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Newly diagnosed multiple myeloma (NDMM) frequently results in renal impairment (RI), and its natural course has not been fully elucidated in the era of novel agents. We aimed to identify the dynamics of renal function after autologous stem cell transplantation (ASCT) following induction treatment using a novel agent in transplantation-eligible NDMM patients with RI (estimated glomerular filtration rate [eGFR] ≤50 mL/min/1.73 m

Accumulation of lipids and their metabolites induces lipotoxicity in diabetic cardiomyopathy. Lowering ceramide concentration could reduce the impact of metabolic damage to target organs. Adiponectin improves lipotoxicity through its receptors (AdiopRs), which have sequence homology with ceramidase enzymes. Therefore, cardioprotective role of AdipoR agonism by AdipoRon was investigated. Sixteen-week-old male db/m and db/db mice were fed a diet containing AdipoRon for four weeks. Phenotypic and metabolic profiles with associated cellular signaling pathways involved in lipid metabolism were investigated in the mice heart and human cardiomyocytes to establish treatment effect of AdipoRon. AdipoRon ameliorated insulin resistance, fibrosis, M1-dominant inflammation, and apoptosis in association with reduced accumulations of free fatty acid, triglycerides, and TLR4-related ceramide in the heart. This resulted in overall reduction in the level of oxidative stress which ameliorated cardiac hypertrophy and its function. AdipoRon increased the expression of AdipoR1 and AdipoR2 via pAMPK/FoxO1-induced Akt phosphorylation resulting from a decrease in PP2A level. It also increased acid ceramidase activity which reduced ceramide and increased sphingosine-1 phosphate levels in the heart of db/db mice and cultured human cardiomyocytes. Consistent upregulation of AdipoRs and their downstream regulatory pathways involving pAMPK/PPARα/PGC-1α levels led to lipid metabolism enhancement, thereby improving lipotoxicity-induced peroxisome biogenesis and oxidative stress. AdipoRon might control oxidative stress, inflammation, and apoptosis in the heart through increased AdipoR expression, acid ceramidase activity, and activation of AMPK-PPARα/PGC-1α and related downstream pathways, collectively improving cardiac lipid metabolism, hypertrophy, and functional parameters.

Aim The aim of this study was to describe the baseline characteristics of autosomal-dominant polycystic kidney disease (ADPKD) in a cohort of Korean patients with chronic kidney disease (CKD). Methods From April 2011 to February 2016, patients with CKD stage 1-5 (pre-dialysis) were enrolled as an ADPKD sub-cohort of the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease. Baseline characteristics, the correlation of kidney and liver volume and kidney function and the factors associated with kidney function were analysed. Results A total of 364 ADPKD patients with a mean estimated glomerular filtration rate (eGFR) of 68.1 ± 33.3 mL/min per 1.73 m2 (50.5% male with a mean age of 47.0 ± 10.6 years) were enrolled from nine hospitals in Korea. Initially, 55.8% of the patients were asymptomatic, and pain was the most common symptom (12.9%); 87.6 and 77.5% of the patients had hypertension and hepatic cysts, respectively. The height-adjusted total kidney volumes (htTKV) were higher in male patients than in female patients. In contrast, the height-adjusted total liver volumes were higher in female patients than in male patients. The decrease rate of eGFR depending on Log(htTKV) was larger in the group aged between 41 and 50 years than the other age groups. Older age, a higher 24-h urine protein excretion, larger htTKV and hyperuricemia were independently associated with lower eGFR, whereas using febuxostat was independently associated with higher eGFR. Conclusion This sub-cohort will provide clinical characteristics and outcomes of Korean ADPKD patients, which can be compared with those of other previous cohorts. We have identified factors associated with advanced-stage CKD in Korean patients with ADPKD.

Objective: Despite the widespread use of conventional percutaneous transluminal angioplasty (PTA), recurrence of cephalic arch stenosis (CAS), and low patency rate after PTA remain challenging problem. We aimed to identify the clinical predictors of recurrence of CAS and evaluate the effect of the access flow reduction on the fistula patency rate in patients with recurrent CAS. Methods: In 1118 angiographies of 220 patients with CAS, access circuit patency rates after PTA and potential clinical predictors of recurrence of CAS were assessed. The effect of the banding procedure was evaluated in terms of post-interventional primary patency rate, and the number of interventions per access-year. Results: At 3, 6, and 12 months after the first PTA on CAS, the post-interventional access circuit primary patency rates were 68.8%, 40.5%, and 25.1%, respectively. High CV to CA ratio (the ratio of the maximal diameter of the distal cephalic vein to the diameter of the cephalic arch) (Hazard ratio (HR), 1.437; 95% confidence interval (CI), 1.036–1.992) and involvement of the proximal segment of cephalic arch (HR, 1.828; 95% CI, 1.194–2.801) were significant predictors of recurrent CAS. For those with recurrent CAS (>3 times/year) and an access flow rate >1.5 L/minute, endovascular banding procedure was performed. The banding procedure significantly reduced the number of interventions per access-year ( t = 3.299, p = 0.005 and t = 2.989, p = 0.007, respectively). Post-interventional access circuit primary patency rate after banding was significantly higher than that before banding ( p = 0.01). Conclusions: High CV to CA ratio and involvement of the proximal segment of the cephalic arch are independent clinical predictors of recurrent CAS. Endovascular banding might delay recurrence of CAS in patients with high CV to CA ratio and high access flow.

Background and Aims Placental growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family. PlGF exerts favorable angiogenetic and lymphangiogenic activity by binding to VEGF-R1 and -R3, respectively. Due to its functional synergy with VEGF-A, it is required for a correct neovascularization during pathological conditions while inactivation of PlGF contributes to decrease of pathological angiogenesis. Because reduced angiogenesis and lymphagiogenesis that contribute to defective lipid drainage are implicated in the progression diabetic kidney disease, we investigated the role of PlGF in the development of diabetic nephropathy by using PlGF-knockout mice. Method Diabetes was induced by a low-dose streptozotocin injection in 9-week-old male C57BL/6J PlGF-KO and wild-type mice and biochemical and morphological parameters were examined at 12 weeks later. Results In diabetic PlGF-KO mice, fasting blood glucose and HbA1c levels increased significantly and the development of glomerular sclerosis and mesangial area expansion were accompanied by albuminuria. Diabetic PlGF-KO mice exhibited increased expression of type IV collagen, transforming growth factor-β1 and glomerular IHC staining for nephrin, PECAM-1 and WT-1-positive cells and VEGF-R1,-R2,-R3 expression decreased, suggesting decreased endothelial cell and podocyte structure. Intrarenal expression of pLKB1, and pAMPK decreased and that of PPARα, PGC1α, ERRα, p-eNOS, and urinary Nox concentration decreased while iNOS increased, indicating disturbed lipid metabolism and endothelial dysfunction in the same group. Increased intrarenal FFA, TG, and cholesterol concentration represents presence of lipid accumulation. F4/80- and TUNEL-positive cells increased, suggesting increased inflammatory cell infiltration and apoptosis. CD68 and arginase-II increased indicating that macrophage subtype M1 polarization is involved in the inflammatory process. Expression of Bcl2/bax decreased and that of SOD1 and 2 decreased, indicating increased apoptosis and oxidative stress, respectively. Increased expression of intrarenal 8-OHdG and urinary isoprostane level indicates increased oxidative stress. Conclusion Impaired angiogenesis and lymphangiogenesis are implicated in PlGF deficiency and this promotes lipotoxicity-induced inflammation, oxidative stress and deteriorates renal functional and phenotypic parameters in the diabetic kidney.

Background and Aims In aging kidney, oxidative stress and inflammation lead to a decrease in renal function. Recent studies related to the aging process of the kidneys have shown that pericyte is a progenitor cell of myofibroblast, and the relationship between renal fibrosis and pericyte has been reported. In this study, we investigated the pericytes changes in aging kidneys and mechanism of aging-related pericyte changes. Method In vivo study, 2, 24-months-old mice and 18-month-old mice treated with pentoxifylline for 6 months were analyzed with western blot. And renal biopsy from KT donors were analyzed. Donors under age 25 were assigned to young group and donors over age 60 to old group. Results Changes of pericytes in mice and human renal tissues were consistent with those in the aging model. In the old age group, pericytes were decreased and interstitial fibrosis was increased. Western blot analysis in mice kidney revealed that IL-1β, IL-6 and TNF-α were significantly increased in old age and significantly decreased in pentoxifylline group. Angiopoietin 2 was increased in old age group and decreased in pentoxifylline group. Conclusion In aging kidney, pericytes have been shown to exhibit numerical reduction and loss of perivascular location as in the aging mice model. These changes in pericytes are thought to be induced by angiopoietin 2 excretion.

Background and Aims Lysophosphatidic Acid (LPA) is a bioactive lysophospholipid that is present in all tissues. It has been reviewed that LPA could induce oxidative stress and inflammation. Oxidative stress is a major characteristic of aging which is a critical risk factor of renal dysfunction. Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that regulates the expression of antioxidants, which could improve cell viability by reducing oxidative stress, is found to be decreased in the aging kidney. Also, LPA regulates the expression of Nrf2 has been reported. In this study, we evaluate the effect of LPA in the aging kidney by elucidating the potential LPA-Nrf2 signaling pathway. Method Male 2- and 24-month-old C57/BL6 mice were used in this study. We measured histological change, oxidative stress, and aging-related protein expression in the kidneys. Results 24-month-old mice displayed increased albuminuria. Creatinine clearance decreased with aging. There were increases in mesangial volume and tubulointerstitial fibrosis in 24-month-old mice. There were also increases in autotaxin, LPAR1, PI3K, Akt, GSK3β expression with aging and Nrf2, NQO1, HO1, SOD1, SOD2 were decreased in 24-month-old mice. Conclusion LPA signaling decreased antioxidants expression via down-regulating Nrf2. Targeting the LPA-Nrf2 pathway provides new evidence to decrease aging-related disease in the kidney.

ObjectivesContrast-enhanced ultrasound (CEUS) enables the assessment of real-time renal microcirculation. This study investigated CEUS-driven parameters as hemodynamic predictors for renal outcomes in patients with acute kidney injury (AKI).MethodsForty-eight patients who were diagnosed with AKI were prospectively enrolled and underwent CEUS at the occurrence of AKI. Parameters measured were the wash-in slope (WIS), time to peak intensity, peak intensity (PI), area under the time-intensity curve (AUC), mean transit time (MTT), time for full width at half maximum, and rise time (RT). The predictive performance of the CEUS-driven parameters for Kidney Disease Improving Global Outcomes (KDIGO) AKI stage, initiation of renal replacement therapy (RRT), AKI recovery, and chronic kidney disease (CKD) progression was assessed. Receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic performance of CEUS.ResultsCortical RT (Odds ratio [OR] = 1.21) predicted the KDIGO stage 3 AKI. Cortical MTT (OR = 1.07) and RT (OR = 1.20) predicted the initiation of RRT. Cortical WIS (OR = 76.23) and medullary PI (OR = 1.25) predicted AKI recovery. Medullary PI (OR = 0.78) and AUC (OR = 1.00) predicted CKD progression. The areas under the ROC curves showed reasonable performance for predicting the initiation of RRT and AKI recovery. The sensitivity and specificity of the quantitative CEUS parameters were 60-83% and 62-77%, respectively, with an area under the curve of 0.69-0.75.ConclusionCEUS may be a supplemental tool in diagnosing the severity of AKI and predicting renal prognosis in patients with AKI.

Background and Aims The accumulation of lipid and its metabolites in tissues, including the heart, causes lipotoxicity. Sphingolipids such as ceramides are particularly deleterious. Lowering the accumulation of ceramide can improve metabolic damage of various tissues. Recent reports showed that adiponectin receptors (AdipoRs) have sequence homology with ceramidase enzymes, and an increase of ceramidase activity with overexpression of adiponectin in mice improves ceramide-dependent lipotoxicity. Therefore, we investigated the possible roles of Adiporon, which mimics the effects of adiponectin, in the view of prevention and development of diabetic cardiomyopathy in diabetic mouse model. Method Male db/db mice and db/m controls were fed either a regular diet chow or a diet containing adiporon (30 mg/kg/day p.o. for 4 weeks from 17 to 20 weeks of age) and biochemical and morphological parameters were examined at 20 weeks of age. Results In db/db mice, left ventricular developed pressure (LVDP), heart rate (HR) and coronary flow rate (CFR) were decreased compared to db/m control mice, indicating cardiovascular dysfunction in diabetic heart. The treatment with AdipoRon remarkably improved the diabetes-induced contractile impairment, without any influence on HR. Adioporon also decreased fibrosis, inflammation cell infiltration and accumulations of free fatty acid, triglycerides and ceramide in the heart. In the molecular level, increased expressions of AdipoR1 and AdipoR2 and acid ceramidase activity in the heart were observed in db/db mice with Adiporon administration. Consistent up-regulations of phosphorylated AMPK and PPAR-α level were associated within the same group. Subsequent improvement of enhanced lipid metabolism and decrement of cellular apoptosis with adiporon treatment were also noted. Conclusion Adiporon may control oxidative stress in heart through AMPK and PPAR-α activated pathway and further contribute to prevent deterioration of cardiac function. The protective role of adiporon against the development of diabetic cardiomyopathy seems to occur through a direct action on the heart independently of systemic effects of adiponectin. Our results suggest adiporon as a promising therapeutic agent of diabetic cardiomyopathy through ameliorating ceramide-dependent lipotoxicity.

To assess the causes of immature hemodialysis arteriovenous fistula and the outcome of endovascular salvage.The outcome of 207 endovascular salvage procedures in 139 patients after the first successful cannulation was analyzed retrospectively from January 2011 to December 2017 in the Catholic University of Korea, Seoul St. Mary's Hospital.Of the 139 patients aged 62 ± 13 years, 45% were women, 59% had diabetes, and 71% were maintained on hemodialysis using central venous catheters. Mean interval between arteriovenous fistula creation and referral to angiography was 87 ± 63 days. While inflow stenosis (54.4%) was the most common cause of immature forearm fistulas (n = 76), both inflow (38.6%) and mixed stenosis (35.1%) were the main causes of immature upper arm fistulas (n = 63). Endovascular salvage procedures included percutaneous transluminal angioplasty (n = 174) and accessory vein obliteration (n = 30). The overall technical and clinical success rates were 97% and 93.4%, respectively. Mean interval between endovascular procedure and the first successful cannulation of the fistula was 28 ± 35 days. At 3, 6, and 12 months following the first successful cannulation, the primary patency rates were 81%, 69.5%, and 57.6%, respectively, and the secondary patency rates were 97.2%, 96%, and 94.8%, respectively. Mixed stenosis was the only determinant of secondary patency rate of immature arteriovenous fistula (hazard ratio = 6.334, confidence interval = 1.364-29.423,Immature arteriovenous fistulas can be successfully salvaged by aggressive and timely endovascular intervention. Mixed stenosis is associated with poor access outcomes.

Background Adiponectin is known to take part in the regulation of energy metabolism. AdipoRon, an orally-active synthetic adiponectin agonist, binds to both adiponectin receptors (AdipoR)1/R2 and ameliorates diabetic complications. Among the lipid metabolites, the ceramide subspecies of sphingolipids have been linked to features of lipotoxicity, including inflammation, cell death, and insulin resistance. We investigated the role of AdipoRon in the prevention and development of type 2 diabetic nephropathy. Methods AdipoRon (30 mg/kg) was mixed into the standard chow diet and provided to db/db mice (db + AdipoRon, n = 8) and age-matched male db/m mice (dm + AdipoRon, n = 8) from 17 weeks of age for 4 weeks. Control db/db (db cont, n = 8) and db/m mice (dm cont, n = 8) were fed a normal diet of mouse chow. Results AdipoRon-fed db/db mice showed a decreased amount of albuminuria and lipid accumulation in the kidney with no significant changes in serum adiponectin, glucose, and body weight. Restoring expression of adiponectin receptor-1 and -2 in the renal cortex was observed in db/db mice with AdipoRon administration. Consistent up-regulation of phospho-Thr172 AMP-dependent kinase (AMPK), peroxisome proliferative-activated receptor α (PPARα), phospho-Thr473 Akt, phospho-Ser79Acetyl-CoA carboxylase (ACC), and phospho-Ser1177 endothelial NO synthase (eNOS), and down-regulation of protein phosphatase 2A (PP2A), sterol regulatory element-binding protein-1c (SREBP-1c), and inducible nitric oxide synthase (iNOS) were associated within the same group. AdipoRon lowered cellular ceramide levels by activation of acid ceramidase, which normalized ceramide to sphingosine-1 phosphate (S1P) ratio. In glomerular endothelial cells (GECs) and podocytes, AdipoRon treatment markedly decreased palmitate-induced lipotoxicity, which ultimately ameliorated oxidative stress and apoptosis. Conclusions AdipoRon may prevent lipotoxicity in the kidney particularly in both GECs and podocytes through an improvement in lipid metabolism, as shown by the ratio of ceramide to sphingosines, and further contribute to prevent deterioration of renal function, independent of the systemic effects of adiponectin. The reduction in oxidative stress and apoptosis by AdipoRon provides protection against renal damage, thereby ameliorating endothelial dysfunction in type 2 diabetic nephropathy.

The trabecular bone score (TBS) is a textural index that indirectly assesses bone trabecular microarchitecture using lumbar spine images obtained by dual-energy X-ray absorptiometry (DXA). This study compared the TBS of patients with end-stage kidney disease (ESKD) with that of matched controls to identify risk factors associated with a low TBS. TBS and bone mineral density (BMD) were assessed in ESKD patients (n = 76) and age- and sex-matched control subjects (n = 76) using DXA. The TBS of both groups was then compared, and risk factors associated with a low TBS (defined as ≤ 1.31) were evaluated. The mean TBS in the ESKD group was significantly lower than that in the control group (1.34 ± 0.15 vs. 1.43 ± 0.08, respectively; p

Aims: Oxidative stress plays a crucial role in the pathogenesis of diabetic nephropathy (DN). We evaluated whether extracellular superoxide dismutase (EC-SOD) has a renoprotective effect through activation of adenosine monophosphate-activated protein kinase (AMPK) in diabetic kidneys. Results: Human recombinant EC-SOD (hEC-SOD) was administered to 8-week-old male C57BLKS/J db/db mice through intraperitoneal injection once a week for 8 weeks. Renal SOD3 expression was suppressed in db/db mice, which was significantly enhanced by hEC-SOD treatment. hEC-SOD improved albuminuria, mesangial expansion, and interstitial fibrosis in db/db mice. At the molecular level, hEC-SOD increased phosphorylation of AMPK, activation of peroxisome proliferative-activated receptor γ coactivator 1α (PGC-1α), and dephosphorylation of forkhead box O transcription factor (FoxO)1 and FoxO3a. The protective effects of hEC-SOD were attributed to enhanced nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) and subsequently increased expression of NAD(P)H dehydrogenase 1 and heme oxygenase-1. Consequently, hEC-SOD recovered from systemic and renal inflammation and apoptosis, as reflected by the decreases of serum and renal monocyte chemoattractant protein-1 and tumor necrosis factor-α levels and increases of BCL-2/BAX ratio in diabetic kidney. hEC-SOD also improved oxidative stress and resulted in increased renal and urinary 8-hydroxy-2′-deoxyguanosine and 8-isoprostane levels in db/db mice. In cultured human glomerular endothelial cells, hEC-SOD ameliorated apoptosis and oxidative stress caused by high glucose exposure through activation of AMPK and PGC-1α and dephosphorylation of FoxOs. Innovation: These findings demonstrated for the first time that EC-SOD can potentially ameliorate hyperglycemia-induced oxidative stress, apoptosis, and inflammation through activation of AMPK and its downstream pathways in diabetic kidneys. Conclusions: EC-SOD is a potential therapeutic target for treatment of type 2 DN through intrarenal AMPK-PGC-1α-Nrf2 and AMPK-FoxOs signaling. Antioxid. Redox Signal. 28, 1543–1561.

Background: The suppression of tumorigenicity 2 (ST2) is associated with cardiac remodeling and tissue fibrosis. It is well known as a novel biomarker on predictor of cardiovascular events in patients with heart failure. In patients needed to start dialysis treatment, most of them had congestive heart failure. However, the prognostic implications of serum ST2 level are unknown in incident hemodialysis patients. Methods: A total 182 patients undergoing incident hemodialysis were consecutively enrolled from November 2011 to December 2014. These patients were classified into two groups according to their median ST2 levels. The two groups were subsequently compared with respect to their major adverse cerebro-cardiovascular events (MACCE) including all-cause mortality, heart failure admission, acute coronary syndrome, and nonfatal stroke. Results: The median duration of follow up was 628 days (interquartile range 382 to 1,052 days). ST2 was significant correlated with variable echocardiographic parameters. The parameters of diastolic function, deceleration time of the early filing velocity and maximal tricuspid regurgitation velocity were independently associated with the ST2 levels. High ST2 group had significantly higher incidence of all-cause mortality, and MACCE. High ST2 was a significant independent predictor of MACCE (adjusted hazard ratio 2.33, 95% confidence interval 1.12 to 4.87, p=0.024). Conclusion: The ST2 is associated with diastolic function and may be a predictor of clinical outcomes in incident hemodialysis patients.

Studies investigating diabetic nephropathy (DN) have mostly focused on interpreting the pathologic molecular mechanisms of DN, which may provide valuable tools for early diagnosis and prevention of disease onset and progression. Currently, there are few therapeutic drugs for DN, which mainly consist of antihypertensive and antiproteinuric measures that arise from strict renin-angiotensin-aldosterone system inactivation. However, these traditional therapies are suboptimal and there is a clear, unmet need for treatments that offer effective schemes beyond glucose control. The complexity and heterogeneity of the DN entity, along with ambiguous renal endpoints that may deter accurate appraisal of new drug potency, contribute to a worsening of the situation. To address these issues, current research into original therapies to treat DN is focusing on the intrinsic renal pathways that intervene with intracellular signaling of anti-inflammatory, antifibrotic, and metabolic pathways. Mounting evidence in support of the favorable metabolic effects of these novel agents with respect to the renal aspects of DN supports the likelihood of systemic beneficial effects as well. Thus, when translated into clinical use, these novel agents would also address the comorbid factors associated with diabetes, such as obesity and risk of cardiovascular disease. This review will provide a discussion of the promising and effective therapeutic agents for the management of DN.

Background: This study was performed to determine the clinical usefulness of measurement of visceral fat area (VFA) using bioimpedance analysis in relation with left ventricular hypertrophy (LVH), diastolic dysfunction parameters, and decreased estimated glomerular filtration rate (eGFR). Methods: A cross-sectional analysis was performed on 1028 patients with eGFR≥60 ml/min/1.73m2, aged 40 - 64 years, and who underwent routine health check-ups. Subjects were divided into tertiles based on their VFA. Associations of VFA with echocardiographic parameters and eGFR were evaluated. Results: Across the VFA teriltes, there was a significant trend for increasing left ventricular mass index (LVMi), left atrial diameter (LAD), and ratio of early mitral inflow velocity to peak mitral annulus velocity (E/E' ratio) and that for decreasing ratio of early to late mitral inflow peak velocities (E/A ratio) and eGFR. In multivariate linear regression analysis, log-transformed VFA was significantly associated with increased LVMi, LAD, and E/E' ratio, and with decreased E/A ratio and eGFR. After adjustment for body mass index, log-transformed VFA remained as a significant determinant for E/A ratio. Conclusion: VFA may be associated with LV structure and diastolic function, and decreased eGFR in middle-aged adults with normal or mildly impaired renal function.

The prevalence rate and the incidence rate of hemodialysis and functioning kidney transplant recipients have continuously increased; on the contrary, those of peritoneal dialysis have continuously decreased since 2006. Dialysis patients have been getting older and have been maintained on dialysis longer. Diabetic nephropathy was the leading cause of end stage renal disease. The type of hemodialysis vascular access has been stable during the last 5 years (arteriovenous fistulas 76%, arteriovenous grafts 16%, central venous catheters 8% at 2016). Peritoneal dialysis catheter was mostly inserted surgically (67%), and swan neck straight tip peritoneal dialysis catheter was the most commonly used (48%). Vascular access was managed by radiologists and surgeons, and the management was fragmented among them in the past. However, since the nephrologists became interested in and knowledgeable about the vascular access, they began to play roles in vascular access management. Vascular access has been mostly created by vascular surgeons (≈60%); tunneled central venous hemodialysis catheter insertion and endovascular intervention such as percutaneous transluminal angioplasty (PTA) and thrombectomy have been mostly performed by radiologists (≈70%). Tunneled hemodialysis catheter insertion and endovascular intervention by nephrologists have slowly but consistently increased. Recently, the number of central venous hemodialysis catheter insertion has decreased, and tunneled hemodialysis catheter has been inserted more than non-tunneled hemodialysis catheter, indicating that vascular access has been created timely and the vascular access team has been educated about and following international guidelines.

Adiponectin, an adipokine secreted by adipocytes, exerts favorable effects in the milieu of diabetes and metabolic syndrome through its anti-inflammatory, antifibrotic, and antioxidant effects. It mediates fatty acid metabolism by inducing AMP-activated protein kinase (AMPK) phosphorylation and increasing peroxisome proliferative-activated receptor (PPAR)-α expression through adiponectin receptor (AdipoR)1 and AdipoR2, respectively, which in turn activate PPAR gamma coactivator 1 alpha (PGC-1α), increase the phosphorylation of acyl CoA oxidase, and upregulate the uncoupling proteins involved in energy consumption. Moreover, adiponectin potently stimulates ceramidase activity associated with its two receptors and enhances ceramide catabolism and the formation of its anti-apoptotic metabolite, sphingosine 1 phosphate (S1P), independently of AMPK. Low circulating adiponectin levels in obese patients with a risk of insulin resistance, type 2 diabetes, and cardiovascular diseases, and increased adiponectin expression in the state of albuminuria suggest a protective and compensatory role for adiponectin in mitigating further renal injury during the development of overt diabetic kidney disease (DKD). We propose AdipoRon, an orally active synthetic adiponectin receptor agonist as a promising drug for restoration of DKD without inducing systemic adverse effects. Its renoprotective role against lipotoxicity and oxidative stress by enhancing the AMPK/PPARα pathway and ceramidase activity through AdipoRs is revealed here.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, and its pathogenesis is complex and has not yet been fully elucidated. Abnormal glucose and lipid metabolism is key to understanding the pathogenesis of DN, which can develop in both type 1 and type 2 diabetes. A hallmark of this disease is the accumulation of glucose and lipids in renal cells, resulting in oxidative and endoplasmic reticulum stress, intracellular hypoxia, and inflammation, eventually leading to glomerulosclerosis and interstitial fibrosis. There is a growing body of evidence demonstrating that dysregulation of 5′ adenosine monophosphate–activated protein kinase (AMPK), an enzyme that plays a principal role in cell growth and cellular energy homeostasis, in relevant tissues is a key component of the development of metabolic syndrome and type 2 diabetes mellitus; thus, targeting this enzyme may ameliorate some pathologic features of this disease. AMPK regulates the coordination of anabolic processes, with its activation proven to improve glucose and lipid homeostasis in insulin-resistant animal models, as well as demonstrating mitochondrial biogenesis and antitumor activity. In this review, we discuss new findings regarding the role of AMPK in the pathogenesis of DN and offer suggestions for feasible clinical use and future studies of the role of AMPK activators in this disorder.

Decreased AMPK-eNOS bioavailability mediates the development of diabetic peripheral neuropathy (DPN) through increased apoptosis and decreased autophagy activity in relation to oxidative stress. Schwann cells are responsible for maintaining structural and functional integrity of neurons and for repairing damaged nerves. We evaluated the neuro-protective effect of cinacalcet on DPN by activating the AMPK-eNOS pathway using db/db mice and human Schwann cells (HSCs). Sciatic nerve of db/db mice was characterized by disorganized myelin, axonal shrinkage, and degeneration that were accompanied by marked fibrosis, inflammation, and apoptosis. These phenotypical alterations were significantly improved by cinacalcet treatment along with improvement in sensorimotor functional parameters. Cinacalcet demonstrated favorable effects through increased expression and activation of calcium-sensing receptor (CaSR)-CaMKKβ and phosphorylation of AMPK-eNOS signaling in diabetic sciatic nerve. Cinacalcet decreased apoptosis and increased autophagy activity in relation to decreased oxidative stress in HSCs cultured in high-glucose medium as well. This was accompanied by increased expression of the CaSR, intracellular Ca++ ([Ca++]i) levels, and CaMKKβ-LKB1-AMPK signaling pathway, resulting in the net effect of increased eNOS phosphorylation, NOx concentration, Bcl-2/Bax ratio, beclin 1, and LC3-II/LC3-I ratio. These results demonstrated that cinacalcet treatment ameliorates inflammation, apoptosis, and autophagy through increased expression of the CaSR, [Ca++]i levels and subsequent activation of CaMKKβ-LKB-1-AMPK-eNOS pathway in the sciatic nerve and HSCs under diabetic condition. Therefore, cinacalcet may play an important role in the restoration and amelioration of DPN by ameliorating apoptosis and improving autophagy.

Recent studies have demonstrated that chronic inflammation-induced lymphangiogenesis plays a crucial role in the progression of various renal diseases, including diabetic nephropathy. SAR131675 is a selective vascular endothelial cell growth factor receptor-3 (VEGFR-3)-tyrosine kinase inhibitor that acts as a ligand for VEGF-C and VEGF-D to inhibit lymphangiogenesis. In this study, we evaluated the effect of SAR131675 on renal lymphangiogenesis in a mouse model of type 2 diabetes. Male C57BLKS/J db/m and db/db mice were fed either a regular chow diet or a diet containing SAR131675 for 12 weeks from 8 weeks of age. In addition, we studied palmitate-induced lymphangiogenesis in human kidney-2 (HK2) cells and RAW264.7 monocytes/macrophages, which play a major role in lymphangiogenesis in the kidneys. SAR131475 ameliorated dyslipidemia, albuminuria, and lipid accumulation in the kidneys of db/db mice, with no significant changes in glucose and creatinine levels and body weight. Diabetes-induced systemic inflammation as evidenced by increased systemic monocyte chemoattractant protein-1 and tumor necrosis factor-α level was decreased by SAR131475. SAR131475 ameliorated the accumulation of triglycerides and free fatty acids and reduced inflammation in relation to decreased chemokine expression and pro-inflammatory M1 macrophage infiltration in the kidneys. Downregulation of VEGF-C and VEGFR-3 by SAR131475 inhibited lymphatic growth as demonstrated by decreased expression of LYVE-1 and podoplanin that was further accompanied by reduced tubulointerstitial fibrosis, and inflammation in relation to improvement in oxidative stress and apoptosis. Treatment with SAR131475 improved palmitate-induced increase in the expression of VEGF-C, VEGFR-3, and LYVE-1, along with improvement in cytosolic and mitochondrial oxidative stress in RAW264.7 and HK2 cells. Moreover, the enhanced expression of M1 phenotypes in RAW264.7 cells under palmitate stress was reduced by SAR131475 treatment. The results suggest that modulation of lymphatic proliferation in the kidneys is a new treatment approach for type 2 diabetic nephropathy and that SAR131675 is a promising therapy to ameliorate renal damage by reducing lipotoxicity-induced lymphangiogenesis.

Lymphangiogenesis occurs in response to renal injury and is correlated with interstitial fibrosis. Diabetes- and high-fat diet (HFD)-induced intrarenal lipotoxicity and their relationships with lymphangiogenesis are not established. We used PPARα agonist, fenofibrate, to unravel the linkage between lipotoxicity and lymphangiogenesis. Eight-week-old male C57BLKS/J db/db mice and HFD Spontaneously hypertensive rats (SHRs) were fed fenofibrate for 12 weeks. HK-2 and RAW264.7 cells were used to investigate their lymphangiogenic capacity in relation to lipotoxicity. Fenofibrate improved intrarenal lipotoxicity by increasing expression of PPARα and phosphorylation of AMPK. Lymphatic proliferation was attenuated; expression of lymphatic endothelial hyaluronan receptor-1 (LYVE-1), podoplanin, vascular endothelial growth factor-C (VEGF-C), and vascular endothelial growth factor receptor-3 (VEGFR-3) was decreased. In parallel, extent of tubulointerstitial fibrosis, apoptosis and inflammatory cell infiltration was reduced. In HK2 cells, palmitate- and high glucose-induced over expression of lymphatic makers was diminished by fenofibrate via activation of PPARα-AMPK-pACC signaling. Enhanced expression of M1 phenotype in RAW264.7 cells correlated with increased lymphatic growth. A causal relationship between lipotoxicity and lymphatic proliferation with a cellular link to macrophage activation can be speculated; pro-inflammatory M1 type macrophage is involved in the development of lymphangiogenesis through stimulation of VEGF-C and by its transdifferentiation into lymphatic endothelial cells.

BACKGROUND Inflammatory activity of the artery can be assessed by measuring 18F-fluorodeoxyglucose (18F-FDG) uptake with positron emission tomography computed tomography (PET/CT). Improvement in vascular function after renal transplantation has been reported, but no studies have used 18F-FDG PET/CT to examine the changes in vascular inflammation. This study investigated the changes in the inflammatory activity in the carotid artery after renal transplantation in patients with chronic kidney disease (CKD). MATERIAL AND METHODS 18F-FDG PET/CT was performed before and at 4 months after transplantation. We quantified 18F-FDG uptake as the target-to-background ratio (TBR) in the carotid artery in 10 CKD patients. TBR was evaluated in the whole carotid artery (WH) and most-diseased segment (MDS), and the mean and maximum values were analyzed. The concentrations of inflammatory cytokines, including tumor necrosis factor-alpha, interleukin-6, plasminogen activator inhibitor-1, and endothelin-1, were measured. RESULTS Eight patients showed a decrease in mean or maximum TBR. The average mean or maximum TBRs in the WH and MDS of the right and left arteries were all reduced after transplantation. The average mean TBR for the right WH decreased significantly (% reduction [95% CI]) by -5.74% [-15.37, -0.02] (p=0.047). TBRs did not correlate significantly with cytokine concentrations. The changes in cytokine concentrations after transplantation varied. CONCLUSIONS 18F-FDG uptake by the WH and MDS tended to reduce after renal transplantation. Therefore, renal transplantation may confer an anti-inflammatory effect on carotid atherosclerosis in patients with CKD; however, this effect is not large enough to be demonstrated in this study with small sample size.

Apoptosis and autophagy are harmoniously regulated biological processes for maintaining tissue homeostasis. AMP-activated protein kinase (AMPK) functions as a metabolic sensor to coordinate cellular survival and function in various organs, including the kidney. We investigated the renoprotective effects of cinacalcet in high-glucose treated human glomerular endothelial cells (HGECs), murine podocytes and C57BLKS/J-db/db mice. In cultured HGECs and podocytes, cinacalcet decreased oxidative stress and apoptosis and increased autophagy that were attributed to the increment of intracellular Ca2+ concentration and the phosphorylation of Ca2+/calmodulin-dependent protein kinase kinaseβ (CaMKKβ)-Liver kinase B1 (LKB1)-AMPK and their downstream signals including the phosphorylation of endothelial nitric oxide synthase (eNOS) and increases in superoxide dismutases and B cell leukemia/lymphoma 2/BCL-2-associated X protein expression. Interestingly, intracellular chelator BAPTA-AM reversed cinacalcet-induced CaMKKβ elevation and LKB1 phosphorylation. Cinacalcet reduced albuminuria without influencing either blood glucose or Ca2+ concentration and ameliorated diabetes-induced renal damage, which were related to the increased expression of calcium-sensing receptor and the phosphorylation of CaMKKβ-LKB1. Subsequent activation of AMPK was followed by the activation of peroxisome proliferator-activated receptor γ coactivator-1α and phospho-Ser1177eNOS-nitric oxide, resulting in a decrease in apoptosis and oxidative stress as well as an increase in autophagy.Our results suggest that cinacalcet increases intracellular Ca2+ followed by an activation of CaMKKβ-LKB1-AMPK signaling in GECs and podocytes in the kidney, which provides a novel therapeutic means for type 2 diabetic nephropathy by modulation of apoptosis and autophagy.

Background and aims This study evaluated the effects of resveratrol on arterial aging and the renin–angiotensin system (RAS) in mice and vascular smooth muscle cells (VSMCs). Methods Aging mice were divided into control and resveratrol groups. Histological changes, inflammation, oxidative stress, RAS components, and the expression of AMP-activated protein kinase (AMPK), silent information regulator T1 (SIRT1), peroxisome proliferator-activated receptor-γ co-activator 1α (PGC-1α), and anti-oxidative enzymes was measured in thoracic aortas of 24-month-old mice. The effect of resveratrol on fibrosis, cell senescence, and RAS components was also investigated in VSMCs stimulated by angiotensin (Ang) II. Results Aorta media thickness, inflammation, fibrosis, and oxidative stress were significantly lower in the resveratrol group than in the control group. Resveratrol treatment decreased serum Ang II level and the aortic expression of prorenin receptor (PRR) and angiotensin converting enzyme (ACE), and increased serum Ang-(1–7) level and the expression of ACE2, Ang II type 2 receptor (AT2R), and Mas receptor (MasR). Resveratrol increased the expression of phosphorylated AMPK, SIRT1, PGC-1α, phosphorylated endothelial nitric oxide synthase and superoxide dismutase 1 and 2, and decreased that of NADPH oxidase 2 and 4. In Ang II-stimulated VSMCs, resveratrol treatment markedly decreased the number of senescence associated β-galactosidase stained cells and pro-fibrotic protein expression and increased the expression of AT2R and MasR. Conclusions Resveratrol protects against arterial aging and this effect is associated with reduced activity of the PRR–ACE–Ang II axis and stimulation of the ACE2–Ang-(1–7)–ATR2–MasR axis.

Adiponectin exerts renoprotective effects against diabetic nephropathy (DN) by activating the AMP-activated protein kinase (AMPK)/peroxisome proliferative-activated receptor–α (PPARα) pathway through adiponectin receptors (AdipoRs). AdipoRon is an orally active synthetic adiponectin receptor agonist. We investigated the expression of AdipoRs and the associated intracellular pathways in 27 patients with type 2 diabetes and examined the effects of AdipoRon on DN development in male C57BLKS/J db/db mice, glomerular endothelial cells (GECs), and podocytes. The extent of glomerulosclerosis and tubulointerstitial fibrosis correlated with renal function deterioration in human kidneys. Expression of AdipoR1, AdipoR2, and Ca(2+)/calmodulin-dependent protein kinase kinase–β (CaMKKβ) and numbers of phosphorylated liver kinase B1 (LKB1)– and AMPK-positive cells significantly decreased in the glomeruli of early stage human DN. AdipoRon treatment restored diabetes-induced renal alterations in db/db mice. AdipoRon exerted renoprotective effects by directly activating intrarenal AdipoR1 and AdipoR2, which increased CaMKKβ, phosphorylated Ser(431)LKB1, phosphorylated Thr(172)AMPK, and PPARα expression independently of the systemic effects of adiponectin. AdipoRon-induced improvement in diabetes-induced oxidative stress and inhibition of apoptosis in the kidneys ameliorated relevant intracellular pathways associated with lipid accumulation and endothelial dysfunction. In high-glucose–treated human GECs and murine podocytes, AdipoRon increased intracellular Ca(2+) levels that activated a CaMKKβ/phosphorylated Ser(431)LKB1/phosphorylated Thr(172)AMPK/PPARα pathway and downstream signaling, thus decreasing high-glucose–induced oxidative stress and apoptosis and improving endothelial dysfunction. AdipoRon further produced cardioprotective effects through the same pathway demonstrated in the kidney. Our results show that AdipoRon ameliorates GEC and podocyte injury by activating the intracellular Ca(2+)/LKB1-AMPK/PPARα pathway, suggesting its efficacy for treating type 2 diabetes–associated DN.

Background Retinopathy and left ventricular hypertrophy (LVH) are representative markers of microvascular and cardiac dysfunction in patients with chronic kidney disease (CKD). However, their relationship and their combined effects on clinical outcomes are unknown. Methods We included 401 patients with nondialysis-dependent CKD stage 3–5 who had been examined with fundus photography for diabetic or hypertensive retinopathy. The presence of LVH was identified by echocardiography. The clinical significance of retinopathy and LVH was evaluated in terms of the rate of renal function decline and for any cardiovascular event (CVE)/death. Results CKD patients with retinopathy had a higher prevalence of LVH than those without retinopathy (38.9% vs. 27.6%, P =0.017). The presence of retinopathy was independently associated with LVH (odds ratio 1.69, 95% confidence interval [CI] 1.02, 2.80). Compared with subjects without either retinopathy or LVH, the coexistence of retinopathy and LVH was independently associated with rapid renal function decline (β=−3.28; 95% CI −6.52, −0.04), whereas retinopathy or LVH alone were not. Patients with both retinopathy and LVH had a higher risk of CVE/death (adjusted hazard ratio 2.75; 95% CI 1.44, 5.26) than patients with either factor alone. A significant synergistic interaction was observed between retinopathy and LVH to predict CVE/death ( P for interaction=0.049). Conclusions Retinopathy was independently associated with LVH. The coexistence of retinopathy and LVH was associated with higher risks of CKD progression and CVE/death than was either factor alone, and their combined effects synergized to predict the risk of CVE/death.

Organ shortage is a critical issue in Korea as well as in other countries. In Korea, in 2013, the number of end-stage renal disease patients on the waiting list was 14,600; however, only 1,759 patients received transplantation during 2013. Recent advances in immunosuppression and antibody removal protocols have made ABO-incompatible kidney transplantation (ABO IKT) feasible, and have increased the opportunities for patients to undergo transplantation, especially for patients who do not have an ABO-compatible donor. The first ABO IKT was reported in 1955, but was unsuccessful due to the absence of an effective preparation protocol for antibody removal. In the 1980s, Alexandre used a protocol for removal of anti-ABO antibodies for the first time; however, the outcome was still inferior to that of ABO-compatible KT. Since 2000, with the advancement of immunosuppression and plasmapheresis, the outcome of ABO IKT has shown significant improvement and is now comparable to that of ABO-compatible KT. However, there are still several undetermined issues in ABO IKT. For example, issues regarding anti-ABO antibody titer, pretransplant desensitization method, immune suppressant regimen, and the role of C4d have still not been established. In this article, we reviewed the current status and protocol of ABO IKT and addressed to the undetermined issues in this field.

Background/AIMS: We investigated the impact of the baseline anti-A/B antibody titer on the clinical outcome in ABO-incompatible kidney transplantation (IKT). Methods: We included 183 patients who had undergone KT (40 ABO IKT and 143 ABO-compatible KT). Eight patients with a baseline titer of ≥1:512 were assigned to the high-titer group and 32 patients with a baseline titer of ≤1:256 were assigned to the low-titer group. Patients who underwent ABO-compatible KT were used as the control group. We compared the clinical outcomes of the three groups. Results: Before transplantation, the high-titer group displayed more frequent antibody rebound, as shown in a lower titer reduction rate, and more difficulty reaching the target titer (1:16) than the low-titer group. During the postoperative period and out-clinic follow-up, antibody rebound was more frequent, and the rate of acute rejection and infection were significantly higher and allograft function was lower in the high-titer group than in the low-titer and control groups. Multivariate analysis showed that high baseline antibody titer was an independent risk factor for acute rejection. Conclusion: ABO IKT in the high-titer group (baseline titer ≥1:512) required greater caution compared to the low-titer group because of the higher tendency of antibody rebound and the risk for acute rejection.

Background: Nephrotic syndrome (NS) and proteinuria are uncommon, often unrecognized manifestations of graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT). Only a few isolated case reports and case series involving smaller number of patients who developed NS after HSCT have been published. Methods: We reviewed the renal histopathological examination findings and clinical records of 15 patients who developed proteinuria after HSCT at Seoul and Yeouido St. Mary′s Hospital (Seoul, Korea). We also measured the anti-PLA2R antibodies (M-type phospholipase A2 receptor) in the serum samples from the seven patients at the time of renal biopsy. Results: All patients had GVHD. The most common indication for biopsy was proteinuria (>1 g/day), with nine patients having nephrotic range proteinuria. The most common histopathological finding was membranous nephropathy (MN; n = 12). Other findings were membranoproliferative glomerulonephritis, C1q nephropathy, and diabetic nephropathy. Eleven patients were treated with immunosuppressive agents, and three patients were treated only with angiotensin II receptor blocker. The overall response rate, including complete remission (urinary protein level