Thibault Dolley-Hitze

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

Background. 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.

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

BACKGROUND 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.

Angiotensin-2 receptors (AT1-R and AT2-R), new prognostic factors for renal clear-cell carcinoma?

Background:The growth factor Angiotensin-2 signals through Angiotensin receptor type 1 (AT1-R) in a broad range of cell types and tumours and through the type-2 receptor (AT2-R) in a more restricted group of cell types. Although numerous forms of cancer have been shown to overexpress AT1-R, expression of AT1-R and AT2-R by human renal clear-cell carcinoma (RCCC) is not well understood. In this study, the expression of both angiotensin receptors was quantified in a retrospective series of RCCC and correlated with prognostic factors.Methods:Angiotensin receptor type 1 and AT2-R expressions were quantified on tumour tissues by immunohistochemistry (IHC), western blot and quantitative reverse transcriptase PCR (qRT–PCR). IHC results were correlated to Fuhrmans grade and patient progression-free survival (PFS).Results:A total of 84 RCCC were analysed. By IHC, AT1-R and AT2-R were expressed to a greater level in high-grade tumours (AT1-R: P<0.001, AT2-R: P<0.001). Univariate analysis showed a correlation between PFS and AT1-R or AT2-R expression (P=0.001). By multivariate analysis, only AT2-R expression correlated with PFS (HR 1.021, P=0.006) and cancer stage (P<0.001). By western blot, AT1-R and AT1-R were also found to be overexpressed in higher Fuhrmans grade (P<0.01 and P=0.001 respectively). By qRT–PCR, AT1-R but not AT2-R mRNA were downregulated (P=0.001 and P=0.118, respectively).Conclusion:Our results show that AT1-R and AT2-R proteins are overexpressed in the most aggressive forms of RCCC and that AT2-R expression correlates with PFS. AT1-R or AT2-R blockage could, therefore, offer novel directions for anti-RCCC therapy.

[Renin-angiotensin system and urological cancers].

INTRODUCTION A controversy animates the literature on the potential role of the renin-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.

Système rénine-angiotensine et cancers urologiques

INTRODUCTION A controversy animates the literature on the potential role of the renin-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.

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.

Oseltamivir dose adjustment in an H1N1 patient requiring haemodialysis

Dear Editor, In September 2009, a 59-year-old man was admitted to the intensive care unit (ICU) for acute respiratory failure. His medical history was notable for restrictive chest wall disorder due to the sequelae associated with poliomyelitis. The symptoms of myalgia and dry cough had started 10 days previously. Chest radiography showed bilateral infiltrates. The nasal swab was positive for the 2009 pandemic influenza A (H1N1). A 10day course of oseltamivir was started. Acute respiratory syndrome, multiorgan failure and anuria rapidly developed. Daily haemodialysis (HD) sessions were performed from day 2 to day 9. The patient showed a complete recovery of renal function and was discharged from the ICU at day 34. Oseltamivir was administered by nasogastric tube, initially as 150 mg q12h, and was decreased to 75 mg after each HD when anuria developed. Drug monitoring was designed to determine pharmacokinetic parameters of oseltamivir and carboxylate oseltamivir, its active metabolite. Drug concentrations were measured by tandem-mass spectrometry [1]. Samples were collected when dialysis lines were connected and disconnected before and after HD as well as upstream and downstream of the dialysis membrane within 2 h of the beginning of each session. Parameters included urea Kt/V, drug reduction rates (RR), dialysis clearance (Cl) and total mass eliminated in dialysate (TM) and were determined as follows:

Drug-Induced Acute Interstitial Nephritis with Nifedipine

Background. 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 Raynauds 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 nifedipine.

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 epithelial layers of the glomerular basement membrane, with activation of the endothelin signaling system and loss of glomerular slit diaphragm integrity. The aim of this in vitro study was to determine sunitinib effects on normal podocytes and glomerular endothelial cells. Methods: The glomerular microvascular endothelial (GMVEC) and human glomerular visceral 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.

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

INTRODUCTION A controversy animates the literature on the potential role of the renin-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.