Autophagy Precedes Apoptosis in Angiotensin II-Induced Podocyte Injury.

BACKGROUND/AIMS: Angiotensin II (Ang II) induces podocyte injury resulting in apoptosis in vitro and in vivo. However, the relationship between autophagy and apoptosis in Ang II-induced podocyte injury is unknown and the role of Ang II-induced autophagy in podocyte survival or death remains unclear. We investigated the sequential relationship between autophagy and apoptosis in Ang II-induced podocytes as well as the role of phosphatidylinositide 3-kinase (PI3-kinase). METHODS: Mouse podocytes were incubated in media containing various concentrations of Ang II and at different incubation times. The changes of podocyte autophagy and apoptosis were observed by electron microscopy, confocal imaging, western blotting, and FACS assay according to the presence of Ang II. RESULTS: Ang II enhanced the podocyte expression of the autophagic proteins, LC3A/B-II and beclin-1, and also increased the number of autophagosomes compared with control cells at early phase of 12 hours in a dose-dependent manner. This effect was inhibited by pretreatment with 3-methyladenine (3-MA), a PI3-kinase class III inhibitor. Thereafter, the Ang II-induced enhancement in autophagy decreased, whereas, podocyte apoptosis appeared later at 24 hours in concentration- and time-dependent manners in FACS and TUNEL assays. 3-MA and LY294002, a pan PI3-kinase inhibitor, further increased Ang II-induced podocyte apoptosis. Suppression of autophagy by Atg5 siRNA could induce podocyte apoptosis and further augment high-dose Ang II-induced podocyte apoptosis. CONCLUSION: These findings suggest that Ang II promotes autophagy in podocytes before apoptosis as an early adaptive cytoprotective mechanism for podocyte survival after Ang II treatment, and the transitional imbalance between autophagy and apoptosis causes podocyte injury.

Montelukast improves the changes of cytoskeletal and adaptor proteins of human podocytes by interleukin-13.

OBJECTIVE AND DESIGN: Interleukin-13 (IL-13) has recently been reported to be a potential cytokine in the pathogenesis of minimal-change nephrotic syndrome (MCNS). However, the mechanistic insights associated with podocyte dysfunction mediated by IL-13-induced changes in various slit diaphragm (SD) and cytoskeletal molecules have not yet been shown in cultured human podocytes in vitro. MATERIALS: Human conditionally immortalized podocytes were used. TREATMENT: Podocytes were incubated with various concentrations of IL-13 during the indicated time periods (6, 12, and 24 h) and montelukast was administered with the dose of 0.1 µg. RESULTS: Treatment of IL-13 resulted in a progressive decrease in distinct processes or projections of the human podocytes and high dose of IL-13 increased podocyte permeability in vitro at 6 h. IL-13 had a substantial impact on the redistribution and rearrangement of zonula occludens (ZO)-1, synaptopodin, α-actinin, CD2-associated protein (CD2AP) in podocytes and disrupted the cytoskeletal connections in a concentration-dependent manner on confocal microscopy. IL-13 also down-modulated ZO-1, synaptopodin, α-actinin, CD2AP, and p130Cas at protein levels and upregulated ß-catenin and B7-1 in podocytes. Furthermore, we demonstrated that down-modulated changes in various SD and cytoskeletal structures of human podocytes induced by IL-13 was significantly restored after treatment with montelukast with upregulation of B7-1. CONCLUSION: Our results suggest that targeting IL-13 may be one of the important cytokines in the pathogenesis of MCNS and targeting IL-13 could be one of the potential therapeutic strategies in MCNS.

Puromycin aminonucleoside increases podocyte permeability by modulating ZO-1 in an oxidative stress-dependent manner.

Puromycin aminonucleoside (PAN)-induced nephrosis is a widely studied animal model of human idiopathic nephrotic syndrome because PAN injection into rats results in increased glomerular permeability with the characteristic ultrastructural changes in podocytes similar to human nephrosis. To investigate the role of zonula occludens (ZO)-1 and oxidative stress on PAN-induced podocyte phenotypical changes and hyperpermeability in vitro, we cultured rat and mouse podocytes and treated with various concentrations of PAN. PAN treatment increased oxidative stress level of podocytes significantly with the induction of Nox4. In addition, PAN changed the ultrastructure of podocytes, such as shortening and fusion of microvilli, and the separation of intercellular gaps, which were improved by anti-oxidative vitamin C and Nox4 siRNA. PAN also disrupted the intercellular linear ZO-1 staining and induced inner cytoplasmic re-localization of ZO-1 protein, resulting in increased podocyte intercellular permeability. PAN reduced ZO-1 protein amount and mRNA expression in a dose-dependent manner, which means that PAN could also modulate ZO-1 protein transcriptionally. However, the decreased ZO-1 protein of podocytes by PAN was improved by Nox4 siRNA transfection. Furthermore, vitamin C mitigated the quantitative and distributional disturbances of ZO-1 protein caused by PAN. Our results demonstrate that the phenotypical changes of intercellular ZO-1 by oxidative stress via Nox4 likely contribute to the glomerular hyperpermeability caused by PAN.

Clinical outcomes after rescue extracorporeal cardiopulmonary resuscitation for out-of-hospital cardiac arrest.

AIM: Extracorporeal cardiopulmonary resuscitation (ECPR) has been shown to have survival benefit in patients who had in-hospital cardiac arrest (IHCA). However, limited data are available on the role of extracorporeal membrane oxygenation (ECMO) for out-of-hospital cardiac arrest (OHCA). Therefore, we aimed to investigate clinical outcomes and predictors of in-hospital mortality in patients who had OHCA and who underwent ECPR. METHODS: From January 2004 to December 2013, 235 patients who received ECPR were enrolled in a retrospective, single-centre, observational registry. Among those, we studied 35 adult patients who had OHCA. The primary outcome was in-hospital mortality. RESULTS: Among 35 patients with a median age of 55 years (IQR 45-64), 29 (82.9%) of whom were male, ECMO implantation was successful in all and 10 patients (28.6%) lived to be discharged from the hospital. In 18 cases (51.4%), first monitored rhythms were identified as ventricular tachycardia/ventricular fibrillation, that is, shockable rhythm. There were no differences between in-hospital survivors and non-survivors regarding median time of arrest to cardiopulmonary resuscitation (CPR) (survivors: 23.5 min (IQR 18.8-27.3) vs non-survivors: 20.0 min (IQR 15.0-24.5); p=0.41) and median time of CPR to ECMO pump-on (survivors: 61.0 min (IQR 39.8-77.8) vs non-survivors 50.0 min (IQR 44.0-72.5); p=0.50). In 23 cases (65.7%), ischaemic heart disease was diagnosed and successful revascularisation was achieved in a significantly higher proportion of the survivor group (8/10 (80.0%)) than the non-survivor group (8/25 (32.0%)) (p=0.02). Witnessed arrest (HR=3.96; 95% CI 1.38 to 11.41; p=0.01), bystander CPR (HR=4.05; 95% CI 1.56 to 10.42; p=0.004) and successful revascularisation (HR=2.90; 95% CI 1.23 to 6.86; p=0.02) were independent predictors of survival-to-discharge in patients who had OHCA in univariate Cox regression analysis. CONCLUSION: Survival rate for ECPR in the setting of OHCA remains poor. Our findings suggest that ECMO implantation should be very carefully considered in highly selected patients who had OHCA with little no-flow time and a reversible cause.

Lactate clearance and mortality in septic patients with hepatic dysfunction.

BACKGROUND: Serum lactate clearance (LC) during initial resuscitation is a potentially useful prognostic marker in patients with severe sepsis or septic shock. However, it is unclear whether LC is also associated with the outcome in septic patients with hepatic dysfunction that may impair lactate elimination, which may contribute to elevated serum lactate levels or decreased LC. METHODS: The relationships between LC measured within 6 and 24h after initial resuscitation and hospital mortality were evaluated with multiple logistic regression analysis. RESULTS: Of 770 patients with severe sepsis or septic shock, 208 (27%) with hepatic dysfunction were included in the analysis. The median LC within 6h in survivors (31.4%) was significantly higher than that of non-survivors (9.3%) (P=.010). In addition, the median LC within 24h was also significantly different between groups (51% vs. 12%, P<.001). Low LCs, defined as less than 10% of clearance, at 6 and 24h were associated with in-hospital mortality. After adjusting for potential confounding factors, low LCs at 6 and 24h remained associated with hospital mortality (adjusted OR 4.940, 95% CI 1.762-13.854 at 6h; adjusted OR 5.997, 95% CI 2.149-16.737 at 24h). However, LC at 24h (area under the curve of 0.704) had higher discriminatory power to predict hospital mortality than LC at 6h (area under the curve of 0.608) (P=.033). CONCLUSIONS: LC may be useful for predicting outcomes in septic patients with hepatic dysfunction.

Angiotensin II Modulates p130Cas of Podocytes by the Suppression of AMP-Activated Protein Kinase.

Angiotensin II (Ang II) induces the pathological process of vascular structures, including renal glomeruli by hemodynamic and nonhemodynamic direct effects. In kidneys, Ang II plays an important role in the development of proteinuria by the modification of podocyte molecules. We have previously found that Ang II suppressed podocyte AMP-activated protein kinase (AMPK) via Ang II type 1 receptor and MAPK signaling pathway. In the present study, we investigated the roles of AMPK on the changes of p130Cas of podocyte by Ang II. We cultured mouse podocytes and treated them with various concentrations of Ang II and AMPK-modulating agents and analyzed the changes of p130Cas by confocal imaging and western blotting. In immunofluorescence study, Ang II decreased the intensity of p130Cas and changed its localization from peripheral cytoplasm into peri-nuclear areas in a concentrated pattern in podocytes. Ang II also reduced the amount of p130Cas in time and dose-sensitive manners. AMPK activators, metformin and AICAR, restored the suppressed and mal-localized p130Cas significantly, whereas, compound C, an AMPK inhibitor, further aggravated the changes of p130Cas. Losartan, an Ang II type 1 receptor antagonist, recovered the abnormal changes of p130Cas suppressed by Ang II. These results suggest that Ang II induces the relocalization and suppression of podocyte p130Cas by the suppression of AMPK via Ang II type 1 receptor, which would contribute to Ang II-induced podocyte injury.

Diabetic conditions downregulate the expression of CD2AP in podocytes via PI3-K/Akt signalling.

BACKGROUND: Proteinuria is typically accompanied by structural and compositional changes of the foot processes and of the slit diaphragms between podocytes. CD2-associated protein (CD2AP) in podocytes serves as an adaptor protein binding to nephrin and podocin, anchoring these slit diaphragm proteins to actin filaments of podocyte cytoskeleton and sending signals inward or outward. METHODS: In the present study, we prepared streptozotocin-induced diabetic renal tissues and cultured podocytes in diabetic conditions to investigate podocyte phenotypical changes, including quantitative and distributional changes of CD2AP protein and search for the signalling mechanisms in diabetic conditions. We prepared cultured rat glomerular epithelial cells and mouse podocytes to study how high glucose and advanced glycosylation end products (AGE) induce phenotypical changes of cultured podocyte, under (1) normal glucose (5 mM, = control), (2) high glucose (30 mM), (3) AGE-added or (4) high glucose plus AGE-added conditions. RESULTS: According to diabetic duration, density of CD2AP in renal tissue of experimental diabetic nephropathy became conglomerulated and diminished. In cultured podocytes, CD2AP co-localized with nephrin and zonula occludens-1 by confocal imaging. High glucose and high glucose plus AGE induced the relocalization and concentration of CD2AP at internal cytoplasmic and perinuclear areas of podocytes. High glucose plus AGE-added condition also decreased CD2AP protein amount and its mRNA expression compared with normal glucose or osmotic control conditions. In addition, LY294002, a phosphoinositide 3-kinase inhibitor, prevented the quantitative and distributional changes of CD2AP induced by high glucose and AGE. CONCLUSIONS: These findings suggest that diabetic conditions induce the phenotypical changes of podocyte CD2AP possibly via phosphoinositide 3-kinase/Akt signalling.

Erratum: efficacy and tolerability of anticholinergics in korean children with overactive bladder: a multicenter retrospective study.

[This corrects the article on p. 1550 in vol. 29, PMID: 25408588.].

Desmopressin alone versus desmopressin and an anticholinergic in the first-line treatment of primary monosymptomatic nocturnal enuresis: a multicenter study.

BACKGROUND: The aim of this study was to compare the efficacy of combination therapy with desmopressin and an anticholinergic to desmopressin monotherapy for the first-line treatment of children with primary monosymptomatic nocturnal enuresis (PMNE). METHODS: A total of 98 children with PMNE (male:female 71:27) aged 5-16 (mean age 7.18 ± 1.8) years were retrospectively analyzed. The patients were divided into two groups: the monotherapy group (n = 49) was given oral desmopressin alone, and the combination therapy group (n = 49) was given desmopressin plus an anticholinergic (propiverine 10 mg) as a first-line treatment. The two groups were matched according to the following criteria: age, gender, and baseline frequency of nocturnal enuresis. The efficacy was evaluated by International Children's Continence Society criteria at 1 and 3 months after treatment initiation. RESULTS: The combination therapy group showed a higher rate of complete response than the monotherapy group (20.4 vs. 6.1% at 1 month of treatment; 46.9 vs. 22.4% at 3 months of treatment). In terms of success (response and complete response), there was a significant difference between the two groups after 3 months of treatment (P = 0.002). CONCLUSIONS: Our results indicate that combination therapy with desmopressin plus an anticholinergic is quicker and more effective than desmopressin monotherapy in reducing PMNE.

Efficacy and tolerability of anticholinergics in Korean children with overactive bladder: a multicenter retrospective study.

We investigated the efficacy and tolerability of various anticholinergics in Korean children with non-neurogenic overactive bladder (OAB). A total of 326 children (males:females= 157:169) aged under 18 yr (mean age 7.3±2.6 yr) who were diagnosed with OAB from 2008 to 2011 were retrospectively reviewed. The mean duration of OAB symptoms before anticholinergic treatment was 16.9±19.0 months. The mean duration of medication was 5.6±7.3 months. Urgency urinary incontinence episodes per week decreased from 1.9±3.1 to 0.4±1.5 times (P<0.001). The median voiding frequency during daytime was decreased from 9.2±5.4 to 6.3±4.2 times (P<0.001). According to 3-day voiding diaries, the maximum and average bladder capacity were increased from 145.5±66.9 to 196.8±80.3 mL and from 80.8±39.6 to 121.8±56.5 mL, respectively (P<0.001). On uroflowmetry, maximum flow rate was increased from 17.6±8.4 to 20.5±8.2 mL/sec (P<0.001). Adverse effects were reported in 14 (4.3%) children and six children (1.8%) discontinued medication due to adverse effects. Our results indicate that anticholinergics are effective to improve OAB symptoms and tolerability was acceptable without severe complications in children.

Ginsenoside Rg3 inhibits lipopolysaccharide-induced adhesion molecule expression in human umbilical vein endothelial cell and C57BL/6 mice.

Intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), P- and E-selectin play a key role for initiation of vascular inflammation. Ginsenoside, a class of steroid glycosides, is abundant in Panax ginseng root, which has been used for health promotion in Korea. In this study, we investigated the mechanism by which ginsenoside Rg3 may inhibit ICAM-1 and VCAM-1 expressions stimulated with lipopolysaccharide (LPS) in human umbilical vein endothelial cell (HUVEC) and C57BL/6 mice. LPS increased ICAM-1 and VCAM-1 expression. Ginsenoside Rg3 prevented LPS-mediated increase of ICAM-1 and VCAM-1 expression. LPS induced IkappaBα (IκBα) degradation within 1 hr. Ginsenoside Rg3 prevented the IκBα degradation stimulated with LPS. Moreover, ginsenoside Rg3 reduced LPS-mediated THP-1 monocyte adhesion to HUVEC, in a concentration-dependent manner. In C57BL/6 mice, injection of LPS increased aortic ICAM-1 and VCAM-1 expression, which was prevented by ginsenoside Rg3. These data provide a novel mechanism where the ginsenoside Rg3 may provide direct vascular benefits with inhibition of leukocyte adhesion into vascular wall thereby providing prevention against vascular inflammatory disease.

Liberation from Mechanical Ventilation in Critically Ill Patients: Korean Society of Critical Care Medicine Clinical Practice Guidelines.

BACKGROUND: Successful liberation from mechanical ventilation is one of the most crucial processes in critical care because it is the first step by which a respiratory failure patient begins to transition out of the intensive care unit and return to their own life. Therefore, when devising appropriate strategies for removing mechanical ventilation, it is essential to consider not only the individual experiences of healthcare professionals, but also scientific and systematic approaches. Recently, numerous studies have investigated methods and tools for identifying when mechanically ventilated patients are ready to breathe on their own. The Korean Society of Critical Care Medicine therefore provides these recommendations to clinicians about liberation from the ventilator. METHOD: Meta-analyses and comprehensive syntheses were used to thoroughly review, compile, and summarize the complete body of relevant evidence. All studies were meticulously assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) method, and the outcomes were presented succinctly as evidence profiles. Those evidence syntheses were discussed by a multidisciplinary committee of experts in mechanical ventilation, who then developed and approved recommendations. RESULT: Recommendations for nine population, intervention, comparator, outcome (PICO) questions about ventilator liberation are presented in this document. This guideline includes seven conditional recommendations, one expert consensus recommendation, and one conditional deferred recommendation. CONCLUSIONS: We developed these clinical guidelines for mechanical ventilation liberation to provide meaningful recommendations. These guidelines reflect the best treatment for patients seeking liberation from mechanical ventilation.

Liberation from mechanical ventilation in critically ill patients: Korean Society of Critical Care Medicine Clinical Practice Guidelines.

BACKGROUND: Successful liberation from mechanical ventilation is one of the most crucial processes in critical care because it is the first step by which a respiratory failure patient begins to transition out of the intensive care unit and return to their own life. Therefore, when devising appropriate strategies for removing mechanical ventilation, it is essential to consider not only the individual experiences of healthcare professionals, but also scientific and systematic approaches. Recently, numerous studies have investigated methods and tools for identifying when mechanically ventilated patients are ready to breathe on their own. The Korean Society of Critical Care Medicine therefore provides these recommendations to clinicians about liberation from the ventilator. METHODS: Meta-analyses and comprehensive syntheses were used to thoroughly review, compile, and summarize the complete body of relevant evidence. All studies were meticulously assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) method, and the outcomes were presented succinctly as evidence profiles. Those evidence syntheses were discussed by a multidisciplinary committee of experts in mechanical ventilation, who then developed and approved recommendations. RESULTS: Recommendations for nine PICO (population, intervention, comparator, and outcome) questions about ventilator liberation are presented in this document. This guideline includes seven conditional recommendations, one expert consensus recommendation, and one conditional deferred recommendation. CONCLUSIONS: We developed these clinical guidelines for mechanical ventilation liberation to provide meaningful recommendations. These guidelines reflect the best treatment for patients seeking liberation from mechanical ventilation.

Angiotensin II suppresses adenosine monophosphate-activated protein kinase of podocytes via angiotensin II type 1 receptor and mitogen-activated protein kinase signaling.

BACKGROUND: Adenosine monophosphate (AMP)-activated protein kinase (AMPK), as a sensor of cellular energy status, has been known to play an important role in the pathophysiology of diabetes and its complications. As AMPK is also expressed in podocytes, it is possible that podocyte AMPK would be an important contributing factor in the development of diabetic proteinuria. We investigated the roles of AMPK in the pathological changes of podocytes induced by angiotensin II (Ang II), a major injury inducer in diabetic proteinuria. METHODS: Mouse podocytes were incubated in media containing various concentrations of Ang II and AMPK-modulating agents. The changes of AMPKα were analyzed by confocal imaging and Western blotting in response to Ang II. RESULTS: Ang II changed the localization of AMPKα from peripheral cytoplasm into internal cytoplasm and peri- and intranuclear areas in podocytes. Ang II also reduced AMPKα (Thr172) phosphorylation in time- and dose-sensitive manners. In particular, 10(-7 )M Ang II reduced phospho-AMPKα significantly and continuously at 6, 24, and 48 h. AMPK activators, metformin and 5-aminoimidazole-4-carboxamide-1ß-riboside, restored the suppressed AMPKα (Thr172) phosphorylation. Losartan, an Ang II type 1 receptor antagonist, also recovered the suppression and the mal-localization of AMPKα, which were induced by Ang II. PD98059, a mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor, also restored the AMPKα (Thr172) phosphorylation suppressed by Ang II. CONCLUSION: We suggest that Ang II induces the relocation and suppression of podocyte AMPKα via Ang II type 1 receptor and MAPK signaling pathway, which would be an important mechanism in Ang II-induced podocyte injury.

A nationwide study of mass urine screening tests on Korean school children and implications for chronic kidney disease management.

BACKGROUND: Since 1998, urine screening tests have been performed on school children in Korea. We report the findings of the screening program that analyzed patients with proteinuria and/or hematuria. METHODS: Between 1999 and 2008, 5,114 children were referred to pediatric nephrologists at seven nationwide hospitals. Renal biopsies were performed on 1,478 children [28.79 % of total subjects; 26.77 % for isolated hematuria (IH), 9.09 % for isolated proteinuria (IP), and 51.19 % for combined hematuria and proteinuria (CHP)] who showed abnormal renal function, persistent hematuria and/or proteinuria for more than 6 months, nephrotic-range proteinuria, or those with underlying systemic diseases. RESULTS: Chronic glomerulonephritis (GN) was detected in 25 % of all visiting subjects. The most common findings in renal biopsies were immunoglobulin A (IgA) nephropathy in 38.97 %, mesangial proliferative GN in 24.29 %, and thin basement membrane nephropathy in 13.13 %. Compared with the relative frequency of renal diseases associated with urinary abnormalities, CHP (46.90 %) and nephrotic-range proteinuria (69.96 %) groups had more frequent GN than the others. Abnormal findings on renal ultrasound with or without Doppler scan were noted in 462 cases (suspected nutcracker phenomenon, 159; increased parenchymal echogenicity, 92; hydronephrosis, 75; simple cyst, 47). CONCLUSION: Mass urine screening tests could detect asymptomatic GN in its early stages. Initial aggressive diagnosis and treatment for CHP and nephrotic-range groups may prove helpful as interventions that delay chronic kidney disease progression. These findings may assist in the development of diagnostic and management guidelines for relatively mild urinary abnormalities, such as IH or low-grade IP.

Ginsenoside rg2 inhibits lipopolysaccharide-induced adhesion molecule expression in human umbilical vein endothelial cell.

Vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), P- and E-selectin play a pivotal role for initiation of atherosclerosis. Ginsenoside, a class of steroid glycosides, is abundant in Panax ginseng root, which has been used for prevention of illness in Korea. In this study, we investigated the mechanism(s) by which ginsenoside Rg2 may inhibit VCAM-1 and ICAM-1 expressions stimulated with lipopolysaccharide (LPS) in human umbilical vein endothelial cell (HUVEC). LPS increased VCAM-1 and ICAM-1 expression. Ginsenoside Rg2 prevented LPS-mediated increase of VCAM-1 and ICAM-1 expression. On the other hand, JSH, a nuclear factor kappa B (NF-κB) inhibitor, reduced both VCAM-1 and ICAM-1 expression stimulated with LPS. SB202190, inhibitor of p38 mitogen-activated protein kinase (p38 MAPK), and wortmannin, phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, reduced LPS-mediated VCAM-1 but not ICAM-1 expression. PD98059, inhibitor of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) did not affect VCAM-1 and ICAM-1 expression stimulated with LPS. SP600125, inhibitor of c-Jun N-terminal kinase (JNK), reduced LPS-mediated ICAM-1 but not VCAM-1 expression. LPS reduced IkappaBα (IκBα) expression, in a time-dependent manner within 1 hr. Ginsenoside Rg2 prevented the decrease of IκBα expression stimulated with LPS. Moreover, ginsenoside Rg2 reduced LPS-mediated THP-1 monocyte adhesion to HUVEC, in a concentration-dependent manner. These data provide a novel mechanism where the ginsenoside Rg2 may provide direct vascular benefits with inhibition of leukocyte adhesion into vascular wall thereby providing protection against vascular inflammatory disease.

Successful treatment of propofol-related infusion syndrome in critically ill patient receiving low-dose propofol infusion: a case report.

Propofol is widely used to sedate agitated patients in intensive care units. However, it can cause a rare but fatal complication, propofol-related infusion syndrome (PRIS). The pathophysiology of PRIS is not clear, and there is no definitive diagnosis and treatment. We report a successfully treated case of PRIS in a critically ill patient receiving low-dose propofol infusion. A 59-year-old male patient complaining of sudden chest pain repeatedly collapsed in an ambulance and the emergency room, and veno-arterial extracorporeal membrane oxygenation was delivered. He was diagnosed with a total occluded left anterior descending coronary artery in coronary angiography. On day 20, he showed arrhythmia, increased creatinine kinase (CK), and increased CK-MB and troponin I, accompanied by unstable hemodynamic status despite high-dose vasopressors. He was administered propofol for 20 days at an average dose of 1.3 mg/kg/hr owing to issues with agitation and ventilator synchrony. We strongly suspected PRIS and immediately discontinued propofol infusion, and he was successfully treated with aggressive supportive care. PRIS can occur in patients administered propofol for a prolonged period at low doses. Thus, clinicians should use propofol with caution for PRIS and change to alternative sedatives for long-term sedation.

Upregulation of NADH/NADPH oxidase 4 by angiotensin II induces podocyte apoptosis.

BACKGROUND: Angiotensin II induces glomerular and podocyte injury via systemic and local vasoconstrictive or non-hemodynamic effects including oxidative stress. The release of reactive oxygen species (ROS) from podocytes may participate in the development of glomerular injury and proteinuria. We studied the role of oxidative stress in angiotensin II-induced podocyte apoptosis. METHODS: Mouse podocytes were incubated in media containing various concentrations of angiotensin II at different incubation times and were transfected with NADH/NADPH oxidase 4 (Nox4) or angiotensin II type 1 receptor for 24 hours. The changes in intracellular and mitochondrial ROS production and podocyte apoptosis were measured according to the presence of angiotensin II. RESULTS: Angiotensin II increased the generation of mitochondrial superoxide anions and ROS levels but suppressed superoxide dismutase activity in a dose- and time-dependent manner that was reversed by probucol, an antioxidant. Angiotensin II increased Nox4 protein and expression by a transcriptional mechanism that was also reversed by probucol. In addition, the suppression of Nox4 by small interfering RNA (siRNA) reduced the oxidative stress induced by angiotensin II. Angiotensin II treatment also upregulated AT1R protein. Furthermore, angiotensin II promoted podocyte apoptosis, which was reduced significantly by probucol and Nox4 siRNA and also recovered by angiotensin II type 1 receptor siRNA. CONCLUSION: Our findings suggest that angiotensin II increases the generation of mitochondrial superoxide anions and ROS levels via the upregulation of Nox4 and angiotensin II type 1 receptor. This can be prevented by Nox4 inhibition and/or antagonizing angiotensin II type 1 receptor as well as use of antioxidants.

Dense deposit disease in Korean children: a multicenter clinicopathologic study.

The purpose of this study was to investigate the clinical, laboratory, and pathologic characteristics of dense deposit disease (DDD) in Korean children and to determine whether these characteristics differ between Korean and American children with DDD. In 2010, we sent a structured protocol about DDD to pediatric nephrologists throughout Korea. The data collected were compared with previously published data on 14 American children with DDD. Korean children had lower 24-hr urine protein excretion and higher serum albumin levels than American children. The light microscopic findings revealed that a higher percentage of Korean children had membranoproliferative glomerulonephritis patterns (Korean, 77.8%; American, 28.6%, P = 0.036), whereas a higher percentage of American children had crescents (Korean, 0%; American, 78.6%, P < 0.001). The findings from the electron microscopy revealed that Korean children were more likely to have segmental electron dense deposits in the lamina densa of the glomerular basement membrane (Korean, 100%; American, 28.6%, P = 0.002); mesangial deposit was more frequent in American children (Korean, 66.7%; American, 100%, P = 0.047). The histological findings revealed that Korean children with DDD were more likely to show membranoproliferative glomerulonephritis patterns than American children. The degree of proteinuria and hypoalbuminemia was milder in Korean children than American children.

2021 KSCCM clinical practice guidelines for pain, agitation, delirium, immobility, and sleep disturbance in the intensive care unit.

We revised and expanded the "2010 Guideline for the Use of Sedatives and Analgesics in the Adult Intensive Care Unit (ICU)." We revised the 2010 Guideline based mainly on the 2018 "Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption (PADIS) in Adult Patients in the ICU," which was an updated 2013 pain, agitation, and delirium guideline with the inclusion of two additional topics (rehabilitation/mobility and sleep). Since it was not possible to hold face-to-face meetings of panels due to the coronavirus disease 2019 (COVID-19) pandemic, all discussions took place via virtual conference platforms and e-mail with the participation of all panelists. All authors drafted the recommendations, and all panelists discussed and revised the recommendations several times. The quality of evidence for each recommendation was classified as high (level A), moderate (level B), or low/very low (level C), and all panelists voted on the quality level of each recommendation. The participating panelists had no conflicts of interest on related topics. The development of this guideline was independent of any industry funding. The Pain, Agitation/Sedation, Delirium, Immobility (rehabilitation/mobilization), and Sleep Disturbance panels issued 42 recommendations (level A, 6; level B, 18; and level C, 18). The 2021 clinical practice guideline provides up-to-date information on how to prevent and manage pain, agitation/sedation, delirium, immobility, and sleep disturbance in adult ICU patients. We believe that these guidelines can provide an integrated method for clinicians to manage PADIS in adult ICU patients.