Understanding the Korean Dialysis Cohort for Mineral, Vascular Calcification, and Fracture (ORCHESTRA) Study: Design, Method, and Baseline Characteristics.

INTRODUCTION: End-stage renal disease (ESRD) is a growing disease worldwide, including Korea. This is an important condition that affects patient outcome. To provide optimal management for mineral disturbance, vascular calcification, and bone disease in ESRD patients, the Korean dialysis cohort for mineral, vascular calcification, and fracture (ORCHESTRA) study was conducted by enrolling Korean dialysis patients. METHODS: Sixteen university-affiliated hospitals and one Veterans' Health Service Medical Center participated in this study. This prospective cohort study enrolled approximately 900 consecutive patients on dialysis between May 2019 and January 2021. Enrolled subjects were evaluated at baseline for demographic information, laboratory tests, radiologic imaging, and bone mineral densitometry (BMD) scans. After enrollment, regular assessments of the patients were performed, and their biospecimens were collected according to the study protocol. The primary outcomes were the occurrence of major adverse cardiovascular events, invasive treatment for peripheral artery disease, and osteoporotic fractures. The secondary outcomes were hospitalization for cerebrovascular disease or progression of abdominal aortic calcification. Participants will be assessed for up to 3 years to determine whether primary or secondary outcomes occur. RESULTS: Between May 2019 and January 2021, all participating centers recruited 900 consecutive dialysis patients, including 786 undergoing hemodialysis (HD) and 114 undergoing peritoneal dialysis (PD). The mean age of the subjects was 60.4 ± 12.3 years. Males accounted for 57.7% of the total population. The mean dialysis vintage was 6.1 ± 6.0 years. The HD group was significantly older, had a longer dialysis vintage, and more comorbidities. Overall, the severity of vascular calcification was higher and the level of BMD was lower in the HD group than in the PD group. CONCLUSION: This nationwide, multicenter, prospective cohort study focused on chronic kidney disease-mineral and bone disorder and aimed to provide clinical evidence to establish optimal treatment guidelines for Asian dialysis patients.

L-Carnitine protects against tacrolimus-induced renal injury by attenuating programmed cell death via PI3K/AKT/PTEN signaling.

Reducing immunosuppressant-related complications using conventional drugs is an efficient therapeutic strategy. L-carnitine (LC) has been shown to protect against various types of renal injury. In this study, we investigated the renoprotective effects of LC in a rat model of chronic tacrolimus (TAC) nephropathy. SD rats were injected with TAC (1.5 mg · kg-1 · d-1, sc) for 4 weeks. Renoprotective effects of LC were assessed in terms of renal function, histopathology, oxidative stress, expression of inflammatory and fibrotic cytokines, programmed cell death (pyroptosis, apoptosis, and autophagy), mitochondrial function, and PI3K/AKT/PTEN signaling. Chronic TAC nephropathy was characterized by severe renal dysfunction and typical histological features of chronic nephropathy. At a molecular level, TAC markedly increased the expression of inflammatory and fibrotic cytokines in the kidney, induced oxidative stress, and led to mitochondrial dysfunction and programmed cell death through activation of PI3K/AKT and inhibition of PTEN. Coadministration of LC (200 mg · kg-1 · d-1, ip) caused a prominent improvement in renal function and ameliorated histological changes of kidneys in TAC-treated rats. Furthermore, LC exerted anti-inflammatory and antioxidant effects, prevented mitochondrial dysfunction, and modulated the expression of a series of apoptosis- and autophagy-controlling genes to promote cell survival. Human kidney proximal tubular epithelial cells (HK-2 cells) were treated with TAC (50 µg/mL) in vitro, which induced production of intracellular reactive oxygen species and expression of an array of genes controlling programmed cell death (pyroptosis, apoptosis, and autophagy) through interfering with PI3K/AKT/PTEN signaling. The harmful responses of HK-2 cells to TAC were significantly attenuated by cotreatment with LC and the PI3K inhibitor LY294002 (25 µM). In conclusion, LC treatment protects against chronic TAC nephropathy through interfering the PI3K/AKT/PTEN signaling.

Long-Term Effects of Intensive Low-Salt Diet Education on Deterioration of Glomerular Filtration Rate among Non-Diabetic Hypertensive Patients with Chronic Kidney Disease.

BACKGROUND: Diet modification, especially a decrease in salt intake, might be an important non-pharmacological strategy to improve chronic kidney disease (CKD) prognosis. OBJECTIVES: We conducted a prospective cohort study to investigate whether an intensive low-salt diet education program effectively attenuated the rate of renal function decline in hypertensive patients with CKD. METHODS: This cohort study recruited 171 participants from a previous open-labelled, case-controlled, randomized clinical trial that originally consisted of 245 hypertensive CKD patients who were assigned to two groups, intensive low-salt diet or conventional education. We evaluated the renal outcomes, which included the rate of change in estimated glomerular filtration rate (eGFR) per year, the increase in serum creatinine ≥50%, the decrease in eGFR ≥30%, and the percent change in albuminuria throughout the entire study period. RESULTS: The baseline characteristics of the cohort participants between the two groups were similar at the time of trial phase randomization. During the whole study period, the rate of renal function decline was significantly faster in the conventional group (0.11 ± 4.63 vs. -1.53 ± 3.04 mL/min/1.73 m2/year, p = 0.01). The percent of incremental change in serum creatinine ≥50% was 1.1% in the intensive group and 8.2% in the conventional group (p = 0.025), and the percent of decremental change in eGFR ≥30% was 3.3% in the intensive group and 11.1% in the conventional group (p= 0.048). With logistic regression analysis adjusted for related factors, we found that the conventional group showed a higher risk for deterioration in serum creatinine and eGFR during the entire study period. Especially, we found that the intensive education program preserved eGFR in participants with one, several, or all of the following characteristics at the time of randomization: older age, female, obese, had higher protein intake, higher amounts of albuminuria, higher salt intake. CONCLUSION: This cohort study demonstrated that an intensive low-salt diet education program attenuated the rate of renal function decline in hypertensive CKD patients independent of its effect on lowering salt intake or albuminuria during the 36 months of follow-up.

Impact of acute kidney injury in expanded criteria deceased donors on post-transplant clinical outcomes: multicenter cohort study.

BACKGROUND: The problem of organ shortage is an important issue in kidney transplantation, but the effect of kidney donation on AKI is unclear. The aim of this study was to investigate the impact of acute kidney injury (AKI) on post-transplant clinical outcomes for deceased donor kidney transplantation (DDKT) using standard criteria donors (SCDs) versus expanded criteria donors (ECDs). METHODS: Five-hundred nine KT recipients receiving kidneys from 386 deceased donors (DDs) were included from three transplant centers. Recipients were classified into the SCD-KT or ECD-KT group according to corresponding DDs and both groups were divided into the AKI-KT or non-AKI-KT subgroups according to AKI in donor. We compared the clinical outcomes among those four groups and investigated the interaction between AKI in donors and ECD on allograft outcome. RESULTS: The incidence of delayed allograft function was higher when the donors had AKI within SCD-KT and ECD-KT groups. In allograft biopsies within 3 months, chronic change was more significant in the AKI-ECD-KT subgroup than in the non-AKI-ECD-KT subgroup, but it did not differ between AKI-SCD-KT and non-AKI-SCD-KT group. AKI-ECD-KT showed higher risk for death-censored allograft failure than the other three groups and a significant interaction was observed between AKI in donors and ECD on the allograft outcome. CONCLUSIONS: The presence of AKI in ECDs significantly impacted the long-term allograft outcomes of kidney transplant recipients, but it did not in SCDs.

The Adiponectin Receptor Agonist AdipoRon Ameliorates Diabetic Nephropathy in a Model of Type 2 Diabetes.

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 Ca2+/calmodulin-dependent protein kinase kinase-ß (CaMKKß) 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 CaMKKß, phosphorylated Ser431LKB1, phosphorylated Thr172AMPK, 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 Ca2+ levels that activated a CaMKKß/phosphorylated Ser431LKB1/phosphorylated Thr172AMPK/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 Ca2+/LKB1-AMPK/PPARα pathway, suggesting its efficacy for treating type 2 diabetes-associated DN.

Prediction of clinical outcomes after kidney transplantation from deceased donors with acute kidney injury: a comparison of the KDIGO and AKIN criteria.

BACKGROUND: Acute kidney injury (AKI) is frequently detected in deceased donors (DDs), and it could be associated with adverse clinical outcomes in corresponding kidney transplant recipients (KTRs). In this regard, we sought to identify which criteria is better between the KDIGO and AKIN criteria for the diagnosis of AKI in DDs in the prediction of clinical outcomes after kidney transplantation (KT). METHODS: Two hundred eighty-five cases of deceased donor kidney transplantation (DDKT) were included. We divided them into three groups; the non-AKI by both KDIGO and AKIN criteria group (n = 120), the AKI by KDIGO only group (n = 61), and the AKI by both criteria group (n = 104) according to the diagnosis of AKI using the KDIGO and AKIN criteria in the corresponding 205 DDs. We compared the development of delayed graft function (DGF), the change in allograft function, the allograft survival among the three groups. RESULTS: The incidence of DGF was significantly higher in the AKI by KDIGO only and the AKI by both criteria groups than in the non-AKI by both criteria group (P < 0.05 each). But no difference was detected between the AKI by KDIGO only group and the AKI by both criteria group (P > 0.05). Therefore, the KDIGO criteria had a better predictive value for DGF occurrence than the AKIN criteria (Area under the curve = 0.72 versus 0.63, P < 0.05) in Receiver Operation Characteristic analysis. On comparison of allograft function, the AKI by KDIGO only and the AKI by both criteria groups showed a significantly deteriorating pattern by 6 months after KT in comparison with the non-AKI by both criteria group (P < 0.05). However, the differences disappeared at 1 year from KT and long-term allograft survival did not differ among the three groups. AKI stage either by KDIGO or AKIN in DDs did not affect long-term allograft survival in corresponding KTRs as well. CONCLUSIONS: The KDIGO criteria may be more useful for predicting DGF than the AKIN criteria. However, AKI or AKI stage by either criteria in DDs failed to affect long-term allograft outcomes in KTRs.

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.

Comparison of Outcomes with Arteriovenous Fistula and Arteriovenous Graft for Vascular Access in Hemodialysis: A Prospective Cohort Study.

BACKGROUND: Poor vessel quality and limited life expectancy in the elderly may make arteriovenous fistula (AVF) less ideal than arteriovenous graft (AVG) or catheter for vascular access (VA) in hemodialysis (HD). METHODS: A total of 946 adult incident HD patients from clinical research center registry for end-stage renal disease prospective cohort in South Korea were analyzed for outcomes with AVF and AVG. RESULTS: Overall, AVF was associated with better patient survival only in male (p < 0.001) and diabetic (p = 0.004) patients, although it was superior to AVG in access patency, regardless of diabetes mellitus status and gender. AVG (vs. AVF; hazard ratio (HR) 2.282; 95% CI 1.071-4.861; p = 0.032) was associated with poor patient survival. In elderly patients (≥65 years), AVF was associated with survival benefit only in male (p < 0.001) and diabetic (p = 0.04) patients, and with better access patency only in female (p = 0.05) and diabetic (p = 0.04) patients. AVG (vs. AVF; HR 3.158; 95% CI 1.080-9.238; p = 0.036) was associated with poor patient survival. In septuagenarian patients, AVF was associated only with survival benefit (p = 0.01) and there was no advantage in access patency (p = 0.12). However, AVF was superior to AVG in both access patency (p = 0.001) and patient survival (p = 0.03) even with propensity matching. CONCLUSION: AVF is the more desirable VA and its survival benefits warrant its consideration in septuagenarian patients although a prolonged life expectancy is essential to realize the potential benefits of AVF.

Acute kidney injury induced by thrombotic microangiopathy in a patient with hemophagocytic lymphohistiocytosis.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a fatal clinical syndrome characterized by excessive immune activation and inflammation. It is frequently complicated by acute kidney injury (AKI) that often develops as acute tubular necrosis (ATN). Meanwhile, renal thrombotic microangiopathy (TMA) is a rare pathologic finding that mostly occurs in hemolytic uremic syndrome or thrombotic thrombocytopenic purpura. There are only few reports on TMA developing in patients with HLH. We present here a rare case of TMA associated HLH. CASE PRESENTATION: A 60-year-old woman was admitted for a fever of unknown origin that had persisted for several weeks. She presented with AKI and pancytopenia. Clinical, laboratory and bone marrow biopsy findings met the criteria of HLH. Kidney biopsy showed TMA and minimal ATN, which suggested that the primary cause of AKI was TMA in this case. Because of sustained oliguria, we initiated hemodialysis (HD) and also decided to use chemotherapy composed of dexamethasone, etoposide and cyclosporine for treatment of HLH. Six months after the initiation of chemotherapy, pancytopenia was completely resolved, indicating the resolution of HLH. At the same time, serum creatinine decreased to a normal range without the need for HD, suggesting the resolution of TMA. CONCLUSION: We report a case of renal TMA associated HLH. This case suggests that renal TMA should be considered as a primary cause of AKI in patients with underlying HLH.

Anthocyanin-rich Seoritae extract ameliorates renal lipotoxicity via activation of AMP-activated protein kinase in diabetic mice.

BACKGROUND: Anthocyanins are major constituents of food colours and have been reported to possess anti-diabetic activities for potential medicinal use. The precise role of anthocyanins in diabetic nephropathy is poorly understood. We investigated whether anthocyanin-rich Seoritae extract (SE) can potentially prevent oxidative stress and lipotoxicity, which are the main causes of renal damage in diabetic nephropathy, via activation of AMP-activated protein kinase (AMPK) and the consequent effects on its target molecules. METHODS: Four groups of male C57BLKS/J db/m and db/db mice were used. Diabetic and non-diabetic mice were orally administered 10 mg/kg body weight SE daily for 12 weeks, starting at 8 weeks of age. RESULTS: db/db mice treated with anthocyanins showed decreased albuminuria. Anthocyanins ameliorated intra-renal lipid concentrations in db/db mice with improvement of glomerular matrix expansion and inflammation, which was related to increased phosphorylation of AMPK and activation of peroxisome proliferator-activated receptor (PPAR) α and PPARγ, and inhibited the activity of acetyl-CoA carboxylase and sterol regulatory element-binding protein 1. Anthocyanins reversed diabetes-induced increases in renal apoptosis and oxidative stress. In cultured human glomerular endothelial cells, anthocyanins prevented high glucose-induced oxidative stress and apoptosis through activation of AMPK in the same manner. CONCLUSIONS: The results revealed that anthocyanins ameliorated diabetic nephropathy in db/db mice via phosphorylation of AMPK, the major energy-sensing enzyme, and the consequent effects on its target molecules, which appeared to prevent lipotoxicity-related apoptosis and oxidative stress in the kidney.

Risk factors for postoperative bleeding in ABO-incompatible kidney transplantation.

INTRODUCTION: The outcome of ABO-incompatible kidney transplantation (ABOi KT) has improved and is now comparable to that of ABO-compatible kidney transplantation (ABOc KT). However, ABOi KT may be associated with a higher risk of postoperative bleeding than ABOc KT. METHODS: Seventy patients with ABOi KT were divided into a bleeding group (n = 9) and non-bleeding group (n = 61). General, immunologic, and hematological characteristics were compared to identify the risk factors for postoperative bleeding. RESULTS: Pre-emptive transplantation and a high pre-transplant blood urea nitrogen level were more common in the bleeding group (p = 0.0176 and 0.023, respectively). A high anti-ABO antibody titer after plasmapheresis (median, ≥16; p = 0.0226), a low platelet count of ≤100 000/mm(3) after plasmapheresis (p = 0.0289), a prolonged activated partial thromboplastin time (p = 0.0073), and impaired platelet function (p = 0.0274) were associated with an increased risk of bleeding after ABOi KT. CONCLUSION: Postoperative bleeding after ABOi KT was difficult to control and increased the risk of immediate graft loss (p = 0.015). Our results suggest that changes in coagulability associated with uremia and plasmapheresis may increase the risk of bleeding after ABOi KT.

Fimasartan, a Novel Angiotensin-Receptor Blocker, Protects against Renal Inflammation and Fibrosis in Mice with Unilateral Ureteral Obstruction: the Possible Role of Nrf2.

OBJECTIVES: A newly developed angiotensin II receptor blocker, fimasartan, is effective in lowering blood pressure through its action on the renin-angiotensin system. Renal interstitial fibrosis, believed to be due to oxidative injury, is an end-stage process in the progression of chronic kidney disease. Nuclear factor erythroid 2-related factor 2 (Nrf2) is known to regulate cellular oxidative stress and induce expression of antioxidant genes. In this study we investigated the role of Nrf2 in fimasartan-mediated antioxidant effects in mice with renal fibrosis induced by unilateral ureteral obstruction (UUO). MATERIALS AND METHODS: UUO was induced surgically in mice, followed by either no treatment with fimasartan or the intraperitoneal administration of fimasartan (3 mg/kg/day). On day 7, we evaluated the changes in the renin-angiotensin system (RAS) and the expression of Nrf2 and its downstream antioxidant genes, as well as renal inflammation, apoptosis, and fibrosis in the obstructed kidneys. The effect of fimasartan on the Nrf2 pathway was also investigated in HK-2 cells stimulated by tumor necrosis factor-α. RESULTS: The mice with surgically induced UUO showed increased renal inflammation and fibrosis as evidenced by histopathologic findings and total collagen content in the kidney. These effects were attenuated in the obstructed kidneys of the fimasartan-treated mice. Fimasartan treatment inhibited RAS activation and the expression of Nox1, Nox2, and Nox4. In contrast, fimasartan upregulated the renal expression of Nrf2 and its downstream signaling molecules (such as NQO1; HO-1; GSTa2 and GSTm3). Furthermore, it increased the expression of antioxidant enzymes, including CuSOD, MnSOD, and catalase. The fimasartan-treated mice had significantly less apoptosis on TUNEL staining, with decreased levels of pro-apoptotic protein and increased levels of anti-apoptotic protein. In the HK-2 cells, fimasartan treatment inhibited RAS activation, decreased expression of mitogen-activated protein kinases (MAPKs), and upregulated the Nrf2 pathway. CONCLUSIONS: These results suggest that fimasartan has beneficial effects in reducing renal oxidative stress, inflammation, and fibrosis. Possible mechanisms to explain these effects are inhibition of RAS and MAPKs and upregulation of Nrf2 signaling, with subsequent induction of antioxidant pathways.

Assessment of tubular reabsorption of phosphate as a surrogate marker for phosphate regulation in chronic kidney disease.

BACKGROUND/AIMS: Fibroblast growth factor 23 (FGF23) and soluble α-Klotho are emerging potential biomarkers of phosphorus and vitamin D metabolism which change in concentration in early chronic kidney disease (CKD) in order to maintain normal phosphorus levels. Tubular reabsorption of phosphate (TRP) has been commonly used to assess renal tubular phosphate transport. The aim of this study was to evaluate the usefulness of TRP as a surrogate marker of parameters of CKD-mineral bone disease (CKD-MBD) in CKD. METHODS: A cross-sectional study was performed in 93 stable patients with predialysis CKD stage 1-5. In all patients, TRP, estimated glomerular filtration rate (eGFR), calcium, phosphate, intact parathyroid hormone (iPTH), 25-hydroxyvitamin D, serum FGF23 and urine soluble α-Klotho levels were measured. RESULTS: As renal function declined, TRP significantly decreased (P < 0.001; r = 0.763) and both iPTH and serum FGF23 increased (P < 0.001; r = -0.598, P < 0.001; r = -0.453, respectively). The prevalence of hyperphosphatemia, secondary hyperparathyroidism, FGF23 excess and abnormal TRP increased progressively with declining eGFR. Although TRP level changed later than FGF23, abnormal levels of both TRP and FGF23 were observed earlier than changes in iPTH and serum phosphate. Decreased TRP was found to be independently associated with decreased eGFR and increased iPTH but was not associated with urine soluble α-Klotho or serum FGF23 level in multiple linear regression analysis. CONCLUSION: TRP is a simple, useful and cost-saving surrogate marker of the assessment of altered mineral metabolism in CKD patients and can be used as an alternative to serum FGF23, especially for mild to moderate renal insufficiency.

Urinary adiponectin and albuminuria in non-diabetic hypertensive patients: an analysis of the ESPECIAL trial.

BACKGROUND: Although adiponectin levels have been reported to be correlated with albuminuria, this issue remains unresolved in non-diabetic hypertensive subjects, particularly when urinary adiponectin is considered. METHODS: Urinary adiponectin levels were examined using an enzyme-linked immunosorbent assay in 229 participants. who used olmesartan as a hypertensive agent. Their albuminuria levels were measured for 16 weeks after randomization and initiation of conventional or intensive diet education. Linear or logistic regression models were applied, as appropriate, to explore the relationship with albuminuria itself or its response after the intervention. RESULTS: Urinary adiponectin levels were positively related to baseline albuminuria level (r = 0.529). After adjusting for several covariates, the adiponectin level was associated with the albuminuria level (ß = 0.446). Among the 159 subjects with baseline macroalbuminuria, the risk of consistent macroalbuminuria (> 300 mg/day) at 16 weeks was higher in the 3(rd) tertile of adiponectin than in the 1(st) tertile (odds ratio = 6.9), despite diet education. In contrast, among all subjects, the frequency of the normoalbuminuria achievement (< 30 mg/day) at 16 weeks was higher in the 1(st) tertile than in the 3(rd) tertile (odds ratio = 13.0). CONCLUSIONS: Urinary adiponectin may be a useful biomarker for albuminuria or its response after treatment in non-diabetic hypertensive patients.

Delayed treatment with oleanolic acid attenuates tubulointerstitial fibrosis in chronic cyclosporine nephropathy through Nrf2/HO-1 signaling.

BACKGROUND: Nuclear factor erythroid-2-related factor-2 (Nrf2) is known to protect against tissue injury by orchestrating antioxidant and detoxification responses to oxidative stress. This study investigated whether upregulation of Nrf2-dependent signaling by oleanolic acid (OA), which is known to activate Nrf2, could attenuate renal inflammation and fibrosis in cyclosporine (CsA)-induced kidney injury. METHODS: Male ICR mice were divided into four treatment groups: Vehicle (VH, n = 6), VH + OA (n = 6), CsA (n = 8), and CsA + OA (n = 8). For the OA-treated groups, OA (25 mg/kg/day) was administered by intraperitoneal injection for the final week of the 4-week experimental period. Renal function, morphologies and signaling were evaluated at the end of the study. RESULTS: Treatment with CsA resulted in decreased kidney function and urine osmolality and increased urine volume and urinary albumin levels. The CsA-induced changes were improved by OA treatment. Specifically, administration of OA decreased tubulointerstitial fibrosis and inflammation scores that were increased in CsA-treated mice. Furthermore, OA treatment decreased urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-epi-prostaglandin F2α (8-iso-PGF2α) levels. The beneficial effects of OA were attributed to an increased ratio of nuclear/total Nrf2 and subsequently enhanced expression of heme oxygenase (HO)-1, as well as a stable level of Kelch-like ECH-associated protein 1 (Keap1) expression, indicating that OA enhanced nuclear translocation of Nrf2. Increased apoptotic cell death and a high ratio of B cell leukaemia/lymphoma 2 (Bcl-2)-associated X protein (Bax) to Bcl-2 in CsA-treated mice were also significantly ameliorated by OA treatment. CONCLUSION: Our results suggest that OA activates Nrf2/HO-1 signaling in chronic CsA nephropathy, which may have beneficial effects on inflammation and oxidative stress.

Clinical impact of the baseline donor-specific anti-human leukocyte antigen antibody measured by Luminex single antigen assay in living donor kidney transplant recipients after desensitization therapy.

The aim of this study is to investigate the clinical impact of donor-specific anti-HLA-antibody (HLA-DSA) baseline levels, measured using the Luminex single antigen assay (LSA), in living donor kidney transplantation (LDKT). Total 129 cases of LDKT were divided into four groups according to baseline mean fluorescence intensity (MFI) HLA-DSA values: Strong (n = 6), >10,000; Moderate (n = 8), 5,000-10,000; Weak (n = 11), 1,000-5,000, Negative (n = 104), <1,000. Pretransplant desensitization (DSZ) was performed to decrease the MFI to weak or negative values before KT. Clinical outcomes in the four groups were compared. After DSZ, HLA-DSA decreased to weak or negative levels in all patients; Acute rejections developed more frequently in strong group [5/6 (83.3%)] compared with other three groups (P < 0.05), and especially acute antibody-mediated rejection (AAMR) developed almost exclusively in strong group [4/6 (66.7%)]. Strong HLA-DSA levels at baseline were more predictive of AAMR than either type of XM (complement-dependent lymphocytotoxicity or flow cytometry) in ROC analysis. Allograft function in this group showed significant deterioration during follow-up compared with the other groups. In conclusion, strong HLA-DSA levels at baseline are associated with worse allograft outcome even after successful desensitization; therefore, strict monitoring and strong maintenance immunosuppression may be required in such patients.

A low-salt diet increases the estimated net endogenous acid production in nondiabetic chronic kidney disease patients treated with angiotensin receptor blockade.

BACKGROUND/AIMS: An acid-base imbalance precedes renal disease progression in patients with chronic kidney disease (CKD). Little is known about the effects of a low-salt diet (LSD) on net endogenous acid production (NEAP) levels in CKD patients using angiotensin receptor blockade. METHODS: We enrolled a total of 202 nondiabetic CKD patients who underwent an 8-week treatment with olmesartan from the original trial [Effects of Low Sodium Intake on the Antiproteinuric Efficacy of Olmesartan in Hypertensive Patients with Albuminuria (ESPECIAL) trial: NCT01552954]. The patients were divided into good- and poor-LSD-compliance groups. RESULTS: During the interventional 8 weeks, the NEAP in the good-compliance group increased compared to the control group (12.9 ± 32.0 vs. -2.0 ± 35.0 mmol/day, p = 0.002). NEAP was positively associated with the good-LSD-compliance group in the fully adjusted analyses (r = 0.135, p = 0.016). The additional reduction of 2.39 g/day of protein intake with a reduction of 1 g/day of salt intake did not increase the NEAP under angiotensin II receptor blockade (ARB) treatment with an LSD (r = 0.546, p < 0.001). CONCLUSION: We found that an LSD may increase the NEAP in nondiabetic CKD patients using ARB, which suggests that additional acid producing-protein restriction should be required to prevent the NEAP from rising.

Urinary sodium excretion has positive correlation with activation of urinary renin angiotensin system and reactive oxygen species in hypertensive chronic kidney disease.

It is not well described the pathophysiology of renal injuries caused by a high salt intake in humans. The authors analyzed the relationship between the 24-hr urine sodium-to-creatinine ratio (24HUna/cr) and renal injury parameters such as urine angiotensinogen (uAGT/cr), monocyte chemoattractant peptide-1 (uMCP1/cr), and malondialdehyde-to-creatinine ratio (uMDA/cr) by using the data derived from 226 hypertensive chronic kidney disease patients. At baseline, the 24HUna/cr group or levels had a positive correlation with uAGT/cr and uMDA/cr adjusted for related factors (P<0.001 for each analysis). When we estimated uAGT/cr in the 24HUna/cr groups by ANCOVA, the uAGT/cr in patients with ≥200 mEq/g cr was higher than in patients with <100 mEq/g cr (708 [95% CI, 448-967] vs. 334 [95% CI, 184-483] pg/mg cr, P=0.014). Similarly, uMDA/cr was estimated as 0.17 (95% CI, 0.14-0.21) pM/mg cr in patients with <100 mEq/g cr and 0.27 (95% CI, 0.20-0.33) pM/mg cr in patients with ≥200 mEq/g cr (P=0.016). During the 16-week follow-up period, an increase in urinary sodium excretion predicted an increase in urinary angiotensinogen excretion. In conclusion, high salt intake increases renal renin-angiotensin-system (RAS) activation, primarily, and directly or indirectly affects the production of reactive oxygen species through renal RAS activation.

Benefits of a continuous ambulatory peritoneal dialysis (CAPD) technique with one icodextrin-containing and two biocompatible glucose-containing dialysates for preservation of residual renal function and biocompatibility in incident CAPD patients.

In a prospective randomized controlled study, the efficacy and safety of a continuous ambulatory peritoneal dialysis (CAPD) technique has been evaluated using one icodextrin-containing and two glucose-containing dialysates a day. Eighty incident CAPD patients were randomized to two groups; GLU group continuously using four glucose-containing dialysates (n=39) and ICO group using one icodextrin-containing and two glucose-containing dialysates (n=41). Variables related to residual renal function (RRF), metabolic and fluid control, dialysis adequacy, and dialysate effluent cancer antigen 125 (CA125) and interleukin 6 (IL-6) levels were measured. The GLU group showed a significant decrease in mean renal urea and creatinine clearance (-Δ1.2 ± 2.9 mL/min/1.73 m(2), P=0.027) and urine volume (-Δ363.6 ± 543.0 mL/day, P=0.001) during 12 months, but the ICO group did not (-Δ0.5 ± 2.7 mL/min/1.73 m(2), P=0.266; -Δ108.6 ± 543.3 mL/day, P=0.246). Peritoneal glucose absorption and dialysate calorie load were significantly lower in the ICO group than the GLU group. The dialysate CA125 and IL-6 levels were significantly higher in the ICO group than the GLU group. Dialysis adequacy, ß2-microglobulin clearance and blood pressure did not differ between the two groups. The CAPD technique using one icodextrin-containing and two glucose-containing dialysates tends to better preserve RRF and is more biocompatible, with similar dialysis adequacy compared to that using four glucose-containing dialysates in incident CAPD patients. [Clincal Trial Registry, ISRCTN23727549].