Système rénine-angiotensine et cancers urologiques / Renin-angiotensin system and urological cancers.

International audienceIntroduction: A controversy animates the literature on the potential role of the rennin-angiotensin system (RAS) in tumorogenesis. The objective of this review was to determine the involvement of this pathway in cancer, and more specifically in urological cancers. Material and Method: We made a systematic review of articles referenced in Pubmed, using the following keywords alone or combined: cancer, renin, angiotensin, VEGF, AT1R, antagonists of angiotensin-2 receptors, inhibitors of angiotensinogen converting. Results: Many types of cancers overexpress AT1-R in their tumoral tissues (breast, stomach, bladder, astrocytoma, glioblastoma, ovary, uterus, pancreas, kidney, prostate, adrenal gland). Ang-II can induce VEGF-A expression and promote neoangiogenesis, but also can trigger different molecular pathways involved in cell proliferation or inhibit apoptosis. Several xenograft murin models demonstrated anti-tumoral efficacy of RAS blockers, alone or using combined therapies, targeting angiogenesis and slowing down tumor growth. Retrospective studies in patients have also revealed a better progression-free survival and a better response to therapies in those treated with RAS blockers. Conclusion: Many data seem to demonstrate the involvement of the RAS in carcinogenesis, as well as anti-tumoral effect of RAS blockers in addition to anti-cancer treatments. Clinical data are now expected to confirm these experimental findings

Comparaison de 2 stratégies immunosuppressives d'entretien en transplantation rénale (tacrolimus en monothérapie ou en association)

RENNES1-BU Santé (352382103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

WCN24-739 Impact of dialysis modality on patients' life plans: inclus-dial, a survey for independent patients

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Prolonged hemodialysis: Rationale, practical organization, results

National audienceIn France, long nocturnal dialyses, eight hours three-times a week, are sparsely proposed. However, numerous studies reported that this specific type of dialysis is associated to better blood pressure control, better cardiac remodeling, better mineral and nutritional balance as well as better life quality and survival rate. Material and methods. - In this study, we aimed at quantifying the benefits, risks and obstacles of developing night dialysis and at describing the results of a program that took place in Rennes from 2002 to 2019. Data were collected between 2008 and 2014 for eighteen case-patients and were compared to thirty-six controls that underwent conventional dialysis. Patients were paired according sex, age and year of dialysis start. Results. - The median age for dialysis start was 47.5 years [27-60] with a male prevalence (5/1). After six months, a significant difference was reported for postdialytic, systolic and diastolic pressure (respectively 126 +/- 15 vs 139 +/- 21 [P = 0.04] and 72 +/- 9 vs 81 +/- 14 [P = 0.02]) despite an antihypertensive reduction ranging from 2.4 +/- 1.4 to 1.3 +/- 0.9 per day at six months and 0.7 +/- 0.9 at one year (P = 0.02). An increase of nPCR was evidenced at 6 and 9 months (P = 0.02). At the end of the study, the phosphate level was maintained for both cohorts at the expense of an increased consumption of phosphate binder for the long nocturnal dialysis group (P = 0.025). As a whole, 61% of the patients that pursued long night dialysis maintained a professional activity compared to only 30% for the controls (P = 0.04). This highlights the advantages of night dialysis for maintaining employment but also the bias that represents the employment status in observational study on this specific topic. (C) 2020 Societe francophone de nephrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved

Drug-Induced Acute Interstitial Nephritis with Nifedipine

International audienceBackground. Acute interstitial nephritis (AIN) is a frequent cause of Acute Kidney Injury (AKI). Drug hypersensitivity is the most common etiology and the list of drugs that can induce AIN is not exhaustive yet. Case Report. Here, we describe the case of a 43-year-old man who was treated with nifedipine (Adalate®) for Raynaud's syndrome. After nifedipine introduction, serum creatininemia progressively increased from 91 to 188 μmol/L in a few months and AKI was diagnosed. Laboratory work-up results indicated the presence of tubular proteinuria and nonspecific inflammatory syndrome. Histological analysis found granulomatous interstitial nephropathy without necrosis in 20% of the kidney biopsy without immunofluorescent deposit. Nifedipine was stopped and corticosteroid treatment was started with a rapid but incomplete reduction of serum creatininemia level to 106 μmol/L. Conclusion. This is the first case of AIN caused by nifedipin

Clinical Study Is Anticoagulation Discontinuation Achievable with Citrate Dialysate during HDF Sessions?

Citrate dialysate has been developed for few years to replace acetate and HCl concentrates. In Online Postdilution Hemodiafiltration (OL-POST-HDF), several issues are remaining concerning the possibility of stopping anticoagulation during sessions and the side effects of citrate solutions on calcium metabolism. This 1-year monocentric retrospective study included all patients exposed to citrate in OL-POST-HDF with nadroparin decrease for more than one month. Clotting events, serum calcium, PTH, hemoglobin, CRP, depuration parameters, and treatments administrated were recorded for analysis. 27 patients experienced nadroparin decrease and 5 did not receive nadroparin at the end of the study. Nadroparin decrease and withdrawal were both associated with more clotting events whereas the use of vitamin K antagonists was protective. No significant metabolic side effects were observed. Citrate dialysate does not allow anticoagulation discontinuation or decrease but has no significant side effects on mineral bone metabolism or erythropoiesis

Anti-VEGF Therapy Induces Proteinuria through Endothelial Disorganization Leading to Nephrin Decrease in Podocytes

Background: VEGF is involved in cancer development by stimulating neo-angiogenesis and tumor proliferation. Anti-angiogenic therapies, especially tyrosine kinase inhibitors such as sunitinib, have significantly improved cancer prognosis. Nevertheless, renal side effects, such as proteinuria and thrombotic microangiopathy, have been reported. The underlying physiopathological mechanisms remain unclear, but animal models and clinical similarities with preeclampsia suggest that such therapies affect the function of the endothelial and&nbsp; &nbsp; pithelial layers of the glomerular basement membrane, with activation of the endothelin&nbsp; ignaling system and loss of glomerular slit diaphragm integrity.The aim of this in vitro study&nbsp; as to determine sunitinib effects on normal podocytes and glomerular endothelial cells.Methods: The glomerular microvascular endothelial (GMVEC) and human glomerular&nbsp; isceral epithelial (hGVE) cell lines were incubated with various doses of sunitinib. The MTT Cell Proliferation Assay was used to assess cell proliferation. Expression of nephrin (a major slit diaphragm protein) and endothelin was evaluated by immunofluorescence or western blotting assays.Results: Sunitinib inhibited GMVEC and hGVE cell proliferation in a dose-dependent manner. In GMVEC cells, endothelin transcription and secretion were increased after incubation with sunitinib. Conversely, in hGVE cells, sunitinib did not affect nephrin expression. However, conditioned medium from GMVEC cells incubated with sunitinib modified nephrin expression when added to the culture medium of hVGE cells. This effect was inhibited by pre-incubating hGVE cells with an endothelin inhibitor.Conclusion: This study suggests an indirect toxicity of sunitinib on podocytes through endothelin. Therefore, sunitinib-induced renal side effects could be controlled with endothelin inhibitors.</p

[Angiotensin-2 type 1 receptors (AT1R) and cancers].

International audienceRecently, several meta-analysis suggested an increased risk of cancers linked to the use of antagonists of angiotensin-2 receptors or inhibitors of angiotensinogen converting enzyme. The results of epidemiological studies are conflicting. Meta-analysis as well as retrospective studies are not reliable and biased, since they have never been designed to explore any pro- or antitumoral effect. We lack of prospective studies that could take off the doubt on these drugs. Nevertheless, all experimental researches pointed out potent antitumoral properties. Indeed, direct antiproliferative and neo-angiogenic inhibition have been described on tumor cell cultures as well as on animal models. Moreover, we are convinced that the use of antagonists of angiotensin-2 receptors and inhibitors of angiotensinogen converting enzyme may be then of clinical use in the near future in association with classical antitumor drugs. In this review, we proposed to explore these data by a thorough analysis of recent literature associating epidemiological and experimental studies

All anti-vascular endothelial growth factor drugs can induce 'pre-eclampsia-like syndrome': a RARe study.

International audienceBACKGROUND: Specific therapies that target vascular endothelial growth factor (VEGF) and its receptors have improved the survival of patients with metastatic cancers, but can induce side effects. Renal side effects (proteinuria, hypertension and renal failure) are underestimated. METHODS: The French RARe (Reins sous traitement Anti-VEGF Registre) study collects data on patients with cancer who had a renal biopsy because of major renal side effects during treatment with anti-VEGF drugs. RESULTS: We collected 22 renal biopsies performed 16.2±10.6 months after the beginning of treatment; of which 21 had hypertension, mean proteinuria was 2.97±2.00 g/day and mean serum creatinine, 134±117 µmol/L. Thrombotic microangiopathy (TMA) was observed in 21 biopsy specimens, sometimes associated with acute tubular necrosis (ATN; n=4). TMA histological lesions were more important than the biological signs of TMA could suggest. Patients with ATN of >20% had higher serum creatinine levels than those with only TMA (231 versus 95 µmol/L). Nephrin, podocin and synaptopodin were variably down-regulated in all renal biopsies. VEGF was down-regulated in all glomeruli. CONCLUSION: This study underlines the importance of regular clinical and biological cardiovascular and renal checking during all anti-VEGF therapies for cancer for early detection of renal dysfunction. Collaboration between oncologists and nephrologists is essential. In such cases, renal biopsy might help in appreciating the severity of the renal lesions and after multidisciplinary discussion whether or not it is safe to continue the treatment

Sunitinib combined with angiotensin-2 type-1 receptor antagonists induces more necrosis: a murine xenograft model of renal cell carcinoma

International audienceBACKGROUND: Angiotensin-2 type-1 receptor antagonists not are only antihypertensive drugs but also can inhibit VEGF production. We hypothesised that adding telmisartan to sunitinib could potentiate the antiangiogenic effects. MATERIAL AND METHODS: 786-O cell lines were injected in nude mice. After tumor development, mice were divided into 4 groups: the first was the control group (DMSO), the second group was treated with sunitinib alone, the third group was treated with telmisartan alone, and the fourth group was treated with the combination. Drugs were orally administered every day for four weeks. Animals were sacrificed after treatment. Blood and tumor tissues were collected for analysis by immunohistochemistry, Western Blot, and ELISA methods. RESULTS: All animals developed a ccRCC and ten in each group were treated. Using a kinetic model, tumors tended to grow slower in the combination group compared to others (P = 0.06). Compared to sunitinib alone, the addition of telmisartan significantly increased tissue necrosis (P = 0.038). Central microvascular density decreased (P = 0.0038) as well as circulating VEGF (P = 0.003). There was no significant variation in proliferation or apoptosis markers. CONCLUSION: The combination of sunitinib and telmisartan revealed an enhancement of the blockage of the VEGF pathway on renal tumor resulting in a decrease in neoangiogenesis and an increase in necrosis