Polygenic risk score model for renal cell carcinoma in the Korean population and relationship with lifestyle-associated factors.

BACKGROUND: The polygenic risk score (PRS) is used to predict the risk of developing common complex diseases or cancers using genetic markers. Although PRS is used in clinical practice to predict breast cancer risk, it is more accurate for Europeans than for non-Europeans because of the sample size of training genome-wide association studies (GWAS). To address this disparity, we constructed a PRS model for predicting the risk of renal cell carcinoma (RCC) in the Korean population. RESULTS: Using GWAS analysis, we identified 43 Korean-specific variants and calculated the PRS. Subsequent to plotting receiver operating characteristic (ROC) curves, we selected the 31 best-performing variants to construct an optimal PRS model. The resultant PRS model with 31 variants demonstrated a prediction rate of 77.4%. The pathway analysis indicated that the identified non-coding variants are involved in regulating the expression of genes related to cancer initiation and progression. Notably, favorable lifestyle habits, such as avoiding tobacco and alcohol, mitigated the risk of RCC across PRS strata expressing genetic risk. CONCLUSION: A Korean-specific PRS model was established to predict the risk of RCC in the underrepresented Korean population. Our findings suggest that lifestyle-associated factors influencing RCC risk are associated with acquired risk factors indirectly through epigenetic modification, even among individuals in the higher PRS category.

Chromatin accessibility analysis and architectural profiling of human kidneys reveal key cell types and a regulator of diabetic kidney disease.

Diabetes is the leading cause of kidney disease that progresses to kidney failure. However, the key molecular and cellular pathways involved in diabetic kidney disease (DKD) pathogenesis are largely unknown. Here, we performed a comparative analysis of adult human kidneys by examining cell type-specific chromatin accessibility by single-nucleus ATAC-seq (snATAC-seq) and analyzing three-dimensional chromatin architecture via high-throughput chromosome conformation capture (Hi-C method) of paired samples. We mapped the cell type-specific and DKD-specific open chromatin landscape and found that genetic variants associated with kidney diseases were significantly enriched in the proximal tubule- (PT) and injured PT-specific open chromatin regions in samples from patients with DKD. BACH1 was identified as a core transcription factor of injured PT cells; its binding target genes were highly associated with fibrosis and inflammation, which were also key features of injured PT cells. Additionally, Hi-C analysis revealed global chromatin architectural changes in DKD, accompanied by changes in local open chromatin patterns. Combining the snATAC-seq and Hi-C data identified direct target genes of BACH1, and indicated that BACH1 binding regions showed increased chromatin contact frequency with promoters of their target genes in DKD. Thus, our multi-omics analysis revealed BACH1 target genes in injured PTs and highlighted the role of BACH1 as a novel regulator of tubular inflammation and fibrosis.

Glutamyl-prolyl-tRNA synthetase (EPRS1) drives tubulointerstitial nephritis-induced fibrosis by enhancing T cell proliferation and activity.

Toxin- and drug-induced tubulointerstitial nephritis (TIN), characterized by interstitial infiltration of immune cells, frequently necessitates dialysis for patients due to irreversible fibrosis. However, agents modulating interstitial immune cells are lacking. Here, we addressed whether the housekeeping enzyme glutamyl-prolyl-transfer RNA synthetase 1 (EPRS1), responsible for attaching glutamic acid and proline to transfer RNA, modulates immune cell activity during TIN and whether its pharmacological inhibition abrogates fibrotic transformation. The immunological feature following TIN induction by means of an adenine-mixed diet was infiltration of EPRS1high T cells, particularly proliferating T and γδ T cells. The proliferation capacity of both CD4+ and CD8+ T cells, along with interleukin-17 production of γδ T cells, was higher in the kidneys of TIN-induced Eprs1+/+ mice than in the kidneys of TIN-induced Eprs1+/- mice. This discrepancy contributed to the fibrotic amelioration observed in kidneys of Eprs1+/- mice. TIN-induced fibrosis was also reduced in Rag1-/- mice adoptively transferred with Eprs1+/- T cells compared to the Rag1-/- mice transferred with Eprs1+/+ T cells. The use of an EPRS1-targeting small molecule inhibitor (bersiporocin) under clinical trials to evaluate its therapeutic potential against idiopathic pulmonary fibrosis alleviated immunofibrotic aggravation in TIN. EPRS1 expression was also observed in human kidney tissues and blood-derived T cells, and high expression was associated with worse patient outcomes. Thus, EPRS1 may emerge as a therapeutic target in toxin- and drug-induced TIN, modulating the proliferation and activity of infiltrated T cells.

Rate of benign histology after resection of suspected renal cell carcinoma: multicenter comparison between Korea and the United States.

BACKGROUND: In the United States, the rate of benign histology among resected renal tumors suspected to be malignant is increasing. We evaluated the rates in the Republic of Korea and assessed the racial effect using recent multi-institutional Korean-United States data. METHODS: We conducted a multi-institutional retrospective study of 11,529 patients (8,812 from The Republic of Korea and 2,717 from the United States) and compared the rates of benign histology between the two countries. To evaluate the racial effect, we divided the patients into Korean, Asian in the US, and Non-Asian in the US. RESULTS: The rates of benign histology and small renal masses in Korean patients were significantly lower than that in United States patients (6.3% vs. 14.3%, p < 0.001) and (≤ 4 cm, 7.6% vs. 19.5%, p < 0.001), respectively. Women, incidentaloma, partial nephrectomy, minimally invasive surgery, and recent surgery were associated with a higher rate of benign histology than others. CONCLUSIONS: In Korea, the rate of benign histology among resected renal tumors was significantly lower than that in the United States. This disparity could be caused by environmental or cultural differences rather than racial differences. Our findings suggest that re-evaluating current context-specific standards of care is necessary to avoid overtreatment.

Cholecystectomy with the Hugo™ robotic-assisted surgery system: the first general surgery clinical study in Korea.

BACKGROUND: The Hugo™ Robotic-Assisted Surgery (RAS) System is an emergent device in the robotic surgery field. This study aims to describe the first general surgery-focused clinical study in Korea using the novel Hugo™ RAS System. METHODS: This study was a prospective, single-center, single-arm, confirmatory clinical study conducted at Seoul National University Hospital where 20 cholecystectomies were performed. To evaluate the safety and performance of the Hugo™ RAS System the incidence of conversion to laparoscopy or open surgery, major complication (Clavien-Dindo Grade ≥ III) rate, overall complication rate, readmission rate, and reoperation rate were evaluated. All parameters were assessed within 30 days post-procedure. Any device deficiencies encountered during our initial experience and device data such as setup, console, and operative times were also reported. RESULTS: We confirmed that our trial achieved the primary objective with a success rate of at least 95%. This was accomplished with no conversions to other types of surgery due to serious system malfunction and with only one major complication within 24 h post-procedure. The 20 consecutively enrolled patients had a median age and BMI of 58 years old and 23.9 kg/m2, respectively. The major complication rate was 10% (2/20 patients), the overall complication rate was 15% (3/20 patients), the readmission rate was 15% (3/20 patients), and the reoperation rate was 0% (0/20 patients). None of the complications were definitively device related. The median setup, console, and operative times were 16, 17, and 55 min, respectively. The device deficiency rate was 15% (3/20 patients), but all device deficiencies were minor, occurred before the first incision, and did not present a risk to the patient. CONCLUSION: Based on our initial experience with the Hugo™ RAS System, cholecystectomy is feasible and safe. This trial is registered with ClinicalTrials.gov (NCT05715827).

Retrospective Multicenter Analysis of Prognostic Risk Factors for One Year Recurrence in Patient With Renal Cell Carcinoma After Partial or Radical Nephrectomy: Results of Korean Renal Cancer Study Group (KRoCS) Database.

BACKGROUND: We sought to identify prognostic risk factors for one year recurrence in patient with renal cell carcinoma (RCC) after partial or radical nephrectomy. METHODS: We performed a retrospective study of 1,269 patients with RCC after partial or radical nephrectomy and diagnosed recurrence using Korean Renal Cancer Study Group (KRoCS) database between January 1991 and March 2017. Recurrence-free survival (RFS), and overall survival (OS) were calculated using the Kaplan-Meier method and multivariate Cox regression analysis were performed to evaluate independent prognostic factors for recurrence. RESULTS: The median patient age was 56 years and median follow-up period was 67 months. Multivariable analysis demonstrated BMI greater than or equal to 23 and less than 30 (vs. BMI less than 23, hazard ratio [HR]: 0.707, P = 0.020) reduced recurrence one year postoperatively. Eastern Cooperative Oncology Group performance status (ECOG PS) greater than or equal to 1 (vs. ECOG PS 0, HR: 1.548, P = 0.007), high pathological T stage (pT2 vs. pT1, HR: 2.622, P < 0.001; pT3 vs. pT1, HR: 4.256, P < 0.001; pT4 vs. pT1, HR: 4.558, P < 0.001), and tumor necrosis (vs. no tumor necrosis, HR: 2.822, P < 0.001) were independent predictive factors for early recurrence within one year in patients with RCC. Statistically significant differences on RFS and OS were found among pathological T stages (pT2 vs. pT1; pT3 vs. pT1; pT4 vs. pT1, all P < 0.001). CONCLUSION: This large multicenter study demonstrated ECOG PS greater than or equal to 1, high pathological T stage, tumor necrosis and BMI less than 23 were significant prognostic risk factors of early recurrence within one year in patients with RCC who underwent nephrectomy.

Machine learning models for predicting the onset of chronic kidney disease after surgery in patients with renal cell carcinoma.

BACKGROUND: Patients with renal cell carcinoma (RCC) have an elevated risk of chronic kidney disease (CKD) following nephrectomy. Therefore, continuous monitoring and subsequent interventions are necessary. It is recommended to evaluate renal function postoperatively. Therefore, a tool to predict CKD onset is essential for postoperative follow-up and management. METHODS: We constructed a cohort using data from eight tertiary hospitals from the Korean Renal Cell Carcinoma (KORCC) database. A dataset of 4389 patients with RCC was constructed for analysis from the collected data. Nine machine learning (ML) models were used to classify the occurrence and nonoccurrence of CKD after surgery. The final model was selected based on the area under the receiver operating characteristic (AUROC), and the importance of the variables constituting the model was confirmed using the shapley additive explanation (SHAP) value and Kaplan-Meier survival analyses. RESULTS: The gradient boost algorithm was the most effective among the various ML models tested. The gradient boost model demonstrated superior performance with an AUROC of 0.826. The SHAP value confirmed that preoperative eGFR, albumin level, and tumor size had a significant impact on the occurrence of CKD after surgery. CONCLUSIONS: We developed a model to predict CKD onset after surgery in patients with RCC. This predictive model is a quantitative approach to evaluate post-surgical CKD risk in patients with RCC, facilitating improved prognosis through personalized postoperative care.

Tubular damage marker as a predictive factor for pathologically upstaged renal cell carcinoma.

PURPOSE: To investigate if increased tubular damage biomarker can predict pathologically upstaged renal cell carcinoma (RCC), which may possess sub-radiologic invasive behavior, leading to surrounding tubular damage. MATERIALS AND METHODS: We examined 1563 patients with surgically resected RCC between March 2016 and June 2021 from the prospective database SUPER-RCC-Nx. Exclusion criteria were cancer not originating from the kidneys, benign renal tumor, and end-stage renal disease. RESULTS: Of 1297 patients, 131 had a clinically high T stage (T3-4), whereas 1166 had a low one. Patients with a clinically low T stage were subgrouped into identical-stage (n = 1041) and upstaged (n = 125) groups, who were confirmed as a pathologically high T stage. The upstaged group had older age (p = 0.003), larger tumor size (5.72 ± 3.24 vs. 3.12 ± 2.08, p < 0.001), higher Fuhrman grade (grades 3-4) (57.3% vs. 47.1%, p = 0.032), and higher urine N-acetyl-beta-D-glucosaminidase/creatinine (NAG/Cr) (5.13 ± 4.78 vs. 4.05 ± 2.84, p = 0.026). Tumor size (> 4 cm; odds ratio = 10.2, p < 0.001) and urine NAG/Cr (odds ratio = 1.16, p = 0.003) were independently associated with pathological upstaging in patients with normal renal function, while age and tumor size were significant risk factors in those with decreased renal function. The receiver operating characteristic curve analysis showed that the model using tumor size and urine NAG/Cr strongly predicted pathological upstaging (area under the curve, 0.84). CONCLUSION: Urine NAG/Cr may be a useful biomarker predicting pathologically upstaged RCC. Clinicians should be prudent in making management decisions when a large RCC is accompanied by an increased urine NAG/Cr.

Fully automatic volume measurement of the adrenal gland on CT using deep learning to classify adrenal hyperplasia.

OBJECTIVES: To develop a fully automated deep learning model for adrenal segmentation and to evaluate its performance in classifying adrenal hyperplasia. METHODS: This retrospective study evaluated automated adrenal segmentation in 308 abdominal CT scans from 48 patients with adrenal hyperplasia and 260 patients with normal glands from 2010 to 2021 (mean age, 42 years; 156 women). The dataset was split into training, validation, and test sets at a ratio of 6:2:2. Contrast-enhanced CT images and manually drawn adrenal gland masks were used to develop a U-Net-based segmentation model. Predicted adrenal volumes were obtained by fivefold splitting of the dataset without overlapping the test set. Adrenal volumes and anthropometric parameters (height, weight, and sex) were utilized to develop an algorithm to classify adrenal hyperplasia, using multilayer perceptron, support vector classification, a random forest classifier, and a decision tree classifier. To measure the performance of the developed model, the dice coefficient and intraclass correlation coefficient (ICC) were used for segmentation, and area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity were used for classification. RESULTS: The model for segmenting adrenal glands achieved a Dice coefficient of 0.7009 for 308 cases and an ICC of 0.91 (95% CI, 0.90-0.93) for adrenal volume. The models for classifying hyperplasia had the following results: AUC, 0.98-0.99; accuracy, 0.948-0.961; sensitivity, 0.750-0.813; and specificity, 0.973-1.000. CONCLUSION: The proposed segmentation algorithm can accurately segment the adrenal glands on CT scans and may help clinicians identify possible cases of adrenal hyperplasia. KEY POINTS: • A deep learning segmentation method can accurately segment the adrenal gland, which is a small organ, on CT scans. • The machine learning algorithm to classify adrenal hyperplasia using adrenal volume and anthropometric parameters (height, weight, and sex) showed good performance. • The proposed segmentation algorithm may help clinicians identify possible cases of adrenal hyperplasia.

Clinical features and Surgical Outcome of Clear Cell Papillary Renal Cell Tumor: result from a prospective cohort.

BACKGROUND: Clear cell papillary renal cell tumor (CCPRCT) was first reported in 2006 a patient with end stage renal disease. After that it was discovered in the kidney without end stage renal disease in the 2010s and started to be mentioned in pathology and urology. The incidence of CCPRCT is low and most of it is discovered incidentally, so there is a lack of reports on clinical characteristics and surgical outcome. METHODS: This study used clinical data from the Seoul National University Prospectively Enrolled Registry for Renal Cell Carcinoma-Nephrectomy (SUPER-RCC-Nx). Between August 2016 and July 2022, patients who underwent radical or partial nephrectomy with clear cell papillary RCC with pathological finding were included in this study. All patients' pathologic reports were reviewed by 1 pathologist. Clinical characteristics and surgical outcomes were presented through descriptive statistics, and Kaplan-Meier curve used for survival analysis. RESULTS: Of the 2057 patients, CCPRCT was reported in 36 patients (1.8%). The median follow up period was 26.8 months. The median age was 67 years, and there were 10 females and 26 males. The median tumor size was 1.2 cm. Twenty-nine patients underwent partial nephrectomy. Seven patients with end-stage renal disease underwent radical nephrectomy. The median operative time for patients who underwent partial nephrectomy was 97.5 min and the estimated blood loss was 100 cc. The median hospital days was 4 and 30-day complications were 2 cases with clavien-dindo classification III or higher. During the follow-up period, there was no recurrence and cancer specific mortality. CONCLUSIONS: The size of CCPRCT was small and there was no advanced stage at that time of diagnosis. There was no recurrence or cancer specific mortality during the follow-up period. A multi-center study with a large scale is needed in the future. TRIAL REGISTRATION: Seoul National University Hospital (SNUH) Institutional Review Board (IRB) (approval number: 2210-126-1371).

Clinical determinants of recurrence in pTa bladder cancer following transurethral resection of bladder tumor.

BACKGROUND: Non-muscle invasive bladder cancer can be controlled by transurethral resection of bladder (TURB), but suffers from frequent recurrences in 60-70% of cases. Although, recurrence interval after TURB influences treatment course and prognosis, its implication and risk factors have not been fully elucidated. We evaluated the risk factors of early (within 1 yr) and late (after 1 yr) recurrence of pTa bladder cancer and clinical significance of recurrence interval on disease progression and overall survival. METHODS: In this study, pTa bladder cancer patients enrolled in prospective patient registry system of Seoul National University, SUPER-UC, were retrospectively examined to determine the clinical risk factors for recurrence and its significance regarding to recurrence interval. A total of 1067 bladder cancer patients who underwent TURB between March 20 and June 2021 were included and classified into three groups of no recurrence, early, or late recurrence to be comparatively analyzed. RESULTS: Early recurrence was associated with poorer cystectomy-free survival and overall survival than late recurrence. Risk factors for early recurrence included a high number of previous TURB, tumor multiplicity, tumor location, tumor shape, incompleteness of TURB, and high tumor grade. Otherwise, late recurrence was associated with low-grade tumors with insufficient TURB depth. CONCLUSION: Patients with risk factors for early recurrence should be closely followed up with special cautions.

Association between decreased ipsilateral renal function and aggressive behavior in renal cell carcinoma.

BACKGROUND: To assess prognostic value of pre-operative ipsilateral split renal function (SRF) on disease-free survival (DFS) and its association with aggressive pathological features in renal cell carcinoma (RCC) patients.  METHODS: We examined patients registered in SNUG-RCC-Nx who underwent partial or radical nephrectomy at Seoul National University Hospital between January 1, 2010 and December 31, 2020. Patients with the following criteria were excluded from the study. 1) non-kidney origin cancer or benign renal tumor, 2) no pre-operative Tc 99 m-DTPA renal scan, 3) single kidney status or previous partial or radical nephrectomy, and 4) bilateral renal mass. Finally, 1,078 patients were included. RESULTS: Among 1,078 patients, 899 (83.4%) showed maintained ipsilateral SRF on DTPA renal scan; 179 patients (16.6%) showed decreased SRF. The decreased SRF group showed significantly large tumor size (maintained vs. decreased SRF; 3.31 ± 2.15 vs. 6.85 ± 3.25, p < 0.001), high Fuhrman grade (grade 3-4) (41.7% vs. 55.6%, p < 0.001), and high T stage (T stage 3-4) (9.0% vs. 20.1%, p < 0.001). Pathological invasive features, including invasion of the renal capsule, perirenal fat, renal sinus fat, vein, and collecting duct system, were associated with low SRF of the ipsilateral kidney. Univariate Cox regression analysis identified higher SSIGN (The stage, size, grade, and necrosis) score and decreased ipsilateral SRF as significant risk factors, while multivariate analysis showed SSIGN (5-7) (hazard ratio [HR] 11.9, p < 0.001) and SSIGN (8-10) (HR 69.2, p < 0.001) were significantly associated with shortened DFS, while decreased ipsilateral SRF (HR 1.75, p = 0.065) showed borderline significance. Kaplan-Meier analysis showed that decreased ipsilateral SRF (< 45%) group had shorter DFS than the other group (median DFS: 90.3 months vs. not reached, p < 0.001). CONCLUSIONS: Among unilateral RCC patients, those with low ipsilateral SRF showed poor prognosis with pathologically invasive features. Our novel approach may facilitate risk stratification in RCC patients, helping formulate a treatment strategy.

Clinical Significances of Anti-Collagen Type I and Type III Antibodies in Antibody-Mediated Rejection.

It is important to determine the clinical significance of non-human leukocyte antigen (HLA) antibodies and their association with antibody-mediated rejection (ABMR) of kidney allografts. We collected post-transplant sera from 68 ABMR patients, 67 T-cell mediated rejection (TCMR) patients, and 83 control subjects without rejection, and determined the titers of 39 non-HLA antibodies including antibodies for angiotensin II receptor type I and MICA. We compared all these non-HLA antibody titers among the study groups. Then, we investigated their association with the risk of death-censored graft failure in ABMR cases. Among the antibodies evaluated, anti-collagen type I (p = 0.001) and type III (p < 0.001) antibody titers were significantly higher in ABMR cases than in both TCMR cases and no-rejection controls. Both anti-collagen type I [per 1 standard deviation (SD), adjusted odds ratio (OR), 11.72 (2.73-76.30)] and type III [per 1 SD, adjusted OR, 6.22 (1.91-31.75)] antibodies were significantly associated with the presence of ABMR. Among ABMR cases, a higher level of anti-collagen type I [per 1 SD, adjusted hazard ratio (HR), 1.90 (1.32-2.75)] or type III per 1 SD, [adjusted HR, 1.57 (1.15-2.16)] antibody was associated with a higher risk of death-censored graft failure. In conclusion, post-transplant anti-collagen type I and type III antibodies may be novel non-HLA antibodies related to ABMR of kidney allografts.

Efficacy of the Treatment of Intraperitoneal Bladder Perforation during Transurethral Resection of Bladder Tumor with the Urethral Catheter Alone: Retrospective Analysis of over 15 Years Using the Clinical Data Warehouse System.

INTRODUCTION: We investigated the efficacy of a urethral catheter alone for intraperitoneal perforation during transurethral resection of bladder tumor (TURBT). PATIENTS AND METHODS: We retrospectively evaluated the medical records of 4,543 patients who underwent TURBT from January 2000 to December 2017 using the Clinical Data Warehouse system. The clinicopathologic characteristics, recurrence-free survival, and progression-free survival were compared between the patient groups with intraperitoneal perforation treated with the Foley catheter alone, extraperitoneal perforation, and matched control TURBT. RESULTS: Intraperitoneal perforation and extraperitoneal perforation were observed in 16 (35.6%) and 29 (64.4%) patients, respectively. In the intraperitoneal perforation group, 11 (68.8%), 2 (12.5%), and 3 (18.8%) patients were treated with the Foley catheter alone, additional percutaneous drainage, and delayed open surgery, respectively. The use of the Foley catheter alone in patients with intraperitoneal perforation of smaller size than the cystoscope or no pelvic radiotherapy history showed improved efficacy without sequelae or therapeutic delay. One of the 2 patients with the size of the intraperitoneal perforation larger than the cystoscope was successfully treated with the Foley catheter alone, whereas the other patient underwent delayed surgical repair. There was no difference in recurrence-free survival and progression-free survival of the intraperitoneal perforation treated with the Foley catheter alone compared to those of the matched control TURBT (p = 0.909, p = 0.518) and the extraperitoneal perforation (p = 0.458, p = 0.699). CONCLUSIONS: Intraperitoneal perforation rarely occurred during TURBT. In the case of intraperitoneal perforation of size smaller than cystoscopy or without pelvic radiotherapy history, treatment with the Foley alone showed successful improvement and safe oncological results. Therefore, treatment with the urethral catheter alone can be carefully considered when an intraperitoneal perforation smaller than the cystoscope size or without pelvic radiotherapy history occurs.

Machine learning-based prediction model for late recurrence after surgery in patients with renal cell carcinoma.

BACKGROUND: Renal cell carcinoma is characterized by a late recurrence that occurs 5 years after surgery; hence, continuous monitoring and follow-up is necessary. Prognosis of late recurrence of renal cell carcinoma can only be improved if it is detected early and treated appropriately. Therefore, tools for rapid and accurate renal cell carcinoma prediction are essential. METHODS: This study aimed to develop a prediction model for late recurrence after surgery in patients with renal cell carcinoma that can be used as a clinical decision support system for the early detection of late recurrence. We used the KOrean Renal Cell Carcinoma database that contains large-scale cohort data of patients with renal cell carcinoma in Korea. From the collected data, we constructed a dataset of 2956 patients for the analysis. Late recurrence and non-recurrence were classified by applying eight machine learning models, and model performance was evaluated using the area under the receiver operating characteristic curve. RESULTS: Of the eight models, the AdaBoost model showed the highest performance. The developed algorithm showed a sensitivity of 0.673, specificity of 0.807, accuracy of 0.799, area under the receiver operating characteristic curve of 0.740, and F1-score of 0.609. CONCLUSIONS: To the best of our knowledge, we developed the first algorithm to predict the probability of a late recurrence 5 years after surgery. This algorithm may be used by clinicians to identify patients at high risk of late recurrence that require long-term follow-up and to establish patient-specific treatment strategies.

Comprehensive metabolomic profiling in early IgA nephropathy patients reveals urine glycine as a prognostic biomarker.

Identification of a urinary metabolite biomarker with diagnostic or prognostic significance for early immunoglobulin A nephropathy (IgAN) is needed. We performed nuclear magnetic resonance-based metabolomic profiling and identified 26 metabolites in urine samples. We collected urine samples from 201, 77, 47, 36 and 136 patients with IgAN, patients with membranous nephropathy, patients with minimal change disease, patients with lupus nephritis and healthy controls, respectively. We determined whether a metabolite level is associated with the prognosis of IgAN through Cox regression and continuous net reclassification improvement (cNRI). Finally, in vitro experiments with human kidney tubular epithelial cells (hTECs) were performed for experimental validation. As the results, the urinary glycine level was higher in the IgAN group than the control groups. A higher urinary glycine level was associated with lower risk of eGFR 30% decline in IgAN patients. The addition of glycine to a predictive model including clinicopathologic information significantly improved the predictive power for the prognosis of IgAN [cNRI 0.72 (0.28-0.82)]. In hTECs, the addition of glycine ameliorated inflammatory signals induced by tumour necrosis factor-α. Our study demonstrates that urinary glycine may have diagnostic and prognostic value for IgAN and indicates that urinary glycine is a protective biomarker for IgAN.

Fumarate modulates phospholipase A2 receptor autoimmunity-induced podocyte injury in membranous nephropathy.

Downstream mechanisms that lead to podocyte injury following phospholipase A2 receptor (PLA2R) autoimmunity remain elusive. To help define this we compared urinary metabolomic profiles of patients with PLA2R-associated membranous nephropathy (MN) at the time of kidney biopsy with those of patients with minimal change disease (MCD) and to healthy individuals. Among the metabolites differentially expressed in patients with PLA2R-associated MN compared to healthy individuals, fumarate was the only significant differentially expressed metabolite in PLA2R-associated MN compared to MCD [fold-difference vs. healthy controls and vs. MCD: 1.76 and 1.60, respectively]. High urinary fumarate levels could predict the composite outcome of PLA2R-associated MN. Fumarate hydratase, which hydrolyzes fumarate, colocalized with podocalyxin, and its expression was lower in glomerular sections from patients with PLA2R-associated MN than in those from healthy individuals, patients with non-PLA2R-associated MN or MCD. Podocytes stimulated with IgG purified from serum with a high anti-PLA2R titer (MN-IgG) decreased expression of fumarate hydratase and increased fumarate levels. These changes were coupled to alterations in the expression of molecules involved in the phenotypic profile of podocytes (WT1, ZO-1, Snail, and fibronectin), an increase in albumin flux across the podocyte layer and the production of reactive oxygen species in podocytes. However, overexpression of fumarate hydratase ameliorated these alterations. Furthermore, knockdown of fumarate hydratase exhibited synergistic effects with MN-IgG treatment. Thus, fumarate may promote changes in the phenotypic profiles of podocytes after the development of PLA2R autoimmunity. These findings suggest that fumarate could serve as a potential target for the treatment of PLA2R-associated MN.

Role of multiparametric magnetic resonance imaging to predict postoperative Gleason score upgrading in prostate cancer with Gleason score 3 + 4.

BACKGROUND: To evaluate the role of multiparametric magnetic resonance imaging (mpMRI) in Gleason score (GS) 3 + 4 prostate cancer (PCa) and evaluate independent factors in mpMRI that can predict GS upgrading, we compared the outcomes of GS upgrading group and GS non-upgrading group. PATIENTS AND METHODS: We analyzed the data of 539 patients undergoing radical prostatectomy (RP) for biopsy GS 3 + 4 PCa from two tertiary referral centers. Univariate and multivariate analyses were performed to determine significant predictors of GS upgrading. GS upgrading, the study outcome, was defined as GS ≥ 4 + 3 at definitive pathology at RP specimen. RESULTS: GS upgrading rate was 35.3% and biochemical recurrence (BCR) rate was 8.0%. GS upgrading group was significantly older (p = 0.015), had significantly higher prebiopsy serum prostate-specific antigen (PSA) level (p = 0.001) and PSA density (p = 0.003), had a higher number of prostate biopsy (p = 0.026). There were 413 lesions (76.6%) of PI-RADS lesion ≥ 4, 236 (57.1%) for PI-RADS 4 and 177 (42.9%) for PI-RADS 5 lesion. Multivariate logistic regression analysis revealed that age (p = 0.045), initial prebiopsy PSA level (p = 0.002) and presence of PI-RADS lesion ≥ 4 (p = 0.044) are independent predictors of GS upgrading. CONCLUSION: MpMRI can predict postoperative Gleason score upgrading in prostate cancer with Gleason score 3 + 4. Especially, presence of clinically significant PI-RADS lesion ≥ 4, the significant predictor of GS upgrading, in preoperative mpMRI needs to be paid attention and can be helpful for patient counseling on prostate cancer treatment.

Metastatic renal cell carcinoma to the pancreas: Clinical features and treatment outcome.

BACKGROUND AND OBJECTIVES: Metastatic renal cell carcinoma to the pancreas (PM-RCC) is infrequent; we sought to describe the characteristics of PM-RCC and analyze the outcome following treatment. METHODS: Data of 3107 mRCC patients treated between 1992 and 2007 from the Korean Renal Cancer Study Group database were obtained to identify 300 (9.7%) PM-RCC patients. Characteristics and survival were analyzed and compared to the rest of the mRCC, according to the timing of metastasis and surgical treatments received. RESULTS: PM-RCC was younger at initial diagnosis (55.0 vs. 58.2 years), more frequently in women (30.3% vs. 22.3%), and metachronous (65.3% vs. 41.9%) with a longer disease-free period (82.0 vs. 33.0 months). Overall survival (OS) was significantly better in PM-RCC but pancreas metastasectomy was associated with improved OS only among metachronous PM-RCC. In the 132 metachronous PM-RCC with pancreas metastasectomy, median recurrence-free survival was 17.2 months and we found Heng risk group (hazard ratio [HR] = 2.384, 95% confidence interval [CI] = 1.213-4.684), younger age (HR = 0.965, 95% CI = 0.945-0.987), shorter interval to pancreas metastasis (HR = 0.993, 95% CI = 0.986-0.999), and Eastern Cooperative Oncology Group performance status to be predictive of early progression following pancreas metastasectomy. CONCLUSION: Compared to the other mRCC, PM-RCC demonstrated a favorable prognosis. Pancreas metastasectomy was associated with prolonged survival in the metachronous PM-RCC with a long progression-free period.

Targeted therapy response in early versus late recurrence of renal cell carcinoma after surgical treatment: A propensity score-matched study using the Korean Renal Cancer Study Group database.

OBJECTIVES: To investigate the clinicopathological features and outcomes of targeted therapy in patients with recurrence of renal cell carcinoma in <5 years or ≥5 years after the surgical treatment for renal cell carcinoma. METHODS: Patients with metastatic renal cell carcinoma treated with targeted therapy in a multicenter database were retrospectively characterized according to time from surgery to recurrence. Early recurrence was defined as recurrence within 5 years after surgery, and late recurrence was defined as occurring ≥5 years after surgery. The propensity scores for recurrence status were calculated, and patients with late recurrence were matched to patients with early recurrence at a 1:3 ratio. The oncological outcomes of targeted therapy in both groups were compared. RESULTS: Among 716 patients, 512 (71.5%) experienced early recurrence and 204 (28.5%) experienced late recurrence. The patients with late recurrence presented with younger age at surgery, lower tumor stages and Fuhrman grade, and fewer sarcomatoid features and lymphovascular invasion (all P < 0.005). All differences in clinicopathological characteristics before targeted therapy disappeared after matching. Patients with late recurrence had significantly longer median overall survival (56 months vs 36 months; P < 0.0001) and median first-line progression-free survival (12 months vs 8 months; P = 0.031). The early recurrence status was a significantly worse predictor for overall survival and first-line progression-free survival (hazard ratio 1.30, P = 0.007; and hazard ratio 1.76, P < 0.001, respectively). CONCLUSIONS: Late recurrence might have prognostic value in terms of oncological outcomes in metastatic renal cell carcinoma treated with targeted therapy.