Trends in clinical outcomes of older hemodialysis patients: data from the 2023 Korean Renal Data System (KORDS).

With an increasing aging population, the mean age of patients with end-stage kidney disease (ESKD) is globally increasing. However, the current clinical status of elderly patients undergoing hemodialysis (HD) is rarely reported in Korea. The current study analyzed the clinical features and trends of older patients undergoing HD from the Korean Renal Data System (KORDS) database. The patients were divided into three groups according to age: <65 years (the young group), n = 50,591 (35.9%); 65-74 years (the younger-old group), n = 37,525 (26.6%); and ≥75 years (the older-old group), n = 52,856 (37.5%). The proportion of older-old group undergoing HD significantly increased in incidence and decreased in prevalence from 2013 to 2022. The median levels of hemoglobin, serum creatinine, albumin, calcium, phosphorus, and intact parathyroid hormone significantly decreased in the older-old group. The proportions of arteriovenous fistula creation and left forearm placement showed decreased trends with age. Although the utilization of low surface area dialyzers increased with age, the dialysis adequacy, including urea reduction ratio and Kt/V was within acceptable range in the older-old group on HD. Over the past 20 years, the mortality rate in the older-old group has increased, with cardiovascular diseases decreasing and infectious diseases increasing. The incidence of elderly patients undergoing HD has increased over time, but the high mortality of the older-old group needs to be solved. Therefore, it is imperative to develop holistic strategies based on age and individual needs for patients with ESKD.

Status and trends in epidemiologic characteristics of diabetic end-stage renal disease: an analysis of the 2021 Korean Renal Data System.

Korean Renal Data System (KORDS) is a nationwide end-stage renal disease (ESRD) registry database operated by the Korean Society of Nephrology (KSN). Diabetes mellitus is currently the leading cause of ESRD in Korea; this article provides an update on the trends and characteristics of diabetic ESRD patients. The KORDS Committee of KSN collects data on dialysis centers and patients through an online registry program. Here, we analyzed the status and trends in characteristics of diabetic chronic kidney disease stage 5D (CKD 5D) patients using data from 2001 to 2021. In 2021, the dialysis adequacy of hemodialysis (HD) was lower in diabetic CKD 5D patients than in nondiabetic CKD 5D patients, while that of peritoneal dialysis (PD) was similar. Diabetic CKD 5D patients had a higher proportion of cardiac and vascular diseases and were more frequently admitted to hospitals than nondiabetic CKD 5D patients, and the leading cause of death was cardiac disease. From 2001 to 2020, diabetic CKD 5D patients had a higher mortality rate than nondiabetic CKD 5D patients, but in 2021 this trend was reversed. Diabetic PD patients had the highest mortality rate over 20 years. The mortality rate of diabetic HD patients was higher than that of nondiabetic HD patients until 2019 but became lower starting in 2020. There was a decreasing trend in mortality rate in diabetic CKD 5D patients, but cardiac and vascular diseases were still prevalent in diabetic CKD 5D patients with frequent admissions to hospitals. More specialized care is needed to improve the clinical outcomes of diabetic CKD 5D patients.

Multi-Organ Relapse following COVID-19 in Myeloperoxidase-Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis: A Case Report.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a complex systemic autoimmune disease characterized by small vessel vasculitis. Typically, the relapse rate is lower in patients with end-stage kidney disease (ESKD) than in those with chronic kidney disease, prior to dialysis. Here, we report a rare case of multi-organ relapse in a patient with myeloperoxidase (MPO)-AAV who underwent hemodialysis following coronavirus disease 2019 (COVID-19). A man in his 70s with type 2 diabetes and hypertension was undergoing maintenance hemodialysis for ESKD resulting from MPO-AAV glomerulonephritis. Following severe acute respiratory syndrome coronavirus 2 infection, the patient was hospitalized for persistent nausea and vomiting. No significant findings were observed, including in endoscopy. However, the patient experienced severe symptoms that hindered oral intake and was refractory to pharmacological therapy. Additionally, despite receiving antibiotics and antituberculosis treatment, the patient experienced persistent unexplained pleural effusion. Moreover, the patient's level of consciousness rapidly deteriorated during hospitalization. Although C-reactive protein levels and MPO-ANCA titers were elevated, no evidence of infection was detected on brain imaging or cerebrospinal fluid analysis. Therefore, we diagnosed this case as a relapse of AAV and promptly administered methylprednisolone pulse therapy and rituximab. Subsequently, all aforementioned symptoms in the patient improved, and the current ANCA levels remain negative. Thus, the relapse of AAV after COVID-19 is rare; however, it can present in several ways in patients undergoing dialysis. Therefore, clinicians should closely monitor ANCA titers and subtle symptoms, even in patients with dialysis-dependent AAV.

The paradoxical effect of aldosterone on cardiovascular outcome in maintenance hemodialysis patients.

BACKGROUND: Patients with end-stage kidney disease face increased risk of cardiovascular events, and left ventricular diastolic dysfunction (LVDD) contributes to the high occurrence of cardiovascular mortality (CM). Although a high serum aldosterone (sALD) level is involved in the development of cardiovascular complications in the general population, this association is unclear in patients undergoing hemodialysis. We aimed to determine the impact of sALD on LVDD and CM among hemodialysis patients (HDPs). METHODS: We performed a prospective cohort study of maintenance HDPs without cardiovascular disease. The patients were divided into two groups according to the median level of sALD. All patients underwent baseline echocardiography to evaluate diastolic dysfunction (E/e' ratio > 15). The LVDD and CM rates were compared between the high and low aldosterone groups. RESULTS: We enrolled a total of 60 adult patients (mean age, 57.9 ± 12.1 years; males, 30.0%). The low aldosterone group had an increased left ventricular diastolic dimension compared with the high aldosterone group (52.2 ± 8.4 mm vs. 50.3 ± 5.2 mm, respectively; p = 0.03). Low log-aldosterone (odds ratio [OR], 0.40; 95% confidence interval [CI], 0.19-0.86) and large left atrial dimension (OR, 1.31; 95% CI, 1.11-1.54) were independent risk factors for LVDD at baseline. In addition, Cox regression analysis demonstrated that low sALD was an independent predictor of CM in HDPs (hazard ratio, 0.46; 95% CI, 0.25-0.85; p = 0.01) during follow-up. CONCLUSION: Low sALD was not only associated with LVDD but was also an independent predictor of CM among HDPs regardless of their interdialytic weight gain.

Changes in duplex ultrasound parameters during maturation according to arteriovenous access types in incident hemodialysis patients.

BACKGROUND: Little is known about the changes in hemodynamic parameters during arteriovenous (AV) access maturation using duplex ultrasound according to radiocephalic fistula (RCF), brachiocephalic fistula (BCF), and AV graft (AVG) in incident hemodialysis (HD) patient. The objective of this study was to evaluate changes and differences in brachial artery flow rate (BAFR) and related parameters affecting maturation by duplex ultrasound in incident HD patients according to access type. METHODS: This study was an observational study conducted from March 2019 to October 2020. During the study period, 109 incident patients underwent new AV access creation, of which 100 were included in the study. The duplex ultrasound was performed on the day prior to access creation, further, day 1, 2 weeks, and 4 weeks later after access creation in incident HD patients. RESULTS: Among all the patients, 38 (38%) received BCF, while 26 (26%) underwent RCF. Of the patients with AVG, 18 (50%) had a forearm loop AVG. The overall mean age was 62.2 ± 13.8 years (range, 32-89). The BAFR increased about 6.9 times in the RCF, 17.4 times in the BCF, and 19.5 times in the AVG at day 1. The median BAFR measured on day 1 was 580.4 mL/min for RC, 1029.0 mL/min for BC, and 1133.0 mL/min for AVG. Relative to the values measured in week 4, the BAFR on day 1 was 69.5% in RCF, 90.6% in BCF, and 93.9% in AVG. The acceleration decreased most significantly on day 1(p < 0.05). The acceleration time increased significantly on day 1 (p < 0.05) and beyond during maturation in the RCF and BCF. The BAFR of the RCF had a significantly negative correlation with the pulsatility index. The BAFR of the BCF showed a significantly positive correlation with the systolic and diastolic blood pressure but negatively correlated with pulse rate. The BAFR of the AVG showed a significant positive correlation with the diameter of the outflow vein. CONCLUSIONS: There were differences in the clinical and duplex parameters during maturation according to access type. The most dramatic changes of duplex parameters were on the day after AV access creation regardless of AV access types. Though RCF had a lower BAFR rate compared to BCF and AVG, it already had a sufficient BAFR required for adequate HD treatment the day after creation. The BAFR of BCF was not different from that of AVG.

Association between copeptin levels and treatment responses to hypertonic saline infusion in patients with symptomatic hyponatremia: a prospective cohort study.

BACKGROUND: Copeptin is secreted in equimolar amounts as arginine vasopressin, main hormone regulating body fluid homeostasis. A recent study reported a copeptin-based classification of osmoregulatory defects in syndromes of inappropriate antidiuresis that may aid in prediction of therapeutic success. We investigated usefulness of copeptin for differentiating etiologies of hyponatremia and predicting efficacy and safety of hypertonic saline treatment in hyponatremic patients. METHODS: We performed a multicenter, prospective cohort study of 100 inpatients with symptomatic hyponatremia (corrected serum sodium [sNa] ≤ 125 mmol/L) treated with hypertonic saline. Copeptin levels were measured at baseline and 24 hours after treatment initiation, and patients were classified as being below or above median of copeptin at baseline or at 24 hours, respectively. Correlations between target, under correction, and overcorrection rates of sNa within 24 hours/24-48 hours and copeptin levels at baseline/24 hours were analyzed. RESULTS: Mean sNa and median copeptin levels were 117.9 and 16.9 pmol/L, respectively. Ratio of copeptin-to-urine sodium allowed for an improved differentiation among some (insufficient effective circulatory volume), but not all hyponatremia etiologic subgroups. Patients with below-median copeptin levels at baseline achieved a higher target correction rate in 6/24 hours (odds ratio [OR], 2.97; p = 0.02/OR, 6.21; p = 0.006). Patients with below-median copeptin levels 24 hours after treatment showed a higher overcorrection rate in next 24 hours (OR, 18.00, p = 0.02). CONCLUSION: There is a limited diagnostic utility of copeptin for differential diagnosis of hyponatremia. However, copeptin might be useful for predicting responses to hypertonic saline treatment in hyponatremic patients.

Clinical significance of central systolic blood pressure in LV diastolic dysfunction and CV mortality.

BACKGROUND AND AIMS: Cardiovascular (CV) disease is the major cause of death in patients with end-stage kidney disease (ESKD). Left ventricular (LV) diastolic dysfunction reflects LV pressure overload and is common in patients with ESKD. Recently, there have been studies on the usefulness of central blood pressure (BP); however, the relationship between central BP and LV diastolic dysfunction is not clear in dialysis patients with preserved systolic function. The purpose of this study was to investigate the clinical implication of central BP on LV diastolic dysfunction and CV mortality in the ESKD patients with preserved LV systolic function. METHODS: This prospective observational cohort study investigated the effect of LV diastolic dysfunction on CV mortality in the ESKD patients with preserved systolic function using echocardiography. Vascular calcification was evaluated using the abdominal aortic calcification score, and aortic stiffness was determined by measuring pulse wave velocity (PWV). The predictors of CV mortality were analyzed using Cox proportional hazard analysis. RESULTS: The subjects were comprised of 61 patients, with an average age of 54 years, 20 males (32.8%), and 25 diabetics (41.0%). There were 39 patients on hemodialysis and 22 patients receiving peritoneal dialysis treatment. During the mean follow-up period of 79.3 months, 16 patients (26.2%) died, and 7 patients (11.4%) died of CV events. The central systolic BP and diabetes were independent risk factors for LV diastolic dysfunction. In addition, patients with LV diastolic dysfunction had an increased CV mortality. When left atrial volume index and PWV were adjusted, the E/E' ratio was found to be a predictor of CV mortality. CONCLUSIONS: Central systolic BP and diabetes were found to be significant risk factors for LV diastolic dysfunction. LV diastolic dysfunction can independently predict CV mortality in dialysis patients with preserved LV systolic function.

Trends in epidemiologic characteristics of end-stage renal disease from 2019 Korean Renal Data System (KORDS).

BACKGROUND: The Korean Society of Nephrology (KSN) has maintained a nationwide end-stage renal disease (ESRD) registry data from Korean Renal Data System (KORDS) since 1985, as the representative registry of ESRD patients in Korea. This review is aimed to update the status of domestic ESRD and to provide evidence on the direction of dialysis therapy. METHODS: The KORDS Committee of KSN has collected data on dialysis centers and patients through an online registry program, and the data from 1986 to 2019 were analyzed. RESULTS: The incidence and prevalence of ESRD patients in Korea are increasing. The ESRD population numbered more than 100,000 in 2019, doubling during the 10 years since 2010. The proportion of diabetes mellitus as a major cause of ESRD seems to have reached a plateau. The increasing number of elderly dialysis patients is a constant trend, with more than half for the proportion of patients older than 65 years old in 2019. All-cause mortality decreased for the last approximately 20 years, regardless of sex, age, and cause of ESRD. The 5-year patient survival rate in both hemodialysis and peritoneal dialysis increased from 2001 to 2013. Since 2013, the patient survival rates in peritoneal dialysis were similar to those in hemodialysis. Cardiovascular complications were the leading cause of death in ESRD patients. CONCLUSIONS: The incidence and prevalence of Korean ESRD patients have increased over time, although patient survival has also steadily increased. The establishment of a surveillance method to address the major cause of mortality in ESRD patients will help improve outcomes.

Comparison of dynamic arterial and venous pressure between metal needles and plastic cannulas in incident hemodialysis patients with arteriovenous graft.

BACKGROUND AND OBJECTS: We hypothesized that plastic cannulae with 17-gauge inner needle compared to 16-gauge metal needles can have stable dynamic venous and arterial pressure maintaining prescribed blood flow safely during a hemodialysis treatment. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: A single-center, prospective, randomized, open-label clinical trial was conducted involving 16 incident hemodialysis patients who had arteriovenous graft placed as their first arteriovenous access. Subjects were randomized to metal needle group (n = 8) versus plastic cannula group (n = 8). We measured serial dynamic pre-pump arterial and venous pressure under five different blood pump flow rates (150, 200, 250, 300, and 350 mL/min). RESULTS: The mean age of patients was 67.6 ± 8.5 (range: 51-81) years, and six patients (37.5%) were male. Patients with plastic cannula showed less negative arterial pre-pump pressures and lower venous pressures than those with metal needles at all prescribed blood flow rates, and the difference was statistically significant (P < 0.001). CONCLUSION: The plastic cannula had more stable arterial and venous pressures at prescribed blood pump flow rates than those pressures of the metal needle in incident patients with arteriovenous graft during hemodialysis.

Custom-made Doppler ultrasound flow simulator for dialysis access using continuous renal replacement therapy machine.

The purpose of this article was to introduce an easy and inexpensive way of making a simulator for training in Doppler ultrasound flow rate measurement using a continuous renal replacement therapy machine and home-made phantoms. A Doppler ultrasound flow simulator was made using a continuous renal replacement therapy machine and vascular phantoms for flow rate assessment of dialysis access with readily accessible components including rubber tube, keyboard cleaning gel, and freeze-dried instant coffee granules. The simulator is an affordable and easy method of Doppler ultrasound flow rate measurement training for dialysis staff using materials readily available in dialysis centers.

Malnutrition, inflammation, progression of vascular calcification and survival: Inter-relationships in hemodialysis patients.

BACKGROUND AND AIMS: Malnutrition and inflammation are closely linked to vascular calcification (VC), the severity of which correlate with adverse outcome. However, there were few studies on the interplay between malnutrition, inflammation and VC progression, rather than VC presence per se. We aimed to determine the relationship of malnutrition, inflammation, abdominal aortic calcification (AAC) progression with survival in hemodialysis (HD) patients. METHODS: Malnutrition and inflammation were defined as low serum albumin (< 40 g/L) and high hs-CRP (≥ 28.57 nmol/L), respectively. We defined AAC progression as an increase in AAC score using lateral lumbar radiography at both baseline and one year later. Patients were followed up to investigate the impact of AAC progression on all-cause and cardiovascular mortality. RESULTS: AAC progressed in 54.6% of 97 patients (mean age 58.2±11.7 years, 41.2% men) at 1-year follow-up. Hypoalbuminemia (Odds ratio 3.296; 95% confidence interval 1.178-9.222), hs-CRP (1.561; 1.038-2.348), low LDL-cholesterol (0.976; 0.955-0.996), and the presence of baseline AAC (10.136; 3.173-32.386) were significant risk factors for AAC progression. During the mean follow-up period of 5.9 years, 38(39.2%) patients died and 27(71.0%) of them died of cardiovascular disease. Multivariate Cox regression analysis adjusted for old age, diabetes, cardiovascular history, and hypoalbuminemia determined that AAC progression was an independent predictor of all-cause mortality (2.294; 1.054-4.994). CONCLUSIONS: Malnutrition and inflammation were significantly associated with AAC progression. AAC progression is more informative than AAC presence at a given time-point as a predictor of all-cause mortality in patients on maintenance HD.

Serum alkaline phosphatase and γ-glutamyl transferase in acute pyelonephritis.

BACKGROUND: Elevated serum alkaline phosphatase (AP) and γ-glutamyl transferase (γ-GT) are commonly observed in patients with acute pyelonephritis. The goal of this study was to examine the clinical significance of elevated serum AP and γ-GT levels and to explore the mechanisms underlying these changes. METHODS: We examined serum AP and γ-GT levels in 438 patients with acute pyelonephritis. Urine AP/creatinine (Cr), urine γ-GT/Cr, fractional excretion of AP, and fractional excretion of γ-GT (FEγ-GT) were evaluated in patients with elevated and normal serum levels. AP isoenzymes were also examined. RESULTS: We identified 77 patients (17.6%) with elevated serum AP and 134 patients (30.6%) with elevated serum γ-GT. Among them, both enzymes were elevated in 64 patients (14.6%). Older age, longer hospital stay, elevated baseline serum Cr, and complicated pyelonephritis were associated with increases in serum AP and γ-GT. Multivariate analysis showed that high serum AP levels were significantly correlated with renal impairment (odds ratio, 2.13; 95% confidence interval, 1.08-4.19; P = 0.029). FEγ-GT was significantly lower in patients with elevated serum enzyme levels. The liver fraction for AP isoenzyme profile did not increase in patients with elevated serum AP. CONCLUSION: Our results demonstrated that elevated serum AP and γ-GT levels are associated with complicated pyelonephritis and renal impairment. Lower FEγ-GT levels in patients with elevated serum enzymes may be the result of decreased urinary excretion of these enzymes.

Anatomical variants of upper arm veins on preoperative mapping venography for hemodialysis access in Korean adults.

INTRODUCTION: The number of elderly patients requiring hemodialysis has increased, along with the need for multiple vascular access placements. Thus, the frequency of access creation using the upper arm veins, including transposed basilic arteriovenous fistula, has also increased. The purpose of this study was to identify the prevalence of anatomical variations in the upper arm veins on preoperative mapping venography and to investigate the implications of such variants on access creation. METHODS: A total of 494 venograms were performed on 251 patients for primary access creation from June 2014 to June 2017 in this single-center, retrospective study. The venograms were classified into eight subtypes, based on the anatomical relationship between the basilic and brachial veins. The presence of bifid cephalic arches and brachial-basilic ladders was also examined. RESULTS: The presence of bifid cephalic arches and brachial-basilic ladders was identified in 8.7% and 14.0% of cases, respectively. Paired brachial veins joined separately with the basilic vein in 67.4% of venograms, whereas these veins merged into a common brachial vein before connecting to the basilic vein in 13.1% of cases. A single brachial vein was present in 19.3% of cases. 15.7% of cases were considered unsuitable for basilic vein transposition due to the early confluence of the brachial-basilic vein, posing a risk of obliterating the deep venous drainage if transposed. CONCLUSION: There are significant anatomical variations of upper arm veins, and the recognition of certain variants can affect surgical planning and outcomes of access placement. It is important to identify anatomical variants of the upper arm veins during preoperative vein mapping.

Current treatment status and medical costs for hemodialysis vascular access based on analysis of the Korean Health Insurance Database.

BACKGROUND/AIMS: The Republic of Korea is a country where the hemodialysis population is growing rapidly. It is believed that the numbers of treatments related to vascular access-related complications are also increasing. This study investigated the current status of treatment and medical expenses for vascular access in Korean patients on hemodialysis. METHODS: This was a descriptive observational study. We inspected the insurance claims of patients with chronic kidney disease who underwent hemodialysis between January 2008 and December 2016. We calculated descriptive statistics of the frequencies and medical expenses of procedures for vascular access. RESULTS: The national medical expenses for access-related treatment were 7.12 billion KRW (equivalent to 6.36 million USD) in 2008, and these expenses increased to 42.12 billion KRW (equivalent to 37.67 million USD) in 2016. The population of hemodialysis patients, the annual frequency of access-related procedures, and the total medical cost for access-related procedures increased by 1.6-, 2.6-, and 5.9-fold, respectively, over the past 9 years. The frequency and costs of access care increased as the number of patients on hemodialysis increased. The increase in vascular access-related costs has largely been driven by increased numbers of percutaneous angioplasty. CONCLUSION: The increasing proportion of medical costs for percutaneous angioplasty represents a challenge in the management of end-stage renal disease in Korea. It is essential to identify the clinical and physiological aspects as well as anatomical abnormalities before planning angioplasty. A timely surgical correction could be a viable option to control the rapid growth of access-related medical expenses.

The relationship between autophagy, increased neutrophil extracellular traps formation and endothelial dysfunction in chronic kidney disease.

In chronic kidney disease (CKD), the number of circulating neutrophils are increased, and this is usually accompanied by an increased basal activation state. However, the possible association between neutrophil extracellular traps (NETs) with vascular complications has not been evaluated. We assessed the relationship between NETs, autophagy and endothelial dysfunction in maintenance hemodialysis (MHD) patients. NET formation, neutrophil elastase (NE) activities, and serum nucleosome levels were measured in MHD (n = 60) and controls (n = 20). Basal NET formation were markedly increased in MHD patient compared to controls. After PMA stimulation, MHD neutrophils showed significantly increased NETs formation response than controls. The degree of NETs was strongly associated with lower flow-mediated dilatation(%) of brachial artery even after adjustment for cardiovascular risk factors and uremic toxins. Moreover, MHD neutrophils showed increased basal autophagy activity. Interestingly, the levels of NETs were markedly augmented after autophagy inhibition, suggesting a protective role of autophagy in excessive NET formation.

Prediction of vascular access stenosis: Blood temperature monitoring with the Twister versus static intra-access pressure ratio.

BACKGROUND: The Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines recommend intra-access flow (Qa) measurement as the preferred vascular access surveillance method over static intra-access pressure ratio (SIAPR). Recently, it has become possible to perform Qa measurement during hemodialysis using thermodilution method called blood temperature monitoring (BTM) with the Twister device. The aim of this study was to investigate the correlation between Qa by BTM and SIAPR and to compare the performance of two tests in prediction of vascular access stenosis. METHODS: The study was performed from January 2016 to November 2017 and included 97 patients with arteriovenous fistulas (AVF). Qa by BTM and SIAPR were simultaneously measured every 1~3 months with a total of 449 measurements during study period. RESULTS: In our study population, mean age was 59.9±10.0 years and 61.9% were diabetes. The mean Qa obtained by BTM was 1186±588 mL/min. There was no correlation between Qa by BTM and venous SIAPR (r = 0.061, P = 0.196). Angiography identified 36 stenotic AVFs (37.1%) among the study subjects. They included 13 cases with only inflow stenosis, 6 with only outflow stenosis, and 17 with stenosis on both sides. Receiver-operating characteristic (ROC) curve analysis showed that Qa by BTM had higher discriminative ability to diagnose vascular access stenosis compared to SIAPR (P <0.001). The Qa less than 583 mL/min showed the highest diagnostic accuracy in vascular stenosis prediction. CONCLUSION: Intradialytic measurement of Qa by BTM showed better diagnostic power over venous SIAPR in prediction of vascular access stenosis.

Adiponectin receptor agonist AdipoRon decreased ceramide, and lipotoxicity, and ameliorated diabetic nephropathy.

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.

Resveratrol increases AdipoR1 and AdipoR2 expression in type 2 diabetic nephropathy.

BACKGROUND: Adiponectin has multiple functions including insulin sensitization, anti-inflammation and antiatherogenesis in various organs. Adiponectin activates 5'-adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor (PPAR)α via the adiponectin receptor (AdipoR) 1 and 2, which are critical for regulating lipids and glucose homeostasis and for controlling oxidative stress. We investigated whether resveratrol can inhibit renal damage in type 2 diabetic db/db mice and the underlying mechanisms of its effects. METHODS: Four groups of male C57 BLKS/J db/m and db/db mice and human glomerular endothelial cells (HGECs) were used. Resveratrol was administered to diabetic and nondiabetic mice by oral gavage for 12 weeks starting at 8 weeks of age. RESULTS: In db/db mice, resveratrol increased serum adiponectin levels and decreased albuminuria, glomerular matrix expansion, inflammation and apoptosis in the glomerulus. Resveratrol increased the phosphorylation of AMPK and silent information regulator T1 (SIRT1), and decreased phosphorylation of downstream effectors class O forkhead box (FoxO)1 and FoxO3a via increasing AdipoR1 and AdipoR2 in the renal cortex. Furthermore, resveratrol increased expression of PPARγ coactivator (PGC)-1α, estrogen-related receptor-1α, and phosphorylated acetyl-CoA carboxylase and decreased sterol regulatory element-binding protein 1. This effect lowered the content of nonesterified fatty acid and triacylglycerol in the kidneys, decreasing apoptosis, oxidative stress and activating endothelial nitric oxide synthase. Resveratrol prevented cultured HGECs from undergoing high-glucose-induced oxidative stress and apoptosis by activating the AMPK-SIRT1-PGC-1α axis and PPARα through increases in AdipoR1 and AdipoR2 expression. CONCLUSIONS: These results suggest that resveratrol prevents diabetic nephropathy by ameliorating lipotoxicity, oxidative stress, apoptosis and endothelial dysfunction via increasing AdipoR1 and AdipoR2 expression.

Leptin, pre-existing vascular disease, and increased arteriovenous fistula maturation failure in dialysis patients.

BACKGROUND: The adipocytokine leptin is an independent cardiovascular risk factor and exerts proatherogenic effect. Pre-existing vascular disease is an important cause of arteriovenous fistula (AVF) maturation failure. We explored the association between serum leptin, pre-existing vascular disease, and AVF maturation failure in incident hemodialysis patients. METHODS: Vein samples from 62 patients were collected at the time of AVF creation. Pre-existing vascular disease was evaluated with histologic changes and immunohistochemical characteristics of cellular phenotypes in intima. AVF maturation failure was defined as an AVF that could not be used successfully by the third month after its creation. RESULTS: The prevalence of body mass index ≥30 kg/m2 was 17%, and AVF maturation failure occurred in 28 (45%) patients. Patients within the highest leptin tertile showed significantly higher maturation failure rate, independent of age, gender, diabetes, and body mass index. On histologic examination, significant differences in intimal hyperplasia (13.3 ± 4.5 vs 18.2 ± 5.2 vs 30.3 ± 14.3 µm) and medial thickening (76.8 ± 23.7 vs 103.9 ± 33.6 vs 109.3 ± 36.5 µm) were observed across leptin tertiles. Similarly, medial fibrosis was most severe in the highest tertile. According to the immunohistochemical staining, most intimal cells were α-smooth muscle actin-positive, vimentin-positive, desmin-negative myofibroblasts. However, in the lowest tertile, desmin-positive contractile smooth muscle cells were also frequently observed, suggesting relatively slow phenotypic changes in this group. Furthermore, as leptin tertiles increased, the expression of leptin receptor in the luminal border of intima was significantly decreased. CONCLUSIONS: Obesity-related higher fistula maturation failure rate may be partly mediated by higher leptin level-associated pre-existing vascular diseases in end-stage renal disease patients. Decreased expression of leptin receptor may be related to this association.