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Alport syndrome (AS) is a hereditary nephritis characterized by structural abnormalities in the glomerular basement membrane resulting from pathogenic variants in the COL4A3, COL4A4, and COL4A5 genes. Conventional pathological evaluations reveal nonspecific light microscopic changes and diagnostic clues can be obtained through electron microscopy. Type IV collagen staining elucidates distinct patterns based on AS inheritance, aiding in subtype classification. However, limitations arise, particularly in autosomal dominant cases. Genetic testing, particularly next-generation sequencing, gains prominence due to its ability to identify diverse mutations within COL4A3, COL4A4, and COL4A5.

Background: Despite the widespread impact of the severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019, COVID-19) and vaccination in South Korea, our understanding of kidney diseases following these events remains limited. We aimed to address this gap by investigating the characteristics of glomerular diseases following the COVID-19 infection and vaccination in South Korea., Methods: Data from multiple centers were used to identify de novo glomerulonephritis (GN) cases with suspected onset following COVID-19 infection or vaccination. Retrospective surveys were used to determine the COVID-19-related histories of patients who were initially not implicated. Bayesian structural time series and autoregressive integrated moving average models were used to determine causality., Results: Glomerular diseases occurred shortly after the infection or vaccination. The most prevalent postinfection GN was podocytopathy (42.9%), comprising primary focal segmental glomerulosclerosis and minimal change disease, whereas postvaccination GN mainly included immunoglobulin A nephropathy (IgAN; 57.9%) and Henoch-Schönlein purpura nephritis (HSP; 15.8%). No patient progressed to end-stage kidney disease. Among the patients who were initially not implicated, nine patients with IgAN/HSP were recently vaccinated against COVID-19. The proportion of glomerular diseases changed during the pandemic in South Korea, with an increase in acute interstitial nephritis and a decrease in pauci-immune crescentic GN., Conclusion: This study showed the characteristics of GNs following COVID-19 infection or vaccination in South Korea. Understanding these associations is crucial for developing effective patient management and vaccination strategies. Further investigation is required to fully comprehend COVID-19's impact on GN.

Background: This study aimed to develop a machine learning-based 2-year risk prediction model for early identification of patients with rapid progressive immunoglobulin A nephropathy (IgAN). We also assessed the model's performance to predict the long-term kidney-related outcome of patients., Methods: A retrospective cohort of 1,301 patients with biopsy-proven IgAN from two tertiary hospitals was used to derive and externally validate a random forest-based prediction model predicting primary outcome (30% decline in estimated glomerular filtration rate from baseline or end-stage kidney disease requiring renal replacement therapy) and secondary outcome (improvement of proteinuria) within 2 years after kidney biopsy., Results: For the 2-year prediction of primary outcomes, precision, recall, area-under-the-curve, precision-recall-curve, F1, and Brier score were 0.259, 0.875, 0.771, 0.242, 0.400, and 0.309, respectively. The values for the secondary outcome were 0.904, 0.971, 0.694, 0.903, 0.955, and 0.113, respectively. From Shapley Additive exPlanations analysis, the most informative feature identifying both outcomes was baseline proteinuria. When Kaplan-Meier analysis for 10-year kidney outcome risk was performed with three groups by predicting probabilities derived from the 2-year primary outcome prediction model (low, moderate, and high), high (hazard ratio [HR], 13.00; 95% confidence interval [CI], 9.52-17.77) and moderate (HR, 12.90; 95% CI, 9.92-16.76) groups showed higher risks compared with the low group. From the 2-year secondary outcome prediction model, low (HR, 1.66; 95% CI, 1.42-1.95) and moderate (HR, 1.42; 95% CI, 0.99-2.03) groups were at greater risk for 10-year prognosis than the high group., Conclusion: Our machine learning-based 2-year risk prediction models for the progression of IgAN showed reliable performance and effectively predicted long-term kidney outcome.

Objectives: Neuroendocrine tumors (NETs) are a heterogeneous group of tumors that arise at various sites throughout the body. The gastroenteropancreatic (GEP) tract is the most common site of NETs. We investigated the clinicopathologic features of patients with GEP-NETs and the utility of digital image analysis, which was compared to eyeball estimation, a conventional method used to determine the Ki-67 labeling index., Methods: The clinicopathologic data of GEP-NET patients at Gangnam Severance Hospital from January 2008 to October 2019 were retrospectively analyzed. Each case was reclassified according to the 2019 World Health Organization classification system, to which the classification of grade 3 was added. Comparisons between eyeball estimation and the digital image analysis method for Ki-67 index assessment were performed by calculating Cohen's kappa (k) coefficient., Results: In total, 345 patients with GEP-NETs were enrolled. The mean age was 49.3 (range 13-79) years, with more male (61.1%) than female patients. The primary tumor sites were the rectum (70.1%), pancreas (12.5%), stomach (6.7%), and duodenum (5.8%). Overall, 298 (86.4%), 35 (10.1%), 2 (0.6%), and 10 (2.9%) patients exhibited grade 1, 2, and 3 and neuroendocrine carcinoma, respectively. Statistical analysis revealed that age > 50 years, tumor size > 2 cm, and presence of lymphovascular invasion, nodal metastasis, and distant metastasis were significantly associated with short overall survival. Additionally, 283 patients underwent digital image analysis of the Ki-67 index, and substantial agreement was found between the two methods (κ value: 0.765)., Conclusions: Eyeball estimation revealed non-inferior results compared with digital image analysis. Further research is needed to evaluate the possibility of using digital image analysis as an alternative analysis method., Competing Interests: None., (IJCEP Copyright © 2023.)

This study investigated whether histopathological classification and histologic lesion scores could significantly and independently predict the progression to end-stage kidney disease (ESKD) in Korean patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis-glomerulonephritis (AAV-GN). This study included 113 patients with AAV-GN confirmed by kidney biopsy. The glomerular, tubulointerstitial, and vascular lesions were systematically assessed using a scoring system. The scoring system was adopted from the Banff scoring system but also the Oxford study and the revision of the ISN/RPS. For comparison, the scores were classified into two groups; the low, and the high, and the difference was investigated between ESKD and non-ESKD groups using Cox proportional analysis. At diagnosis, the median age was 59.0 years and 33.6% were males. Of 113 patients, 44.2% had ESKD progression during follow-up. There were significant differences in several kidney-, inflammation-, and AAV-pathogenesis-related variables between AAV-GN patients with ESKD and those without. The sclerotic class exhibited the worst renal prognosis among the four histopathological classes. Among histopathological features, high interstitial fibrosis, tubular atrophy and global glomerulitis scores were significantly associated with ESKD progression. Whereas multivariable Cox analysis revealed only a high global glomerulitis score which means global endocapillary hypercellularity in a larger number of glomeruli is an independent predictor of ESKD progression. Moreover, among clinical and histopathological features, a high global glomerulitis score could also predict ESKD progression in addition to serum blood urea nitrogen and creatinine. This study demonstrated the worst renal prognosis for the sclerotic class and first discovered that a high global glomerulitis score was an independent predictor of ESKD in patients with AAV-GN., (© 2023. Springer Nature Limited.)

Rationale: The World Health Organization defines a perivascular epithelioid cell tumor (PEComa) as a mesenchymal neoplasia composed of perivascular epithelioid cells with characteristic morphological and immunohistochemical features. Although PEComas have the potential to behave in a malignant fashion, malignant PEComas are extremely rare., Patient Concerns: An 83-year-old man visited our clinic presented with palpable, painless, and movable mass in the right knee area., Diagnoses: Malignant PEComa was diagnosed by incisional biopsy. No metastases was confirmed by radiologic imaging including PET/CT, magnetic resonance imaging, high resolution computed tomography., Interventions: We performed wide excision of the mass and used an anterolateral thigh free flap to reconstruct the defect on the right knee., Outcomes: The permanent histopathology showed malignant PEComa was totally resected. The flap which was performed to cover the defect was survived and the patient discharge without any complications., Lessons: PEComa can metastasize to various anatomical regions. Although there is no established standardized treatment, radical resection is still considered the cornerstone of treatment. Rapid and appropriate defect coverage is important to improve the patient's prognosis., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Free tissue transfer is the preferred method of reconstructing head and neck defects, with a success rate of approximately 95%. Although flap failure is uncommon, it has a major impact on patient morbidity and diminishes quality of life, making it is important to investigate the causes of flap failure., Methods: This retrospective chart review analyzed patients who underwent free tissue transfer during head and neck reconstruction at a single institution between 2016 and 2021., Results: During the study period, 58 patients underwent 60 free flap procedures. Revision surgery was needed in 14 patients. Subsequent free flap surgery was performed in one patient, and three free flaps (5%) could not be salvaged. Cardiovascular disease was significantly associated with flap failure, and venous congestion (thrombosis) was the most common reason for revision surgery., Conclusion: Cardiovascular disease clearly emerged as a factor related to the failure of free flap surgery, and this issue warrants particular attention in patients for whom free tissue transfer is planned.

The National Institutes of Health (NIH) lupus nephritis activity and chronicity indices, which comprise six activity scores and four chronicity scores, have a long development history. The 2018 revised International Society of Nephrology/Renal Pathology Society classification for lupus nephritis adopted the most recent NIH indices to replace subclasses A, C, and A/C. Although an evidence-based approach should further evaluate the clinical significance of the modified NIH indices, recent validation studies demonstrated that the modified chronicity indices have a strong correlation with kidney outcome of lupus nephritis.

Background: Acute lung injury (ALI) is the most serious complication of subarachnoid hemorrhage (SAH). We investigated role of autophagy and inflammatory signaling pathways in lung damage and therapeutic effects of dexmedetomidine (DEX)., Methods: Fifty male Wistar rats were randomly divided into five groups: sham, SAH, SAH+ DEX5, SAH+DEX25, and SAH+DEX50. SAH was induced using endovascular perforation technique. All rats received mechanical ventilation for 60 minutes. At 2 and 24 h of SAH induction, SAH+DEX groups were treated with 5, 25, and 50 µg/kg of DEX, respectively. Histological ALI score and pulmonary edema were assessed after 48 h. Lung expression of LC3B, ATG3, p62, TLR4, TLR9, and NFκB was assessed using western blotting and quantitative PCR. Blood levels of IL-6, IL-1β, IFN-γ, and TNFα were also assessed., Results: SAH induced ALI and pulmonary edema, which were attenuated in SAH+DEX5 (P < 0.001 for both) and SAH+DEX25 groups (P = 0.001 and P < 0.001 for ALI and edema, respectively). Lung expressions of LC3B and ATG3 were upregulated in SAH group, which was attenuated in SAH+DEX5 and SAH+DEX25 groups. Lung expressions of TLR4, TLR9, and NFκB were increased in SAH group, which was attenuated in SAH+DEX5 group. Blood IL-6 level was increased in SAH group and attenuated in SAH+DEX5 and SAH+DEX25 groups. Blood IFN-γ level was lower in SAH group than in sham group, and it was increased in SAH+DEX25 group., Conclusions: Low-dose DEX treatment after SAH may protect against ALI by disrupting pathological brain-lung crosstalk and alleviating autophagy flux and TLR-dependent inflammatory pathways.

Tubulointerstitial fibrosis is characterized by accumulation of the extracellular matrix in the interstitium. Lysyl oxidase-like 2 (LOXL2), a member of the lysyl oxidase family, is known for promoting cancer metastasis, invasion and stromal fibrosis in various organs. Our previous study demonstrated expression of LOXL2 in kidney podocytes and tubular epithelial cells, and the association between elevated LOXL2 and tubulointerstitial fibrosis. The present study evaluated the effect of LOXL2 inhibition using an inhibitory monoclonal antibody (AB0023) on tubulointerstitial fibrosis in a folic acid-induced tubulointerstitial fibrosis mouse model. The association of LOXL2 with epithelial-mesenchymal transformation-related molecules was also evaluated in vitro using HK-2 cells. The present data demonstrated that AB0023 prevented the progression of tubulointerstitial fibrosis significantly, as determined by trichrome and picro-sirius red staining, as well as the total collagen assay. The mean expression of phosphorylated Smad2 and Smad4 was lower in the AB0023-treated group although it was not statistically significant. Following transforming growth factor-β (TGF-β) challenge, LOXL2-deficient HK-2 cells exhibited significantly lower expression of the mesenchymal markers vimentin and fibronectin than control HK-2 cells. In conclusion, LOXL2 inhibition ameliorates renal fibrosis through the TGF-β/Smad signalling pathway., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Choi et al.)

Background: The International IgA Nephropathy Prediction Tool has been recently developed to estimate the progression risk of immunoglobulin A nephropathy (IgAN). This study aimed to evaluate the clinical performance of this prediction tool in a large IgAN cohort in Korea., Methods: The study cohort was comprised of 2,064 patients with biopsy-proven IgAN from four medical centers between March 2012 and September 2021. We calculated the predicted risk for each patient. The primary outcome was occurrence of a 50% decline in estimated glomerular filtration rate (eGFR) from the time of biopsy or end-stage kidney disease. The model performance was evaluated for discrimination, calibration, and reclassification. We also constructed and tested an additional model with a new coefficient for the Korean race., Results: During a median follow-up period of 3.8 years (interquartile range, 1.8-6.6 years), 363 patients developed the primary outcome. The two prediction models exhibited good discrimination power, with a C-statistic of 0.81. The two models generally underestimated the risk of the primary outcome, with lesser underestimation for the model with race. The model with race showed better performance in reclassification compared to the model without race (net reclassification index, 0.13). The updated model with the Korean coefficient showed good agreement between predicted risk and observed outcome., Conclusion: In Korean IgAN patients, International IgA Nephropathy Prediction Tool had good discrimination power but underestimated the risk of progression. The updated model with the Korean coefficient showed acceptable calibration and warrants external validation.

Background: Although the transcatheter closure of atrial septal defect was established as the treatment of choice several decades ago, the process of device neoendothelialization (NE) in humans is not well understood. We aimed to measure the extent of device NE using cardiac computed tomography angiography and analyze its risk factors., Methods: Between January 2005 and February 2021, we retrospectively reviewed 164 devices of 112 patients on cardiac computed tomography angiography. We investigated device shape, contrast opacification within the device that differentiated device NE, and device-related thrombosis or vegetation. Risk factor analysis for major adverse cardiovascular events and incomplete NE according to the postprocedural period was performed., Results: Seventy patients (62.5%) were women, with a median (range) age at the time of device closure of 44.5 (0.6-79.2) years. The mean (±SD) defect size was 16.6 (±7.8) mm, and patients were followed for 35.9±33.9 months. After 6 months of device implantation, 35% of the devices (42/120) had incomplete NE. The intensity of intradevice opacification shifted from complete to partial or nonopacification over time ( P <0.001), and a similar pattern was observed in the shunt flow ( P <0.001). The bulkiness of devices also decreased in proportion to the postprocedural period ( P <0.001). Risk analysis revealed device diameter (hazard ratio, 1.18 [95% CI, 1.04-1.27]; P <0.001) as the only significant factor of incomplete NE and major adverse events., Conclusions: Incomplete NE of atrial septal defect devices was identified on cardiac computed tomography angiography in significant numbers after 6 months of the procedure. The device diameter was related to incomplete NE and major adverse events. Further prospective and multicenter studies are warranted to validate this new assessment of device NE.

Microsatellite instability (MSI)/defective DNA mismatch repair (dMMR) is receiving more attention as a biomarker for eligibility for immune checkpoint inhibitors in advanced diseases. However, due to high costs and resource limitations, MSI/dMMR testing is not widely performed. Some attempts are in progress to predict MSI/dMMR status through histomorphological features on H&E slides using artificial intelligence (AI) technology. In this study, the potential predictive role of this new methodology was reviewed through a systematic review. Studies up to September 2021 were searched through PubMed and Embase database searches. The design and results of each study were summarized, and the risk of bias for each study was evaluated. For colorectal cancer, AI-based systems showed excellent performance with the highest standard of 0.972; for gastric and endometrial cancers they showed a relatively low but satisfactory performance, with the highest standard of 0.81 and 0.82, respectively. However, analyzing the risk of bias, most studies were evaluated at high-risk. AI-based systems showed a high potential in predicting the MSI/dMMR status of different cancer types, and particularly of colorectal cancers. Therefore, a confirmation test should be required only for the results that are positive in the AI test.

Background/aims: Despite controversy regarding the benefits of immunosuppressive therapy in immunoglobulin A nephropathy (IgAN), clinical outcomes may vary depending on the patient's responsiveness to this therapy. This study evaluated long-term kidney outcomes according to the extent of proteinuria reduction after immunosuppression in IgAN patients., Methods: Among 927 patients with biopsy-proven IgAN, 127 patients underwent immunosuppression. Time-averaged urine protein-creatinine ratio before and within 1 year after start of immunosuppression were calculated, and responsiveness to immunosuppression was assessed as the reduction of proteinuria between the two periods. Patients were classified into tertiles according to the extent of proteinuria reduction. We compared the slopes of estimated glomerular filtration rate (eGFR) decline using a linear mixed model, and estimated hazard ratios (HRs) for disease progression (defined as development of a ≥ 30% decline in eGFR or end-stage renal disease) using a Cox proportional hazard model., Results: Median extent of proteinuria reduction was -2.1, -0.9, and -0.2 g/gCr in the first, second, and third tertiles, respectively. There were concomitant changes in the slopes of annual eGFR decline: -2.03, -2.44, and -4.62 mL/min/1.73 m2 among the first, second, and third tertiles, respectively. In multivariable Cox analysis, the HRs (95% confidence intervals) for disease progression were 0.30 (0.12 to 0.74) in the first tertile and 0.70 (0.34 to 1.45) in the second tertile compared with the thirdtertile., Conclusion: This study showed that greater proteinuria reduction after immunosuppression was associated with a lower risk of disease progression in patients with IgAN, suggesting that responsiveness to immunosuppression may be an important determinant of kidney outcomes.

Background : Frameshift indels have emerged as a predictor of immunotherapy response but were not evaluated yet to predict anti-angiogenetic agent (AAA) response or prognosis in clear cell renal cell carcinoma (ccRCC). Methods : Here, to develop biomarkers that predict survival and response to AAA, we evaluated the immunohistochemical expression of proteins whose genes frequently harbor frameshift indels in 638 ccRCC patients and correlated the individual and integrated markers with prognosis and AAA response. The mutational landscape was evaluated using targeted next-generation sequencing in 12 patients concerning protein markers. Immune gene signatures were retrieved from TCGA RNA seq data. Results : Five proteins (APC, NOTCH1, ARID1A, EYS, and filamin A) were independent adverse prognosticators and were incorporated into the Neo-fs index. Better overall, disease-specific and recurrence-free survival were observed with high Neo-fs index in univariate and multivariate survival analyses. Better AAA responses were observed with a high Neo-fs index, which reflected increased MHC class I, CD8+ T cell, cytolytic activity, and plasmacytoid dendritic cell signatures and decreased type II-IFN response signatures, as well as greater single-nucleotide variant (SNV) and indel counts. Conclusions : Neo-fs index, reflecting antitumor immune signature and more SNVs. and indels, is a powerful predictor of survival and AAA response in ccRCC.

Interleukin-4 (IL-4) expression is implicated in the pathogenesis of nephrotic syndrome (NS). This study aimed to investigate the changes in the transcriptomes of human podocytes induced by IL-4 treatment and to analyze whether these changes could be affected by simultaneous steroid treatment. Three groups of human podocytes were treated with control, IL-4, and IL-4 plus dexamethasone (DEX), respectively. We performed whole-transcriptome sequencing to identify differentially expressed genes (DEGs) between the groups. We investigated relevant biological pathways using Gene Ontology (GO) enrichment analyses. We also attempted to compare and validate the DEGs with the genes listed in PodNet, a literature-based database on mouse podocyte genes. A total of 176 genes were differentially expressed among the three groups. GO analyses showed that pathways related to cytoskeleton organization and cell signaling were significantly enriched. Among them, 24 genes were listed in PodNet, and 12 of them were previously reported to be associated with IL-4-induced changes in human podocytes. Of the 12 genes, the expression levels of BMP4 , RARB , and PLCE1 were reversed when podocytes were simultaneously treated with DEX. In conclusion, this study explored changes in the transcriptome profiles of human podocytes treated with IL-4. Few genes were reported in previous studies and were previously validated in experiments with human podocytes. We speculate that IL-4 may exert pathogenic effects on the transcriptome of human podocytes, and a few genes may be involved in the pathogenesis.

Background: Complement activation has been highlighted in immunoglobulin (Ig) A nephropathy pathogenesis. However, whether the complement system can affect the downstream phenotype of IgA nephropathy remains unknown. Herein, we investigated the association of mesangial C3 deposition with the Oxford classification and their joint effects on worsening kidney function., Methods: We investigated 453 patients with biopsy-proven IgA nephropathy. C3 deposition was defined as an immunofluorescence intensity of C3 ≥2+ within the mesangium. The subjects were classified according to the combination of C3 deposition and Oxford classification lesions. The primary endpoint was a composite of ≥30% decline in the estimated glomerular filtration rate or an increase in proteinuria ≥3.5 g/g during follow-up., Results: Among the Oxford classification lesions, mesangial hypercellularity (M1), segmental glomerulosclerosis (S1) and tubulointerstitial fibrosis (T1-2) and crescentic lesion significantly correlated with C3 deposition. During a median follow-up of 33.0 months, the primary endpoint occurred more in patients with M1, S1, T1-2 and mesangial C3 deposition than in those without. In individual multivariable-adjusted Cox analyses, the presence of M1, S1, T1-2 and C3 deposition was significantly associated with higher risk of reaching primary endpoint. In the combined analyses of C3 deposition and the Oxford classification lesions, the hazard ratios for the composite outcome were significantly higher in the presence of C3/M1, C3/S1 and C3/crescent than in the presence of each lesion alone., Conclusions: Complement deposition can strengthen the significance of the Oxford classification, and the presence of both components portends a poorer prognosis in IgA nephropathy., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Extracellular adenosine 5'-triphosphate (ATP) is a well-known inflammasome-activating signal. Emerging evidence demonstrates a critical role for inflammasome activation in vitiligo pathogenesis. However, the specific molecular mechanism of inflammasome-dependent melanocyte degeneration in vitiligo is still not clear. This study presents how extracellular ATP, released from keratinocytes by oxidative stress, affects melanocyte survival in vitiligo skin. H 2 O 2 -induced oxidative injury increased ATP release from keratinocytes and skin tissues. The high concentration of extracellular ATP induced both ROS production and cell death in melanocytes. Treatment with ATP caused the activation of caspase-1 as well as the production of active forms of IL-1β and IL-18 via P2X7 receptor in keratinocytes and melanocytes. Lesional and perilesional skin of vitiligo showed higher levels of ATP as well as upregulation of active caspase-1 compared with nonlesional skin, suggesting its possible role in inflammasome activation in vitiligo. Moreover, the elevated expression of CXCL9 in keratinocytes, mediated through ATP/P2X7 receptor-dependent inflammasome activation, was responsible for CLA + CD8 + T-cell chemotaxis into the skin. These results demonstrate that extracellular ATP as a danger signal activates the inflammasome pathway and increases cutaneous chemotaxis of CD8 + T cells via CXCL9 in vitiligo. Therefore, targeting ATP-P2X7 signaling may be a potential strategy for vitiligo treatment., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Backgrounds: Glomerular diseases, a set of debilitating and complex disease entities, are related to mortality and morbidity. To gain insight into pathophysiology and novel treatment targets of glomerular disease, various types of biospecimens linked to deep clinical phenotyping including clinical information, digital pathology, and well-defined outcomes are required. We provide the rationale and design of the KOrea Renal biobank NEtwoRk System TOward Next-generation analysis (KORNERSTONE)., Methods: The KORNERSTONE, which has been initiated by Korea Centres for Disease Control and Prevention, is designed as a multi-centre, prospective cohort study and biobank for glomerular diseases. Clinical data, questionnaires will be collected at the time of kidney biopsy and subsequently every 1 year after kidney biopsy. All of the clinical data will be extracted from the electrical health record and automatically uploaded to the web-based database. High-quality digital pathologies are obtained and connected in the database. Various types of biospecimens are collected at baseline and during follow-up: serum, urine, buffy coat, stool, glomerular complementary DNA (cDNA), tubulointerstitial cDNA. All data and biospecimens are processed and stored in a standardised manner. The primary outcomes are mortality and end-stage renal disease. The secondary outcomes will be deterioration renal function, remission of proteinuria, cardiovascular events and quality of life., Discussion: Ethical approval has been obtained from the institutional review board of each participating centre and ethics oversight committee. The KORNERSTONE is designed to deliver pioneer insights into glomerular diseases. The study design allows comprehensive, integrated and high-quality data collection on baseline laboratory findings, clinical outcomes including administrative data and digital pathologic images. This may provide various biospecimens and information to many researchers, establish the rationale for future more individualised treatment strategies for glomerular diseases., Trial Registration: NCT03929887 .

A new species of Diosaccus Boeck, 1873 (Arthropoda, Hexanauplia, Harpacticoida) was recently discovered in Korean waters. The species was previously recognized as D. ezoensis Itô, 1974 in Korea but, here, is described as a new species, D. koreanus sp. nov. , based on the following features: 1) second inner seta on exopod of fifth thoracopod apparently longest in female, 2) outer margin of distal endopodal segment of second thoracopod ornamented with long setules in male, 3) caudal seta VII located halfway from base of rami (vs. on anterior extremity in D. ezoensis ), and 4) sixth thoracopod with three setae in female (vs. 2 setae in D. ezoensis ). In addition, there is also a mitochondrial COI sequence difference of more than 19.93% with D. ezoensis registered in NCBI. A key to Diosaccus species of the world is also provided, and new morphological features and DNA sequences are presented for two other harpacticoid species, Parathalestris verrucosa Itô, 1970 and Peltidium quinquesetosum Song & Yun, 1999. In order to clearly identify harpacticoids at the species level, both morphological and DNA sequence characteristics should be considered., (Byung-Jin Lim, Hyun Woo Bang, Heejin Moon, Jinwook Back.)

The mitochondrial genome of a dogielinotid amphipod, Haustorioides koreanus , was completely sequenced for the first time. The total mitogenome length of H . koreanus was 14,839 bp with 13 protein-coding genes, two ribosomal RNA genes, and 22 transfer RNA genes. The phylogenetic tree confirmed that H. koreanus belongs to the families Hyalellidae in the same clade and to the suborder Senticaudata within Amphipoda. This is the first record of the complete mitochondrial genome sequence of the family Dogielinotidae., Competing Interests: The authors declare no conflict of interest. The authors alone are responsible for the content and writing of the paper., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

The present study reports, for the first time, the complete mitochondrial genome (mitogenome) of Undinula vulgaris . The total mitogenome length of U. vulgaris was 15,303 bp with 13 protein-coding genes (PCGs), 2 ribosomal RNAs (rRNAs), 22 transfer RNAs (tRNAs), and 1 non-coding region. Phylogenetic analysis showed that U. vulgaris belonged to the same family. This is the second report of the complete mitogenome sequence of the family Calanidae., Competing Interests: The authors declare that they do not have any conflict of interest. The authors alone are responsible for the content and writing of the paper., (© 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Objective: To develop a diagnostic model for superficial soft tissue lesions to differentiate epidermal cyst (EC) from other lesions based on ultrasound (US) features., Materials and Methods: This retrospective study included 205 patients who had undergone US examinations for superficial soft tissue lesions and subsequent surgical excision. The study population was divided into the derivation set (n = 112) and validation set (n = 93) according to the imaging date. The following US features were analyzed to determine those that could discriminate EC from other lesions: more-than-half-depth involvement of the dermal layer, "submarine sign" (focal projection of the hypoechoic portion to the epidermis), posterior acoustic enhancement, posterior wall enhancement, morphology, shape, echogenicity, vascularity, and perilesional fat change. Using multivariable logistic regression, a diagnostic model was constructed and visualized as a nomogram. The performance of the diagnostic model was assessed by calculating the area under the curve (AUC) of the receiver operating characteristic curve and calibration plot in both the derivation and validation sets., Results: More-than-half-depth involvement of the dermal layer (odds ratio [OR] = 3.35; p = 0.051), "submarine sign" (OR = 12.2; p < 0.001), and morphology (OR = 5.44; p = 0.002) were features that outweighed the others when diagnosing EC. The diagnostic model based on these features showed good discrimination ability in both the derivation set (AUC = 0.888, 95% confidence interval [95% CI] = 0.825-0.950) and validation set (AUC = 0.902, 95% CI = 0.832-0.972)., Conclusion: More-than-half-depth of involvement of the dermal layer, "submarine sign," and morphology are relatively better US features than the others for diagnosing EC., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2019 The Korean Society of Radiology.)

Henoch-Schönlein purpura (HSP) is the most common systemic vasculitis in children, and renal involvement (HSP nephritis, HSPN) is a severe manifestation. HSPN is histologically classified by the International Study of Kidney Disease in Children (ISKDC) based on mesangial hypercellularity and the extent of glomerular crescents. Macrophages, categorized as M1 or M2, frequently infiltrate in various glomerular and tubulointerstitial diseases and infiltration of specific subtypes is associated with disease progression. Therefore, to identify whether infiltration of M1 or M2 macrophages has clinical significance, we quantified the subtypes of macrophages in 49 HSPN specimens and correlated the counts with histologic features and clinical parameters. Higher tubulointerstitial M2 counts were associated with chronic renal failure (CRF), ISKDC classes III-IV, and crescents ( P <0.001, 0.002, 0.001). Glomerular M2 counts were significantly related to ISKDC classes III-IV and crescents (area under curve, AUC 0.804, 0.833). Tubulointerstitial M2 counts were associated with CRF, ISKDC classes III-IV, and crescents (AUC 0.872, 0.778, 0.830). Tubulointerstitial M2 counts also revealed higher AUC than tubulointerstitial M1 counts for CRF ( P =0.036) and ISKDC classes III-IV ( P =0.047). Glomerular M2 counts revealed higher AUC than glomerular M1 counts for ISKDC classes III-IV ( P =0.024). Tubulointerstitial M2 counts were the most powerful parameter for CRF (AUC 0.872) and revealed even higher AUC than ISKDC classification (AUC 0.716) with borderline significance ( P =0.086) for CRF. In summary, tubulointerstitial M2 counts were a superior parameter to tubulointerstitial M1 counts and even to ISKDC classification indicating the presence of CRF.

Human cytomegalovirus (HCMV) infection can cause inflammatory tissue-invasive end-organ diseases upon lytic replication. In humans, mature miR-200b-3p and -200c-3p suppress the synthesis of HCMV immediate early 2 (IE2) protein by binding to the 3'-UTR of the mRNA encoded by the unique long (UL) 122-123 region in human foreskin fibroblasts and pre-transplant peripheral blood mononuclear cells stimulated with HCMV. The present study aimed to quantitate the expression of Homo sapiens (hsa)-miR-200b-3p and 200c-3p in HCMV-infected tissues. We collected 240 HCMV-infected and 154 HCMV-non-infected, formalin-fixed, paraffin-embedded tissue samples of the gastrointestinal (GI) tract and bronchi/lungs. MiRNAs, HCMV, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were quantitated by quantitative reverse transcription-PCR (qRT-PCR) and quantitative PCR (qPCR) on the basis of standard curves generated using miRNA mimics, the HCMV strain from National Institute for Biological Standards and Control (NIBSC) 09/162, and GAPDH control. To avoid the effect of cell counts on the qRT-PCR and qPCR results, the data were normalized to GAPDH levels. HCMV-infected tissues had significantly lower levels of 200b-3p/GAPDH (3.03 ± 1.50 compared with 3.98 ± 1.08 log 10 copies/μl, P <0.001) and 200c-3p/GAPDH (4.67 ± 1.84 compared with 6.35 ± 1.47 log 10 copies/μl, P <0.001) than normal tissues. The values for 200b-3p/GAPDH ( r = -0.51, P <0.001) and 200c-3p/GAPDH ( r = -0.54, P <0.001) were significantly inversely correlated with HCMV load. Low tissue levels of 200b-3p and 200c-3p in humans are associated with cytopathic inflammation due to HCMV infection., (© 2018 The Author(s).)

Background: Platelet-derived growth factor receptor α (PDGFRα) expression is increased in activated hepatic stellate cells (HSCs) in cirrhotic liver, while normal hepatocytes express PDGFRα at a negligible level. However, cancerous hepatocytes may show upregulation of PDGFRα, and hepatocellular carcinoma is preceded by chronic liver injury. The role of PDGFRα in non-cancerous hepatocytes and liver fibrosis is unclear. We hypothesized that upon liver injury, PDGFRα in insulted hepatocytes contributes to liver fibrosis by facilitating intercellular crosstalk between hepatocytes and HSCs., Methods: Hepatocytes were isolated from normal and thioacetamide (TAA)-induced cirrhotic livers for assessment of PDGFRα expression. Conditional knock-out (KO) C57BL/6 mice, in which PDGFRα was selectively deleted in hepatocytes, were generated. Liver fibrosis was induced by injecting TAA for 8 weeks. Hep3B cells were transfected with a small interfering RNA (siRNA) (PDGFRα or control) and co-cultured with LX2 cells., Results: PDGFRα expression was increased in hepatocytes from fibrotic livers compared to normal livers. Conditional PDGFRα KO mice had attenuated TAA-induced liver fibrosis with decreased HSC activation and proliferation. Immunoblot analyses revealed decreased expression of phospho-p44/42 MAPK in TAA-treated KO mice; these mice also showed almost complete suppression of the upregulation of mouse double minute 2. Although KO mice exhibited increased expression of transforming growth factor (TGF)-β and Smad2/3, this was compensated for by increased expression of inhibitory Smad7. LX2 cells co-cultured with PDGFRα siRNA-infected Hep3B cells showed decreased PDGFRα, α smooth muscle actin, collagen α1(I), TGFβ, and Smad2/3 expression. LX2/PDGFRα-deleted hepatocyte co-culture medium showed decreased PDGF-BB and PDGF-CC levels., Conclusions: Deletion of PDGFRα in hepatocytes attenuated the upregulation of PDGFRα in HSCs after TAA treatment, resulting in decreased liver fibrosis and HSC activation. This suggests that in the event of chronic liver injury, PDGFRα in hepatocytes plays an important role in liver fibrosis by affecting PDGFRα expression in HSCs.

Several experimental studies implicate uric acid in renal injury and fibrosis. The objective of this study was to examine the association between uric acid level and allograft fibrosis after kidney transplantation. 241 adult patients who underwent kidney transplantation between 2003 and 2014 were divided into three groups according to the sex specific tertiles of mean uric acid level within the first post-transplant year. The renal biopsies performed during 1 to 5 post-transplant year were analyzed to compare the degree of interstitial fibrosis and tubular atrophy (IF/TA). Mean interval between kidney transplantation and biopsy was similar between groups (23.7 ± 15.3 vs. 30.0 ± 18.6 vs. 27.5 ± 18.5 months, P = 0.072). The higher tertile uric acid level was, the more advanced grade of IF/TA was shown (P = 0.001). Multivariate analysis identified uric acid tertile was independent risk factor for severe IF/TA (odds ratio [95% confidence interval] was 3.16 [1.13-8.82] for tertile 2 and 3.70 [1.25-10.93] for tertile 3, versus tertile 1, respectively). Other independent factors were estimated glomerular filtration rate at 1year post-transplant (0.80 [CI 0.65-0.98]) and biopsy-proven rejection (2.34 [1.05-5.21]). Graft survival over 10 years was significantly lower in tertile 3 (P = 0.041). The results showed that higher uric acid level after kidney transplantation was associated with more severe IF/TA.

Background: Warthin-like variant of papillary thyroid carcinoma (WLV-PTC) is a relatively rare variant of papillary thyroid carcinoma with favorable prognosis. However, preoperative diagnosis using fine-needle aspiration (FNA) specimens is challenging especially with lymphocytic thyroiditis characterized by Hürthle cells and lymphocytic background. To determine a helpful cytological differential point, we compared WLV-PTC FNA findings with conventional papillary thyroid carcinoma with lymphocytic thyroiditis (PTC-LT) and conventional papillary thyroid carcinoma without lymphocytic thyroiditis (PTC) regarding infiltrating inflammatory cells and their distribution. Preoperative diagnosis or potential for WLV-PTC will be helpful for surgeons to decide the scope of operation., Methods: Of the 8,179 patients treated for papillary thyroid carcinoma between January 2007 and December 2012, 16 patients (0.2%) were pathologically confirmed as WLV-PTC and four cases were available for cytologic review. For comparison, we randomly selected six PTC-LT cases and five PTC cases during the same period. The number of intratumoral and background lymphocytes, histiocytes, neutrophils, and the presence of giant cells were evaluated and compared using conventional smear and ThinPrep preparations., Results: WLV-PTC showed extensive lymphocytic smear with incorporation of thyroid follicular tumor cell clusters and frequent histiocytes. WLV-PTC was associated with higher intratumoral and background lymphocytes and histiocytes compared with PTC-LT or PTC. The difference was more distinct in liquid-based cytology., Conclusions: The lymphocytic smear pattern and the number of inflammatory cells of WLV-PTC are different from those of PTC-LT or PTC and will be helpful for the differential diagnosis of WLV-PTC in preoperative FNA.

Mucin1 (MUC1), a heterodimeric oncoprotein, containing tandem repeat structures with a high proportion of threonine, is aberrantly overexpressed in many human cancers including pancreatic cancer. Since the overall survival rate of pancreatic cancer patients has remained low for several decades, novel therapeutic approaches are highly needed. Intestinal mucin has been known to be affected by dietary threonine supply since de novo synthesis of mucin proteins is sensitive to luminal threonine concentration. However, it is unknown whether biosynthesis of MUC1 is regulated by threonine in human cancers. In this study, data provided suggests that threonine starvation reduces the level of MUC1 and inhibits the migration of MUC1-expressing pancreatic cancer cells. Interestingly, knockdown of threonyl-tRNA synthetase (TRS), an enzyme that catalyzes the ligation of threonine to its cognate tRNA, also suppresses MUC1 levels but not mRNA levels. The inhibitors of TRS decrease the level of MUC1 protein and prohibit the migration of MUC1-expressing pancreatic cancer cells. In addition, a positive correlation between TRS and MUC1 levels is observed in human pancreatic cancer cells. Concurrent with these results, the bioinformatics data indicate that co-expression of both TRS and MUC1 is correlated with the poor survival of pancreatic cancer patients. Taken together, these findings suggest a role for TRS in controlling MUC1-mediated cancer cell migration and provide insight into targeting TRS as a novel therapeutic approach to pancreatic cancer treatment.

Chronic glomerular injury is associated with eventual development of tubulointerstitial fibrosis. Here we aimed to assess whether, and how, mild chronic tubulointerstitial injury affects glomeruli. For this, we generated mice expressing different toxin receptors, one on their proximal tubular epithelial cells (diphtheria toxin receptor [DTR]) and the other only on podocytes (human CD25 [IL-2R] driven by the nephrin promoter [Nep25]), allowing serial induction of tubule-specific and glomerular (podocyte)-specific injury, respectively. Six weeks after diphtheria toxin injection, mild interstitial fibrosis was found in Nep25 + /DTR + , but not in Nep25 + /DTR - mice. However, atubular glomeruli and neuronal nitric oxide synthase, a mediator of tubuloglomerular feedback, were higher in Nep25 + /DTR + than in DTR - mice and these atubular glomeruli had less podocyte density as assessed by WT-1 biomarker expression. Peritubular capillary density, hypoxia-inducible factor-1 and -2, and cyclooxygenase 2 expression were similar at week six in the two groups. At week seven, all mice were given the immunotoxin LMB-2, which binds to CD25 to induce podocyte injury. Ten days later, proteinuria, podocyte injury, and glomerulosclerosis were more severe in Nep25 + /DTR + than Nep25 + /DTR - mice with more severe sclerosis in the tubule-connected glomeruli. This supports the concept that even mild preexisting tubulointerstitial injury sensitizes glomeruli to subsequent podocyte-specific injury. Thus, increased atubular glomeruli and abnormal tubuloglomerular feedback significantly contribute to the crosstalk between the tubulointerstitium and glomeruli., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Proteinuria is a major determinant of adverse renal outcome, and its reduction slows renal progression in glomerular diseases. However, the optimal target of proteinuria in glomerular diseases is unclear, and discrepancies in the definition of proteinuria produce ambiguous findings. Here we investigated the optimal target of proteinuria by using different definitions of proteinuria. We analyzed 574 IgA nephropathy (IgAN), 175 membranous nephropathy (MGN), and 177 focal segmental glomerulosclerosis (FSGS) cases from 3 Korean kidney centers. We evaluated the impact of proteinuria on renal outcome with 2 definitions: time-average proteinuria (TAP) and time-varying proteinuria (TVP). The endpoint was renal progression, defined as a 50% decline in glomerular filtration rate or end-stage renal disease. During a median follow-up of 57.3 months, the primary outcome occurred in 54 patients with IgAN, 26 with MGN, and 30 with FSGS. Multivariate Cox regression using TAP indicated that there was a linear association between proteinuria and risk of renal progression in IgAN. However, moderate proteinuria was not associated with an increased risk of renal progression in MGN and FSGS. In contrast, the analysis by TVP showed that the risk significantly increased in proportion to proteinuria during follow-up in all 3 diseases. Our findings suggest that TVP-based model can delineate association between proteinuria and risk of renal progression better than TAP-based model, considering that TVP reflects the dynamic change of proteinuria over time. Thus, proteinuria reduction to the lowest possible level is required to improve renal outcomes in patients with glomerular diseases.

Hypoxia-inducible factor (HIF) is a key transcriptional factor in the response to hypoxia. Although the effect of HIF activation in chronic kidney disease (CKD) has been widely evaluated, the results have been inconsistent until now. This study aimed to investigate the effects of HIF-2α activation on renal fibrosis according to the activation timing in inducible tubule-specific transgenic mice with non-diabetic CKD. HIF-2α activation in renal tubular cells upregulated mRNA and protein expressions of fibronectin and type 1 collagen associated with the activation of p38 mitogen-activated protein kinase. In CKD mice, activation of HIF-2α at the beginning of CKD significantly aggravated renal fibrosis, whereas it did not lead to renal dysfunction. However, activation at a late-stage of CKD abrogated both renal dysfunction and fibrosis, which was associated with restoration of renal vasculature and amelioration of hypoxia through increased renal tubular expression of VEGF and its isoforms. As with tubular cells with HIF-2α activation, those under hypoxia also upregulated VEGF, fibronectin, and type 1 collagen expressions associated with HIF-1α activation. In conclusion, late-stage renal tubular HIF-2α activation has protective effects on renal fibrosis and the resultant renal dysfunction, thus it could represent a therapeutic target in late stage of CKD.

Background: Most of the previous studies reported that tacrolimus (TAC) with sirolimus (SRL) was associated with worse post-transplant outcomes in kidney transplantation, compared with TAC with mycophenolate mofetil (MMF). These might be attributable to high-dose SRL. However, outcomes using low-dose SRL with TAC for kidney transplantation are uncertain. The aim of this study was to assess the efficacy and safety of low-dose SRL with extended-release tacrolimus (ER-TAC) versus MMF with ER-TAC., Methods: We randomly assigned 158 renal transplant patients to receive low-dose SRL or MMF in combination with ER-TAC and corticosteroid. The primary endpoint was the composite efficacy failure rate, including biopsy-proven acute rejection (BPAR), graft loss, death or loss to follow-up, within 12 months post-transplantation. This trial is registered with ClinicalTrial.gov (number NCT01680952)., Results: The efficacy failure rate was 6.6% in the low-dose SRL group and 13.3% in the MMF group in the intention-to-treat population (absolute difference, 6.8%; 95% confidence interval, -2.8% to 16.3%). The incidence of BPAR within 12 months post-transplantation was 5.3% in the low-dose SRL group and 13.3% in the MMF group (P = 0.09). The mean estimated glomerular filtration rate at 12 months post-transplantation was 53.2 mL/min/1.73 m2 in the low-dose SRL group and 52.4 mL/min/1.73 m2 in the MMF group (P = 0.76). The incidences of adverse events and serious adverse events were similar between groups., Conclusion: Low-dose SRL with ER-TAC was not inferior to MMF with ER-TAC with respect to efficacy and safety. When used for immunosuppression in kidney transplantation, low-dose SRL with ER-TAC can effectively prevent acute rejection and preserve renal function., (© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Gymnogobius heptacanthus is a small intertidal species belonging to the family Gobiidae. Herein, we report the first sequencing and assembly of the complete mitochondrial genome of G. heptacanthus . The complete mitochondrial genome is 16,529 bp long and has the typical vertebrate mitochondrial gene arrangement, consisting of 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes, and a control region. Phylogenetic analysis using mitochondrial genomes of 12 species showed that G. heptacanthus is clustered with G. urotaenia and G. petschiliensis and rooted with other Gobiidae species. This mitochondrial genome provides potentially important resources for addressing taxonomic issues and studying molecular evolution., Competing Interests: The authors report no conflict of interests. The authors alone are responsible for the content and writing of the paper., (© 2016 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Focal segmental glomerulosclerosis (FSGS) is characterized by focal and segmental obliteration of glomerular capillary tufts with increased matrix. FSGS is classified as collapsing, tip, cellular, perihilar and not otherwise specified variants according to the location and character of the sclerotic lesion. Primary or idiopathic FSGS is considered to be related to podocyte injury, and the pathogenesis of podocyte injury has been actively investigated. Several circulating factors affecting podocyte permeability barrier have been proposed, but not proven to cause FSGS. FSGS may also be caused by genetic alterations. These genes are mainly those regulating slit diaphragm structure, actin cytoskeleton of podocytes, and foot process structure. The mode of inheritance and age of onset are different according to the gene involved. Recently, the role of parietal epithelial cells (PECs) has been highlighted. Podocytes and PECs have common mesenchymal progenitors, therefore, PECs could be a source of podocyte repopulation after podocyte injury. Activated PECs migrate along adhesion to the glomerular tuft and may also contribute to the progression of sclerosis. Markers of activated PECs, including CD44, could be used to distinguish FSGS from minimal change disease. The pathogenesis of FSGS is very complex; however, understanding basic mechanisms of podocyte injury is important not only for basic research, but also for daily diagnostic pathology practice., Competing Interests: No potential conflict of interest relevant to this article was reported.

Common bile duct (CBD) stones are generally associated with greater elevations of alkaline phosphatase and gamma-glutamyl transpeptidase levels than aspartate aminotransferase and alanine aminotransferase levels. However, some patients with CBD stones show markedly increased aminotransferase levels, sometimes leading to the misdiagnosis of liver disease. Therefore, the aim of this study was to investigate the clinicopathologic features of patients with CBD stones and high aminotransferase levels.This prospective cohort study included 882 patients diagnosed with CBD stones using endoscopic retrograde cholangiopancreatography (ERCP). Among these patients, 38 (4.3%) exhibited aminotransferase levels above 400 IU/L without cholangitis (gallstone hepatitis [GSH] group), and 116 (13.2%) exhibited normal aminotransferase levels (control group). We compared groups in terms of clinical features, laboratory test results, radiologic images, and ERCP findings such as CBD diameter, CBD stone diameter and number, and periampullary diverticulum. Liver biopsy was performed for patients in the GSH group.GSH patients were younger and more likely to have gallbladder stones than control patients, implying a higher incidence of gallbladder stone migration. Also, GSH patients experienced more severe, short-lasting abdominal pain. ERCP showed narrower CBDs in GSH patients than in control patients. Histological analysis of liver tissue from GSH patients showed no abnormalities except for mild inflammation.Compared with control patients, GSH patients were younger and showed more severe, short-lasting abdominal pain, which could be due to a sudden increase of CBD pressure resulting from the migration of gallstones through narrower CBDs. These clinical features could be helpful not only for the differential diagnosis of liver disease but also for investigating the underlying mechanisms of liver damage in obstructive jaundice. Moreover, we propose a new definition of "gallstone hepatitis" based on the specific clinicopathologic characteristics observed in our patients., Competing Interests: The authors have no funding and conflicts of interest to disclose.

Dapagliflozin, a new type of drug used to treat diabetes mellitus (DM), is a sodium/glucose cotransporter 2 (SGLT2) inhibitor. Although some studies showed that SGLT2 inhibition attenuated reactive oxygen generation in diabetic kidney the role of SGLT2 inhibition is unknown. We evaluated whether SLT2 inhibition has renoprotective effects in ischemia-reperfusion (IR) models. We evaluated whether dapagliflozin reduces renal damage in IR mice model. In addition, hypoxic HK2 cells were treated with or without SGLT2 inhibitor to investigate cell survival, the apoptosis signal pathway, and the induction of hypoxia-inducible factor 1 (HIF1) and associated proteins. Dapagliflozin improved renal function. Dapagliflozin reduced renal expression of Bax, renal tubule injury and TUNEL-positive cells and increased renal expression of HIF1 in IR-injured mice. HIF1 inhibition by albendazole negated the renoprotective effects of dapagliflozin treatment in IR-injured mice. In vitro, dapagliflozin increased the expression of HIF1, AMP-activated protein kinase (AMPK), and ERK and increased cell survival of hypoxic HK2 cells in a dose-dependent manner. In conclusion, dapagliflozin attenuates renal IR injury. HIF1 induction by dapagliflozin may play a role in renoprotection against renal IR injury.

Glomerular IgG deposition is frequently observed in patients with IgA nephropathy. However, the association between glomerular IgG deposition and progression of IgA nephropathy is uncertain. Six hundred and twenty-seven patients with biopsy-proven IgA nephropathy were recruited. Histological variables of the Oxford classification (Oxford-MEST) and the presence of glomerular IgG deposits were assessed. Renal progression defined as end-stage renal disease or 50% reduction in estimated glomerular filtration rate was analyzed using Kaplan-Meier methods and Cox regression analysis. Of the study population, 200 patients (31.9%) had glomerular IgG deposition on immunofluorescence staining. During a mean follow-up of 56.8±37.5 months, the rate of renal progression was significantly higher in the IgA nephropathy patients with glomerular IgG deposition compared with the IgA nephropathy patients without glomerular IgG deposition (39.8 vs 12.3 per 1000 patient-years; P<0.001). Of patients with IgG deposition, 178 (28.3%), 20 (3.2%), and 2 (0.3%) patients had mild, moderate, and marked glomerular IgG deposits, receptively. Kaplan-Meier analysis revealed that cumulative renal survival was significantly lower in IgA nephropathy patients with the higher intensity of glomerular IgG deposits (P<0.001). In addition, Cox regression analysis revealed that moderate and marked glomerular IgG deposits significantly predicted renal outcome independent of Oxford-MEST and clinical variables (HR, 2.97; 95% CI, 1.01-8.77; P=0.04). This study showed that that glomerular IgG deposition was independently associated with poor renal outcome in patient with IgA nephropathy.

Background: Segmental glomerulosclerosis without significant mesangial or endocapillary proliferation is rarely seen in IgA nephropathy (IgAN), which simulates idiopathic focal segmental glomerulosclerosis (FSGS). We recently recognized aberrant blood vessels running through the adhesion sites of sclerosed tufts and Bowman's capsule in IgAN cases with mild glomerular histologic change., Methods: To characterize aberrant blood vessels in relation to segmental sclerosis, we retrospectively reviewed the clinical and histologic features of 51 cases of FSGS-like IgAN and compared them with 51 age and gender-matched idiopathic FSGS cases., Results: In FSGS-like IgAN, aberrant blood vessel formation was observed in 15.7% of cases, 1.0% of the total glomeruli, and 7.3% of the segmentally sclerosed glomeruli, significantly more frequently than in the idiopathic FSGS cases (p = .009). Aberrant blood vessels occasionally accompanied mild cellular proliferation surrounding penetrating neovessels. Clinically, all FSGS-like IgAN cases had hematuria; however, nephrotic range proteinuria was significantly less frequent than idiopathic FSGS., Conclusions: Aberrant blood vessels in IgAN are related to glomerular capillary injury and may indicate abnormal repair processes in IgAN.

Idiopathic nephrotic syndrome (INS) in children is characterized by massive proteinuria and hypoalbuminemia. Minimal change nephrotic syndrome (MCNS) is the most common form of INS in children. The pathogenesis of MCNS still remains unclear, however, several hypotheses have been recently proposed. For several decades, MCNS has been considered a T-cell disorder, which causes the impairment of the glomerular filtration barrier with the release of different circulating factors. Increased levels of several cytokines are also suggested. Recently, a "two-hit" theory was proposed that included the induction of CD80 (B7-1) and regulatory T-cell (Treg) dysfunction, with or without impaired autoregulatory functions of the podocyte. In contrast to the well-established involvement of T cells, the role of B cells has not been clearly identified. However, B-cell biology has recently gained more attention, because rituximab (a monoclonal antibody directed against CD20-bearing cells) demonstrated a very good therapeutic response in the treatment of childhood and adult MCNS. Here, we discuss recent insights into the pathogenesis of MCNS in children.

The aim of this study was to evaluate the influence of cyclosporine A (CsA) on glomerular growth and the effect of mizoribine (MZR) and losartan (LSAR) on CsA-induced nephropathy in young rats. Six-week-old male Sprague-Dawley rats maintained on a low salt diet were given CsA (15 mg/kg), CsA and LSRT (30 mg/kg/day), CsA and MZR (5 mg/kg), or a combination of CsA, LSRT, and MZR for 4 and 7 weeks (two experiments) and compared with control group (olive oil-treated). Histopathology and glomerular size, inflammatory and fibrotic factors were studied. The score of acute CsA toxicity significantly decreased in the CsA + MZR group compared to the CsA group (p < 0.01). MZR and MZR + LSRT reduced tubulointerstitial fibrosis and TGF-β1 mRNA expression at 7 weeks. Osteopontin (OPN) mRNA expression was decreased at 7 weeks in MZR + LSRT (p < 0.01). Glomerular area decreased CsA group and recovered in MZR (p < 0.01) and MZR + LSRT (p < 0.01) at 7 weeks. This study demonstrated that MZR and LSRT had suppressive effects on inflammatory process in chronic CsA nephropathy and led to improvement of tubular damage, tubulointerstitial fibrosis and arteriolopathy by down regulation of OPN and TGF-β1 and glomerular size contraction.

Background/aims: There has been controversy about the role of Toll-like receptor 2 (TLR2) in renal injury following ureteric obstruction. Although inhibition of the renin angiotensin system (RAS) reduces TLR2 expression in mice, the exact relationship between TLR2 and RAS is not known. The aim of this study was to determine whether the RAS modulates TLR2., Methods: We used 8-week-old male wild type (WT) and TLR2-knockout (KO) mice on a C57Bl/6 background. Unilateral ureteral obstruction (UUO) was induced by complete ligation of the left ureter. Angiotensin (Ang) II (1,000 ng/kg/min) and the direct renin inhibitor aliskiren (25 mg/kg/day) were administrated to mice using an osmotic minipump. Molecular and histologic evaluations were performed., Results: Ang II infusion increased mRNA expression of TLR2 in WT mouse kidneys (p < 0.05). The expression of renin mRNA in TLR2-KO UUO kidneys was significantly higher than that in WT UUO kidneys (p < 0.05). There were no differences in tissue injury score or mRNA expression of monocyte chemotactic protein 1 (MCP-1), osteopontin (OPN), or transforming growth factor β (TGF-β) between TLR2-KO UUO and WT UUO kidneys. However, aliskiren decreased the tissue injury score and mRNA expression of TLR2, MCP-1, OPN, and TGF-β in WT UUO kidneys (p < 0.05). Aliskiren-treated TLR2-KO UUO kidneys showed less kidney injury than aliskiren-treated WT UUO kidneys., Conclusions: TLR2 deletion induced activation of the RAS in UUO kidneys. Moreover, inhibition of both RAS and TLR2 had an additive ameliorative effect on UUO injury of the kidney.

Tubulointerstitial nephritis (TIN) is the most common form of renal involvement in IgG4-related disease. It is characterized by a dominant infiltrate of IgG4-positive plasma cells in the interstitium and storiform fibrosis. Demonstration of IgG4-positive plasma cells is essential for diagnosis, but the number of IgG4-positive cells and the ratio of IgG4-positive/IgG-positive plasma cells may vary from case to case and depending on the methods of tissue sampling even in the same case. IgG4-positive plasma cells can be seen in TIN associated with systemic lupus erythematosus, Sjögren syndrome, or anti-neutrophil cytoplasmic antibody-associated vasculitis, which further add diagnostic confusion and difficulties. To have a more clear view of IgG4-TIN and to delineate differential points from other TIN with IgG4-positive plasma cell infiltrates, clinical and histological features of IgG4-TIN and its mimickers were reviewed. In the rear part, cases suggesting overlap of IgG4-TIN and its mimickers and glomerulonephritis associated with IgG4-TIN were briefly described.

To evaluate clinical values of clinicopathologic and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT)-related parameters for prediction of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation in colorectal cancer (CRC) and to investigate their variability depending on C-reactive protein (CRP) levels. In total, 179 CRC patients who underwent PET/CT scans before curative resection and KRAS mutation evaluation following surgery were enrolled. Maximum standardized uptake value (SUV max), peak standardized uptake value (SUV peak), metabolic tumor volume, and total lesion glycolysis were determined semiquantitatively. Associations between clinicopathologic and PET/CT-related parameters and KRAS expression were analyzed. Elevated CRP (> 6.0 mg/L; n = 47) was associated with higher primary tumor size, higher SUV max, SUV peak, metabolic tumor volume, and total lesion glycolysis, compared with those for the group with a CRP lower than that the cutoff value (< 6.0 mg/L; n = 132). Interestingly, the CRC patients (having CRP < 6.0 mg/L) with KRAS mutations had significantly higher (P < 0.05) SUV max and SUV peak values than the patients expressing wild-type KRAS mutations. Multivariate analysis revealed SUV max and SUV peak to be significantly associated with KRAS mutations (odds ratio = 3.3, P = 0.005, and odds ratio = 3.9, P = 0.004), together with histologic grade and lymph node metastasis. 18F-FDG uptake was significantly higher in CRC patients with KRAS mutations and with normal CRP levels. A severe local inflammation with raised CRP levels, however, might affect accurate 18F-FDG quantification in CRC tumors. Positron emission tomography/computed tomography-related parameters could supplement genomic analysis to determine KRAS expression in CRC; however, care should be exercised to guarantee proper patient selection.

Purpose: Smoking reportedly exerts deleterious effects on renal function; however, its effects on histology have not been clarified in patients with IgA nephropathy (IgAN)., Materials and Methods: Renal histology was evaluated in a cohort of 397 patients diagnosed with IgAN according to smoking status and dose in relation to renal function., Results: Among the study cohort, which was predominantly male (88.5%), 52 patients (13%) were current smokers. These current smokers demonstrated more frequent hypertension and higher serum creatinine levels than non/ex-smokers at the time of diagnosis, which was apparent with increased smoking dose. The percentages of global glomerulosclerosis and arteriolar hyalinosis increased with increased smoking dose, whereas tubulointerstitial fibrosis or arterial intimal thickening did not. Glomerular mesangial alpha-smooth muscle actin expression were similar between current and non/ex-smokers matched for age, gender, hypertension, and histologic severity, although the number of glomerular CD68+ cells was significantly fewer in smokers. Initial serum creatinine level, estimated glomerular filtration rate (eGFR), and global glomerulosclerosis were found to be risk factors of serum creatinine doubling in both smokers and non/ex-smokers by univariate analysis during a mean follow-up of 3.8 years., Conclusion: In addition to dose dependent renal functional decline and hypertension, smoking contributes to renal disease progression by eliciting microvascular injury in IgAN patients.