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NEPHROLOGY 2014; 19 (Supp. 2), 4–22

doi:10.1111/nep.12235

ABSTRACTS SY1-01 CLINICAL SIGNIFICANCE OF URINARY LIVER TYPE FATTY ACID BINDING PROTEIN (L-FABP) IN DIABETIC NEPHROPATHY KAMIJO-IKEMORI ATSUKO1,2, SUGAYA TAKESHI1, KIMURA KENJIRO1 1 Department of Nephrology and Hypertension, Internal Medicine, St. Marianna University School of Medicine, Japan; 2Department of Anatomy, St. Marianna University School of Medicine, Japan Deterioration of diabetic nephropathy (DN) is largely determined by the degree of tubulointerstitial changes rather than the extent of histological changes in the glomeruli. Therefore, a tubular marker that accurately reflects tubulointerstitial damage may be an excellent biomarker for early detection or prediction of DN. Liver-type fatty-acid binding protein (L-FABP) is a 14 kDa small molecule that is expressed in the cytoplasm of human proximal tubules. Because renal L-FABP is not endogenously expressed in the kidneys of mice, we generated human L-FABP chromosomal transgenic (Tg) mice and evaluated the dynamics and pathophysiological role of renal L-FABP. With regard to DN, a streptozotocin (STZ)-induced diabetic model, which has type 1 diabetes, was used and tubulointerstitial damage was provoked. Our findings revealed that renal human L-FABP gene expression was up-regulated (around 9-fold increase) and that urinary excretion of human L-FABP increased (around 9-fold increase) in the STZ-induced diabetic Tg mice compared with control mice at 8 weeks after STZ injection. From the observation of lipid accumulation in human proximal tubules in DN, it could be suggested that lipid or peroxidation product generated in the proximal tubules of DN might promote the up-regulation of renal L-FABP expression. Our Tg mice were generated by microinjections of the genomic DNA of human L-FABP including its promoter region; therefore, it is possible for the transcription of the human L-FABP gene in the Tg mice to be regulated in the same mode as in humans. The dynamics of human L-FABP in the experimental diabetic model might mimic those under pathological conditions in humans. In recent clinical studies of patients with type 2 diabetes, we showed that urinary L-FABP concentrations increased with the progression of DN and reflected DN severity. Urinary L-FABP levels were significantly higher in patients with normoalbuminuria than in control subjects. This result indicated that urinary L-FABP accurately reflected severity of diabetic kidney disease and may be a suitable biomarker for early detection of diabetic kidney disease. In the prospective study, urinary L-FABP was an independent predictor of progression of DN, which was defined as advancement to the next higher stage in patients with all stages of DN without the requirement of dialysis or kidney transplantation; analysis of a subgroup with an estimated GFR (eGFR) >60 ml/ min per 1.73 m2 showed results consistent with the former result. A high urinary L-FABP value at study entry was a higher risk factor for progression of DN than the presence of albuminuria at entry. Although without significance (P = 0.45), the AUC for predicting the progression of DN by urinary L-FABP (AUC = 0.762) was higher than that by urinary albumin (AUC = 0.675) in the subgroup with an eGFR >60 ml/min per 1.73 m2. Urinary L-FABP may be a useful biomarker for predicting progression of DN. Moreover, therapeutic interventions with renoprotective effects were reported to reduce urinary L-FABP concentrations by another studies. Urinary L-FABP measured using the Human L-FABP ELISA Kit developed by CMIC Co., Ltd. (Tokyo, Japan) was confirmed as a newly established tubular biomarker by the Ministry of Health, Labour and Welfare in Japan in 2010. This presentation summarizes the clinical significance of urinary L-FABP in type 2 DN.

SY1-02 CLINICO-PATHOLOGICAL FACTORS ASSOCIATED WITH OUTCOMES IN DIABETIC KIDNEY DISEASE FURUICHI KENGO1, WADA TAKASHI2 1 Division of Blood Purification, and Department of Nephrology, Kanawaza University Hospital, Japan; 2Department of Nephrology, Kanawaza University Hospital, Japan Diabetic kidney disease is the leading cause of end stage kidney disease requiring dialysis or transplantation in Japan and many other countries. A high urinary albumin-to-creatinine ratio (UACR) and low estimated glomerular filtration rate (eGFR) have been believed to be predictors for diabetic end stage kidney disease. However, relationship between clinical manifestation and pathological characteristics of type 2 diabetes is not fully elucidated. We would like to discuss these points in this presentation.

Clinical manifestations in progression of diabetic kidney disease in type 2 diabetes were diverse. Decreasing GFR and increasing UACR are more heterogeneous in type 2 diabetes than type 1 diabetes. Many types of variances of reduced eGFR and/or increased UACR were observed in type 2 diabetes. Our historical cohort study of 4328 Japanese participants with type 2 diabetes from 10 centers (median follow-up period 7.0 years, interquartile range 3.0–8.0 years) revealed that increased UACR levels were closely related to the increase in risks for renal, cardiovascular events and all-cause mortality. Moreover, an association between high levels of UACR and reduced eGFR was a strong predictor for renal events. These findings reinforced the importance of increased UACR levels and reduced eGFR as prognosis predictors in type 2 diabetes. These clinical manifestations of reduced eGFR and/or increased UACR should depend on pathological changes in kidney. In type 1 diabetes, pathological natural history of diabetic kidney disease, such as basement membrane thickening and increased mesangial matrix, were observed accompanied with reduced GFR and increased UACR. However, pathological changes in kidney, as well as clinical manifestation, are thought to be more heterogeneous in type 2 diabetes than type 1 diabetes. Although pathological changes should affect on UACR and/or eGFR, particulars of clinic-pathological relationship were unclear so far in type 2 diabetes. To clarify the relation of two major clinical factors (UACR and eGFR) and pathological changes, we are now collecting and evaluating more than two hundred kidney biopsy findings and clinical data from twelve centers in Japan. These data will reveal that some characteristic pathological changes in diabetic kidney disease would participate clinical manifestations of reduced eGFR and/or increased UACR. In addition to the relationship between clinical manifestations and pathological changes, these pathological changes might contribute to kidney prognosis and/or cardiovascular events. Recent our study revealed the relation of pathological changes in diabetic kidney disease and kidney prognosis, cardiovascular events, and all-cause mortality. Kidney biopsy findings and clinical data of 260 Japanese type 2 diabetic patients (mean follow-up period 8.1 years) revealed that glomerular lesions, IFTA, and arteriosclerosis were predictors for renal events, arteriosclerosis for cardiovascular events, and IFTA for all-cause mortality. Therefore, these characteristic pathological changes in diabetic kidney disease in type 2 diabetes would be good predictors not only for kidney prognosis but also for cardiovascular events. To clarify these clinico-pathological prognosis factors in diabetic kidney disease would be valuable to prevent the progression of kidney disease, cardiovascular events, and mortality in patients with type 2 diabetes.

SY1-03 THE ROLE OF METALLOTHIONEIN IN DIABETIC NEPHROPATHY OGAWA DAISUKE Department of Diabetic Nephropathy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan Diabetic nephropathy is the leading cause of end-stage renal disease worldwide and an independent risk factor for cardiovascular disease. Several mechanisms contribute to the onset and progression of diabetic nephropathy, including genetic and hemodynamic factors, oxidative stress, and inflammation. Numerous studies have suggested that hyperglycaemia is associated with enhanced generation of reactive oxygen species (ROS), and oxidative stress has been implicated in the development of diabetic nephropathy. Emerging evidence also suggests that inflammatory pathways are crucially involved in the pathogenesis of diabetic nephropathy. The regulation of oxidative stress and inflammation could thus represent a major therapeutic target in diabetic nephropathy. Metallothionein (MT) is an intracellular metal-binding protein characterized by a low molecular mass, high cysteine content, and no aromatic or histidine residues. Although four isoforms have been characterized, MT-1 and -2 (MT-1/2), are widely distributed as the major isoforms throughout the body. MT plays an important role in heavy metal detoxification and essential metal homeostasis. In addition, MT has a potent antioxidant function and is an adaptive protein that protects cells and tissues from oxidative stress. Previous studies have reported neuroprotective effects of MT in mouse models of Parkinson’s disease. We previously demonstrated that MT was expressed mainly in renal proximal tubular epithelial cells, and that high-glucose-induced oxidative stress may enhance the expression of MT in diabetic kidney (Exp Diabetes Res, 2011). These results suggest that MT is upregulated in compensation to protect kidneys from oxidative stress induced by diabetic conditions; however, the role of MT in the pathogenesis of diabetic nephropathy remains poorly understood.

© 2014 The Authors Nephrology © 2014 Asian Pacific Society of Nephrology, 19 (Supp. 2), 4–22

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The Abstracts of the 14th Asian Pacific Congress of Nephrology

The present study therefore aimed to investigate the role of MT in protecting the kidney from high-glucose-induced oxidative stress under diabetic conditions, using MT deficient (MT-/-) and MT+/+ mice. We also used murine proximal tubular epithelial (mProx24) cells cultured under normal or high-glucose conditions to determine if knockdown of MT by small interfering RNA (siRNA) induced mitochondrial ROS, leading to inflammation. Diabetes was induced by streptozotocin injection in MT-/- and MT+/+ mice. Urinary albumin excretion, histological changes, markers for ROS and kidney inflammation were measured. mProx24 cells were used to further elucidate the role of MT under high-glucose conditions. Parameters of diabetic nephropathy and markers of ROS and inflammation were accelerated in diabetic MT-/- mice compared with diabetic MT+/+ mice, despite equivalent levels of hyperglycaemia. MT deficiency accelerated interstitial fibrosis and macrophage infiltration into the interstitium in diabetic kidney. Electron microscopy revealed abnormal mitochondrial morphology in proximal tubular epithelial cells in diabetic MT-/- mice. In vitro studies demonstrated that knockdown of MT by small interfering RNA enhanced mitochondrial ROS generation and inflammation-related gene expression in mProx24 cells cultured under high-glucose conditions. The results of this study suggest that MT may play a key role in protecting the kidney against high glucose-induced ROS and subsequent inflammation in diabetic nephropathy.

SY1-04 PATHOGENESIS AND TREATMENT OF DIABETIC NEPHROPATHY, WHAT WE HAVE LEARNED FROM PROTEOMICS AND miRNA FAN QIULING, WANG LINING Department of Nephrology, The First Affiliated Hospital, China Medical University, China Background: Diabetic Nephropathy (DN) has become the leading cause of end-stage renal disease and is a major healthcare problem worldwide. The pathogenesis of DN has multiple factors including genetic and environmental factors that activate a multitude of renal pathways. But the underlying mechanism of DN is still unclear. The systematic biology approaches such as proteomics and miRNA array may provide valuable information regarding the underlying biology of DN, with the hope of early detection and development of novel therapeutic strategies. Methods: The glomerular and tubular protein and miRNA expression profile of KKAy mice treated by losartan was analyzed by 2D-DIGE, MALDI-TOF mass spectrometry and miRNA arrays. The protein expression profile of human renal mesangial cells (hMCs) and human aortic endothelial cells (hAEcs) cultured under high glucose was also investigated. To explore the pathogenesis and the biomarkers for early detection of DN, the circulating miRNA expression profile of DN patients was analyzed by AB Taqman human miRNA array. On the basis of the systematic biological study, we focus on PI3K/AKT/mTOR pathway, the effects of ursolic acid on autophagy, epithelial-mesenchymal transition (EMT) and PI3K/AKT/mTOR pathway in podocyte and mesangial cells cultured by high glucose was investigated. Results: 6 proteins were found to be differentially expressed between the KKAy non-treatment mice and C57BL/6 mice glomeruli, and their differential expression were suppressed by losartan treatment, including mitochondrial ATP synthase subunit d, GRP75 and selenium-binding protein 1 et al. The expression of 10 miRNAs was higher and the expression of 12 miRNAs was lower in the glomeruli of the KKAy non-treated mice than that of the CL57BL/6 mice. The expression of 4 miRNAs was down-regulated in the glomeruli of the KKAy losartan-treated mice compared with that of the non-treated mice. Among them, the expression of miRNA-503 and miRNA-181d was higher in the glomeruli of the KKAy non-treated mice and was inhibited by losartan treatment. Along with the progression of diabetes and diabetic nephropathy, circulating miR-1179 was gradually increased (2.03 times in DM/N and 2.14 times in DN/DM) , and circulating miR-148b, miR-150 were gradually reduced (2.04 times in DM/N, 2.02 times in DN/DM and 2.03 times in DM/N, 2.02 times in DN/DM respectively). The differentially expressed proteins and the targets of miRNAs induced by high glucose involved in mitochondrial oxidative stress, autophagy and EMT. Ursolic acid and LY294002 inhibited HG-induced mesangial cell proliferation and decreased ROS generation. The expression of podocin, ZO-1 was downregulated and the expression of α-SMA was up-regulated in podocyte cultured by high glucose and inhibited by ursolic acid. The cells exposed to HG for 48h showed up-regulated p85PI3K, pAkt, pmTOR and down-regulated LC3BII expression. Ursolic acid down-regulated p85PI3K, p62/SQSTMI, pAkt, pmTOR and GSK3β expression and up-regulated Wnt5a, LC3BII expression in mesangial cell and podocyte cultured by HG. Mass abnormal mitochondrion and decreased autophagosomes were observed by electron microscopy in cells cultured by HG for 48h and ursolic acid decreased autophagosomes expression.

Conclusion: The differentially expressed proteins and the target of miRNAs induced by high glucose involved in mitochondrial oxidative stress, autophagy and epithelial-mesenchymal transition. The over-expression of miR-503 and miR-181d in KKAy mice glomeruli may be responsible for the pathogenesis of DN by regulating the expression of the target proteins, such as heat shock protein 75, GRP75 and GRP78 et al. The differentially expression of serum miR-1179, miR148b and miR-150 may be responsible for the pathogenesis of diabetic nephropathy and are potential biomarkers for DN. Ursolic acid can regulate autophagy and EMT and ameliorate high glucose induced podocyte and mesangial cell injury by inhibiting PI3K/AKT/mTOR pathway, implying that ursolic acid could be a potential treatment for diabetic nephropathy.

SY1-05 OVERVIEW OF DIABETES AND ITS COMPLICATION (IN ASIA) PRANOTO AGUNG1,2 1 Surabaya Diabetes & Nutrition Center; 2Endocrinology Division, Department of Internal Medicine, Dr Soetomo General Hospital, Airlangga University Teaching Hospital, Faculty of Medicine, Airlangga University, Indonesia Diabetes can be found in every country. Without effective prevention and management programs, the burden will continue to increase worldwide. Some 382 million people worldwide, by 2035, some 592 million people, will have diabetes. People with diabetes are at risk of developing a number of disabling and lifethreatening complications. Consistently high blood glucose levels can lead to serious diseases affecting the heart and blood vessels, eyes, kidneys, and nerves. People with diabetes are also at increased risk of developing infections (IDF Diabetes Atlas 2013). The DiabCare Asia 2008 study has been conducted in Asia Countries and the A1chieve Study will give figures of diabetes complication. The DiabCare Indonesia 2008, this was a non-interventional, cross-sectional study. It was recruited 1785 patients from secondary and tertiary medical centers across Indonesia that it was eligible for analysis. The mean age of the patients was 58.9 ± 9.6 years. The mean duration of diabetes was 8.5 ± 7.0 years. Majority (97.5%) of the patients had type 2 diabetes. 67.9% had poor control of diabetes (A1c:8.1 ± 2.0%). 47.2% had FPG>130 mg/dL (161.6 ± 14.6 mg/dL). Dyslipidemia was reported in 60% (834/1390) and 74% (617/834) of those received lipid lowering treatment. Neuropathy was most common complication (63.5%); other complications were: Diabetic retinopathy 42%, nephropathy 7.3%, severe late complications 16.9%, macrovascular complications 16%, microvascular complications 27.6%. About 81.3% of patients were on OADs (± insulin), 37.7% were on insulin (±OADs). Majority used biguanides followed by sulfonylureas. Majority of the WHO-5 well being index responses fell in positive territory (Pradana et al, 2010). The DiabCare Malaysia 2008, analysis from 1549 patients showed deteriorating glycemic control with mean HbA1c of 8.66 +/- 2.09% with only 22% of the patients achieving ADA target of 2.6 mmol/L; 19.8% had triglycerides > 2.2 mmol/L; 27.4% had HDL < 1 mmol/L despite 85% of the patients being on lipid lowering agents. Microvascular, macrovascular and severe late complications were reported in 75%, 28.9% and 25.4% patients respectively. The rates of diabetic complications were cataract 27.2%, microalbuminuria 7%, neuropathy symptoms 45.9%, leg amputation 3.8% and history of angina pectoris was 18.4%. Quality of life evaluation showed that about one third of patients have poor quality of life (Mafauzy et al, 2012). The DiabCare Philippines, a total of 770 diabetics were recruited from general hospitals, diabetes clinics and referral clinics, out of which 724 were type 2 diabetic patients. Results: The mean HbA1c was 8.03 ± 1.96 % and only 15.0% of the patients achieved ADA target of 2.6 mmol/L; 14.3% had triglycerides >2.2 mmol/L; 19.2% had HDL < 1 mmol/L and 53.9% of the patients were on lipid lowering agents. 68.4% patients were hypertensive and 64.4% were receiving anti-hypertensive medication. Microvascular, macrovascular and severe late complications were reported in 68.1%, 14.8% and 9.4% patients respectively. The rates of diabetic complications were cataract 32.7%, neuropathy symptoms 45.2%, microalbuminuria 15.8%, history of angina pectoris 10.7% and cerebral stroke 4.7% (Jimeno et al, 2012). The DiabCare Bangladesh 2008, results from 1860 diabetics showed deteriorating glycaemic control with mean HbA1c of 8.6±2.0% with only 23.1% of the patients achieving American Diabetes Association (ADA) target of 2.6 mmol/L; 43.8% had triglycerides >2.2 mmol/L; 44.1% had HDL249 micromol/l) more frequently developed persistent proteinuria compared with those with uric acid in the three lower quartiles. Studies such as these indicate the potential role for uric acid in the development of diabetic nephropathy. To uncover the pathological role of uric acid in the diabetic kidney, we studied the db/db mouse model of diabetic nephropathy. Interestingly, this db/db mouse features higher level of serum uric acid compared to control mice. Lowering uric acid by allopurinol was found to slow the progression of tubulointerstitial injury while no effects were observed in glomerular disease. These findings suggest that tubular epithelial cell could be one of targets for uric acid in diabetes. What is the precise role for uric acid in diabetic tubulointerstitial injury? First, we would like to seek a responsible factor which increases uric acid level in diabetes. While there are several factors, one of the most likely candidates could be “fructose” as uric acid is produced as a consequence of fructose metabolism. Importantly, glucose is enzymatically converted to fructose and therefore glucosederived fructose could be high in diabetic patients. In fact, there is a clinical study showing that urinary fructose level is higher in diabetic patients than nondiabetic patients. Consistent with this hypothesis, our group recently reported a mouse study demonstrating that high glucose resulted in an increase in fructose content in such organs as liver and kidney. Given these facts, it is likely that endogenous fructose can be produced as a consequence of the metabolism of glucose to fructose via the polyol pathway, followed by the metabolism of fructose resulting in the generation of uric acid within the tubular cell. In order to investigate the role of fructose, we tested the effect of dietary fructose and examined renal effect in the rats. Dietary fructose for several weeks developed tubulointerstitial injury in accompanied with tubular dilatation, epi-

NEPHROLOGY 2014; 19 (SUPP. 2)

thelial cell proliferation and macrophage infiltration. Importantly, epithelial cell in proximal tubules was found to express both fructose transporters and fructokinase, a latter of which is a rate limiting enzyme for fructose metabolism. Hence, it is likely that fructose was directly taken into cytosol of proximal tubular epithelial cells via fructose transporters and is metabolized into uric acid. Consistently, our in-vitro study documented that fructose induced high level of intracellular uric acid while blocking uric acid production with allopurinol prevented inflammatory response in cultured proximal tubular epithelial cells. In addition, we may want to introduce our recent experimental result, in which blocking fructokinase slowed the progression of diabetic tubular injury in accompanied by a lowering uric acid in mice. Taken together, we will discuss the pathological role of endogenous fructose-uric acid axis as a novel mechanism for the development of diabetic tubular injury.

SY2-01 AN OVERVIEW FOR TOPICS OF ACUTE KIDNEY INJURY YASUDA HIDEO1, FUJIGAKI YOSHIHIDE2 1 First Department of Medicine, Hamamatsu University School of Medicine; 2 Department of Internal Medicine, Teikyo University School of Medicine, Japan Acute kidney injury (AKI) has emerged as a major public health problem. The major problems of AKI were picked up: 1) high mortality, 2) high morbidity, 3) remote effects to other organs and 4) progressive or new onset chronic kidney disease (CKD) after AKI. The incidence of AKI has been reported to be about 2,000 per million populations. Rates of AKI in hospitalized patients have been reported to be between 3.2% and 20%, and AKI rates in intensive care units (ICUs) have been reported to be between 22% and 67%. The severity of AKI is associated with an increase in hospital mortality. Sepsis is a precipitating factor in about a half of patients in ICU and associated with a very high mortality. Any episode of AKI in a patient with underlying CKD inflicts additional damages on already compromised kidneys and increases the rate of transition to end-stage renal disease (ESRD). AKI can bring remote effects on pulmonary and cardiac damages and synergistically worsen outcomes with multi organ dysfunctions. To solve these problems of AKI, some advances of diagnosis and improving prognosis of AKI have been expected by the development of biomarkers, methods of blood purification and drug therapy for AKI. The vigorous basic studies could promise the clarification of pathogensis of AKI, especially AKI induced by sepsis. In addition, epidemiological studies have recently proposed several topics in AKI. In this symposium, I would introduce topics of AKI: 1) Fluid management, 2) Acute-on-chronic kidney disease and 3) Onco-nephrology. Then, the international specialists will give a talk on pathogensis, biomarker, blood purification and drug therapy for AKI.

SY2-02 PATHOGENESIS OF ACUTE KIDNEY INJURY JO SANG KYUNG Department of Internal Medicine, Korea University Medical College, Korea Pathogenesis of ischemia/reperfusion (I/R) induced acute kidney injury (AKI) is multifactorial, involving hemodynamic alteration, endothelial and epithelial injury and inflammation. Endothelial cell injury results in predominant vasoconstriction that is combined with enhanced leukocyte-endothelial interaction, activation of coagulation system and further compromise microcirculation in outer medulla. Tubular epithelial cell injury is most predominant in S3 segment of proximal tubule where demand for oxygen and ATP is high due to multiple transport functions. Damaged tubular cells show loss of polarity, disruption of actin-cytoskeleton or undergo apoptosis or necrosis and this leads to increased backleak of glomerular filtrate and enhanced preglomerular arteriolar vasoconstriction due to enhanced tubuloglomerular feedback. In addition, damaged tubular cells upregulate multiple inflammatory cytokines as well as Toll like receptors (TLRs), costimulatory molecules, contributing to inflammation or immune activation. Both innate and adaptive immune system are activated and play important roles in injury and repair following I/R. Activation of innate immune system comprises trafficking of neutrophil, macrophage, NK cells and NKT cells and also activation of resident kidney dendritic cells. These cells of innate immunity participate in initial kidney injury by producing multiple enzymes such as protease, myeloperoxidase or proinflammatory cytokines. In contrast to CD4+ T cells that are known to contribute to injury, CD4+ CD25+ Foxp3+ regulatory T cells with antinflammatory property are thought to promote repair. Better understanding of exact pathogenetic mechanisms of injury and repair following I/R injury is needed for the development of preventive or therapeutic strategies.

© 2014 The Authors Nephrology © 2014 Asian Pacific Society of Nephrology, 19 (Supp. 2), 4–22

The Abstracts of the 14th Asian Pacific Congress of Nephrology

SY2-03 URINARY BIOMARKER FOR ACUTE KIDNEY INJURY (AKI) YUZAWA YUKIO, HAYASHI HIROKI, HASEGAWA MIDORI Department of Nephrology, Fujita Health University School of Medicine, Japan Although the KDIGO GL for AKI 2013 contains clear indicators for early or mild AKI, the time lag before serum Cr elevation in response to changes in acutephase GFR leads to delays in AKI diagnosis. A group of kidney-specific urinary biomarkers such as NGAL, IL18, KIM-1 and L-FABP has recently been identified. Clinical application of these biomarkers to enable earlier AKI diagnosis is eagerly anticipated. Since the diagnostic potential of each biomarker is limited, it is important to create a panel that simultaneously measures multiple biomarkers to increase diagnostic accuracy by combining the strengths of each and compensating for their shortcomings. The clinical use of AKI biomarkers has yet to progress past the level of prospective observational cohort studies during clinical research regarding biomarker evaluation. RCTs are required to further evaluate each biomarker regarding clinical usefulness, prognosis, and cost-effectiveness.

SY2-04 ACUTE BLOOD PURIFICATION FOR AKI DOI KENT1, NOIRI EISEI2, IWAGAMI MASAO2, NANGAKU MASAOMI2, YAHAGI NAOKI1 1 Department of Emergency and Critical Care Medicine, The University of Tokyo, Japan; 2Department of Hemodilaysis and Apheresis, The University of Tokyo, Japan Acute blood purification plays a crucial role in the treatment of acute kidney injury (AKI) occurring in an ICU because no specific drug that can treat AKI sufficiently is clinically available. Many clinical studies have examined treatment settings of acute blood purification and provided verifiable results, but some critical issues remain unresolved. This presentation will overview the evidence related to 1) optimal therapeutic dose of renal replacement therapy (RRT), 2) early initiation of RRT, and 3) potential role of endotoxin absorption for septic AKI. 1) Optimal dose for RRT in AKI has been evaluated by two large randomized controlled trials (VA/NIH ATN and RENAL studies) and the control groups in these studies received higher doses of RRT compared with the Japanese standard doses. However, this may not indicate the outcomes of AKI in Japan are worse than other counties such as US and AU/NZ. We need to clarify the lowest dose that will not reduce the effects of RRT for AKI. 2) It is still unclear when to start RRT for AKI. Early initiation sometimes is realized as “non-renal indication” because no evidence of renal injury evaluated by serum creatinine elevation is observed at RRT initiation. However, emerging AKI biomarkers may guarantee early RRT initiation even under the condition of no serum creatinine elevation. In addition, fluid overload has recently been recognized as one of the most important risk factors for mortality of AKI. RRT initiation based on fluid balance will also promote earlier initiation of RRT. 3) A multicenter randomized controlled trial of EUPHAS study partly demonstrated the protective effects of endotoxin absorption therapy against sepsis caused by intra-abdominal infection, but also caused several controversies about this treatment. We recently examined the performance of endotoxin absorption therapy by using the national administrative database of the Diagnosis Procedure Combination (DPC). Propensity-matched analysis revealed that endotoxin absorption therapy did not show any survival benefit for the overall study population with abdominal septic shock. We are currently conducting a further investigation to identify the responder of this treatment.

SY2-05 DRUG THERAPY FOR ACUTE RENAL INJURY: WE NEED BETTER THERAPY FROM BENCH TO BEDSIDE TERADA YOSHIO, OODE KAZU, MATSUMOTO TATSUKI, TANIGUCHI YOSHINORI, HORINO TARO Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi Univesity, Japan Acute kidney injury (AKI) is common in hospitalized patients and is associated with significant morbidity and mortality especially in critically ill condition.

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Unfortunately, prevention trials of AKI are especially difficult to conduct. Attention should be given to assessment of volume status and fluid administration because volume depletion is a common and modifiable risk factor for AKI. Prevention or prompt management of complications like fluid overload, hyperkalemia and metabolic acidosis improves outcomes. Immediate initiation of renal replacement therapy is indicated in the presence of life threatening changes in fluid, electrolyte and acid-base balance. Other measures like treating the underlying cause of AKI, adapting dosage of drugs to renal function, treatment of infections and providing adequate nutrition is important. In the recent Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guideline (2012), the use of diuretics, low-dose dopamine, ANP is not suggested for the treatments of AKI. Diuretics are frequently used in patients at risk of AKI and in the management of these who develop AKI. Since fluid overload in one of the major symptoms of AKI. However, diuretics can also be harmful, by reducing the circulating volume excessively and adding a prerenal insult, worsening established AKI. Therefore, it is essential to evaluate usefulness of diuretics to improve outcome of AKI, not just fluid management. Dopamine was once commonly used for renal protection in the critically ill. However, because of the multiple negative studies, its use has been abandoned by most. Doppler ultrasound study found that dopamine significantly increased renal vascular resistance in AKI patients. The KDIGO guideline recommended not using low-dose dopamine to prevent or treat AKI. Several natriuretic pepetide are in clinical use or in development for treatment of congestive heart failure or renal dysfunction, and could potentially be useful to prevent or treat AKI. However, there have been several negative studies of prophylactic ANP therapy, ANP failed to prevent primary renal transplant dysfunction and ANP prophylaxis also failed prevent contrast-induced AKI. As mentioned above, besides renal replacement therapy, no other supportive measures are available for patients with AKI. The best therapy for patients with AKI seems to be the avoidance of further injury to the kidney through titrated resuscitation and discontinuation or avoidance of any unnecessary nephrotoxic drugs. Recent basic studies regarding pathogenesis, the new agents concerning inflammation, mitochondria biogenesis may possible new therapeutic targets for AKI. Novel biomarker-guided early diagnosis of AKI may facilitate exploration of novel anti-inflammatory and antioxidant therapies in specific AKI syndromes, such as sepsis-induced AKI, and open new avenues to facilitate renal recovery and prevent short and long-term complications. Recently, survivors of episodes of AKI who are at risk for the development or worsening of CKD need greater attention. The burden of CKD on the global health care system is well documented, so the importance of preventing or minimizing CKD progression in survivors of AKI episodes cannot be overstated. To this end, the recent KDIGO clinical practice guideline proposed a new conceptual model, called acute kidney disease, to highlight the need to follow survivors of AKI episodes in the near term and monitor development of signs and symptoms of CKD, with a focus on screening for markers of kidney damage (i.e., proteinuria) and/or reduced GFR. Major risk factors for CKD progression after AKI include advanced age, diabetes mellitus, hypertension, heart failure, preexisting CKD (as defined by proteinuria or educed GFR), and low levels of serum albumin, a dual marker of nutrition and inflammation. The presence of these risk factors should alert practitioners to be especially vigilant for CKD development after an episode of AKI. The survive episodes of AKI be followed regularly to assess for early evidence of CKD (i.e., development of hypertension, proteinuria, or reduced GFR) to slow progression of diagnosed CKD to ESRD. In this section, many drug therapy including renin-angiotensin system blocker is available. In summary besides renal replacement therapy, no other supportive drugs are available for patients with AKI. The best therapy for patients with AKI seems to be the avoidance of further injury to the kidney. AKI to CKD transition should be cared by monitoring by change of GFR, presence of proteinuria or hypertension.

SY3-01 VARIANTS IN GENES ENCODING COMPLEMENT REGULATORY PROTEINS AFFECT IgA INITIATED COMPLEMENT ACTIVATION IN IgA NEPHROPATHY ZHANG HONG Renal Division, Department of Medicine, Peking University First Hospital & Peking University Institute of Nephrology, China IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and widely considered to be a polygenic disease. Although exact pathogenesis is still unclear, multi-hit mechanism was proposed for this disease. To further clarify genetic factors involved in IgAN and draw clues to the underlying patho-

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genesis, three groups of scientists from England, US and China, independently performed genome-wide association studies (GWAS) in IgAN and identified several IgAN susceptible loci. One of the identified genomic region 1q32 contains complement factor H (CFH) and the related CFHR3, CFHR1, CFHR4, CHFR2, CFHR5 genes. In this region, rs6677604 in CFH was the top SNP, and a deletion spanning CFHR3 and CFHR1 (CFHR3-1Δ) was the top signal in the genome-wide copy number polymorphism (CNP) analysis. In IgAN, complement system has attracted great attention. In patients with IgAN, except for the characteristic IgA deposition, C3 is the most commonly co-deposited molecule, approximately affects 90% patients. Serological complement activation was also found in IgAN. Additionally, the elevated urine factor H level in patients with IgAN was reported in recent study. Accumulating evidences from plasma, urine and renal biopsy samples suggested the involvement of factor H and complement activation in IgAN pathogenesis. CFH, CFHR3 and CFHR1 are regulators of complement system, which is a key system for immune surveillance and homeostasis. In systemic autoimmune diseases, such as SLE, activation of the complement system is involved in pathogenesis. In recent years, following the identification of aberrant glycosylated IgA1 and anti-glycan antibodies in patients with IgAN, it have been convinced that IgAN is an autoimmune disease, in which IgA1-containing immune complexes were the initiator for glomerular injury. In our recent study, we enrolled two populations, Beijing Discovery Cohort of IgAN-GWAS and Beijing Follow-up Cohort, to explore the genetic mechanism of variants in CFH, CFHR3 and CFHR1 on IgAN. In the Beijing Discovery Cohort, we found the top SNP rs6677604 was associated with glomerular mesangial C3 deposition by genotype-phenotype correlation analysis. In the Beijing Follow-up Cohort, after the confirmation of tight linkage between rs6677604-A and CFHR3-1Δ, we found rs6677604-A was associated with higher factor H levels and lower complement activation split product C3a, which implied less system complement activation. Furthermore, factor H levels were positively associated with circulating C3 levels and negatively associated with mesangial C3 deposition, indicated the important role of factor H in controlling complement activation in IgAN. Besides rs6677604, serum IgA levels and galactose deficient IgA1 levels, which were pathogenic initiator of IgA nephropathy, were also found to be associated with mesangial C3 deposition in IgAN. Our findings, together with our present understanding of IgAN pathogenesis, suggested that variants in CFH, CFHR3 and CFHR1 regulated pathogenic IgA1 induced system complement activation due to its effect on factor H levels, which might influence circulating IgA1-containing immune complex formation and the following mesangium deposition, and at last contributed to IgAN susceptibility. Key words: IgA nephropathy, CFH, CFHR3-1Δ deletion, complement activation

SY3-02 WHOLE EXOME SEQUENCING ANALYSIS OF JAPANESE FAMILIAL IgA NEPHROPATHY GOTO SHIN1, HOSOMICHI KAZUYOSHI2, TSUKAGUCHI HIROYASU3, WATANABE HIROFUMI1, INOUE ITURO2, NARITA ICHIEI1 1 Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Japan; 2Division of Human Genetics, National Institute of Genetics, Japan; 3Second Department of Internal Medicine, Kansai Medical University, Japan Introduction: Genetic predisposition to IgA nephropathy (IgAN) has been suggested by the familial clustering of this disease. Although genome-wide linkage analysis of IgAN has revealed several susceptibility loci, the causative genes have not been identified. From the point of view of genetic heterogeneity of familial IgAN, an oligo/polygenic and multiple susceptibility gene model for the disease has been proposed. Recently, exome sequencing has emerged as a powerful and cost-effective strategy for dissecting the genetic basis of diseases. Methods: To identify the genetic causality of familial IgAN, we applied exome sequencing to a family comprising four biopsy-proven IgAN patients clustered in a dominant transmission mode. The whole exomes of four affected, two unmanifested carriers, and two unaffected individuals were captured and subjected to massive parallel sequencing. Variants identified by exome sequencing were filtered on the basis of variant annotation, functional expectation, and allele frequency. The affected individuals in the family were expected to share the same causal variant. Genome-wide linkage analysis was concurrently performed for the family using the high-throughput linkage analysis system SNP HiTLink. Sequence analysis of the EEA1 gene was performed in other members of the family and in 27 additional cases with IgAN. The Human Genetic Variation database was used as a reference for the exome sequence data of the Japanese population.

Results: Several filtering procedures for extracting candidates with diseasecausing variants were effectively used as follows. The first step involved performing variant annotation on the basis of dbSNP entries, 1000 Genome Project, and amino acid substitutions to retain novel nonsynonymous variants. The next filtering stage was performed on the basis of allele frequency, and an interval of 30%–70% was used as the cut-off threshold. Finally, 13 variants that were shared only by the affected individuals in the family were selected as candidate genes for familial IgAN. Linkage analysis of the family revealed linkage signals at nine loci. Among the candidates, a novel missense variant F161Y in EEA1 that encodes early endosome antigen 1 (a Rab5 effector protein that facilitates the docking and tethering of incoming endocytic vesicles) was located within a linkage locus with a maximum LOD score of 1.68. Furthermore, the F161Y variant completely cosegregated in the family, and this variant is present in a highly conserved region across zebrafish to human. Sequence analysis of EEA1 revealed that among the additional 27 familial IgAN cases, six families carried three other variants (R1262W, N1072K, and E1010G) within EEA1 with reduced penetrance. The frequencies of these EEA1 variants in familial IgAN were significantly higher than those in the Human Genetic Variation database. Conclusion: Our data indicate that EEA1 is a susceptibility gene for Japanese familial IgAN, and defective endosomal trafficking may be implicated in the pathogenesis of familial IgAN.

SY3-03 NEW INSIGHTS INTO THE PATHOGENESIS OF IGA NEPHROPATHY BARRATT JONATHAN John Walls Renal Unit & Depatment of Infection, Immunity & Inflammation, University of Leicester, UK Changes in the physicochemical properties of the IgA1 molecule, in particular the hinge region O-linked sugars, have been shown to alter the pathogenicity of IgA both in vivo and in vitro. We have been studying how the IgA1 hinge region glycans may change the 3-dimensional shape of the IgA1 molecule and therefore alter IgA interactions with mesangial matrix proteins, cell surface receptors and other serum proteins. Using a combination of analytical ultracentrifugation, neutron and X-ray scattering we have been able to determine the 3 dimensional shape of IgA1 molecules in health and in IgA nephropathy. Our early data suggests that changes in the IgA1 hinge region sugars leads to unravelling of the IgA1 molecule, which in turn may explain the presentation of neo-epitopes for autoantibody formation and altered interactions of IgA with other proteins and cell surface receptors in IgA nephropathy. One interaction we believe is key to determining the risk of progressive kidney disease in IgA nephropathy is the interaction between filtered IgA immune complexes and proximal tubule cells. Activation of proximal tubule cells and transformation into a pro-inflammatory and pro-fibrotic phenotype drives progressive tubulointerstitial scarring. There is emerging evidence that loss of the permselective barrier in IgA nephropathy is associated with increased filtration of IgA immune complexes and exposure of proximal tubule cells to pathogenic IgA. Proximal tubule cells express a number of putative IgA receptors and we have in vitro data to show that in IgA nephropathy there is specific activation of proximal tubule cells by polymeric IgA. Clearly defining this interaction may help us in the future better stratify patients for the propensity to develop tubulointerstitial scarring and therefore endstage renal disease in IgA nephropathy.

SY3-04 IgA NEPHROPATHY: PATHOGENETIC PATHWAYS AND IMPLICATIONS FOR DISEASE-SPECIFIC TREATMENT AND BIOMARKERS NOVAK JAN Department of Microbiology, University of Alabama at Birmingham, USA IgA nephropathy was described as a clinical entity in 1968 and since then has been recognized as the most common primary glomerulonephritis in the world and an important cause of end-stage renal disease. Analysis of IgA eluted from the glomerular deposits showed it to be IgA1 with galactose-deficient O-glycans in the hinge-region (Gd-IgA1). Later studies indicated that most of the circulatory Gd-IgA1 was within immune complexes, bound to anti-glycan antibodies. To explain the pathogenic mechanisms of disease, we proposed a “multi-hit” hypothesis for an autoimmune kidney disease. Specifically, patients with IgA nephropathy have elevated levels of circulatory Gd-IgA1 (autoantigen, hit 1);

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the IgA1 hinge-region glycoforms are recognized by anti-glycan antibodies (autoantibodies, hit 2). Subsequently, immune complexes are formed (hit 3) and some of them deposit in the glomeruli and activate mesangial cells (hit 4) that subsequently proliferate and overproduce extracellular matrix and cytokines. Some of these cytokines likely cause podocyte injury and induce proteinuria and hematuria. These pathogenic steps are affected by environmental and genetic factors, some of which act up-stream and/or down-stream of these major hits. New tools, models, and approaches have been developed, including immortalized IgA1-secreting cells from patients with IgA nephropathy and healthy controls, monoclonal and recombinant antibodies specific for Gd-IgA1, highresolution mass spectrometry workflows, engineering of Gd-IgA1-containing immune complexes in vitro, a model using cultured mesangial cells for assessment of biological activity of Gd-IgA1-containing immune complexes, and a passive animal model. These tactics have provided unique insights into the nature of pathogenic IgA1-containing immune complexes, their formation, composition, and role in the disease process. Recent progress in high-resolution mass spectrometry allowed us to start to define, at the molecular level, the nature of the Gd-IgA1 hinge-region O-glycans. Understanding the heterogeneity of the autoantigen will allow investigators to assess the specificity and heterogeneity of anti-glycan autoantibodies and thus define the spectrum of the major Gd-IgA1 epitopes in patients with IgA nephropathy. Immortalized IgA1-producing cells from patients with IgA nephropathy have been used to analyze the process and major pathways in the biosynthesis of Gd-IgA1, and to assess cellular responses of these cells to cytokines and growth factors. Comparative studies of IgA1-producing cells from patients with IgA nephropathy vs. those from healthy controls revealed differences in O-glycosylation of the secreted IgA1, associated with differential expression and activity of several key enzymes and responses to cytokines, such as IL-6. Specifically, we found elevated expression of N-acetylgalactosamine (GalNAc)-specific sialyltransferase (ST6GalNAc-II) and, conversely, decreased expression and activity of a galactosyltransferase (C1GalT1) and decreased expression of the C1GalT1-associated chaperone Cosmc. These findings were confirmed by siRNA knock-down of the corresponding genes and by in vitro enzymatic reactions. Expression and activity of these enzymes can be regulated by some cytokines, such as IL-6, that further enhance the imbalance of the activity of the glycosyltransferases and, consequently, enhance the galactose deficiency of the IgA1 O-glycans. Serum levels of anti-Gd-IgA1 autoantibodies correlate with disease severity, manifested as proteinuria. Moreover, elevated serum levels of Gd-IgA1 or antiGd-IgA1 autoantibodies are predictive of disease progression. As both components, Gd-IgA1 and the corresponding autoantibodies, are required to form immune complexes, we developed a model to engineer immune complexes in vitro, using Gd-IgA1 and recombinant anti-Gd-IgA1 autoantibody; we then assessed the biological activities of such complexes. We found that these complexes induced proliferation of cultured human mesangial cells. Furthermore, when injected intravenously into immunoglobulin-free mice, they deposited in the glomeruli, accompanied by murine complement C3. The kidneys showed mesangial proliferation and matrix expansion, thus reproducing pathologic changes characteristic of the human disease. These results support the multi-hit hypothesis wherein Gd-IgA1, the key autoantigen in IgA nephropathy, is produced as a result of dysregulation of multiple enzymes in IgA1-producing cells and forms nephritogenic immune complexes with anti-glycan autoantibodies. These findings provide insight into the mechanisms of disease in IgA nephropathy and offer clues for future development of disease-specific therapy and biomarkers.

SY3-05 PATHOLOGICAL ROLE OF PALATINE TONSIL IN IGA NEPHROPATHY SUZUKI YUSUKE, SUZUKI HITOSHI, MUTO MASAHIRO, OKAZAKI KEIKO, NAKATA JUNICHIRO, TOMINO YASUHIKO Juntendo University Faculty of Medicine, Japan Impaired immune regulation along the “mucosa-bone marrow axis” has been postulated to play an important role in the pathogenesis of IgA nephropathy (IgAN) (1). Accumulating evidence from experimental approaches with animal models suggests that there is dysregulation of innate immunity in IgAN resulting in changes in the mucosal immune system (2, 3). Our recent experimental studies with IgAN prone mice revealed that mucosal activation of Toll like receptors (TLR) in B cells and dendritic cells are involved in the production of nephritogenic IgA and IgA immune complex (IC) (4–6). On the other hand, the nephritogenic roles of galactose-deficient IgA1 (GdIgA1) and Gd-IgA1 bound with anti-glycan IgG in IC (IgA/IgG-IC) have been

discussed in human IgAN (7). Although many clinical studies indeed show serum elevation of GdIgA1 and IgA/IgG IC in IgAN patients and association between these serum levels and the disease activity (8), their production sites and relevant cell types remain unclear. Our recent clinical studies indicate that the tonsils may be one of major sites for the production of GdIgA1 and tonsillar TLR9 activation may contribute to the extent of glomerular injury via the GdIgA1 production (5, 9). Moreover, we also recently found that aberrant overexpression of B cell related cytokines such as a proliferation-inducing ligand (APRIL) and its receptors are involved in the IgA/IgG IC formation. In this symposium, we would like to discuss the pathological roles of palatine tonsils and underlying molecular mechanisms in IgAN. REFERENCES 1. Suzuki Y, Tomino Y. The mucosa-bone-marrow axis in IgA nephropathy. Contrib Nephrol. 2007;157:70–9. 2. Suzuki Y, Tomino Y. Potential immunopathogenic role of the mucosa-bone marrow axis in IgA nephropathy: insights from animal models. Semin Nephrol. 2008;28:66–77. 3. Suzuki Y, Suzuki H, Sato D et al. Reevaluation of the mucosa-bone marrow axis in IgA nephropathy with animal models. Adv Otorhinolaryngol. 2011; 72:64–7. 4. Suzuki H, Suzuki Y, Narita I, et al. Toll-like receptor 9 affects severity of IgA nephropathy. J Am Soc Nephrol. 2008; 19:2384–95. 5. Kajiyama T, Suzuki Y, Kihara M, et al. Different pathological roles of toll-like receptor 9 on mucosal B cells and dendritic cells in murine IgA nephropathy. Clin Dev Immunol. 2011; 2011:819646. 6. Maiguma M, Suzuki Y, Suzuki H, et al. Dietary zinc is a key environmental modifier in the progression of IgA nephropathy. PLoS One. 2014; 28;9:e90558. 7. Moldoveanu Z, Wyatt RJ, Lee JY, et al. Patients with IgA nephropathy have increased serum galactose-deficient IgA1 levels. Kidney Int. 2007;71:1148–54. 8. Suzuki H, Kiryluk K, Novak J, et al. The pathophysiology of IgA nephropathy. J Am Soc Nephrol. 2011; 22:1795–803. 9. Nakata J, Suzuki Y, Suzuki H, et al. Changes in Nephritogenic Serum Galactose-Deficient IgA1 in IgA Nephropathy following Tonsillectomy and Steroid Therapy. PLoS One. 2014; 21;9:e89707.

SY4-01 SALT-SENSITIVE HYPERTENSION WANG JI-GUANG Centre for Epidemiological Studies and Clinical Trials, The Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, China Excessive sodium in the human body, as a consequence of either increased dietary intake or decreased urinary excretion, is a well-established risk factor of hypertension. However, the blood pressure response to dietary sodium intake varies substantially between individuals. For instance, even within a population of a similar modern lifestyle, people may have quite different levels of blood pressure and different risks of hypertension. If the blood pressure response to a certain amount of sodium intake is typically greater, this phenomenon is called “saltsensitive”. The opposite is called “salt-insensitive” or “salt-resistant”. Saltsensitive hypertension is more likely to be seen in Asians than other populations and often shows a non-dipping pattern. The mechanism of salt-sensitive phenomenon is complex and influenced by many factors, such as renal function, functions of the neuronal and hormonal regulatory system, and the structure and function of the vascular system. Salt-sensitive can be inherited genetically or acquired in the lifetime. Among the complex mechanisms for salt-sensitive, renal sodium handling must play a major role in the determination of the interindividual variability in the blood pressure response to dietary sodium intake, because the kidney determines whether sodium is reabsorbed back to the blood or excreted into the urine. Our recent data has indicated that proximal renal tubular reabsorption of sodium impacts the relationship between dietary sodium intake and blood pressure, especially during sleeping night-time hours. When the proximal tubular reabsorption is high, blood pressure is high at the current usual range of dietary sodium intake. However, when the proximal tubular reabsorption is low, blood pressure is positively associated with dietary sodium intake. Renal tubular dysfunction might be a cause of salt-sensitive volume expansion hypertension.

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SY4-02 HYPERTENSION AND TARGET ORGAN DAMAGES WITH METABOLIC RISK FACTORS PARK CHANG GYU Cardiovascular Center, Department of Internal Medicine, Guro Hospital, Korea University, Korea Hypertension is one of the most important components of metabolic syndrome and the risk of cardiovascular disease is almost two times higher in hypertensive patients with metabolic syndrome. There are three major mechanisms of hypertension in metabolic syndrome: excessive stimulation of the sympathetic nervous system, activation of reninangiotensin system and dysfunction of vascular endothelial cell. More than 80% of hypertensive patients have multiple cardiovascular riskfactors or co-morbidities. Hypertensive metabolic syndrome further increases subclinical organ damage such as left ventricular hypertrophy, thickening or atherosclerotic plaques of carotid arteries, microalbuminuria and deranged renal function. These target organ damages are associated with increased prevalence of strokes, coronary artery diseases and chronic renal diseases and results in an increased risk of fatal and non-fatal cardiovascular events.

SY4-03 RENAL SYMPATHETIC NERVOUS SYSTEM AND HYPERTENSION MORIMOTO SATOSHI, ICHIHRA ATSUHIRO Department of Medicine II, Endocrinology and Hypertension, Tokyo Women’s Medical University, Japan Essential hypertension accounts for the vast majority of hypertensive cases (about 10%). Although the etiology of this condition is incompletely understood, one of the most common forms of hypertension has been considered to be neurogenic hypertension, defined as high blood pressure with increased sympathetic nerve activity (SNA). It has been reported that in addition to cardiac and skeletal muscle SNA, renal SNA is increased in hypertensive patients. The renal sympathetic nervous system supplies the kidneys by a rich network of efferent, exclusively noradrenergic, sympathetic fivers located in the adventitia of the renal arteries and returns signals to the central nervous system via afferent sympathetic fivers likewise located in the adventitia. These signals are transmitted to several brain regions including the paraventricular nucleus of the hypothalamus, and are integrated to rostral ventrolateral medulla (RVLM), the center of tonic source of supraspinal sympathoexcitatory outflow, to elevate SNA. This vicious cycle increasing SNA is important in the pathogenesis, initial pathological events, development and end organ damages of hypertension. Therefore, medical and operative interventions have been applied terminate this vicious cycle. Current standard treatment of options to decrease SNA include lifestyle modifications (for example, weight loss, physical activity, and smoking cessation) and pharmacological treatment with angiotensin-converting enzyme (ACE) inhibitors, angiotensin type 1 receptor (AT1-R) blockers, β-adrenergic blockers, α-adrenergic blockers, and central α2-adrenergic agonists. Perhaps the most striking evidence in support of a dominant role of the SNA in human blood pressure control is the effect of surgical sympathectomy. This procedure revealed a profound improvement in blood pressure. This beneficial effect was counterbalanced by significant operative morbidity and mortality and unwanted side effects that, together with the advent of effective antihypertensive medications described above, led to abandonment of this procedure in the early 1970s. Nonetheless, the experience lends undisputable support to the important role of the SNA in blood pressure control and confirms that a favorable blood pressure response can be achieved by a reduction in sympathetic tone. In addition to this treatment, several surgical or device treatments have been tested. Since the first report by Jannetta et al. in 1978, several clinical studies have indicated that neurovascular compression of the RVLM may be causally related to essential hypertension via increased SNA. We showed in an experimental rat model that pulsatile compression of the RVLM revealed increases in blood pressure, heart rate, and SNA. Furthermore, we and others found that in patients with essential hypertension, neurovascular decompression of the RVLM showed prominent decreases in blood pressure, suggesting that this procedure might be a feasible treatment option for hypertensive patients with neurovascular compression of the RVLM. Catheter-based renal denervation (RDN) has been applied to de selectively denervate the kidneys in patients with treatment-resistant hypertension since 2009. In this approach, renal nerve ablation is achieved percutaneously via the lumen of the renal artery using a catheter connected to a radiofrequency (RF)

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generator. After the treatment catheter is introduced, several discrete RF ablations are applied and separated both longitudinally and rotationally within each renal artery. Prominent blood pressure reductions without major complications have been reported in patients with treatment-resistant hypertension in several clinical studies. However, SYMPLICITY HTN-3 Trial designed as a prospective, randomized, masked procedure, and single-blind trial evaluating the safety and effectiveness of catheter-based RND for the treatment of resistant hypertension was reported to have failed to meet primary efficacy endpoint while meeting primary safety endpoint. Baroreceptors are stretch-sensitive mechanoreceptors that are most sensitive in the carotid sinuses and the aortic arch. The stretch receptors become activated when high-pressure blood becomes ejected into the vessels and promotes a feedback loop, which activate the vagal nuclei in the medulla, which in turn inhibits the sympathetic and actives the parasympathetic nervous system and allows immediate correction of this abnormal pressure. The baroreceptor has been shown to not only modulate blood pressures with great effect but also be adaptable to new baselines. Baroreflex activation therapy (BAT) where the carotid baroreceptors are electrically stimulated were invented and significant blood pressure reduction was shown in a double-blind, randomized, prospective, placebo-controlled clinical trial in patients with treatment-resistant hypertension. Recent progress of the elucidation of the central pathways contributing to the genesis of neurogenic hypertension may participate the next generation of therapeutic strategies for hypertensive patients with increased SNA. Future research will be needed to search for more advanced treatment strategies and to determine the appropriate indications of these treatment strategies.

SY4-04 CHRONIC KIDNEY DISEASE AND CARDIOVASCULAR RISK NAKAMURA SATOKO, KAWANO YUHEI Division of Hypertension and Nephrology, National Cerebral and Cardiovascular Center, Japan Recently, chronic kidney disease (CKD) has become a major public health problem and a risk factor for all-cause mortality and cardiovascular disease (CVD). CVD is the leading cause of morbidity and mortality in patients with CKD. The increased risk of CVD begins during the earlier stages of CKD. Although patients with CKD have a very high prevalence of traditional CVD risk factors such as diabetes and hypertension, they are also exposed to other nontraditional, uremia-related risk factors such as abnormal calcium-phosphorus metabolism and inflammation. Although some of the burden of CVD in CKD may be due to atherosclerosis, it is apparent that patients with CKD also have a high prevalence of arteriosclerosis and disorders of left ventricular structure and function. Proteinuria has been shown to be an independent risk factor for CVD outcomes in the Framingham and other observational studies. We observed the microalbuminuria was associated with CVD outcomes and kidney dysfunction in the Japanese elderly hypertensive patients without previous cardiovascular complications. There are several reasons why microalbuminuria may be an independent risk factor for CVD. Microalbuminuria may represent an early stage of kidney disease, with an associated risk of subsequent CKD progression and development of macroalbuminuria. Microalbuminuria may also reflect systemic endothelial damage, inflammation and/or abnormalities in the coagulation and fibrinolytic systems. Hypertension is both a cause and a result of kidney disease. In the United States, about 70 to 80 % of patients with stage 1 to 4 CKD have hypertension, and the prevalence of hypertension increases as GFR declines. In a cohort study of urban Japanese population (the Suita Study) shows that subjects with CKD (8.9% for men and 11.3% for women) were older and had higher prevalence of hypertension (41.1% for men and 42.6% for women). In this cohort study, CKD was a risk factor for stroke and myocardial infarction. The association between blood pressure and the incidence of CVD was closer in subjects with CKD compared to those without CKD. Therefore, to prevent CVD, it may be necessary to control blood pressure by lifestyle modification and proper clinical treatment for subjects with CKD. Recent studies indicated that the decreased kidney function was associated with the incidence of coronary artery disease, heart failure, cerebral vascular disease and cardiovascular mortality. There are several reasons why decreased GFR is an independent risk factor for CVD. The presence of traditional and nontraditional risk factors associated with CKD may be responsible, at least partly, for the development of CVD. Additionally, reduced kidney function may be a marker of the severity of either diagnosed or undiagnosed vascular disease.

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Finally, patients with CKD may not receive sufficient therapy to prevent CVD, including medications such as aspirin, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and diagnostic and therapeutic procedures. Atrial fibrillation (AF) is common clinically significant arrhythmia in patients with hypertension. AF is significant risk factor for ischemic stroke and heart failure events. In 1118 consecutive hypertensive patients of our hospital, the new-onset AF was found in 1.1% per year during follow-up period (4.5 year). CKD was associated with an increased risk of new-onset AF, and the impact of CKD on the incidence of AF was independent of left ventricular hypertrophy and left atrial dilation. In particular, advanced stages of CKD were closely related to the increasing occurrence of AF. Therefore, in managing hypertensive patients, it may be important to prevent the progression of renal dysfunction in prevention of the occurrence of AF. Clinical markers of renal damage such as proteinuria and reduced GFR were revealed as strong risk factors for CVD. Recently, the attention to markers of subclinical renal damage has been growing because of their predictive value of cardiovascular outcome. Renal Doppler ultrasonography has been used to explore the capacity of resistive index (RI) calculated from blood flow velocity in the prediction of the renal outcome in patients with hypertension, diabetes and CKD. In 426 consecutive hypertensive patients of our hospital, the increased RI on the baseline Doppler ultrasonography was associated with an increased risk of cardiovascular and renal outcomes and the combination of high RI and low GFR was a powerful predictor of poor outcome in hypertensive patients. RI evaluation will complement screening for cardiovascular risk. In conclusion, CKD markers such as proteinuria, GFR and RI were useful predictor for CVD outcomes. Therefore, the evaluation and control of CKD markers may be important to prevent CVD.

SY4-05 CKD AND BLOOD PRESSURE, JAPANESE EPIDEMIOLOGICAL EVIDENCE YAMAMOTO TAE1, MIYAZAKI MARIKO1, NAKAYAMA MASAAKI2, MATSUSHIMA MASATO3, SATO HIROSHI4, ITO SADAYOSHI1 1 Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Japan; 2Division of Nephrology, Endocrinology Vascular Medicine and Diabetology, Fukushima Medical University, Japan; 3 Department of Clinical research, The Jikei University School of Medicine, Japan; 4 Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Japan

Conclusions: Low blood pressure, especially DBP