Claudins in kidney health and disease

Claudins are strategically located to exert their physiologic actions along with the nephron segments from the glomerulus. Claudin-1 is normally located in the Bowman’s capsule, but its overexpression can reach the podocytes and lead to albuminuria. In the proximal tubule (PT), claudin-2 forms paracellular channels selective for water, Na+, K+, and Ca2+. Claudin-2 gene mutations are associated with hypercalciuria and kidney stones. Claudin-10 has two splice variants, -10a and -10b; Claudin-10a acts as an anion-selective channel in the PT, and claudin-10b functions as a cation-selective pore in the thick ascending limb (TAL). Claudin-16 and claudin-19 mediate paracellular transport of Na+, Ca2+, and Mg2+ in the TAL, where the expression of claudin-3/16/19 and claudin-10b are mutually exclusive. The claudin-16 or -19 mutation causes familial hypomagnesemia with hypercalciuria and nephrocalcinosis. Claudin- 14 polymorphisms have been linked to increased risk of hypercalciuria. Claudin-10b mutations produce HELIX syndrome, which encompasses hypohidrosis, electrolyte imbalance, lacrimal gland dysfunction, ichthyosis, and xerostomia. Hypercalciuria and magnesuria in metabolic acidosis are related to downregulation of PT and TAL claudins. In the TAL, stimulation of calcium-sensing receptors upregulates claudin-14 and negatively acts on the claudin-16/19 complex. Claudin-3 acts as a general barrier to ions in the collecting duct. If this barrier is disturbed, urine acidification might be impaired. Claudin-7 forms a nonselective paracellular channel facilitating Cl– and Na+ reabsorption in the collecting ducts. Claudin-4 and -8 serve as anion channels and mediate paracellular Cl– transport; their upregulation may contribute to pseudohypoaldosteronism II and salt-sensitive hypertension.

Predictive Role of Lung Injury Prediction Score in the Development of Acute Respiratory Distress Syndrome in Korea

Purpose@#Early recognition and therapeutic intervention are important in patients at high risk of acute respiratory distress syndrome (ARDS). The lung injury prediction score (LIPS) has been used to predict ARDS development; however, it was developed based on the previous definition of ARDS. We investigated the predictive role of LIPS in ARDS development according to its Berlin definition in the Korean population. @*Materials and Methods@#This was a retrospective study that enrolled adult patients admitted to the intensive care unit (ICU) at a single university-affiliated hospital in Korea from September 1, 2018, to August 31, 2019. LIPS at the time of ICU admission and the development of ARDS were evaluated. @*Results@#Of the 548 enrolled patients, 33 (6.0%) fulfilled the Berlin ARDS definition. The LIPS for non-ARDS and ARDS groups were 4.96±3.05 and 8.53±2.45, respectively (p6 predicted the development of ARDS with a sensitivity of 84.8% and a specificity of 67.2% [area under the curve (AUC)=0.82]. A modified LIPS model adjusted for age and severity at ICU admission predicted ICU mortality in patients with ARDS (AUC=0.80), but not in those without ARDS (AUC=0.54). @*Conclusion@#LIPS predicted the development of ARDS as diagnosed by the Berlin definition in the Korean population. LIPS provides useful information for managing patients with ARDS.

Predictive Role of Lung Injury Prediction Score in the Development of Acute Respiratory Distress Syndrome in Korea

Purpose@#Early recognition and therapeutic intervention are important in patients at high risk of acute respiratory distress syndrome (ARDS). The lung injury prediction score (LIPS) has been used to predict ARDS development; however, it was developed based on the previous definition of ARDS. We investigated the predictive role of LIPS in ARDS development according to its Berlin definition in the Korean population. @*Materials and Methods@#This was a retrospective study that enrolled adult patients admitted to the intensive care unit (ICU) at a single university-affiliated hospital in Korea from September 1, 2018, to August 31, 2019. LIPS at the time of ICU admission and the development of ARDS were evaluated. @*Results@#Of the 548 enrolled patients, 33 (6.0%) fulfilled the Berlin ARDS definition. The LIPS for non-ARDS and ARDS groups were 4.96±3.05 and 8.53±2.45, respectively (p6 predicted the development of ARDS with a sensitivity of 84.8% and a specificity of 67.2% [area under the curve (AUC)=0.82]. A modified LIPS model adjusted for age and severity at ICU admission predicted ICU mortality in patients with ARDS (AUC=0.80), but not in those without ARDS (AUC=0.54). @*Conclusion@#LIPS predicted the development of ARDS as diagnosed by the Berlin definition in the Korean population. LIPS provides useful information for managing patients with ARDS.

Association between Left Ventricular Systolic Dysfunction and Mortality in Patients with Septic Shock

Association between Left Ventricular Systolic Dysfunction and Mortality in Patients with Septic Shock

BACKGROUND@#The impact of myocardial damage on the prognosis of patients with septic shock is not clearly elucidated because complex hemodynamic changes in sepsis obscure the direct relationship. We evaluated left ventricular (LV) conditions that reflect myocardial damage independently from hemodynamic changes in septic shock and their influence on the prognosis of patients.@*METHODS@#We retrospectively enrolled 208 adult patients who were admitted to the intensive care unit and underwent echocardiography within 7 days from the diagnosis of septic shock. Patients who were previously diagnosed with structural heart disease or coronary artery disease were excluded. Left ventricular ejection fraction (LVEF) was divided into four categories: normal, ≥ 50%; mild, ≥ 40%; moderate, ≥ 30%; and severe dysfunction, < 30%. Wall motion impairment was categorized into the following patterns: normal, diffuse, ballooning, and focal.@*RESULTS@#There were 141 patients with normal LVEF. Among patients with impaired LV wall motion, the diffuse pattern was the most common (34 patients), followed by the ballooning pattern (26 patients). Finally, 102 patients died, and in-hospital mortality was significantly higher in patients with severe LV systolic dysfunction (hazard ratio [HR], 1.97; 95% confidence interval [CI], 1.04–3.75; P = 0.039) and in patients with diffuse pattern of LV wall motion impairment (HR, 2.28; 95% CI, 1.19–4.36; P = 0.013) than in those with a normal LV systolic function.@*CONCLUSION@#Severe LV systolic dysfunction and diffuse pattern of LV wall motion impairment significantly affected in-hospital mortality in patients with septic shock. Conventional echocardiographic evaluation provides adequate information on the development of myocardial damage and accurately predicts the prognosis of patients with septic shock.

Organizing an in-class hackathon to correct PDF-to-text conversion errors of Genomics & Informatics 1.0

This paper describes a community effort to improve earlier versions of the full-text corpus of Genomics & Informatics by semi-automatically detecting and correcting PDF-to-text conversion errors and optical character recognition errors during the first hackathon of Genomics & Informatics Annotation Hackathon (GIAH) event. Extracting text from multi-column biomedical documents such as Genomics & Informatics is known to be notoriously difficult. The hackathon was piloted as part of a coding competition of the ELTEC College of Engineering at Ewha Womans University in order to enable researchers and students to create or annotate their own versions of the Genomics & Informatics corpus, to gain and create knowledge about corpus linguistics, and simultaneously to acquire tangible and transferable skills. The proposed projects during the hackathon harness an internal database containing different versions of the corpus and annotations.

Association of Proteinuria with Urinary Concentration Defect in Puromycin Aminonucleoside Nephrosis

Background@#Puromycin aminonucleoside (PA) can induce nephrotic syndrome in rats, and proteinuria is an important mediator of tubulointerstitial injury in glomerulopathy. We assumed that glomerular proteinuria may affect tubular function, such as urinary concentration, and investigated whether a urinary concentration defect is associated with proteinuria in puromycin aminonucleoside nephrosis (PAN). We also investigated the defect response to enalapril. @*Methods@#Glomerular proteinuria was induced by a single intraperitoneal injection of PA (150 mg/kg BW) in male Sprague-Dawley rats. In a half of these rats, enalapril (35 mg/kg BW) was administered daily in a food mixture for two weeks.After the animal experiment, kidneys were harvested for immunoblot analysis and histopathologic examination. @*Results@#Compared with the control group, PA-treated rats had severe proteinuria, polyuria, and a lower urine osmolality. PA treatment induced remarkable tubulointerstitial injury and significant reductions in protein abundances of aquaporin-1 and Na-K-2Cl co-transporter type 2 (NKCC2). Proteinuria significantly correlated with osteopontin expression in the kidney and inversely correlated with renal expression of aquaporin-1, aquaporin-2, and NKCC2. The degree of tubulointerstitial injury significantly correlated with proteinuria, urine output, and osteopontin expression and inversely correlated with urine osmolality and renal expression of aquaporin-1, aquaporin-2, and NKCC2. No significant differences in parameters were found between PA-treated rats with and without enalapril. @*Conclusion@#In PAN, glomerular proteinuria was associated with tubulointerstitial injury and water diuresis. Downregulation of aquaporin-1 and NKCC2 can impair countercurrent multiplication and cause a urinary concentration defect in PAN.

Association between Left Ventricular Systolic Dysfunction and Mortality in Patients with Septic Shock

BACKGROUND@#The impact of myocardial damage on the prognosis of patients with septic shock is not clearly elucidated because complex hemodynamic changes in sepsis obscure the direct relationship. We evaluated left ventricular (LV) conditions that reflect myocardial damage independently from hemodynamic changes in septic shock and their influence on the prognosis of patients.@*METHODS@#We retrospectively enrolled 208 adult patients who were admitted to the intensive care unit and underwent echocardiography within 7 days from the diagnosis of septic shock. Patients who were previously diagnosed with structural heart disease or coronary artery disease were excluded. Left ventricular ejection fraction (LVEF) was divided into four categories: normal, ≥ 50%; mild, ≥ 40%; moderate, ≥ 30%; and severe dysfunction, < 30%. Wall motion impairment was categorized into the following patterns: normal, diffuse, ballooning, and focal.@*RESULTS@#There were 141 patients with normal LVEF. Among patients with impaired LV wall motion, the diffuse pattern was the most common (34 patients), followed by the ballooning pattern (26 patients). Finally, 102 patients died, and in-hospital mortality was significantly higher in patients with severe LV systolic dysfunction (hazard ratio [HR], 1.97; 95% confidence interval [CI], 1.04–3.75; P = 0.039) and in patients with diffuse pattern of LV wall motion impairment (HR, 2.28; 95% CI, 1.19–4.36; P = 0.013) than in those with a normal LV systolic function.@*CONCLUSION@#Severe LV systolic dysfunction and diffuse pattern of LV wall motion impairment significantly affected in-hospital mortality in patients with septic shock. Conventional echocardiographic evaluation provides adequate information on the development of myocardial damage and accurately predicts the prognosis of patients with septic shock.

Organizing an in-class hackathon to correct PDF-to-text conversion errors of Genomics & Informatics 1.0

This paper describes a community effort to improve earlier versions of the full-text corpus of Genomics & Informatics by semi-automatically detecting and correcting PDF-to-text conversion errors and optical character recognition errors during the first hackathon of Genomics & Informatics Annotation Hackathon (GIAH) event. Extracting text from multi-column biomedical documents such as Genomics & Informatics is known to be notoriously difficult. The hackathon was piloted as part of a coding competition of the ELTEC College of Engineering at Ewha Womans University in order to enable researchers and students to create or annotate their own versions of the Genomics & Informatics corpus, to gain and create knowledge about corpus linguistics, and simultaneously to acquire tangible and transferable skills. The proposed projects during the hackathon harness an internal database containing different versions of the corpus and annotations.

Association of Proteinuria with Urinary Concentration Defect in Puromycin Aminonucleoside Nephrosis

Background@#Puromycin aminonucleoside (PA) can induce nephrotic syndrome in rats, and proteinuria is an important mediator of tubulointerstitial injury in glomerulopathy. We assumed that glomerular proteinuria may affect tubular function, such as urinary concentration, and investigated whether a urinary concentration defect is associated with proteinuria in puromycin aminonucleoside nephrosis (PAN). We also investigated the defect response to enalapril. @*Methods@#Glomerular proteinuria was induced by a single intraperitoneal injection of PA (150 mg/kg BW) in male Sprague-Dawley rats. In a half of these rats, enalapril (35 mg/kg BW) was administered daily in a food mixture for two weeks.After the animal experiment, kidneys were harvested for immunoblot analysis and histopathologic examination. @*Results@#Compared with the control group, PA-treated rats had severe proteinuria, polyuria, and a lower urine osmolality. PA treatment induced remarkable tubulointerstitial injury and significant reductions in protein abundances of aquaporin-1 and Na-K-2Cl co-transporter type 2 (NKCC2). Proteinuria significantly correlated with osteopontin expression in the kidney and inversely correlated with renal expression of aquaporin-1, aquaporin-2, and NKCC2. The degree of tubulointerstitial injury significantly correlated with proteinuria, urine output, and osteopontin expression and inversely correlated with urine osmolality and renal expression of aquaporin-1, aquaporin-2, and NKCC2. No significant differences in parameters were found between PA-treated rats with and without enalapril. @*Conclusion@#In PAN, glomerular proteinuria was associated with tubulointerstitial injury and water diuresis. Downregulation of aquaporin-1 and NKCC2 can impair countercurrent multiplication and cause a urinary concentration defect in PAN.

Prognostic Value of Admission Blood Glucose Level in Critically Ill Patients Admitted to Cardiac Intensive Care Unit according to the Presence or Absence of Diabetes Mellitus

BACKGROUND: Admission blood glucose (BG) level is a predictor of mortality in critically ill patients with various conditions. However, limited data are available regarding this relationship in critically ill patients with cardiovascular diseases according to diabetic status. METHODS: A total of 1,780 patients (595 with diabetes) who were admitted to cardiac intensive care unit (CICU) were enrolled from a single center registry. Admission BG level was defined as maximal serum glucose level within 24 hours of admission. Patients were divided by admission BG level: group 1 (< 7.8 mmol/L), group 2 (7.8–10.9 mmol/L), group 3 (11.0–16.5 mmol/L), and group 4 (≥ 16.6 mmol/L). RESULTS: A total of 105 patients died in CICU (62 non-diabetic patients [5.2%] and 43 diabetic patients [7.9%]; P = 0.105). The CICU mortality rate increased with admission BG level (1.7%, 4.8%, 10.3%, and 18.8% from group 1 to group 4, respectively; P < 0.001). On multivariable analysis, hypertension, mechanical ventilator, continuous renal replacement therapy, acute physiology and chronic health evaluation II (APACHE II) score, and admission BG level significantly influenced CICU mortality in non-diabetic patients (group 1 vs. group 3: hazard ratio [HR], 3.31; 95% confidence interval [CI], 1.47–7.44; P = 0.004; group 1 vs. group 4: HR, 6.56; 95% CI, 2.76–15.58; P < 0.001). However, in diabetic patients, continuous renal replacement therapy and APACHE II score influenced CICU mortality but not admission BG level. CONCLUSION: Admission BG level was associated with increased CICU mortality in critically ill, non-diabetic patients admitted to CICU but not in diabetic patients.

Successful Retrieval of a Fractured and Entrapped 0.035-Inch Terumo Wire in the Femoral Artery Using Biopsy Forceps

A 0.035-inch guide wire fracture and entrapment in a peripheral artery is a very rare complication, but when it does occur it may lead to life-threatening complications, such as perforation, thrombus formation, embolization, and subsequent limb ischemia. We describe our experience of successfully retrieving a fractured 0.035-inch Terumo guide wire in the external iliac artery using a biopsy forcep.

Two Cases of High Output Heart Failure Caused by Hereditary Hemorrhagic Telangiectasia

High-output cardiac failure is a rare complication of hereditary hemorrhagic telangiectasia (HHT) usually caused by shunting of blood through atriovenous malformations (AVMs) in the liver. We describe two cases of high output heart failure due to large hepatic AVMs. Clinical suspicion of HHT based on detailed history taking and physical examination is essential for early detection and proper management of heart failure associated with HHT.

Effects of Dietary Salt Restriction on Puromycin Aminonucleoside Nephrosis: Preliminary Data

Proteinuria is a major promoter that induces tubulointerstitial injury in glomerulopathy. Dietary salt restriction may reduce proteinuria, although the mechanism is not clear. We investigated the effects of dietary salt restriction on rat kidneys in an animal model of glomerular proteinuria. Male Sprague-Dawley rats were used and divided into 3 groups: vehicle-treated normal-salt controls, puromycin aminonucleoside (PA)-treated normal-salt rats, and PA-treated low-salt rats. PA was given at a dose of 150 mg/kg BW at time 0, followed by 50 mg/kg BW on days 28, 35, and 42. Sodium-deficient rodent diet with and without additional NaCl (0.5%) were provided for normal-salt rats and low-salt rats, respectively. On day 63, kidneys were harvested for histopathologic examination and immunohistochemistry. PA treatment produced overt proteinuria and renal damage. Dietary salt restriction insignificantly reduced proteinuria in PA-treated rats, and PA-treated low-salt rats had lower urine output and lower creatinine clearance than vehicle-treated normal-salt controls. When tubulointerstitial injury was semiquantitatively evaluated, it had a positive correlation with proteinuria. The tubulointerstitial injury score was significantly increased by PA treatment and relieved by low-salt diet. ED1-positive infiltrating cells and immunostaining for interstitial collagen III were significantly increased by PA treatment. These changes appeared to be less common in PA-treated low-salt rats, although the differences in PA-treated normal-salt versus low-salt rats did not reach statistical significance. Our results suggest that renal histopathology in PA nephrosis may potentially be improved by dietary salt restriction. Non-hemodynamic mechanisms induced by low-sodium diet might contribute to renoprotection.

The Role of Proximal Nephron in Cyclophosphamide-Induced Water Retention: Preliminary Data

Cyclophosphamide is clinically useful in treating malignancy and rheumatologic disease, but has limitations in that it induces hyponatremia. The mechanisms by which cyclophosphamide induces water retention in the kidney have yet to be identified. This study was undertaken to test the hypothesis that cyclophosphamide may produce water retention via the proximal nephron, where aquaporin-1 (AQP1) and aquaporin-7 (AQP7) water channels participate in water absorption. To test this hypothesis, we gave a single dose of intraperitoneal cyclophosphamide to male Sprague-Dawley rats and treated rabbit proximal tubule cells (PTCs) with 4-hydroperoxycyclophosphamide (4-HC), an active metabolite of cyclophosphamide. In the short-term 3-day rat study, AQP1 protein expression was significantly increased in the whole kidney homogenates by cyclophosphamide administration at 48 (614 +/- 194%, P < 0.005), and 96 (460 +/- 46%, P < 0.05) mg/kg BW compared with vehicle-treated controls. Plasma sodium concentration was significantly decreased (143 +/- 1 vs. 146 +/- 1 mEq/L, P < 0.05) by cyclophosphamide 100 mg/kg BW in the long-term 6-day rat study. When primary cultured rabbit PTCs were treated with 4-HC for 24 hours, the protein expressions of AQP1 and AQP7 were increased in a dose-dependent manner. Quantitative polymerase chain reaction revealed no significant changes in the mRNA levels of AQP1 and AQP7 from cyclophosphamide-treated rat renal cortices. From these preliminary data, we conclude that the proximal nephron may be involved in cyclophosphamide-induced water retention via AQP1 and AQP7 water channels. Further studies are required to demonstrate intracellular mechanisms that affect the expression of AQP proteins.

Effects of Increased Uric Acid Intake on the Abundance of Urate-anion exchanger and Organic Anion Transporter Proteins in the Rat Kidney

Renal handling of uric acid mainly occurs in the proximal tubule, and bidirectional transport of urate may involve apical absorption via the urate-anion exchanger (URAT1) and basolateral uptake via organic anion transporters (OAT1 and OAT3). In rat kidneys, we investigated whether the protein abundance of URAT1, OAT1, and OAT3 is affected by the increase in uric acid intake. Male Sprague-Dawley rats were randomly divided into control and uric acid-supplemented groups, and uric acid-supplemented rats were given 0.75 g of uric acid per 180 g body weight per day for 8 days. After the animal experiment, kidneys were harvested and semi-quantitative immunoblotting was carried out from cortical homogenates using polyclonal peptide-derived antibodies to URAT1, OAT1, and OAT3. Serum uric acid level showed an increasing tendency (p=0.055) in the uric acid-supplemented rats (2.60+/- 0.27 mg/dL) compared with control rats (1.97+/-0.29 mg/dL), whereas urinary uric acid excretion was not significantly different between the uric acid-supplemented rats (3.27+/-0.40 mg/d) and control rats (2.61+/-0.34 mg/d). URAT1 protein abundance in cortical homogenates was not significantly different between the uric acid-supplemented rats (132+/-14%) and control rats (100+/-7%). However, OAT1 protein abundance was significantly (p<0.05) increased in the uric acid-supplemented rats (148+/-13%) compared with the control rats (100+/-8%). OAT3 protein abundance was not significantly different between the uric acid-supplemented rats (131+/-12%) and control rats (100+/-17%). In conclusion, OAT1 may have a regulatory role in response to the increase in uric acid intake in the rat kidney. The up-regulation of OAT1 would exert stimulation of urinary uric acid excretion and might contribute to protection from hyperuricemia.