16^th European Nephrology Conference October 02-03, 2017 Barcelona, Spain

Biography:

Jia L Zhuo is a Full Professor and the Director of Receptor and Signal Transduction Laboratory in the Department of Pharmacology and Toxicology at the University of Mississippi Medical Center, Jackson, USA. He has over 30 years of sponsored research experience on the roles of Endocrine, Paracrine, and Intracrine Angiotensin II in the kidney and hypertension, supported by National Health and Medical Research Council of Australia (NHMRC) and National Institute of Health (NIH). He has authored >110 peer-reviewed articles and book chapters with many recognized by editorials, cover highlights, and the Faculty of 1000. He is a Fellow of The American Association for The Advancement of Science (AAAS), American Heart Association (AHA), and American Society of Nephrology (ASN), a permanent member for NIH/Center for Scientific Review Hypertension and Microcirculation Study Section. His research is currently supported by grants from National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of General Medical Sciences (NIGMS), and National Heart, Lung, and Blood Institute (NHLBI) respectively. 

Abstract:

It is well established that a physiological pressure natriuretic response plays a key role in maintaining normal blood pressure and body salt and fluid balance, but the mechanisms underlying the pressure natriuresis response and its resetting to higher pressures in hypertension remain incompletely understood. Here we used wild-type (WT), global (Nhe3^-/-), kidney- (tgNhe3^-/-) or proximal tubule-specific knockout (PT-Nhe3^-/-) of the Na⁺/H⁺ exchanger 3 (NHE3) to test the hypothesis that NHE3 in the proximal tubule of the kidney plays a critical role in the pressure natriuretic response and the development of angiotensin II (ANG II)-induced hypertension. 3 groups (n=8-12 per group) of adult male WT, Nhe3^-/-, tgNhe3^-/-_, and PT-Nhe3^-/- mice (n=8-12 per group) were prepared for the standard pressure natriuretic experiment and ANG II-induced hypertension, respectively. The pressure natriuresis response was studied using the mesenteric and celiac occlusion technique to elevate renal perfusion pressure equally by 25 mmHg in all strains of mice. Under basal conditions, Nhe3^-/-, tgNhe3^-/-, and PT-Nhe3^-/- mice had significantly lower systolic blood pressure (p<0.01) and mean intra-arterial blood pressure than WT mice (p<0.01). 24 h fecal Na⁺ excretion was significantly increased (p<0.01), whereas 24 h urinary Na⁺ excretion was significantly reduced in both Nhe3^-/- and tgNhe3^-/- mice (p<0.01). However, no difference was found in fecal Na⁺ excretion between WT and PT-Nhe3^-/- mice, whereas 24 h urinary Na⁺ excretion was significantly increased in PT-Nhe3^-/- mice (p<0.01). In response to increased renal perfusion pressure, the pressure natriuresis response increased 4-folds in WT mice (p<0.01), and only 2-fold in Nhe3^-/- and tgNhe3^-/- mice (p<0.01). By comparison, the pressure natriuresis response increased 7-folds in PT-Nhe3^-/- mice (p<0.01). To determine the role of NHE3 in ANG II-induced hypertension, ANG II was infused in WT, Nhe3^-/-, tgNhe3^-/-_, and PT-Nhe3^-/- mice for 2 weeks (1.5 mg/kg/day, i.p.). ANG II induced robust hypertension in WT mice (p<0.01), as expected, but the hypertensive response to ANG II was significantly attenuated in global Nhe3^-/-, kidney-selective tgNhe3^-/-, and PT-Nhe3^-/- mice. Our results support the hypothesis that NHE3 in the proximal tubule of the kidney plays a key role in the regulation of physiological pressure natriuretic responses and the development of ANG II-induced hypertension.

Biography:

Nicolas Gilles has completed his PhD at Paris Descartes University. He is pioneering the investigation of animal toxins acting on GPCRs, the largest therapeutic target class. His strongest expertise lies in Receptor Pharmacology, Synthetic Production of Disulfide-Linked Animal Toxins and in vivo experiments. He has published more than 70 papers and three patents. His strongest interest is now to stimulate the therapeutic development of animal toxins for the benefit of human health. 

Abstract:

Autosomal dominant polykystose kidney disease affect 1 over 1,000 peoples, leading to end-stage renal disease. The blockage of the Vasopressin type 2 receptor (V2R) is a validated therapeutic line in human by preventing the vasopressin-induced elevation in intracellular cAMP concentration. Currently, only tolvaptan (jirnac) succeed to reach the market but with many concerns. Scorpions, spiders, snakes, conus, insects, miriapodes are often seen as dangerous, frightening and ugly animals. Their venoms are extremely rich in toxins historically identified for their toxicities. We believe that animal toxins are highly valuable in the context of human use and drug development. We developed a specific strategy in order to identified toxins with the purpose of discover novel drug candidates. Mambaquaretin was discovered in the green mamba venom by a bioguidage strategy directed against the V2R. This toxin belongs to the Kunitz fold peptide family, and its displays a nanomolar affinity for the V2R. Molecular pharmacological essays demonstrated that mambaquaretin is the most selective V2R antagonist. Daily injection of 13 µg of mambaquaretin to pcy mice, a model of juvenile recessive kidney polykystose, over a period of 99 days, allowed the drug candidate to inhibit cyst growth area by almost 30%. No apparent toxicity was observed in treated animals. Mambaquaretin is a promising drug candidate with an original mode of action. Molecular modelling and structure function analysis allowed us to propose a model of interaction of the mambaquaretin/V2R complex.

Biography:

Stefanie Steiger has studied Bioengineering at the Martin-Luther University Halle, Germany from 2000 until 2006 followed by a working contract at Boehringer Ingelheim for two years. In 2008, she completed her PhD in Medical Science at Malaghan Institute of Medical Research, Victoria University Wellington, New Zealand, and two years of Post-doctoral fellowship. She moved to University of Munich, Germany in 2014, where she established her own group. Her research focus is the bidirectional impact of uric acid and chronic kidney disease.

Abstract:

Uric acid (UA) and chronic kidney disease (CKD) have a bidirectional relationship. The development of CKD has been associated with increased UA levels due to decreased urinary excretion of UA and resultant hyperuricemia, a major risk factor for gouty arthritis. Mild CKD often leads to an increased prevalence of gouty arthritis, as prospective observational studies have demonstrated, whereas advanced CKD and end-stage renal disease (ESRD) leads to a drop in the prevalence despite massive hyperuricemia. Conversely, there is evidence that gout and associated hyperuricemia may independently impair kidney function. Hyperuricemia in the presence or absence of gout, the use of gout medications, and the deposition of UA microcrystals in the medullary interstitium can potentially be harmful to the kidney, increase the risk for developing CKD, and are progressive factors for worsening CKD. However, these clinical data are conflicting and currently, there is no ideal animal model available to investigate the molecular effects of UA and gout in CKD in more detail, which raises the following unanswered questions: What is chicken-and-egg, CKD causes hyperuricemia but does hyperuricemia also lead to the progression of CKD? and by what mechanism? Which further raises the question: do CKD patients profit from uricostatic pharmacotherapy? What are the molecular mechanisms behind an increased prevalence of gouty arhtritis in mild CKD and a drop-in prevalence in advanced CKD? Does hyperuricemia affect UA crystal-induced inflammation by priming inflammatory cells, and is therefore responsible for the lower risk of acute gouty arthritis with advanced CKD and ESRD? These questions will be addressed in the oral presentation with supportive clinical data and an in vivo animal model.

Biography:

Mesothelial-to-mesenchymal transition (MMT) is an auto-regulated physiological process of tissue repair that in uncontrolled conditions such as peritoneal dialysis (PD) can lead to peritoneal fibrosis. The maximum expression of peritoneal fibrosis induced by PD fluids and other peritoneal processes is the encapsulating peritoneal sclerosis (EPS) for which no specific treatment exists. Tamoxifen a synthetic estrogen has successfully been used to treat retroperitoneal fibrosis and EPS associated with PD. Hence, we used in vitro and animal model approaches to evaluate the efficacy of Tamoxifen to inhibit the MMT as a trigger of peritoneal fibrosis. In vitro studies were carried out using omentum-derived mesothelial cells (MCs) and effluent-derived MCs. Tamoxifen blocked the MMT induced by transforming growth factor (TGF)-β1, as it preserved the expression of E-cadherin and reduced the expression of mesenchymal-associated molecules such as Snail, fibronectin, collagen-I, α-smooth muscle actin, and matrix metalloproteinse-2. Tamoxifen-treatment preserved the fibrinolytic capacity of MCs treated with TGF-β1 and decreased their migration capacity. Tamoxifen did not reverse the MMT of non-epitheliod MCs from effluents, but it reduced the expression of some mesenchymal molecules. In mice PD model, Tamoxifen significantly reduced peritoneal thickness, angiogenesis, invasion of the compact zone by mesenchymal MCs and improved peritoneal function. Tamoxifen also decreased the accumulation advanced glycation end-products and reduced the effluent levels of VEGF and leptin. These results demonstrate that Tamoxifen is a therapeutic option to treat peritoneal fibrosis, and that its protective effect is mediated via modulation of MMT process.

Abstract:

Mesothelial-to-mesenchymal transition (MMT) is an auto-regulated physiological process of tissue repair that in uncontrolled conditions such as peritoneal dialysis (PD) can lead to peritoneal fibrosis. The maximum expression of peritoneal fibrosis induced by PD fluids and other peritoneal processes is the encapsulating peritoneal sclerosis (EPS) for which no specific treatment exists. Tamoxifen a synthetic estrogen has successfully been used to treat retroperitoneal fibrosis and EPS associated with PD. Hence, we used in vitro and animal model approaches to evaluate the efficacy of Tamoxifen to inhibit the MMT as a trigger of peritoneal fibrosis. In vitro studies were carried out using omentum-derived mesothelial cells (MCs) and effluent-derived MCs. Tamoxifen blocked the MMT induced by transforming growth factor (TGF)-β1, as it preserved the expression of E-cadherin and reduced the expression of mesenchymal-associated molecules such as Snail, fibronectin, collagen-I, α-smooth muscle actin, and matrix metalloproteinse-2. Tamoxifen-treatment preserved the fibrinolytic capacity of MCs treated with TGF-β1 and decreased their migration capacity. Tamoxifen did not reverse the MMT of non-epitheliod MCs from effluents, but it reduced the expression of some mesenchymal molecules. In mice PD model, Tamoxifen significantly reduced peritoneal thickness, angiogenesis, invasion of the compact zone by mesenchymal MCs and improved peritoneal function. Tamoxifen also decreased the accumulation advanced glycation end-products and reduced the effluent levels of VEGF and leptin. These results demonstrate that Tamoxifen is a therapeutic option to treat peritoneal fibrosis, and that its protective effect is mediated via modulation of MMT process.

Biography:

Xiao C Li is a Senior Research Scientist in the Receptor and Signal Transduction Laboratory in the Department of Pharmacology and Toxicology at University of Mississippi Medical Center, Jackson, Mississippi, USA. She has received Postdoctoral research training in Cardiovascular Pharmacology at Monash University, Melbourne, Australia, and in Molecular Pharmacology at University of Michigan, USA respectively. She has more than 20 years of research experience in G Protein-Coupled Receptor Pharmacology and angiotensin II-dependent hypertension, and authored more than 40 peer-reviewed articles in high impact journals such as Hypertension, Kidney International, Clinical Science, Biochemical Pharmacology, American Journal of Physiology, and Pharmacological Research etc., and a book in the renin-angiotensin system research field, and many were recognized by editorial commentaries, color cover highlights, and the faculty of 1000. Currently, she is working as a Co-Investigator in several research grants from National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of General Medical Sciences (NIGMS), and National Heart, Lung, and Blood Institute (NHLBI). 

Abstract:

We have recently shown that angiotensin (ANG II)-induced hypertension was attenuated in mice with global (Nhe3^-/-) and Nhe3^-/- mice with transgenic rescue of the NHE3 gene selectively in small intestines (tgNhe3^-/-), suggesting a significant role of NHE3 in the development of ANG II-dependent hypertension. The present study tested whether the pharmacological inhibition of NHE3 mainly in the proximal tubule of the kidney attenuates ANG II-dependent hypertension induced by a slow pressor dose of ANG II supplemented with 2% high salt diet. 9 groups (n=6-12) of adult male C57BL/6J mice were infused with or without ANG II (500 μg/kg/day, i.p. via mini pump) and supplemented with or without a 2% NaCl diet to slowly and moderately increase blood pressure (SBP) in 2 weeks. ANG II alone increased SBP from 116±2 mmHg to 140±2 mmHg (p<0.01), and supplement of ANG II with a 2% NaCl diet further increased SBP to 147±4 mmHg (p<0.05). Concurrent treatment with an orally active, absorbable NHE3 inhibitor AVE0657 (Sanofi-Aventis; 20 mg/kg/day, p.o.) significantly decreased SBP to 125±4 mmHg in ANG II-infused mice (p<0.01), and to 134±6 mmHg in ANG II-infused mice supplemented with 2% NaCl (p<0.01), respectively. Further treatment with AVE0657 and losartan, an AT₁ receptor blocker (20 mg/kg/day, p.o.), completely normalize SBP in mice treated with ANG II and 2% NaCl to control (115±5 mmHg, p<0.01). AVE0657 significantly increased 24 h urinary Na⁺ excretion (p<0.01) but had no effect on 24 h fecal Na⁺ excretion in control or ANG II-infused mice. These results provide preclinical evidence that orally absorbable NHE3 inhibitors may be pharmacologically beneficial to treat ANG II-dependent hypertension by inhibiting NHE3 and Na⁺ reabsorption in the proximal tubule of the kidney.

Biography:

Nariaki Asada graduated from Kyoto University. He researched a new testing on a diaper for urinary tract infection at pediatrics department of Ota Memorial Hospital. He is currently persuing PhD at pediatrics department of Keio University School of Medicine. Current research interests are anemia of prematurity and polycythemia in patients born preterm with low birth weight. 

Abstract:

Patient 1 and 2, born at 25 weeks of gestation with birth weight of 466 g and 728 g, showed mild proteinuria at age 6 and 8 years, respectively. In association with increasing proteinuria and blood pressure (BP), polycythemia developed in adolescence. Patient 1 and 2 underwent renal biopsy at age 15 and 18 years, when their BP was 143/59 and 137/82 mmHg, eGFR 90 and 114 ml/min/m², hemoglobin 18.7 and 19.0 g/ dL, erythropoietin (EPO) 24.5 and 17.8 U/L, respectively. Polycythemia was considered to be due to increased EPO. Light microscopy showed glomerular hypertrophy, and focal segmental glomerulosclerosis without significant fibrosis. Immunohistochemical staining with CD31 or CD34 antibody revealed PTC rarefaction.

Clinical study: Thirty-six patients with a history of extremely LBW were retrospectively analyzed (male 17, female 19; age at analysis 4-19 years; birth weight 316-998 g; gestational age 22-32 weeks). Twelve patients showed hemoglobin levels more than 2 SD above the mean (polycythemia group, male 7, female 5; age at finding 2-16 years). Polycythemia was associated with lower eGFR (73 ml/min/1.73m² vs 106 ml/min/1.73m²) and smaller birth weight (619 g vs 802 g).

Conclusions: Polycythemia can be observed in patients born preterm with extremely low birth weight, and associated with low eGFR. 

Biography:

Brig Gen Mamun Mostafi is the Chief Physician and Head of Nephrology of Bangladesh Army. He was the Professor of Nephrology and Executive Editor of Journal of Armed Forces Medical College, Bangladesh. He has more than 50 publications. He is the present Editor of Bangladesh Renal Journal. He has presented many papers and provided invited speaker presentations in many national and international forums. 

Abstract:

Background: Deficiency of magnesium is not uncommon in critical care, but a usually ignored electrolyte abnormality. Studies on magnesium in our country are lacking. We have correlated serum magnesium levels in critically ill patients with respect to the mortality, in hospital outcome and length of stay in the critical care.

Methods: A prospective, observational study was conducted in patients who had been admitted to the high dependency unit (HDU) of Combined Military Hospital, Dhaka. Patients were divided into normomagnesemic, hypomagnesemic and hypermagnesemic groups and compared for various parameters.

Results: Out of 60 patients, 32 patients (53.33%) were hypomagnesemic, 20 patients (33.33%) were normomagnesemic and 8 patients (13.33%) were hypermagnesemic. Associated electrolyte abnormalities in hypomagnesemic patients were hypokalemia (56.25%) and hypocalcaemia (62.50%). Most of the hypomagnesemic patients were hypertensive (62.50% vs. 40%) and was presented in drowsy state (50% vs. 40%) compared to normomagnesemic group. Mortality of hypomagnesemic group was 37.50% while that of hypermagnesemic group was 25% and 20% in normomagnesemic. Mean duration of length of stay in HDU was 11.45±3.94 days in hypomagnesemic, 6.83±2.48 days in normomagnesemic and 9.67± 5.68 days in hypermagnesemic group.

Conclusion: Development of magnesium imbalance in critically ill patients is associated with bad prognosis. Monitoring of serum magnesium levels may have prognostic, perhaps therapeutic implication

Biography:

Saeed M Alzabli has completed his MBBS from University of Aden and Arab Board of Pediatrics. He is an Assistant Consultant in Pediatric Nephrology at King Fahad Medical City.

Abstract:

Background: Dense deposit disease (DDD), a subtype of C3 glomerulopathy, is a rare disease secondary to hyperactivity of the alternative complement pathway with characteristic electron-dense deposits in the glomerular basement membrane on renal biopsy. Eculizumab, a monoclonal antibody prevent formation of the membrane attack complex through binding to C5 may be beneficial in its treatment. Reported cases are scarce, particularly in children.

Method: We report three pediatric patients with diagnosis of DDD on native kidney biopsy. All had acute kidney injury, hypertension, proteinuria >1 gram/day, and depressed level of C3. All Patients received methylprednisolone pulse therapy and Mycophenolate Mofetil. One patient required dialysis. Eculizumab was added early in two patients and in the third patient initiated after being on dialysis.

Results: In two patients, in whom Eculizumab started early, proteinuria and renal function improved significantly within weeks of treatment.C3 has been normalized in one patient and still depressed in the other. In the third patient who required dialysis, there was no response, she went into end stage renal disease (ESRD) and maintained on dialysis.

Conclusions: Eculizumab treatment was associated with reduction in proteinuria and improvement in renal function in two patients. Our findings are in agreement with previous reports of Eculizumab beneficial effect in DDD. Additionally, early initiation of Eculizumab may prevent progression to ESRD. 

Biography:

Deepika Jain has completed her MD in New Delhi, India and continued her career in Medicine and then Nephrology in USA at University of Pittsburgh Medical Center. She is currently working in New Jersey as part of Hudson Kidney group affiliated with RWJ St Barnabas health care and CarPoint health systems. She has published several papers on health literacy on dialysis patients.

Abstract:

Health literacy is the capacity of an individual to understand information related to a disease in order to make an informed decision. In patients with kidney diseases, studies have reported increasing impact of limited health literacy on health outcomes. Our paper discusses current literature on health literacy in kidney diseases.

Biography:

Abdulaziz Ahmed Bamhrazhas completed his MBBS from Hadramout University of Science and Technology and have Saudi & Arab Board of General Pediatrics. I am doing my pediatric nephrology fellowship programm under Saudi council for health specialties  at king fahad medical city -riyadh.

Abstract:

Background & Aim: Atypical hemolytic uremic syndrome (aHUS) is ultra-rare disease, characterized by microangiopathy hemolytic anemia, thrombocytopenia and renal impairment. Genetic defects that determine uncontrolled activation of the alternative complement pathway have been well documented, it accounts for about 40%–60% of the cases. In Saudi Arabia, there is up to 56% of consanguinity marriage resulting in higher prevalence of genetic diseases. We are reporting the experience of a tertiary care center in Saudi for children with aHUS who were treated their outcome and genetic background.

Methods: This is a retrospective study, from 2010 till May 2017 in a tertiary care center comparing children with aHUS who had received plasma therapy to those received Eculizumab therapy which was introduced at our center in 2014.

Results: 21 Saudi children who have similar demographic background diagnosed with aHUS, 12 (57%) of them showed complete renal and hematologic recovery (67% in the Eculizumab group versus 33% in plasma therapy group). Six cases (29%) reached End Stage Renal Disease (ESRD), four patients (67%) of these cases from the plasma therapy group; two patients (33%) from Eculizumab group reached ESRD, their genetic mutations were not related to complement dysregulation system. Two of the 21 cases (17%) developed disease recurrence while receiving plasma therapy but no recurrence developed after using eculizumab. 11 (69%) of the 16 cases who underwent genetic testing has identified gene mutations.

Conclusion: In our 21 cases with aHUS, eculizumab was superior to plasma therapy in inducing, maintaining remission, and associated with better renal recovery. Genetic mutations detected among our patients were higher than reported for this ultra-rare disease, most probably related to the high prevalence of consanguinity marriage.

Biography:

Shao-yu Zhang has completed her PhD from Université Paris-Est Créteil Val de Marne, France and Postdoctoral studies at INSERM, France. She is now working as a Researcher at INSERM, France. She has published more than 20 papers in the medical journals.

Abstract:

Paraneoplastic nephrotic syndrome is often a complication in patients with cancer, and various histologic lesions have been described in the kidney. We report the case of a 76-year-old woman who presented with a podocytopathy that was found to be associated with a small cell lung carcinoma (SCLC). One cycle of carboplatin-etoposide combination therapy led to resolution of nephrotic syndrome and remission of the lung carcinoma. C-Maf–inducing protein (CMIP) was overexpressed in both podocytes and cancer cells, but was not found in control kidney and lung tissue samples. CMIP also was absent in SCLC cells from 30 patients without nephrotic syndrome. Exposing cultured podocytes to a sample of our patient’s serum that was collected prior to chemotherapy led to disorganization of the podocyte cytoskeleton and induction of CMIP expression, which was not observed with control serum or our patient’s serum sampled after chemotherapy. These observations suggest that CMIP may play a significant role in SCLC-related podocytopathy and that a circulating factor likely induces its expression in the kidney.