Purpose: Due to chronic toxicity, tacrolimus-sparing is an important issue in kidney transplant recipients (KTRs). Several studies have shown that bisphosphonate use is associated with favorable graft outcomes in KTRs. We investigated whether the association between tacrolimus trough levels (TTLs) and graft outcomes differed according to bisphosphonate use in KTRs. Materials and Methods: We conducted a retrospective study encompassing 1441 KTRs who were administered tacrolimus-based immunosuppressants. The primary exposure was a time-dependent cross-product of TTLs (low TTLs vs. normal-high TTLs with a reference of 6 ng/mL) and bisphosphonate use. Two primary outcomes were evaluated: overall graft loss (death or conversion to kidney replacement) and an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m 2 . Results: During the median follow-up of 6.1 (3.4–9.7) years, overall graft loss occurred in 157 (10.9%) patients. Cox regression revealed that normal-high TTLs without bisphosphonate use were associated with a reduced risk of overall graft loss [adjusted hazard ratio (aHR), 0.65; 95% confidence interval (CI), 0.45–0.95] compared to low TTLs without bisphosphonate use. The use of bisphosphonate in conjunction with normal-high TTLs correlated with an even lower risk of overall graft loss (aHR, 0.25; 95% CI, 0.08–0.80) compared with low TTLs without bisphosphonate use. In patients with low TTLs, bisphosphonate use was associated with a reduced risk of overall graft loss compared with non-use (aHR, 0.20; 95% CI, 0.09–0.43). Similar trends were observed in the eGFR outcome. Conclusion The use of bisphosphonate was associated with favorable graft outcomes, even with low TTLs. Incorporating bisphosphonate into a conventional immunosuppressant regimen may potentially reduce tacrolimus requirement.

Background: The aim of this study is to investigate the specific pathway involved in human leukocyte antigen (HLA) sensitization using single-cell RNA-sequencing analysis and an allo-sensitized mouse model developed with an HLA.A2 transgenic mouse. Methods: For sensitization, wild-type C57BL/6 mouse received two skin grafts from C57BL/6-Tg(HLA-A2.1)1Enge/J mouse (allogeneic mouse, ALLO). For syngeneic control (SYN), skin grafts were transferred from C57BL/6 to C57BL/6. We performed single-cell RNA-sequencing analysis on splenocytes isolated from ALLO and SYN and compared the gene expression between them. Results: We generated 9,190 and 8,890 single-cell transcriptomes from ALLO and SYN, respectively. Five major cell types (B cells, T cells, natural killer cells, macrophages, and neutrophils) and their transcriptome data were annotated according to the representative differentially expressed genes of each cell cluster. The percentage of B cells was higher in ALLO than it was in SYN. Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that the highly expressed genes in the B cells from ALLO were mainly associated with antigen processing and presentation pathways, allograft rejection, and the Th17 cell differentiation pathway. Upregulated genes in the T cells of ALLO were involved in the interleukin (IL)-17 signaling pathway. The ratio of Th17 cluster and Treg cluster was increased in the ALLO. On flow cytometry, the percentage of Th17 (IL-17+/CD4+ T) cells was higher and regulatory T cells (FOXP3+/CD4+ T) was lower in the ALLO compared to those in the SYN. Conclusion Our results indicate that not only the B cell lineage but also the Th17 cells and their cytokine (IL-17) are involved in the sensitization to HLA.

Background: Calcineurin inhibitor (CNI) toxicity is a significant cause of graft dysfunction in kidney transplant recipients, yet distinguishing it from acute rejection (AR) and acute tubular necrosis (ATN) remains challenging. This study investigated the use of urinary mRNA biomarkers as a noninvasive tool for identifying CNI toxicity. Methods: We retrospectively enrolled 110 kidney transplant recipients and classified them into four groups based on pathological findings: stable graft function (n=35), CNI toxicity (n=25), AR (n=30), and ATN (n=20). Candidate biomarkers were selected using the GEO database. Urinary mRNA was extracted from cell pellets, reverse-transcribed, and quantified by real-time polymerase chain reaction. Results: Estimated glomerular filtration rates were comparable among the CNI toxicity, AR, and ATN groups. Four transcripts (LTF, NNMT, WFDC2, and HIF1A) were identified as candidate biomarkers. Urinary mRNA levels of LTF, NNMT, and HIF1A were significantly lower in the CNI toxicity group than the AR group. NNMT and HIF1A levels were also significantly lower than those observed in the ATN group. In contrast, WFDC2 levels did not differ significantly across groups. A three-gene signature (LTF, NNMT, and HIF1A) effectively differentiated CNI toxicity from AR and ATN (area under the curve [AUC], 0.867;95% confidence interval [CI], 0.787–0.947) and significantly enhanced the diagnostic performance of the clinical variable-based model (AUC increased from 0.776; 95% CI, 0.660–0.892, to 0.934; 95% CI, 0.881–0.986). Conclusions Urinary mRNA levels of LTF, NNMT, and HIF1A may serve as useful biomarkers for identifying CNI toxicity in kidney transplant recipients with graft dysfunction.

Background: This study was designed to determine the current status of diagnosis and treatment of valvular heart disease (VHD) in Korea. Methods: A nationwide registry study was conducted in 45 hospitals in Korea involving adult patients with at least moderate VHD as determined by echocardiography carried out between September and October of 2019. Of a total of 4,094 patients with at least moderate VHD, 1,482 had severe VHD (age, 71.3 ± 13.5 years; 49.1% male). Echocar‑ diographic data used for the diagnosis of each case of VHD were analyzed. Experts from each center determined the diagnosis and treatment strategy for VHD based on current guidelines and institutional policy. The clinical out‑ come was in-hospital mortality. Results: Each valve underwent surgical or transcatheter intervention in 19.3% cases of severe mitral stenosis, 31.4% cases of severe primary mitral regurgitation (MR), 7.5% cases of severe secondary MR, 43.7% cases of severe aortic stenosis, 27.5% cases of severe aortic regurgitation, and 7.2% cases of severe tricuspid regurgitation. The overall inhospital mortality rate for patients with severe VHD was 5.4%, and for secondary severe MR and severe tricuspid regur‑ gitation, the rates were 9.0% and 7.5%, respectively, indicating a poor prognosis. In-hospital mortality occurred in 73 of the 1,244 patients (5.9%) who received conservative treatment and in 18 of the 455 patients (4.0%) who received a surgical or transcatheter intervention, which was significantly lower in the intervention group (P = 0.037). Conclusions This study provides important information about the current status of VHD diagnosis and treatment through a nationwide registry in Korea and helps to define future changes.

OBJECTIVES: Observational studies have reported that diabetes is a risk factor that increases the risk of atherosclerotic cardiovascular disease (ASCVD). However, the causal relationship remains a matter of debate. This study aimed to analyze the relationship between fasting serum glucose (FSG) and ASCVD. METHODS: This study used data from the Korean Cancer Prevention Study-II (KCPS-II) Biobank, consisting of 159,844 people recruited with consent from 18 health examination centers from 2004 to 2013. Outcomes were confirmed based on diagnoses on hospital discharge summaries from National Health Insurance System. We used linear and non-linear Mendelian randomization (MR) methods. The outcome data were obtained from KCPS-II, and the exposure data were derived from the Korean Genome Epidemiology Study. RESULTS: First, a prospective cohort study estimated that for each 10 mg/dL increase in FSG level, the risk of ASCVD increased by 4% (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.03 to 1.05). Second, the 2-sample MR study showed that every 10 mg/dL increase in FSG influenced the risk of ASCVD (odds ratio [OR], 1.11; 95% CI, 1.04 to 1.18). Third, the multivariable MR study showed that the OR per 10 mg/dL increase in FSG on ASCVD was 1.14 (p<0.001). Similar results were found for a 10 mg/dL increase in FSG and ischemic heart disease (IHD), but a significant relationship with stroke was not found. When performing non-linear MR, a linear relationship was observed between fasting blood sugar and ASCVD, including IHD and stroke. CONCLUSIONS FSG showed a linear and causal association with IHD, but not with stroke.

OBJECTIVES: Observational studies have reported that diabetes is a risk factor that increases the risk of atherosclerotic cardiovascular disease (ASCVD). However, the causal relationship remains a matter of debate. This study aimed to analyze the relationship between fasting serum glucose (FSG) and ASCVD. METHODS: This study used data from the Korean Cancer Prevention Study-II (KCPS-II) Biobank, consisting of 159,844 people recruited with consent from 18 health examination centers from 2004 to 2013. Outcomes were confirmed based on diagnoses on hospital discharge summaries from National Health Insurance System. We used linear and non-linear Mendelian randomization (MR) methods. The outcome data were obtained from KCPS-II, and the exposure data were derived from the Korean Genome Epidemiology Study. RESULTS: First, a prospective cohort study estimated that for each 10 mg/dL increase in FSG level, the risk of ASCVD increased by 4% (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.03 to 1.05). Second, the 2-sample MR study showed that every 10 mg/dL increase in FSG influenced the risk of ASCVD (odds ratio [OR], 1.11; 95% CI, 1.04 to 1.18). Third, the multivariable MR study showed that the OR per 10 mg/dL increase in FSG on ASCVD was 1.14 (p<0.001). Similar results were found for a 10 mg/dL increase in FSG and ischemic heart disease (IHD), but a significant relationship with stroke was not found. When performing non-linear MR, a linear relationship was observed between fasting blood sugar and ASCVD, including IHD and stroke. CONCLUSIONS FSG showed a linear and causal association with IHD, but not with stroke.

Background: This study was designed to determine the current status of diagnosis and treatment of valvular heart disease (VHD) in Korea. Methods: A nationwide registry study was conducted in 45 hospitals in Korea involving adult patients with at least moderate VHD as determined by echocardiography carried out between September and October of 2019. Of a total of 4,094 patients with at least moderate VHD, 1,482 had severe VHD (age, 71.3 ± 13.5 years; 49.1% male). Echocar‑ diographic data used for the diagnosis of each case of VHD were analyzed. Experts from each center determined the diagnosis and treatment strategy for VHD based on current guidelines and institutional policy. The clinical out‑ come was in-hospital mortality. Results: Each valve underwent surgical or transcatheter intervention in 19.3% cases of severe mitral stenosis, 31.4% cases of severe primary mitral regurgitation (MR), 7.5% cases of severe secondary MR, 43.7% cases of severe aortic stenosis, 27.5% cases of severe aortic regurgitation, and 7.2% cases of severe tricuspid regurgitation. The overall inhospital mortality rate for patients with severe VHD was 5.4%, and for secondary severe MR and severe tricuspid regur‑ gitation, the rates were 9.0% and 7.5%, respectively, indicating a poor prognosis. In-hospital mortality occurred in 73 of the 1,244 patients (5.9%) who received conservative treatment and in 18 of the 455 patients (4.0%) who received a surgical or transcatheter intervention, which was significantly lower in the intervention group (P = 0.037). Conclusions This study provides important information about the current status of VHD diagnosis and treatment through a nationwide registry in Korea and helps to define future changes.

Regardless of the underlying etiology, renal fibrosis is the final histological outcome of progressive kidney disease. Unilateral ureteral obstruction (UUO) is an ideal and reproducible experimental rodent model of renal fibrosis, which is characterized by tubulointerstitial inflammatory responses, accumulation of extracellular matrix, tubular dilatation and atrophy, and fibrosis. The magnitude of UUO-induced renal fibrosis is experimentally manipulated by the species chosen, animal age, and the severity and duration of the obstruction, while relief of the obstruction allows the animal to recover from fibrosis. The pathogenesis of renal fibrosis is complex and multifactorial and is orchestrated by activation of renin-angiotensin system (RAS), oxidative stress, inflammatory response, transforming growth factor beta 1-Smad pathway, activated myofibroblasts, cell death (apoptosis, autophagy, ferroptosis, and necroptosis), destruction of intracellular organelles, and signaling pathway. The current therapeutic approaches have limited efficacy. Inhibition of RAS and use of antioxidants and antidiabetic drugs, such as inhibitors of sodium-glucose cotransporter 2 and dipeptidyl peptidase-4, have recently gained attention as therapeutic strategies to prevent renal scarring. This literature review highlights the state of the art regarding the molecular mechanisms relevant to the management of renal fibrosis caused by UUO.

OBJECTIVES: Observational studies have reported that diabetes is a risk factor that increases the risk of atherosclerotic cardiovascular disease (ASCVD). However, the causal relationship remains a matter of debate. This study aimed to analyze the relationship between fasting serum glucose (FSG) and ASCVD. METHODS: This study used data from the Korean Cancer Prevention Study-II (KCPS-II) Biobank, consisting of 159,844 people recruited with consent from 18 health examination centers from 2004 to 2013. Outcomes were confirmed based on diagnoses on hospital discharge summaries from National Health Insurance System. We used linear and non-linear Mendelian randomization (MR) methods. The outcome data were obtained from KCPS-II, and the exposure data were derived from the Korean Genome Epidemiology Study. RESULTS: First, a prospective cohort study estimated that for each 10 mg/dL increase in FSG level, the risk of ASCVD increased by 4% (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.03 to 1.05). Second, the 2-sample MR study showed that every 10 mg/dL increase in FSG influenced the risk of ASCVD (odds ratio [OR], 1.11; 95% CI, 1.04 to 1.18). Third, the multivariable MR study showed that the OR per 10 mg/dL increase in FSG on ASCVD was 1.14 (p<0.001). Similar results were found for a 10 mg/dL increase in FSG and ischemic heart disease (IHD), but a significant relationship with stroke was not found. When performing non-linear MR, a linear relationship was observed between fasting blood sugar and ASCVD, including IHD and stroke. CONCLUSIONS FSG showed a linear and causal association with IHD, but not with stroke.