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

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.

Local complications are related to poor long-term outcome in patients undergoing curative gastrectomy for advanced gastric cancer

Purpose@#The present study was performed to investigate the effects of local complications (LC) on long-term survival and cancer recurrence in patients undergoing curative gastrectomy for gastric cancer. @*Methods@#We analyzed 2,627 patients after curative gastrectomy for gastric cancer between January 2001 and December 2006. Patients were classified into groups no complications (NC), LC, or systemic complications (SC). @*Results@#Among the 2,627 patients, 475 patients developed complications (LC group [n=374, 14.2%] and SC group [n=101, 3.9%]). The 5-year cancer-specific survival rate was significantly poorer in the LC group compared to the NC and SC groups (LC, 78.0%; NC, 85.4%; SC, 80.2%; P=0.007). The occurrence of LC was identified as a significant independent prognostic factor for overall and cancer-specific survival (hazard ratio [HR], 2.08; 95% confidence interval [CI], 1.46–2.97; P=0.001 and HR, 1.77; 95% CI, 1.12–2.81; P=0.015). The tumor recurrence rates were higher in the LC group than the in other two groups (LC, 23.5%; NC, 15.4%; SC, 15.8%; P<0.001). The occurrence of LC was an independent predictor of tumor recurrence in patients undergoing curative gastrectomy for gastric cancer (HR, 1.55; 95% CI, 1.11–2.17; P=0.011). @*Conclusion@#LC are associated with adverse long-term outcomes in patients after curative gastrectomy for advanced gastric cancer.

A Transient Effect of Convalescent Plasma Therapy in a Patient with Severe Covonavirus Disease 2019: A Case Report / 감염과화학요법

A 65-year-old male patient with an end-stage renal disease was diagnosed with coronavirus disease 2019 (COVID-19) by reverse transcription polymerase chain reaction. The patient complained of cough, sputum, and respiratory distress that worsened three days ago. The patient required mechanical ventilation and extracorporeal mentrane oxygenation. On day 9, convalescent plasma collected from a 34-year old man who recovered from COVID-19 45 days ago was administered. The patient showed immediate clinical improvement. However, on day 14, the patient’s clinical course worsened again. On day 19 and day 24, vancomycin-resistant Enterococcus faecium bacteremia and methicillin-resistant Staphylococcus aureus pneumonia were found. After long-term supportive care, he slowly recovered. He was discharged on day 91 without any oxygen requirement. This case report suggests that convalescent plasma therapy might just provide a short-term relief and that persistent effort for critical care is necessary to save patients from severe COVID-19.

Characteristics of pediatric rhabdomyolysis and the associated risk factors for acute kidney injury: a retrospective multicenter study in Korea

Background@#The clinical features of pediatric rhabdomyolysis differ from those of the adults with rhabdomyolysis; however, multicenter studies are lacking. This study aimed to investigate the characteristics of pediatric rhabdomyolysis and reveal the risk factors for acute kidney injury (AKI) in such cases. @*Methods@#This retrospective study analyzed the medical records of children and adolescents diagnosed with rhabdomyolysis at 23 hospitals in South Korea between January 2007 and December 2016. @*Results@#Among 880 patients, those aged 3 to 5 years old composed the largest subgroup (19.4%), and all age subgroups were predominantly male. The incidence of AKI was 11.3%. Neurological disorders (53%) and infection (44%) were the most common underlying disorder and cause of rhabdomyolysis, respectively. The median age at diagnosis in the AKI subgroup was older than that in the non-AKI subgroup (12.2 years vs. 8.0 years). There were no significant differences in body mass index, myalgia, dark-colored urine, or the number of causal factors between the two AKI-status subgroups. The multivariate logistic regression model indicated that the following factors were independently associated with AKI: multiorgan failure, presence of an underlying disorder, strong positive urine occult blood, increased aspartate aminotransferase and uric acid levels, and reduced calcium levels. @*Conclusions@#Our study revealed characteristic clinical and laboratory features of rhabdomyolysis in a Korean pediatric population and highlighted the risk factors for AKI in these cases. Our findings will contribute to a greater understanding of pediatric rhabdomyolysis and may enable early intervention against rhabdomyolysis-induced AKI.

Geriatric Physiology for Surgical Intensivists: Part I

The elderly population experiences a normal, age-related decline of physiological function in all major organ systems. The age-related changes in lung structure include decreases in chest wall compliance, respiratory muscle strength and elastic recoil, contributing to decreased lung function which increases susceptibility to infection. The age-related changes in cardiovascular structure and function increases the risk of cardiovascular disease. The aging process in the kidney leads to several clinical conditions in the elderly such as impaired drug metabolism and kinetics, loss of homeostasis, and electrolyte abnormalities. With aging, the decrease in gastrointestinal (GI) function in the mouth, esophagus, stomach, small and large intestine, and liver may affect appetite, motility, enzyme and hormone secretion, nutrient digestion and absorption, and gastrointestinal immunity. These changes in GI function may play a significant role in malnutrition and an increased risk of cachexia. Aging leads to inevitable deterioration in cellular and physiological function, which result in impaired homeostasis, decreased ability to adapt to stress, increased vulnerability to disease, and increased age-related mortality. Optimal health care management requires a deep understanding of the normal physiological changes associated with aging, and is necessary to provide insight into the mechanisms of multiple organ impairment and disease in the elderly.

Short Bowel Syndrome from Strangulated Internal Hernia After Childbirth in a Patient With a History of Gastric Bypass Surgery: Case Report

Bariatric patients are at risk of diverse complications, such as bowel obstruction, internal hernia, and mesenteric thrombosis, which can result in massive small bowel resection with short bowel syndrome (SBS) as a consequence. In this study a case of an internal hernia after childbirth in a 36-year-old patient with a history of laparoscopic Roux-en-Y gastric bypass surgery is reported. An emergency laparotomy revealed an internal hernia in Petersen’s space with volvulus, causing extensive small bowel infarction and necrosis. SBS is a complicated multifaceted syndrome which requires a multidisciplinary approach, such as medical, nutritional, and pharmaceutical therapies, to optimize fluid and nutrient absorption over long-term monitoring and with revisions of the care plan. To reduce the morbidity and mortality associated with an internal hernia and volvulus, clinicians must be acutely aware of a potential SBS diagnosis and not delay surgical exploration, even if the vital signs, laboratory results, and imaging studies are normal.

Implementing a multidisciplinary care bundle to reduce colon surgical site infections

Purpose@#The aim of this study was to investigate how rates of surgical site infections (SSI) were changed over 2 years after applying colon SSI bundle in patients who underwent colon surgery. @*Methods@#The multidisciplinary working group developed a care bundle consisting of 8 components, including several recommendations of Surgical Care Improvement Project and monitoring of medical/surgical hand washing. We implemented the care bundle for each patient who underwent colon surgery from April 2013 to December 2014. @*Results@#Overall bundle compliance was 87.9% before implementation, 88.2% in 2013, and 90.5% in 2014. In particular, compliance of the following 3 components was substantial improved during the project period; discontinuation of prophylactic antimicrobial agent within 24 hours of surgery (from 88.3% to 100%), surgical hand washing (from 50.0% to 78.9%), and medical hand washing (from 74.7% to 82.8%). The rate of SSI was 8.0% (12/150) during 3 months before implementation, 3.3% (16/480) from April to December in 2013, and 2.3% (14/607) in 2014. @*Conclusion@#After implementation of multidisciplinary care bundle, the compliance of each component was increased and rates of SSIs were significantly decreased compared to those before the quality improvement project.

Natural History of Untreated Early Gastric Cancer

Early gastric cancer (EGC), which is defined as a lesion confined to the mucosa or the submucosal layer, regardless of metastasis to the lymph node, has a good prognosis than advanced gastric cancer (AGC). Because untreated EGC progresses to AGC, it is important to understand the natural history of EGC to determine the duration, prognosis, and treatment options and timing. However, the natural history of EGC remains unclear and different from AGC. We report a case of an untreated EGC patient who progressed to AGC with cancer perforation at 29 months after diagnosis and metastasized to peritoneum at 40 months after diagnosis.

Geriatric Physiology for Surgical Intensivists: Part I

The elderly population experiences a normal, age-related decline of physiological function in all major organ systems. The age-related changes in lung structure include decreases in chest wall compliance, respiratory muscle strength and elastic recoil, contributing to decreased lung function which increases susceptibility to infection. The age-related changes in cardiovascular structure and function increases the risk of cardiovascular disease. The aging process in the kidney leads to several clinical conditions in the elderly such as impaired drug metabolism and kinetics, loss of homeostasis, and electrolyte abnormalities. With aging, the decrease in gastrointestinal (GI) function in the mouth, esophagus, stomach, small and large intestine, and liver may affect appetite, motility, enzyme and hormone secretion, nutrient digestion and absorption, and gastrointestinal immunity. These changes in GI function may play a significant role in malnutrition and an increased risk of cachexia. Aging leads to inevitable deterioration in cellular and physiological function, which result in impaired homeostasis, decreased ability to adapt to stress, increased vulnerability to disease, and increased age-related mortality. Optimal health care management requires a deep understanding of the normal physiological changes associated with aging, and is necessary to provide insight into the mechanisms of multiple organ impairment and disease in the elderly.

Short Bowel Syndrome from Strangulated Internal Hernia After Childbirth in a Patient With a History of Gastric Bypass Surgery: Case Report

Bariatric patients are at risk of diverse complications, such as bowel obstruction, internal hernia, and mesenteric thrombosis, which can result in massive small bowel resection with short bowel syndrome (SBS) as a consequence. In this study a case of an internal hernia after childbirth in a 36-year-old patient with a history of laparoscopic Roux-en-Y gastric bypass surgery is reported. An emergency laparotomy revealed an internal hernia in Petersen’s space with volvulus, causing extensive small bowel infarction and necrosis. SBS is a complicated multifaceted syndrome which requires a multidisciplinary approach, such as medical, nutritional, and pharmaceutical therapies, to optimize fluid and nutrient absorption over long-term monitoring and with revisions of the care plan. To reduce the morbidity and mortality associated with an internal hernia and volvulus, clinicians must be acutely aware of a potential SBS diagnosis and not delay surgical exploration, even if the vital signs, laboratory results, and imaging studies are normal.

Natural History of Untreated Early Gastric Cancer

Early gastric cancer (EGC), which is defined as a lesion confined to the mucosa or the submucosal layer, regardless of metastasis to the lymph node, has a good prognosis than advanced gastric cancer (AGC). Because untreated EGC progresses to AGC, it is important to understand the natural history of EGC to determine the duration, prognosis, and treatment options and timing. However, the natural history of EGC remains unclear and different from AGC. We report a case of an untreated EGC patient who progressed to AGC with cancer perforation at 29 months after diagnosis and metastasized to peritoneum at 40 months after diagnosis.

Erratum: Puromycin aminonucleoside triggers apoptosis in podocytes by inducing endoplasmic reticulum stress Volume 37, Issue 3, September 2018, Pages 210–221

The authors would like to publish this corrigendum to correct the spells of an author's name in the above article.

Circulating Permeability Factors in Idiopathic Nephrotic Syndrome

Nephrotic syndrome (NS) is a common chronic glomerular disease in children characterized by significant proteinuria with resulting hypoalbuminemia, edema, and hyperlipidemia. Renal biopsy findings of diffuse foot processes effacement on electron microscopy and minimal change disease, focal segmental glomerulosclerosis (FSGS), or diffuse mesangial proliferation on light microscopy. It has been speculated that circulating permeability factors would be implicated in the pathogenesis of NS because they have been reportedly detected in the sera of patients and in experimental models of induced proteinuria. Moreover, a substantial portion of the patients with primary FSGS recurrence shortly after transplantation. This report reviews the current knowledge regarding the role of circulating permeability factors in the pathogenesis of proteinuria in NS and suggests future targeted therapeutic approaches for NS.

Interleukin-13 Increases Podocyte Apoptosis in Cultured Human Podocytes

PURPOSE: Podocytes are important architectures that maintain the crucial roles of glomerular filtration barrier functions. Despite this structural importance, however, the mechanisms of the changes in podocytes that can be an important pathogenesis of minimal change nephrotic syndrome (MCNS) are not clear yet. The aim of this study was to investigate whether apoptosis is induced by interleukin (IL)-13 in cultured human podocytes. METHODS: Human podocytes were treated with different IL-13 doses and apoptotic cells were analyzed using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL assay) and fluorescence-activated cell sorting (FACS). RESULTS: The IL-13 increased the number of TUNEL-positive cells in a dose-dependent manner at 6 and 18 hours (P<0.05 and P<0.05, respectively). The apoptosis rate was appeared to be increased slightly in the IL-13-stimulated podocytes (8.63%, 13.02%, and 14.46%; 3, 10 and 30 ng/mL, respectively) than in the control cells (7.66%) at 12 hours by FACS assay. CONCLUSION: Our study revealed that IL-13 expression may increase podocyte apoptosis. Blocking the IL-13 signal pathway can potentially play an important role in regulating the apoptosis of podocytes.

Puromycin aminonucleoside triggers apoptosis in podocytes by inducing endoplasmic reticulum stress

BACKGROUND: Puromycin aminonucleoside (PAN) is a known podocytotoxin. PAN-induced nephrosis is a widely used animal model for studying human idiopathic nephrotic syndrome. Abnormal protein accumulation associated with podocyte-specific endoplasmic reticulum (ER) stress damages cells structurally and functionally, which in turn induces apoptosis and severe proteinuria. In the present study, we investigated the effect of PAN on ER stress and apoptosis in podocytes in vitro. METHODS: Mouse podocytes were cultured and treated with various concentrations of PAN. ER stress markers were then evaluated by western blotting, and apoptosis was evaluated by fluorescence-activated cell sorting (FACS) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays. RESULTS: PAN treatment increased ER stress markers such as activating transcription factor (ATF) 6α and caspase-12 in a dose-dependent manner at 12 and 24 hours, respectively. These markers were reduced by chemical chaperones, such as sodium 4-phenylbutyric acid and tauroursodeoxycholic acid. PAN treatment also increased 78 kD glucose-regulated protein (GRP78)/binding immunoglobulin protein (BiP) at the earlier stage of 12 hours. PAN significantly induced podocyte apoptosis in concentration- and time-dependent manners, as seen using FACS and TUNEL assays. This result was improved by Nox4 siRNA, ATF6 siRNA, and chemical chaperones. LY294002, a PI3-kinase inhibitor, significantly boosted ER stress and apoptosis. PAN-induced ER stress increased oxidative stress and subsequently induced apoptosis, and could be mitigated by inhibition of PI3-kinase signaling. CONCLUSION: Our findings suggest that PAN induces ER stress in podocytes mainly through the GRP78/BiP, ATF6α, and caspase-12 pathways, which trigger apoptosis via induction of oxidative stress. This stress is mitigated by inhibiting PI3-kinase signaling.

Genetics of hereditary nephrotic syndrome: a clinical review / 소아과

Advances in podocytology and genetic techniques have expanded our understanding of the pathogenesis of hereditary steroid-resistant nephrotic syndrome (SRNS). In the past 20 years, over 45 genetic mutations have been identified in patients with hereditary SRNS. Genetic mutations on structural and functional molecules in podocytes can lead to serious injury in the podocytes themselves and in adjacent structures, causing sclerotic lesions such as focal segmental glomerulosclerosis or diffuse mesangial sclerosis. This paper provides an update on the current knowledge of podocyte genes involved in the development of hereditary nephrotic syndrome and, thereby, reviews genotype-phenotype correlations to propose an approach for appropriate mutational screening based on clinical aspects.

A Case of Orthostatic Proteinuria Progressed to Persistent Proteinuria Associated with Renal Pathology

Orthostatic or postural proteinuria is the most common cause of asymptomatic proteinuria in children. As orthostatic proteinuria (OP) is a benign disease with relatively good prognosis, it has no specific management, and patients only need to be observed. However, if OP shows a persistently high level of proteinuria, in theory, glomerular changes can occur. An 11-year-old girl was referred to the hospital due to asymptomatic proteinuria and was diagnosed as having OP based on the results of clinical and laboratory examinations, urinalysis, and protein/creatinine (TP/Cr) ratio at both supine and erect positions. During follow-up observation, the 24-hour TP/Cr ratio was persistently higher than 1.5 mg/mg for 2 years. We performed renal biopsy, which showed mesangial proliferative glomerular lesions with focal effacement of the podocyte foot processes, but without immune depositions. OP can be accompanied by glomerular lesions if moderate to severe proteinuria persists.

A Case of Orthostatic Proteinuria Progressed to Persistent Proteinuria Associated with Renal Pathology

Orthostatic or postural proteinuria is the most common cause of asymptomatic proteinuria in children. As orthostatic proteinuria (OP) is a benign disease with relatively good prognosis, it has no specific management, and patients only need to be observed. However, if OP shows a persistently high level of proteinuria, in theory, glomerular changes can occur. An 11-year-old girl was referred to the hospital due to asymptomatic proteinuria and was diagnosed as having OP based on the results of clinical and laboratory examinations, urinalysis, and protein/creatinine (TP/Cr) ratio at both supine and erect positions. During follow-up observation, the 24-hour TP/Cr ratio was persistently higher than 1.5 mg/mg for 2 years. We performed renal biopsy, which showed mesangial proliferative glomerular lesions with focal effacement of the podocyte foot processes, but without immune depositions. OP can be accompanied by glomerular lesions if moderate to severe proteinuria persists.

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.

Erratum: Primary Invasive Intestinal Aspergillosis in a Non-Severely Immunocompromised Patient / 대한중환자의학회지

We found an error in this article. The Fig. 1A.