Possible sarcopenia and risk of chronic kidney disease: a four-year follow-up study and Mendelian randomization analysis.

INTRODUCTION: Chronic kidney disease (CKD) is a common risk factor for sarcopenia. However, whether sarcopenia increases the risk of CKD remains unclear. To investigate the longitudinal and causal associations between possible sarcopenia and CKD, this study was performed. METHODS: Possible sarcopenia was defined according to the Asian Working Group for Sarcopenia in 2019. Participants aged ≥ 40 years were recruited from the baseline survey of the China Health and Retirement Longitudinal Study and followed up for four years. Binary logistic regression was used to evaluate the cross-sectional and longitudinal associations between possible sarcopenia, low muscle strength, low physical performance and CKD. Propensity score matching was used to balance the intergroup differences. Subgroup and interactive analyses were adopted to identify potential interactive effects. Mendelian Randomization analysis was used to assess the causal association between appendicular lean mass (ALM) and CKD. RESULTS: After data cleansing, a total of 7296 participants were included in the baseline survey. In the cross-sectional analyses, the odds ratios (ORs) of prevalent CKD were 1.50 (95% CI = 1.23-1.84, p < 0.001) for possible sarcopenia, 1.37 (95% CI = 1.10-1.70, p < 0.01) for low muscle strength and 1.42 (95% CI = 1.16-1.74, p < 0.001) for low physical performance in the full models. No significant interaction effects of covariates were detected (all P for interaction > 0.05). After four years of follow-up, an increased risk of incident CKD was also observed in participants with possible sarcopenia (OR = 1.66, 95% CI = 1.13-2.44, p = 0.010) and low physical performance (OR = 1.69, 95% CI = 1.16-2.45, p = 0.006), but not in participants with low muscle strength (OR = 1.19, 95% CI = 0.75-1.88, p = 0.469). In the Mendelian Randomization analysis, the inverse variance weighted estimator showed that a 1-standard deviation increase of genetically predicted ALM was associated with a lower risk of CKD (OR = 0.92, 95% CI = 0.85-0.99, p = 0.035). All the sensitivity analyses supported the main findings. CONCLUSIONS: Possible sarcopenia is an independent risk factor for CKD and may serve as a predictor of CKD for early identification and intervention.

The association between circadian syndrome and chronic kidney disease in an aging population: a 4-year follow-up study.

Introduction: Circadian syndrome (CircS) is proposed as a novel risk cluster based on reduced sleep duration, abdominal obesity, depression, hypertension, dyslipidemia and hyperglycemia. However, the association between CircS and chronic kidney disease (CKD) remains unclear. To investigate the cross-sectional and longitudinal association between CircS and CKD, this study was performed. Methods: A national prospective cohort (China Health and Retirement Longitudinal Study, CHARLS) was used in this study. To define CKD, the estimated glomerular filtration rate (eGFR) was calculated based on the 2012 CKD-EPI creatinine-cystatin C equation. Participants with eGFR <60 mL.min-1/1.73/m2 were diagnosed with CKD. Multivariate binary logistic regression was used to assess the cross-sectional association between CircS and CKD. Subgroup and interactive analyses were performed to determine the interactive effects of covariates. In the sensitivity analysis, the obese population was excluded and another method for calculating the eGFR was used to verify the robustness of previous findings. In addition, participants without CKD at baseline were followed up for four years to investigate the longitudinal relationship between CircS and CKD. Results: A total of 6355 participants were included in this study. In the full model, CircS was positively associated with CKD (OR = 1.28, 95% CI = 1.04-1.59, P < 0.05). As per one increase of CircS components, there was a 1.11-fold (95% CI = 1.04-1.18, P < 0.05) risk of prevalent CKD in the full model. A significant interactive effect of hyperuricemia in the CircS-CKD association (P for interaction < 0.01) was observed. Sensitivity analyses excluding the obese population and using the 2009 CKD-EPI creatinine equation to diagnose CKD supported the positive correlation between CircS and CKD. In the 2011-2015 follow-up cohort, the CircS group had a 2.18-fold risk of incident CKD (95% CI = 1.33-3.58, P < 0.01) in the full model. The OR was 1.29 (95% CI = 1.10-1.51, P < 0.001) with per one increase of CircS components. Conclusion: CircS is a risk factor for CKD and may serve as a predictor of CKD for early identification and intervention.

Clinicopathologic characteristics and outcomes of prostate cancer incidentally discovered at the time of radical cystoprostatectomy: a population-based cohort study.

OBJECTIVE: This study aimed to comprehensively analyze the clinical characteristics and prognosis of patients with concomitant bladder cancer (BCa) and prostate cancer (PCa) using a large population-based database. METHODS: Within the Surveillance, Epidemiology, and End Results (SEER) database (2000-2019), we identified patient with concomitant PCa at the time of radical cystoprostatectomy (RCP). Logistic regression and propensity score matching (PSM) analyses were employed to identify risk factors and mitigate confounders, respectively. Kaplan-Meier survival curves were used to estimate cancer-specific survival (CSS). RESULTS: A total of 14,199 BCa patients undergoing RCP were identified, with 28.8% incidentally discovered to have concurrent PCa. Among them, 89.9% exhibited organ-confined (T1-2) PCa. An increased risk of concomitant tumors was observed among older age, white race, and high tumor grade of BCa. Survival analysis revealed no significant difference in CSS between patients with BCa alone and those with concurrent PCa (5-year CSS rate: 71.3% vs. 67.2%, P =0.076). Subgroup analysis and multivariable analysis, however, indicated that concurrent high-risk PCa adversely impacted survival (5-year CSS rate: 71.3% vs. 63.4%, HR 1.27, 95% CI 1.01-1.58, P =0.038) compared to solitary BCa. Notably, the presence of low/intermediate-risk PCa did not affect survival outcomes ( P =0.584). CONCLUSION: In conclusion, incidentally discovered PCa in RCP specimens is frequent and characterized by organ-confined presentation, lower PSA levels, and Gleason scores. Patients with concurrent high-risk PCa have a worse prognosis compared to those with solitary BCa, while the presence of low/intermediate-risk PCa does not influence oncological prognosis.

Old drug, new use: The thalidomide-based fluorescent probe for hydrazine detection.

Thalidomide, a widely used ligand for cereblon (CRBN), has been gaining attention for its targeted protein degradation. In this study, we aimed to improve the optical and biocompatible features of hydrazine fluorescent probes by a novel probe called TH-1, based on the thalidomide moiety. Our results demonstrate that TH-1 exhibits remarkable properties including significant colorimetric changes, a fast response time, excellent selectivity, and high sensitivity as a hydrazine fluorescent probe. The mechanism by which TH-1 senses hydrazine has been convincingly verified. Notably, we have successfully applied TH-1 for bioimaging of hydrazine in living A549 cells, highlighting its practical significance. Moreover, the utilization of thalidomide, a clinically approved drug, as a fluorescent skeleton has expanded the repertoire of fluorescent skeleton libraries, paving the way for further on fluorescent probes.

Discovery of a glucocorticoid receptor (GR) activity signature correlates with immune cell infiltration in adrenocortical carcinoma.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine malignancy, of which >40% present with glucocorticoid excess. Glucocorticoids and glucocorticoid receptor (GR) signaling have long been thought to suppress immunity and promote tumor progression by acting on immune cells. Here, we provide new insights into the interaction between GR signaling activity and the immune signature of ACC as a potential explanation for immune escape and resistance to immunotherapy. METHODS: First, GR immunohistochemical staining and immunofluorescence analysis of tumor-infiltrating lymphocyte (CD4 T, CD8 T cells, natural killer (NK) cells, dendritic cells and macrophages) were performed in 78 primary ACC tissue specimens. Quantitative data of immune cell infiltration in ACC were correlated with clinical characteristics. Second, we discovered a GR activity signature (GRsig) using GR-targeted gene networks derived from global gene expression data of primary ACC. Finally, we identified two GRsig-related subtypes based on the GRsig and assessed the differences in immune characteristics and prognostic stratification between the two subtypes. RESULTS: GR was expressed in 90% of the ACC tumors, and CD8+ cytotoxic T lymphocytes were the most common infiltrating cell type in ACC specimens (88%, 8.6 cells/high power field). GR expression positively correlated with CD8+ T cell (Phi=0.342, p<0.001), CD4+ T cell (Phi=0.280, p<0.001), NK cell (Phi=0.280, p<0.001), macrophage (Phi=0.285, p<0.001), and dendritic cell (Phi=0.397, p<0.001) infiltration. Clustering heatmap analysis also displayed high immune cell infiltration in GR high-expressing tumors and low immune cell infiltration in GR-low tumors. High GR expression and high immune cell infiltration were significantly associated with better survival. Glucocorticoid excess is associated with low immune cell abundance and unfavorable prognosis. A GRsig comprizing n=34 GR-associated genes was derived from Gene Expression Omnibus/The Cancer Genome Atlas (TCGA) data sets and used to define two GRsig-related subtypes in the TCGA cohort. We demonstrated distinct differences in the immune landscape and clinical outcomes between the two subtypes. CONCLUSION: GR expression positively correlates with tumor-infiltrating immune cells in ACC. The GRsig could serve as a prognostic biomarker and may be helpful for prognosis prediction and response to immunotherapy. Consequently, targeting the GR signaling pathway might be pivotal and should be investigated in clinical studies.

Expanding the donor pool: Kidney transplantation from serum HBV DNA or HBeAg-positive donors to HBsAg-negative recipients.

BACKGROUND & AIMS: HBsAg-positive (HBsAg[+]) donors are rarely accepted for kidney transplantation (KT), especially when the donor is also HBV DNA-positive (HBV DNA[+]) or HBeAg-positive (HBeAg[+]) serologically. This study aimed to report kidney transplant outcomes from HBsAg(+) donors to HBsAg(-) recipients. METHODS: Consecutive cases were retrospectively identified from 1 July 2017 to 31 December 2020. KTs from HBsAg(-)/HBcAb-positive (HBcAb[+]) donors to HBcAb(-) recipients were selected as the control group. The primary outcomes were de novo HBV infection (DNH), graft and patient survival. RESULTS: We identified 105 HBsAg(-) recipients who received HBsAg(+) kidneys and 516 HBcAb(-) recipients who received HBcAb(+) kidneys. A higher DNH rate was observed after receiving HBsAg(+) kidneys than after receiving HBcAb(+) kidneys after a median follow-up of 23.0 months (4/105[3.8%] vs. 2/516[0.4%], p = .009). All four infected recipients receiving HBsAg(+) kidneys had HBsAg clearance after treatment. Graft and patient survival were comparable between the groups (p = .630, p = .910). The DNH rates were 0/22(0%), 3/70(4.3%) and 1/13(7.7%) after receiving HBsAg(+), HBV DNA(+) and HBeAg(+) kidneys, respectively (p = .455). The DNH rate was lower if the donor had received antiviral treatment (4/42[9.5%] vs. 0/63[0%], p = .023). HBsAb(-) recipients had a higher DNH incidence than HBsAb(+) recipients (3/25[12.0%] vs. 1/80[1.3%], p = .041). CONCLUSIONS: The use of HBsAg(+) donors contributed to comparable graft and patient survival, but HBV DNA(+) or HBeAg(+) donors and HBsAb(-) recipients maybe associated with a higher risk of HBV infection. These findings help expand the donor pool and emphasize the role of donor antiviral treatment and recipient HBV immunity in establishing optimal prophylactic regimens.

Treatment of donors' asymptomatic small kidney stones and post-transplant outcomes: a meta-analysis.

Kidney donors with asymptomatic small kidney stones were increasingly accepted in kidney transplantation (KT) due to organ shortage and advances in endoscopic urology. However, recipients' clinical outcomes using these donors remained unclear. We conducted a meta-analysis to summarize transplant outcomes using these donors with asymptomatic small kidney stones. Finally, 15 retrospective studies were included. The prevalence of asymptomatic small kidney stones was 5.3% (95%CI 3.5-7.8%). After transplantation, low incidence of urinary fistula (0%, 95%CI 0-1.0%), obstruction (0%, 95%CI 0-1.1%), relapse of kidney graft stone (0.3%, 95%CI 0-2.5%), and delayed graft function (0.6%, 95%CI 0-3.5%) was reported. Pooled serum creatinine was 1.3 (95%CI 1.2-1.5) mg/dl and 1.4 (95%CI 1.2-1.6) mg/dl at post-transplant 1 month and 1 year, respectively. Notably, we observed numerically higher relapse rate after conservative management (1.8% [0-9.2%] vs 0% [0-1.8%]) but numerically higher DGF rate after surgical removal of asymptomatic stones (1.8% [0-7.0%] vs 0% [0-1.9%]). Overall, short-term transplant outcomes using kidneys with asymptomatic small stones were acceptable. However, long-term transplant outcomes remained unexplored. Well-designed prospective studies are also needed to compare the efficacy of conservative management with surgical removal of "donors' gifted" asymptomatic kidney stones.

Laparoscopic Living Donor Nephrectomy in a Donor With Situs Inversus Totalis: It is Not a Contraindication to Kidney Transplant.

Situs inversus totalis (SIT) is a rare anatomic anomaly representing 180° inversion of all internal organs. We report a case of laparoscopic living donor nephrectomy in a donor with SIT. A 55-year-old man volunteered to provide a living kidney source for his son. The donor was in good physical condition, with no clinical history of obesity, hypertension, diabetes, and other abnormalities. Preoperative X-ray thoracic and abdominal scans showed that the donor had a total organ transposition inversus. Computed tomographic renal vascular three-dimensional reconstruction scan showed that the patient had 2 left renal arteries and 1 right renal artery. All data collected comply with the Helsinki Congress and the Declaration of Istanbul. We chose to perform a transabdominal route laparoscopic living donor nephrectomy of the right kidney. The donor did not experience operation-related complications and was discharged on the fourth postoperative day. The recipient did not have a rejection reaction, and the recipient recovered successfully. This case illustrates that laparoscopic living donor nephrectomy is fully feasible in this population.

Psoriasis and risk of chronic kidney diseases: A population-based cross-sectional study and Mendelian randomization analysis.

BACKGROUND: Conflicting results have been reported regarding the association between psoriasis and risk of chronic kidney diseases (CKD). Furthermore, the causal nature of the possible association remains unexplored. METHODS: We conducted a population-based cross-sectional study using data from National Health and Nutrition Examination Survey (NHANES). Logistic regression analyses were conducted to estimate potential association between psoriasis and CKD risk. Further, we evaluated causality by performing a Mendelian randomization analysis using large-scale genome-wide association studies of psoriasis and CKD. Inverse variance-weighted (IVW) analysis was used as the primary method. RESULTS: In the observational study, 16 750 participants were included. Overall, 39 of 429 patients with psoriasis had CKD (9.1%) compared with 1481 of 16 321 without psoriasis (9.1%). In the fully adjusted model, psoriasis was not associated with CKD (OR: 0.77, 95%CI: 0.53-1.10). In the MR analysis, 36 single-nucleotide polymorphisms (SNPs) were selected as instrumental variables. The IVW analysis reported that genetically predicted psoriasis was associated with a higher risk of CKD (OR: 1.025, 95%CI: 1.001-1.049). After removing 2 SNPs associated with heterogeneity, the association remained (OR: 1.028, 95%CI: 1.006-1.050). CONCLUSION: Genetically predicted psoriasis was associated with a higher risk of CKD. This association may be important for clinicians to monitor kidney function and prescribe potentially nephrotoxic drugs during psoriasis management.

Incidence, risk factors, and clinical outcomes of HBV reactivation in non-liver solid organ transplant recipients with resolved HBV infection: A systematic review and meta-analysis.

BACKGROUND: Current guidelines do not recommend routine antiviral prophylaxis to prevent hepatitis B virus (HBV) reactivation in non-liver solid organ transplant (SOT) recipients with resolved HBV infection, even in anti-hepatitis B surface antigen (anti-HBs)-negative recipients and those receiving intense immunosuppression. This systematic review and meta-analysis aimed to determine the incidence, risk factors, and clinical outcomes of HBV reactivation in non-liver SOT recipients. METHODS AND FINDINGS: Three databases (PubMed, Embase, and Cochrane Library) were systematically searched up to December 31, 2022. Clinical studies reporting HBV reactivation in non-liver SOT recipients were included. Case reports, case series, and cohort studies with a sample size of less than 10 patients were excluded. Random-effects analysis was used for all meta-analyses. We included 2,913 non-liver SOT recipients with resolved HBV infection from 16 retrospective cohort studies in the analysis. The overall HBV reactivation rate was 2.5% (76/2,913; 95% confidence interval [95% CI 1.6%, 3.6%]; I2 = 55.0%). Higher rates of reactivation were observed in recipients with negative anti-HBs (34/421; 7.8%; 95% CI [5.2%, 10.9%]; I2 = 36.0%) by pooling 6 studies, experiencing acute rejection (13/266; 5.8%; 95% CI [2.3%, 14.5%]; I2 = 63.2%) by pooling 3 studies, receiving ABO blood type-incompatible transplantation (8/111; 7.0%; 95% CI [2.9%, 12.7%]; I2 = 0%) by pooling 3 studies, receiving rituximab (10/133; 7.3%; 95% CI [3.4%, 12.6%]; I2 = 0%) by pooling 3 studies, and receiving anti-thymocyte immunoglobulin (ATG, 25/504; 4.9%; 95% CI [2.5%, 8.1%]; I2 = 49.0%) by pooling 4 studies. Among recipients with post-transplant HBV reactivation, 11.0% (7/52; 95% CI [4.0%, 20.8%]; I2 = 0.3%) developed HBV-related hepatic failure, and 11.0% (7/52; 95% CI [4.0%, 20.8%]; I2 = 0.3%) had HBV-related death. Negative anti-HBs (crude odds ratio [OR] 5.05; 95% CI [2.83, 9.00]; p < 0.001; I2 = 0%), ABO blood type-incompatible transplantation (crude OR 2.62; 95% CI [1.05, 6.04]; p = 0.040; I2 = 0%), history of acute rejection (crude OR 2.37; 95% CI [1.13, 4.97]; p = 0.022; I2 = 0%), ATG use (crude OR 3.19; 95% CI [1.48, 6.87]; p = 0.003; I2 = 0%), and rituximab use (crude OR 3.16; 95% CI [1.24, 8.06]; p = 0.016; I2 = 0%) increased the risk of reactivation. Adjusted analyses reported similar results. Limitations include moderate heterogeneity in the meta-analyses and that most studies were conducted in kidney transplant recipients. CONCLUSIONS: Non-liver SOT recipients with resolved HBV infection have a high risk of HBV-related hepatic failure and HBV-related death if HBV reactivation occurs. Potential risk factors for HBV reactivation include rituximab use, anti-thymocyte immunoglobulin use, anti-HBs negative status, acute rejection history, and ABO blood type-incompatible transplantation. Further research on monitoring and routine antiviral prophylaxis of non-liver SOT recipients at higher risk of HBV reactivation is required.

Magnesium Depletion Score is Associated with Long-Term Mortality in Chronic Kidney Diseases: A Prospective Population-Based Cohort Study.

BACKGROUND: Magnesium deficiency is common in patients with chronic kidney diseases (CKD) due to restricted magnesium intake and impaired magnesium reabsorption. Based on pathophysiological risk factors influencing kidney magnesium reabsorption, a magnesium depletion score (MDS) was developed. Using MDS as a novel indicator for assessing body magnesium status, we hypothesized that it was associated with clinical prognosis. METHODS: We conducted a prospective population-based cohort study using data from the National Health and Nutrition Examination Survey 1999-2014 to explore the impact of MDS on the clinical outcomes of CKD patients. Propensity score-matched analyses were conducted to increase comparability. The primary outcome was all-cause mortality, and the secondary outcomes were cardiovascular-cause and cancer-cause mortality. RESULTS: After propensity score matching, 3294 CKD patients were divided into 2 groups: MDS ≤ 2 (N = 1647), and MDS > 2 (N = 1647). During a median follow-up of 75 months, Kaplan-Meier analyses showed that MDS > 2 was associated with worse 5- and 10-year overall survival (78.5% vs 73.4%; 53.1% vs 43.1%, P < 0.001). After adjusting for confounding variables, MDS was found to be an independent risk factor for all-cause mortality (HR:1.34, 95% CI 1.20-1.50, P < 0.001). MDS > 2 was also associated with higher cardiovascular-cause mortality (16.2% VS 11.6%, P = 0.005). Multivariate competing risk analysis revealed that MDS > 2 was an independent risk factor (HR: 1.33, 95% CI 1.06-1.66, P = 0.012). Subgroup analyses reported that MDS > 2 increased all-cause mortality and cardiovascular-cause mortality only in patients with inadequate magnesium intake (P < 0.001, P < 0.001) but not in those with adequate intake (P = 0.068, P = 0.920). CONCLUSIONS: A magnesium depletion score > 2 was independently associated with higher long-term cardiovascular-cause and all-cause mortality in CKD patients.

Serum uric acid as a risk factor for rejection after deceased donor kidney transplantation: A mono-institutional analysis of paired kidneys.

Background: Deceased donor kidney transplantation (DDKT) is a major therapeutic option for patients with end-stage renal diseases. Although medical techniques improved in recent years, acute or chronic rejection after DDKT is not uncommon and often results in poor graft survival. Therefore, the determination of risk factors is very important to stratify patients and to improve outcomes. This study aims to evaluate the risk factors for treated rejection (TR) of patients after DDKT. Methods: Clinical data of deceased donors and corresponding recipients were retrospectively collected. The primary outcome was TR defined as the treatment for rejection within 24 months after DDKT. Univariate comparisons of baseline characteristics were performed with Chi-square test, t-test, and Mann-Whitney U test. Logistic regression was constructed to analyze potential risk factors. Receiver operating characteristic (ROC) curve and Jordan index were generated to determine the optimal cutoff value. The association between continuous variables and TR was examined and visualized by using restricted cubic spline (RCS) models. Results: Data of 123 deceased donors and 246 recipients were obtained and analyzed. The median age was 41 (4-62) years for recipients and 39 (1-65) years for donors. The recipients who died or suffered graft loss during the follow-up period were 8 (3.3%) and 12 (4.9%), respectively. After univariate analysis and subsequent multivariate analysis, the preoperative serum uric acid (OR, 2.242; 95% CI, 1.037-4.844; P = 0.040), platelet (OR, 2.163; 95% CI, 1.073-4.361, P = 0.031), absolute neutrophil count (OR, 2.183; 95% CI, 1.025-4.649; P = 0.043), and HLA-DQ mismatch (OR, 2.102; 95% CI, 1.093-4.043; P = 0.026) showed statistical significance. RCS models showed that patients with higher levels of uric acid had increased risk of TR. Conclusions: Serum uric acid and other three indicators were found to be the independent risk factors for TR, which may contribute to stratify patients and develop personalized regimen in perioperative period.

Macrophage-Specific Cathepsin as a Marker Correlated with Prognosis and Tumor Microenvironmental Characteristics of Clear Cell Renal Cell Carcinoma.

Background: Cathepsin Z (CTSZ) is a cathepsin family member that plays a dual role in the adhesion and migration of immune and tumor cells. Methods: The expression pattern of CTSZ in clear cell renal cell carcinoma (ccRCC) was observed by immunohistochemistry and validated by using double-labeling immunofluorescence. Publicly available single-cell sequencing data was used to further define the cell type-specific CTSZ expression in ccRCC. Methylation modification, immune infiltration, and tumor-related signaling enrichment analyses involving CTSZ were performed using multi-omics data. Data from two independent cohorts of anti-programmed death-1 (PD-1) therapeutic clinical trials were used to investigate correlations between CTSZ levels and treatment responses. Results: CTSZ was upregulated in ccRCC tissues compared with adjacent normal tissues at the RNA but not in ccRCC cells. Immunohistochemistry indicated that CTSZ was expressed in tumors infiltrated with lymphocytes. Double immunofluorescence demonstrated that CTSZ was co-expressed with CD68 but not CD8. Single-cell transcriptome data showed macrophage-specific expression of CTSZ in ccRCC. High CTSZ expression was significantly correlated with the enrichment of interferon-γ, epithelial-to-mesenchymal transition, cell cycle, apoptosis pathways, and B cell, macrophage, neutrophil, and dendritic cell infiltrations, as well as the expression of immune checkpoints CTLA4, LAG3, HAVCR2, PDCD1LG2, PDCD1, TIGIT, and SIGLEC15. Hypomethylation modification of cg02744249, cg02744249, and cg22145559 were negatively correlated with CTSZ expression, suggesting an epigenetic mechanism for the regulation of CTSZ expression. Clinically, CTSZ levels were associated with the prognosis of patients with ccRCC (hazard ratio=1.5, P=0.007). Notably, patients with higher CTSZ expression had a worse prognosis with anti-PD-1 monotherapy (hazard ratio=1.51, P=0.039). Conclusion: Macrophage-specific CTSZ was associated with activation of epithelial-to-mesenchymal transition, cell cycle signatures, and a higher infiltration level of B cells, macrophages, neutrophils, and dendritic cells in the tumor microenvironment. High expression of CTSZ could be considered as a prognostic and treatment response biomarker for patients with ccRCC receiving anti-PD-1 immunotherapy.

Clinicopathological characteristics and outcomes of synchronous renal cell carcinoma and urothelial carcinoma: A population-based analysis.

Background: To better understand the characteristics, and survival outcomes of synchronous renal cell carcinoma (RCC) and urothelial carcinoma (UC), we described and analyzed the clinical features, factors, and prognosis of patients with synchronous RCC and UC using a large population-based database. Methods: Within the Surveillance, Epidemiology, and End Results (SEER) database (2004-2016), we identified patient with concurrent RCC and UC at initial diagnosis. Their clinicopathological features and prognosis were evaluated. A logistic regression model was used to examine risk factors for the occurrence of concomitant RCC and UC, and Kaplan-Meier survival curves were used to estimate overall survival. Results: A total of 61,454 RCC patients were identified from the SEER database, 704 (1.1%) patients presented with synchronous RCC and UC. Among these patients, concurrent bladder tumors (566/704) are more common. Subsequently, subgroup analysis based on the location of UC indicated that patients with concurrent RCC and upper tract urothelial carcinoma (UTUC) had unfavorable UC characteristics (higher tumor stage and grade), compared with patients with concomitant bladder cancer. An increased risk of concurrent UC was observed among older age, male sex, and white race. Meanwhile, papillary RCC histology [odds ratio (OR) 3.23; 95% confidence interval (CI) 2.13-4.90], and smaller tumor (OR 6.63; 95% CI 4.46-9.87) were independent risk factors for concomitant UTUC. In addition, we found that synchronous RCC and UTUC was associated with worse survival by using Kaplan-Meier and multivariable analysis [hazard ratio (HR) 2.36, 95% CI 1.89-2.95]. However, concomitant bladder cancer did not affect survival outcomes of patients with RCC (HR 1.00, 95% CI 0.86-1.17). Conclusion: We found that synchronous concurrent RCC and UC is relatively uncommon and mostly located in the bladder. Older age, male sex, and white race increase the risk of synchronous RCC and UC. Meanwhile, patients with papillary RCC histology, and smaller tumors are more likely to have concomitant RCC and UTUC. Furthermore, our findings suggest that synchronous RCC and UTUC has a worse prognosis, while, concomitant bladder tumor did not affect the oncological outcomes of RCC.

Cuprotosis-related signature predicts overall survival in clear cell renal cell carcinoma.

Background: Cuprotosis is a new form of programmed cell death induced by copper. We explored the correlation of cuprotosis with clear cell renal cell carcinoma (ccRCC) and constructed a cuprotosis-related signature to predict the prognosis of patients with ccRCC. Methods: The clinical and transcriptomic data of ccRCC patients were downloaded from The Cancer Genome Atlas (TCGA), cBioPortal, and GEO databases, and cuprotosis-related gene sets were contained in the previous study. A cuprotosis-related signature was developed based on data from TCGA and verified by data from cBioPortal and GEO databases. The immune cell infiltrates and the corresponding signature risk scores were investigated. Two independent cohorts of clinical trials were analyzed to explore the correlation of the signature risk score with immune therapy response. Results: A signature containing six cuprotosis-related genes was identified and can accurately predict the prognosis of ccRCC patients. Patients with downregulated copper-induced programmed death had a worse overall survival (hazard ratio: 1.90, 95% CI: 1.39-2.59, p < 0.001). The higher signature risk score was significantly associated with male gender (p = 0.026), higher tumor stage (p < 0.001), and higher histological grade (p < 0.001). Furthermore, the signature risk score was positively correlated with the infiltration of B cells, CD8+ T cells, NK cells, Tregs, and T cells, whereas it was negatively correlated with eosinophils, mast cells, and neutrophils. However, no correlation between cuprotosis and response to anti-PD-1 therapy was found. Conclusion: We established a cuprotosis signature, which can predict the prognosis of patients with ccRCC. Cuprotosis was significantly correlated with immune cell infiltrates in ccRCC.

Transplant outcomes of 100 cases of living-donor ABO-incompatible kidney transplantation.

BACKGROUND: Although ABO-incompatible (ABOi) kidney transplantation (KT) has been performed successfully, a standard preconditioning regimen has not been established. Based on the initial antidonor ABO antibody titers, an individualized preconditioning regimen is developed, and this study explored the efficacy and safety of the regimen. METHODS: From September 1, 2014, to September 1, 2020, we performed 1668 consecutive living-donor KTs, including 100 ABOi and 1568 ABO-compatible (ABOc) KTs. ABOi KT recipients (KTRs) with a lower antibody titer (≤1:8) were administered oral immunosuppressive drugs (OIs) before KT, while patients with a medium titer (1:16) received OIs plus antibody-removal therapy (plasma exchange/double-filtration plasmapheresis), patients with a higher titer (≥1:32) were in addition received rituximab (Rit). Competing risk analyses were conducted to estimate the cumulative incidence of infection, acute rejection (AR), graft loss, and patient death. RESULTS: After propensity score analyses, 100 ABOi KTRs and 200 matched ABOc KTRs were selected. There were no significant differences in graft and patient survival between the ABOi and ABOc groups (P  = 0.787, P  = 0.386, respectively). After using the individualized preconditioning regimen, ABOi KTRs showed a similar cumulative incidence of AR (10.0% υs . 10.5%, P  = 0.346). Among the ABOi KTRs, the Rit-free group had a similar cumulative incidence of AR ( P  = 0.714) compared to that of the Rit-treated group. Multivariate competing risk analyses revealed that a Rit-free regimen reduced the risk of infection (HR: 0.31; 95% CI: 0.12-0.78, P  = 0.013). Notably, antibody titer rebound was more common in ABOi KTRs receiving a Rit-free preconditioning regimen ( P  = 0.013) than those receiving Rit. ABOi KTRs with antibody titer rebound had a 2.72-fold risk of AR (HR: 2.72, 95% CI: 1.01-7.31, P  = 0.048). ABOi KTRs had similar serum creatinine and estimated glomerular filtration rate compared to those of ABOc KTRs after the first year. CONCLUSIONS: An individualized preconditioning regimen can achieve comparable graft and patient survival rates in ABOi KT with ABOc KT. Rit-free preconditioning effectively prevented AR without increasing the risk of infectious events in those with lower initial titers; however, antibody titer rebound should be monitored.

Identification of an amino acid metabolism-associated gene signature predicting the prognosis and immune therapy response of clear cell renal cell carcinoma.

Background: The upregulation of amino acid metabolism is an essential form of metabolic reprogramming in cancer. Here, we developed an amino acid metabolism signature to predict prognosis and anti-PD-1 therapy response in clear cell renal cell carcinoma (ccRCC). Methods: According to the amino acid metabolism-associated gene sets contained in the Molecular Signature Database, consensus clustering was performed to divide patients into two clusters. An amino acid metabolism-associated signature was identified and verified. Immune cell infiltrates and their corresponding signature risk scores were investigated. Two independent cohorts of clinical trials were analyzed to explore the correspondence between the signature risk score and the immune therapy response. Results: Two clusters with different amino acid metabolic levels were identified by consensus clustering. The patients in the two clusters differed in overall survival, progression-free survival, amino acid metabolic status, and tumor microenvironment. We identified a signature containing eight amino acid metabolism-associated genes that could accurately predict the prognosis of patients with ccRCC. The signature risk score was positively correlated with infiltration of M1 macrophages, CD8+ T cells, and regulatory T cells, whereas it was negatively correlated with infiltration of neutrophils, NK cells, and CD4+ T cells. Patients with lower risk scores had better overall survival but worse responses to nivolumab. Conclusion: Amino acid metabolic status is closely correlated with tumor microenvironment, response to checkpoint blockade therapy, and prognosis in patients with ccRCC. The established amino acid metabolism-associated gene signature can predict both survival and anti-PD-1 therapy response in patients with ccRCC.

Cholecalciferol supplementation effectively improved tertiary hyperparathyroidism, FGF23 resistance and lowered coronary calcification score: a prospective study.

Introduction: Tertiary hyperparathyroidism (THPT) and vitamin D deficiency are commonly seen in kidney transplant recipients, which may result in persistently elevated fibroblast growth factor 23 (FGF23) level after transplantation and decreased graft survival. The aim of this study is to evaluate the effect of vitamin D supplementation on THPT, FGF23-alpha Klotho (KLA) axis and cardiovascular complications after transplantation. Materials and methods: Two hundred nine kidney transplant recipients were included and further divided into treated and untreated groups depending on whether they received vitamin D supplementation. We tracked the state of THPT, bone metabolism and FGF23-KLA axis within 12 months posttransplant and explored the predictors and risk factors for intact FGF23 levels, KLA levels, THPT and cardiovascular complications in recipients. Results: Vitamin D supplementation significantly improved FGF23 resistance, THPT and high bone turnover status, preserved better graft function and prevented coronary calcification in the treated group compared to the untreated group at month 12. The absence of vitamin D supplementation was an independent risk factor for THPT and a predictor for intact FGF23 and KLA levels at month 12. Age and vitamin D deficiency were independent risk factors for coronary calcification in recipients at month 12. Conclusion: Vitamin D supplementation effectively improved THPT, FGF23 resistance and bone metabolism, preserved graft function and prevented coronary calcification after transplantation.

Integrated Analysis of Energy Metabolism Signature-Identified Distinct Subtypes of Bladder Urothelial Carcinoma.

Background: Bladder urothelial carcinoma (BLCA) is the most common type of bladder cancer. In this study, the correlation between the metabolic status and the outcome of patients with BLCA was evaluated using data from the Cancer Genome Atlas and Gene Expression Omnibus datasets. Methods: The clinical and transcriptomic data of patients with BLCA were downloaded from the Cancer Genome Atlas and cBioPortal datasets, and energy metabolism-related gene sets were obtained from the Molecular Signature Database. A consensus clustering algorithm was then conducted to classify the patients into two clusters. Tumor prognosis, clinicopathological features, mutations, functional analysis, ferroptosis status analysis, immune infiltration, immune checkpoint-related gene expression level, chemotherapy resistance, and tumor stem cells were analyzed between clusters. An energy metabolism-related signature was further developed and verified using data from cBioPortal datasets. Results: Two clusters (C1 and C2) were identified using a consensus clustering algorithm based on an energy metabolism-related signature. The patients with subtype C1 had more metabolism-related pathways, different ferroptosis status, higher cancer stem cell scores, higher chemotherapy resistance, and better prognosis. Subtype C2 was characterized by an increased number of advanced BLCA cases and immune-related pathways. Higher immune and stromal scores were also observed for the C2 subtype. A signature containing 16 energy metabolism-related genes was then identified, which can accurately predict the prognosis of patients with BLCA. Conclusion: We found that the energy metabolism-associated subtypes of BLCA are closely related to the immune microenvironment, immune checkpoint-related gene expression, ferroptosis status, CSCs, chemotherapy resistance, prognosis, and progression of BLCA patients. The established energy metabolism-related gene signature was able to predict survival in patients with BLCA.