Jai Won Chang

AMP-activated protein kinase inhibits TGF-β-, angiotensin II-, aldosterone-, high glucose-, and albumin-induced epithelial-mesenchymal transition.

The epithelial-mesenchymal transition (EMT) is a novel mechanism that promotes renal fibrosis. Transforming growth factor-β (TGF-β), angiotensin II, aldosterone, high glucose, and urinary albumin are well-known causes of EMT and renal fibrosis. We examined whether and how activation of AMP-activated protein kinase (AMPK) suppressed EMT induced by the above agents in tubular epithelial cells. All experiments were performed using HK-2 cells. Protein expression was measured by Western blot analysis. Intracellular reactive oxygen species (ROS) were analyzed by flow cytometry. Exposure of tubular cells to TGF-β (10 ng/ml), angiotensin II (1 μM), aldosterone (100 nM), high glucose (30 mM), and albumin (5 mg/ml) for 5 days induced EMT, as shown by upregulation of α-smooth muscle actin and downregulation of E-cadherin. ROS and NADPH oxidase 4 (Nox4) expression were increased, and antioxidants such as tiron and N-acetylcysteine inhibited EMT induction. Metformin (the best known clinical activator of AMPK) suppressed EMT induction through inhibition of ROS via induction of heme oxygenase-1 and endogenous antioxidant thioredoxin. An AMPK inhibitor (compound C) and AMPK small interfering RNA blocked the effect of metformin, and another AMPK activator [5-aminoimidazole-4-carboxamide-1β riboside (AICAR)] exerted the same effects as metformin. In conclusion, AMPK activation might be beneficial in attenuating the tubulointerstitial fibrosis induced by TGF-β, angiotensin II, aldosterone, high glucose, and urinary albumin.

Usefulness of Segmental Bioimpedance Ratio to Determine Dry Body Weight in New Hemodialysis Patients: A Pilot Study

Background: The ratio of bioimpedance in the right leg (rl-RBI) may be helpful in adjusting dry body weight (DBW) in new hemodialysis (HD) patients. Methods: rl-RBI was calculated as follows: rl-RBI = impedance at 50 kHz/impedance at 500 kHz, as measured by bioimpedance spectroscopy (BIS). Theoretically, rl-RBI is inversely related to extracellular water. A reference range of rl-RBI was obtained from 137 chronic but stable HD patients already achieving DBW. In 34 new HD patients (females:males = 16:18; age 49 ± 12 years), DBW(s) were stepwise adjusted under the guidance of rl-RBI by modifying the amount of ultrafiltration. Results: The target range of rl-RBI was defined as 1.106–1.150. rl-RBI before the first HD was 1.115 ± 0.027. At the study endpoint, when the target range of rl-RBI was achieved, pretibial pitting edema and pulmonary edema were resolved without any episode of muscle cramping or intradialytic hypotension. Along with an increase in rl-RBI, pre-HD blood pressure tended to decrease at systole (p = 0.072) and diastole (p = 0.005). The cardiothoracic ratio also decreased significantly (p = 0.004). Conclusion: The measurement of rl-RBI by BIS is worthy of further evaluation as an objective and applicable index for determining DBW in new HD patients.

C-Reactive Protein Induces NF-κB Activation through Intracellular Calcium and ROS in Human Mesangial Cells

Background: C-reactive protein (CRP) is known to have a direct proinflammatory effect in endothelial cells. However, little is known about the effect of CRP in intrinsic renal cells. We investigated the effects of CRP on the nuclear factor-ĸB (NF-ĸB) activation and monocyte chemoattractant protein-1 (MCP-1) gene expression in human mesangial cells and also examined whether intracellular calcium and reactive oxygen species (ROS) were involved in the CRP- induced NF-ĸB activation. Methods: NF-ĸB binding activity and MCP-1 mRNA expression were measured by electrophoretic mobility shift assay and Northern blot analysis, respectively.Intracellular calcium was monitored by confocal microscopy using calcium sensitive dye, Fluo-3 and intracellular ROS production was determined, using 2′,7′-dichlorofluorescin diacetate. Results: CRP increased NF-ĸB binding activity in a dose-dependent manner (12.5–100 µg/ml), which was induced within 1 h after incubation and peaked around 3 h. CRP also increased the MCP-1 mRNA expression via activation of NF-ĸB. Both intracellular calcium and ROS was induced by CRP. Calcium chelator, BAPTA-AM and anti-oxidants such as N-acetylcysteine and tiron suppressed CRP-induced NF-ĸB activation. Conclusion: CRP exerted a proinflammatory effect in human mesangial cells by inducing MCP-1 gene expression via NF-ĸB activation, which was mediated, at least in part, through intracellular calcium and ROS.

Fatty acid-bearing albumin induces VCAM-1 expression through c-Src kinase-AP-1/NF-kB pathways: effect of L-carnitine.

Background: Fatty acid-bearing albumin [FA(+) albumin] exerts more deleterious effects in tubular cells than albumin alone. We investigated the effect of FA(+) albumin on the vascular cell adhesion molecule-1 (VCAM-1) expression and elucidated the underlying signaling pathways. We further examined the effect of L-carnitine, since it was known to modulate intracellular fatty acid concentration. Methods: Activation of AP-1 and NF-ĸB was assessed by electrophoretic mobility shift assay. Phosphorylation of protein kinase was examined by Western blot analysis. VCAM-1 mRNA and protein expression were measured by Northern blot analysis and cell ELISA. Results: FA(+) albumin induced VCAM-1 expression via activation of AP-1 and NF-ĸB, which was mediated through activation of c-Src kinase, followed by MAP kinases (p38, ERK 1/2, JNK-1) and IĸB kinase and IĸB-α, respectively. Inhibitors of protein kinase C and tyrosine kinase, anti-oxidants and intracellular calcium chelator suppressed the FA(+) albumin-induced activation of c-Src kinase. L-Carnitine suppressed the FA(+) albumin-induced VCAM-1 expression via inhibition of c-Src kinase. Conclusions: VCAM-1 expression with activation of c-Src kinase-AP-1/NFĸB pathways might be one of the possible mechanisms that linked FA(+) albumin to tubulointerstitial injury. L-Carnitine might be beneficial in attenuating FA(+) albumin-induced tubular injury.

Myoglobin Induces Vascular Cell Adhesion Molecule-1 Expression through c-Src Kinase-Activator Protein-1/Nuclear Factor-ĸB Pathways

Background/Aims: It is not clear whether a sublethal dose of myoglobin induces some pathophysiological changes in tubular cells, potentially affecting tubular injury or tubular regeneration. We investigated the effect of a low dose of myoglobin on vascular cell adhesion molecule-1 (VCAM-1) expression and elucidated the underlying signaling pathways. We further examined the effect of losartan and simvastatin on myoglobin-induced VCAM-1 expression and the signaling pathways. Methods: Activation of nuclear factor (NF)-ĸB and activator protein (AP)-1 was assessed by electrophoretic mobility shift assay. Phosphorylation of protein kinases was examined by Western blot analysis. VCAM-1 mRNA and protein were measured by Northern blot analysis and cell ELISA. Results: A sublethal dose of myoglobin (100 µg/ml) induced VCAM-1 expression via activation of AP-1 and NF-ĸB, which was mediated through activation of c-Src kinase, followed by mitogen-activated protein kinases (p38, ERK 1/2, JNK-1) and the IĸB kinase – IĸB-α. Inhibitors of protein kinase C and tyrosine kinase, antioxidants and intracellular calcium chelator suppressed myoglobin-induced activation of c-Src kinase. Losartan and simvastatin suppressed myoglobin-induced VCAM-1 expression via inhibition of c-Src kinase. Conclusion: VCAM-1 expression via c-Src kinase-AP-1/NF-ĸB pathways might be one of the possible mechanisms linking myoglobin to tubular injury. Losartan and simvastatin might be beneficial in attenuating myoglobin-induced tubular injury.

Comparison of Serum Beta 2-Microglobulin and 24 hour Urinary Creatinine Clearance as a Prognostic Factor in Multiple Myeloma

A new staging system for multiple myeloma (MM) has utilized serum concentrations of beta 2-microglobulin (Sβ2M) and albumin as important prognostic factors for survival. Since Sβ2M is an indicator of glomerular filtration rate, we compared the prognostic values of Sβ2M and 24-hr urinary creatinine clearance (Ccr) in patients with MM. We retrospectively reviewed the records of 170 MM patients from January 1996 to November 2003 whose 24-hr urinary Ccr was available at the time of diagnosis. We found that pretreatment Sβ2M was inversely related to Ccr (Spearmans correlation coefficient=-0.787). In univariate analysis, the hazard ratio (HR) of death was 1.043 (p<0.001) for Sβ2M and 0.985 (p<0.001) for Ccr. Multivariate analysis showed that Sβ2M (HR 1.030, p=0.010) and Ccr (HR 0.993, p=0.059) were significant prognostic factors in patients survival. In conclusion, 24-hr urinary Ccr may be utilized for staging of patients with MM.

Clinical Outcomes of Cryopreserved Arterial Allograft Used as a Vascular Conduit for Hemodialysis

This single center cohort study aimed to test the hypothesis that use of a cryopreserved arterial allograft could avoid the maturation or healing process of a new vascular access and to evaluate the patency of this technique compared with that of vascular access using a prosthetic graft. Between April 2012 and March 2013, 20 patients underwent an upper arm vascular access using a cryopreserved arterial allograft for failed or failing vascular accesses and 53 using a prosthetic graft were included in this study. The mean duration of catheter dependence, calculated as the time interval from upper arm access placement to removal of the tunneled central catheter after successful cannulation of the access, was significantly longer for accesses using a prosthetic graft than a cryopreserved arterial allograft (34.4 ± 11.39 days vs. 4.9 ± 8.5 days, P < 0.001). In the allograft group, use of vascular access started within 7 days in 16 patients (80%), as soon as from the day of surgery in 10 patients. Primary (unassisted; P = 0.314) and cumulative (assisted; P = 0.673) access survivals were similar in the two groups. There were no postoperative complications related to the use of a cryopreserved iliac arterial allograft except for one patient who experienced wound hematoma. In conclusion, upper arm vascular access using a cryopreserved arterial allograft may permit immediate hemodialysis without the maturation or healing process, resulting in access survival comparable to that of an access using a prosthetic graft.

Early continuous renal replacement therapy in septic acute kidney injury could be defined by its initiation within 24 hours of vasopressor infusion

Purpose: The optimal timing for the initiation of early continuous renal replacement therapy (CRRT) is uncertain and requires a practically feasible definition with acceptable evidence. Materials and methods: We investigated the clinical impacts of 3‐time interval parameters on the morbidity and mortality of 177 patients with septic shock–induced acute kidney injury: (1) time from vasopressor initiation to CRRT initiation (Tvaso‐CRRT), (2) time from intensive care unit (ICU) admission to CRRT initation (TICU‐CRRT), and (3) time from endotracheal intubation to CRRT initiation (Tendo‐CRRT). Results: The proportion of the patients with Tvaso‐CRRT less than 24 h (median, 14 h, interquartile range [IQR], 5–30 h) was significantly higher in the survival group than in the non‐survival group (84.3% vs. 58.5%, p < 0.001). Tvaso‐CRRT less than 24 h and Sequential Organ Failure Assessment score were independent factors associated with 28‐day mortality and 90‐day mortality. TICU‐CRRT (median, 17 h, IQR, 5–72 h) and Tendo‐CRRT (median, 13 h, IQR, 4–48 h) were significantly correlated with both the length of ICU stay (p < 0.001) and mechanical ventilation duration (p < 0.001), but not mortality. Conclusions: Considering the possible therapeutic measurement by physician on the basis of the results in this study, early CRRT could be defined by a Tvaso‐CRRT less than 24 h. HighlightsThe optimal timing of RRT initiation is controversial.We found that CRRT initiation from the time of vasopressor infusion was associated with improved survival in septic shock‐induced AKI patients.We suggest that early CRRT in septic AKI could be defined by its initiation within 24 hours of vasopressor treatment.

The effect of zinc deficiency on salt taste acuity, preference, and dietary sodium intake in hemodialysis patients

Introduction High sodium intake is the main cause of fluid overload in hemodialysis (HD) patients, leading to increased cardiovascular mortality. High sodium intake is known to be associated with low salt taste acuity and/or high preference. As the zinc status could influence taste acuity, we analyzed the effect of zinc deficiency on salt taste acuity, preference, and dietary sodium intake in HD patients. Methods A total of 77 HD patients was enrolled in this cross‐sectional study. Zinc deficiency was defined as serum zinc level with below 70 µg/mL. The patients were divided into two groups based on serum zinc level. Salt taste acuity and preference were determined by a sensory test using varying concentrations of NaCl solution, and dietary sodium intake was estimated using 3‐day dietary recall surveys. Findings The mean salt recognition threshold and salt taste preference were significantly higher in the zinc deficient group than in the non‐zinc deficient group. And there was significant positive correlation between salt taste preference and dietary sodium intake in zinc deficient group (ru2009=u20090.43, Pu2009=u20090.002). Although, the dietary sodium intake showed a high tendency with no significance (Pu2009=u20090.052), interdialytic weight gain was significantly higher in the zinc deficient group than in the non‐zinc deficient group (2.68u2009±u20091.02 kg vs. 3.18u2009±u20091.02 kg; Pu2009=u20090.047). Discussion Zinc deficiency may be related to low salt taste acuity and high salt preference, leading to high dietary sodium intake in HD patients.

Impact of transvenous cardiac implantable electronic devices in chronic hemodialysis patients: a single-center, observational comparative study

BackgroundWe investigated the impact of a transvenous cardiac implantable electronic device (CIED) placement on outcomes and arteriovenous vascular access (VA) patency among chronic hemodialysis patients.MethodsThis is a single-center, observational comparative study between chronic hemodialysis patients with ipsilateral and contralateral CIED and VA. Forty-two consecutive patients who underwent both CIED placement and upper-extremity VA for hemodialysis, regardless of the sequence and time interval between these 2 procedures, were identified between January 2001 and December 2017. Patients with ipsilateral (nu2009=u200922, 52%, the ipsilateral group) and contralateral (nu2009=u200920, 48%, the contralateral group) CIED and VA were compared retrospectively; the primary outcome was any-cause mortality and cardiac mortality or the composite of any systemic complications, defined as central venous stenosis or occlusion, any device infections or tricuspid regurgitation; the secondary outcome was CIED or VA malfunction.ResultsDuring the median follow-up period of 101xa0months, primary outcome incidence was significantly higher in the ipsilateral group than the contralateral group (73% vs 40%, Pu2009=u20090.03), although the incidences of any-cause mortality (Pu2009=u20090.28) and cardiac mortality (Pu2009>u20090.99) were similar between the groups. Secondary outcome incidence did not differ significantly between the 2 groups (55% vs 30%, Pu2009=u20090.36). Kaplan–Meier survival analysis revealed similar primary and secondary VA patency rates in both groups. On subgroup analysis, patients with upper arm VA had similar primary and secondary patency to those with forearm VA.ConclusionsDespite some notable limitations of the study, the retrospective study design and small sample size, we found that the any-cause mortality incidence and VA patency did not differ between the 2 groups, but primary outcome incidence was significantly higher among patients with ipsilateral CIED and VA.