with personalised feedback on adherence and resistant hypertension: the (RHYME-RCT) trial protocol of a multi-centre randomised controlled trial.

Background Adherence to antihypertensive drugs (AHDs) is important for adequate blood pressure control. Not taking these drugs as prescribed is one of the main underlying causes for resistant hypertension (RH), which in turn leads to an increased risk of cardiovascular events, stroke and kidney damage. Therefore, correct identification of patients that are non-adherent to AHDs is crucial to improve clinical outcome. For this goal, therapeutic drug monitoring is the most reliable method. The primary objective of this trial is to investigate whether monitoring of drug concentrations with a dried blood spot (DBS) sampling method combined with personalised feedback leads to a decrease in prevalence of RH after 12 months due to an increase in adherence. Secondary objectives include the difference over time in the number of required AHDs as well as the defined daily dose (DDD). Lastly, the cost-utility of SoC versus the intervention in RH is determined. Methods This is a multi-centre single-blinded randomised controlled trial (RHYME-RCT). First, at an eligibility visit, DBS sampling, to monitor drug concentrations in blood, and a 24-h ambulatory blood pressure measurement (24-h ABPM) are performed simultaneously. Patients with a daytime systolic blood pressure (SBP) > 135 and/or diastolic blood pressure (DBP) > 85 mmHg are randomised to SoC or intervention + SoC. The intervention is performed by the treating physician and includes information on drug concentrations and a comprehensive personalised feedback conversation with the use of a communication tool. The follow-up period is one year with visits at 3, 6 and 12 months randomisation and includes 24-h ABPM and DBS sampling. Discussion This will be the first trial that focusses specifically on patients with RH without taking into account suspicion of non-adherence and it combines monitoring of AHD concentrations to identify non-adherence to AHDs with a comprehensive feedback to improve non-adherence. Furthermore, if this trial shows positive outcomes for the intervention it can be directly implemented in clinical practice, which would be a great improvement in the treatment of RH

Cumulative dose of bevacizumab associates with albuminuria rather than podocyturia in cancer patients

Immunopathology of vascular and renal diseases and of organ and celltransplantationIP1

[New insights into the pathogenesis of pre-eclampsia: the role of angiogenesis-inhibiting factors].

The pathogenesis of pre-eclampsia is biphasic. The first phase is characterised by insufficient placentation and the second phase by an increased placental release of 2 anti-angiogenic factors, namely, soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng). Within maternal circulation, sFlt-1 and sEng inhibit the effects of vascular endothelial growth factor (VEGF) and transforming growth factor β (TGFβ). This results in endothelial cell activation and inflammation, and eventually leads to the clinical syndrome of pre-eclampsia. The rise in plasma concentrations of sFlt-1 and sEng precedes the development of pre-eclampsia with 6-8 weeks. Whether elevations in the plasma concentrations of sFlt and sEng, combined with a decrease in placental growth factor concentrations, can be utilised as a predictor for pre-eclampsia is currently under investigation

Evénement culturel de mars 2015

Samedi 28 mars 2015 14-18h Célébration du printemps à la Maison de Kiso fête des poupées (Hina-matsuri) -exposition de poupées-  thé et dégustations japonaises  vente d’ex-voto (ema) au profit des enfants de Fukushima invités en France en 2015  atelier-concours de peinture, origami (prix gagnants : livres, jeux, surprises)  *En été 2015, nous invitons des enfants de la région de Fukushima, comme chaque année depuis 2011. Jardin d’Acclimatation, Paris 16e, Carrefour des Sablons, Boulogne Mét..

Polymorphisms in Endothelial Nitric Oxide Synthase (eNOS) and Vascular Endothelial Growth Factor (VEGF) Predict Sunitinib-Induced Hypertension

Clinical Oncolog

Treatment of hypertension and renal injury induced by the angiogenesis inhibitor sunitinib preclinical study

Common adverse effects of angiogenesis inhibition are hypertension and renal injury. To determine the most optimal way to prevent these adverse effects and to explore their interdependency, the following drugs were investigated in unrestrained Wistar Kyoto rats exposed to the angiogenesis inhibitor sunitinib: the dual endothelin receptor antagonist macitentan; the calcium channel blocker amlodipine; the angiotensin-converting enzyme inhibitor captopril; and the phosphodiesterase type 5 inhibitor sildenafl. Mean arterial pressure was monitored telemetrically. After 8 days, rats were euthanized and blood samples and kidneys were collected. In addition, 24-hour urine samples were collected. After sunitinib start, mean arterial pressure increased rapidly by ∼30 mm Hg. Coadministration of macitentan or amlodipine largely prevented this rise, whereas captopril or sildenafl did not. Macitentan, captopril, and sildenafl diminished the sunitinib-induced proteinuria and endothelinuria and glomerular intraepithelial protein deposition, whereas amlodipine did not. Changes in proteinuria and endothelinuria were unrelated. We conclude that in our experimental model, dual endothelin receptor antagonism and calcium channel blockade are suitable to prevent angiogenesis inhibition-induced hypertension, whereas dual endothelin receptor antagonism, angiotensin-converting enzyme inhibitor, and phosphodiesterase type 5 inhibition can prevent angiogenesis inhibition-induced proteinuria. Moreover, the variable response of hypertension and renal injury to different antihypertensive agents suggests that these side effects are, at least in part, unrelated