Soluble Programmed Cell Death Ligand-1 (sPD-L1) Levels in Various Cancer Types and Normal Populations.

BACKGROUND: To date, PD-L1 expression in tumor tissue, assessed by immunohistochemical stain, is clinically applicable as a predictive companion biomarker for PD-1/PD-L1 inhibitor which has been highlighted over the past several years. Before blood-based sPD-L1 enters clinical use, it is critical to establish the reference range. This study was designed to investigate soluble sPD-L1 levels in various cancer patients and normal population. METHODS: For the detection of sPD-L1, 4 cancer groups (hepatocellular carcinoma, lung cancer, bladder cancer, gastric cancer) and healthy volunteers' samples were analyzed using an ELISA kit. Using a receiver operating characteristic curve, optimal sPD-L1 cutoff levels were determined. RESULTS: The mean serum sPD-L1 level of the normal population was 59.97 pg/mL (range; 23.780 - 115.2 pg/mL). In various cancer types, serum sPD-L1 levels ranged from 38.696 pg/mL to 228.77 pg/mL, and cutoff values under AUC ranged from 60.307 pg/mL to 64.371 pg/mL. CONCLUSIONS: sPD-L1 can be used as a screening biomarker in various cancer patients referring to optimal cutoff levels suggested.

Effects of Exposure to Lead and Cadmium on Health of Inhabitants of Abandoned Metal Mine Area in Korea.

People living near abandoned mines are at increased risk of exposure to toxic metals. We surveyed 4500 inhabitants with the mean age of 68.5 years old (male: 1768, female: 2732) living near 104 abandoned metal mines from 2013 to 2017 (the 2nd phase health survey in Korea). We conducted personal interviews, blood and urine sampling, and analyzed the concentrations of lead (Pb) and cadmium (Cd) in whole blood and Cd in urine using a graphite furnace atomic absorption spectrometer. The geometric means of blood Pb, blood Cd, and urine Cd were 2.27 µg/dL, 1.42 µg/L, and 1.66 µg/g creatinine, respectively. The level of metal exposure was lower than that reported from the first phase health survey in Korea (2008‒2011) but was higher than in the general population of Korea. Blood Pb was higher in males while blood Cd and urine Cd were significantly higher in females. Blood Pb was highest in the 40‒59 age group, while blood and urine Cd levels continuously increased until age 80 or older. The Cd levels in blood and urine were affected by consumption of locally produced rice and duration of residence near abandoned mines. Furthermore, negative correlations were observed between blood Pb and blood and urine Cd levels. Additionally, 252 of the 4500 subjects exceeded the thresholds of blood Cd or urine Cd levels. Together, these findings suggest that Cd has more sustainable and adverse health effects on the abandoned mine inhabitants, who are mostly aged. Therefore, continuous biomonitoring and risk assessment to environmental health risks are necessary for environmental pollution control and health promotion.

Febuxostat ameliorates diabetic renal injury in a streptozotocin-induced diabetic rat model.

BACKGROUND: Oxidative stress and inflammation are known to play central roles in the development of diabetic nephropathy (DN). Febuxostat is a novel non-purine xanthine oxidase (XO)-specific inhibitor developed to treat hyperuricemia. In this study, we investigated whether febuxostat could ameliorate DN via renoprotective mechanisms such as alleviation of oxidative stress and anti-inflammatory actions. METHODS: Male Sprague-Dawley rats were divided into three groups: a normal group, a diabetes group (DM group), and a febuxostat-treated diabetes group (DM+Fx group). We administered 5 mg/kg of febuxostat to experimental rats for 7 weeks and evaluated clinical and biochemical parameters and XO and xanthine dehydrogenase (XDH) activity in hepatic tissue. The degree of oxidative stress and extent of inflammation were evaluated from urine samples and renal tissue collected from each group. RESULTS: Diabetic rats (DM and DM+Fx groups) had higher blood glucose and kidney weight relative to body weight than normal rats. Albuminuria was significantly reduced in febuxostat-treated diabetic rats compared with untreated diabetic rats. Quantitative analysis showed that hepatic XO and XDH activities were higher in the DM groups, but decreased after treatment with febuxostat. Urinary 8-OHdG concentrations and renal cortical nitrotyrosine also indicated reduced oxidative stress in the DM+Fx group relative to the DM group. The number of ED-1-stained cells in the glomerulus and tubule of diabetic renal tissue decreased in febuxostat-treated diabetic rats relative to that of non-treated diabetic rats. Diabetic rats also expressed higher transcript levels of inflammatory genes (E-selectin and VCAM-1), an inflammation-induced enzyme (COX-2), and inflammatory mediators (ED-1 and NF-κB) than control rats; expression of these genes was significantly reduced by treatment with febuxostat. CONCLUSIONS: Febuxostat prevents diabetic renal injury such as albuminuria. This renoprotective effect appears to be due to attenuation of the inflammatory and oxidative effects of diabetes-induced renal damage through inhibition of XO and XDH activities.

Angiotensinogen polymorphisms and post-transplantation diabetes mellitus in Korean renal transplant subjects.

BACKGROUND: Post-transplant diabetes mellitus (PTDM) is a common and serious metabolic complication. Genetic polymorphisms of angiotensin-converting enzyme (ACE) and angiotensinogen (AGT) genes have been reported to be related to diabetes mellitus and insulin sensitivity; however, the role of these genes in the development of PTDM is not known. For this purpose, we investigated the association of ACE and AGT genetic polymorphisms with PTDM. METHODS: A total of 302 subjects without previously diagnosed diabetes who had received kidney transplants were included. One ACE single nucleotide polymorphism (SNP) (rs4291) and two AGT SNPs (rs 699 and rs 4762) were genotyped from genomic DNA with direct sequencing. RESULTS: PTDM developed in 49 (16.2%) of 302 subjects. Subjects in the PTDM were older than those in the non-PTDM. There was a significant difference between the two groups in tacrolimus use (p=0.03). Of the three SNPs, the rs4762 of the AGT gene was significantly associated with the development of PTDM in the dominant models (p = 0.03) after adjusting for age and tacrolimus usage. CONCLUSIONS: AGT gene rs4762 polymorphisms may serve as genetic markers for the development of PTDM. The exact molecular mechanisms still need to be clarified.

Renal involvement in ankylosing spondylitis: prevalence, pathology, response to TNF-a blocker.

Ankylosing spondylitis (AS) is a chronic inflammatory disease primarily involving the spine and sacroiliac joint and rarely the kidneys. This study aimed to define the clinical and histological features and biology of renal disease in AS. We reviewed the medical records of 681 patients diagnosed with AS from November 2008 to November 2009. Baseline characteristics and laboratory and urinalysis results were reviewed. We identified patients with proteinuria or hematuria and analyzed their risk factors. After providing informed consent, 6 patients underwent a renal biopsy to determine the cause of proteinuria or hematuria. Of the 681 enrolled patients, 547 were men and 134 were women; 81 % were HLA B27 positive, and 8 % had abnormal urinalysis findings (proteinuria, 5.9 %; hematuria, 2.8 %; both, 0.7 %). Incidences of peripheral arthritis and uveitis were 29 % and 18.6 %, respectively. Immunoglobulin (Ig)A and uric acid levels were significantly different between patients with and without proteinuria. Erythrocyte sedimentation rate (ESR), total cholesterol, creatinine, and C-reactive protein (CRP) levels were not statistically significantly different between the 2 groups nor were there any significant differences in IgA, uric acid, ESR, total cholesterol, creatinine, and CRP levels between patients with and without hematuria. Six patients who had >1 g/day proteinuria underwent a renal biopsy; 2 were diagnosed with IgA nephropathy, 1 with amyloidosis, and 3 with non-specific glomerulonephropathy. In the amyloidosis patient, severe proteinuria was the dominant feature. For patients with renal amyloidosis and other forms of glomerulonephritis who initially had normal creatinine levels, tumor necrosis factor (TNF)-alpha blocker therapy resolved proteinuria, but this was not the case for patients with initial renal insufficiency. Renal involvement is not a rare complication of AS, and prognoses differ depending on kidney pathology. Serum levels of uric acid and IgA may predict renal involvement in AS. In cases where abnormal urine sediment is identified, renal biopsy is required to determine prognosis and decide the treatment protocol. Baseline serum creatinine level is important for predicting treatment response.

Real-time monitoring of the effects of telmisartan on angiotensin II-induced mechanical changes in live mesangial cells using atomic force microscopy.

BACKGROUND/AIMS: Recent studies have shown that angiotensin II (Ang II) type 1 receptor blockers (ARB) may provide renal protection independent of their blood pressure-lowering effect. However, evidence for this comes from indirect methods, such as genetic or protein expression studies. In this study, we hypothesized that telmisartan, a specific ARB, applied to Ang II-stimulated mesangial cell (MC) would exert a renoprotective effect via modulation of MCs' mechanical properties. METHODS: We investigated the effect of telmisartan on Ang II-induced changes in MCs utilizing real-time atomic force microscopy (AFM) imaging and force-distance curve measurements. RESULTS: Real-time AFM images of live MCs demonstrated that cells contracted towards the center after Ang II exposure, and telmisartan treatment abolished this change. Cellular spring constants showed that telmisartan prevented Ang II-induced MC stiffening (Ang II: 0.109 ± 0.019 N/m, Ang II + telmisartan: 0.051 ± 0.016 N/m, p < 0.005). Telmisartan-treated MCs had a significantly lower adhesion force than those of the control group (control: 0.49 ± 0.22 nN, telmisartan: 0.22 ± 0.06 nN, Ang II: 0.40 ± 0.25 nN, Ang II + telmisartan: 0.27 ± 0.14 nN, p < 0.005). These results demonstrate that the dynamic contraction and mechanical properties of Ang II-stimulated MCs are restored by telmisartan. CONCLUSIONS: We report for the first time the use of AFM force-distance curves on live MCs to directly monitor changes in surface adhesion and stiffness of cells after treatment with telmisartan in real time.

Relationship between glomerulomegaly and clinicopathologic findings in IgA nephropathy.

BACKGROUND: Large glomeruli are a common finding in the early stages of progressive renal disease. We studied the relationship between glomerular surface area (GSA) and clinicopathologic features of IgA nephropathy (IgAN), including renal outcome, to better understand the role of GSA in IgAN. METHODS: We analyzed renal biopsy specimens and clinical information from 34 patients with IgAN. Mean and maximal GSA were determined using a computed imaging analyzer. RESULTS: Mean GSA was 16,811 ± 4,671 µ2 in IgAN patients (n = 34). When we analyzed various clinical parameters of IgAN patients, there were significant correlations between mean or maximal GSA and age, body mass index (BMI), systolic and diastolic blood pressure, estimated glomerular filtration rate (eGFR), and pathologic findings including H.S. Lee' grades, interstitial fibrosis, and tubular atrophy. GSA did not show any relationship with the degree of hematuria and proteinuria. By multivariate regression analysis of age, BMI, blood pressure, H.S. Lee' grades, and eGFR as independent variables, mean GSA was associated with H.S Lee' grades and initial eGFR. The results for maximal GSA were the same as those for mean GSA. When we divided IgAN patients according to their mean levels of GSA, the group with larger GSA had higher blood pressure and H.S. Lee' grades and lower initial and final eGFR. More patients in the larger GSA group showed the decline in eGFR of more than 15 ml/min/1.73 m2 during the followup period compared with the smaller group. CONCLUSION: These results suggest that glomerular size, estimated by measuring GSA, is related to pathologic findings and renal function in IgAN. However, further investigation is required to determine if GSA can be used as a prognostic indicator of IgAN.

Significant associations between CCL5 gene polymorphisms and post-transplantational diabetes mellitus in Korean renal allograft recipients.

BACKGROUND: Post-transplantational diabetes mellitus (PTDM) is a serious metabolic complication that may follow renal transplantation. The expression of chemokine (C-C motif) ligand 5 (CCL5) is inversely related to pancreatic ß-cell function; thus, specific CCL5 gene polymorphisms are considered to be risk factors for diabetes. In this study, we investigated the association between CCL5 gene polymorphisms and the occurrence of PTDM in Korean patients who had undergone renal transplants. METHODS: A total of 311 patients who had received kidney transplants without a prior history of diabetes were included. Three single nucleotide polymorphisms (SNPs) of the CCL5 gene were genotyped from genomic DNA with direct sequencing. RESULTS: PTDM developed in 56 patients (18.0%). The results showed that the allele frequencies of CCL5 gene polymorphisms, rs2107538*T, rs2280789*C and rs3817655*A were significantly higher in the patients with PTDM than in those without PTDM. In multiple logistic regression analysis, 3 SNPs (rs2107538, rs2280789 and rs3817655) of the CCL5 gene were significantly associated with the development of PTDM in the codominant 2 and recessive models. Among haplotypes of the 3 polymorphisms, the frequency of the TCA haplotype was significantly higher in patients with PTDM than in those without PTDM. CONCLUSIONS: Our results indicated that genetic polymorphisms of the CCL5 gene were associated with PTDM, suggesting that the CCL5 gene might confer susceptibility to PTDM in patients who receive renal transplants.

The Predictive Role of Serum Triglyceride to High-Density Lipoprotein Cholesterol Ratio According to Renal Function in Patients with Acute Myocardial Infarction.

OBJECTIVE: A high serum triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio has been reported as an independent predictor for cardiovascular events in the general population. However, the prognostic value of this ratio in patients with renal dysfunction is unclear. We examined the association of the TG/HDL-C ratio with major adverse cardiovascular events (MACEs) according to renal function in patients with acute myocardial infarction (AMI). METHOD: This study was based on the Korea Acute Myocardial Infarction Registry database. Of 13,897 patients who were diagnosed with AMI, the study population included the 7,016 patients with available TG/HDL-C ratio data. Patients were stratified into three groups according to their estimated glomerular filtration rate (eGFR), and the TG/HDL-C ratio was categorized into tertiles. We investigated 12-month MACEs, which included cardiac death, myocardial infarction, and repeated percutaneous coronary intervention or coronary artery bypass grafting. RESULTS: During the 12-month follow up period, 593 patients experienced MACEs. There was a significant association between the TG/HDL-C ratio and MACEs (p<0.001) in the entire study cohort. Having a TG/HDL-C ratio value in the highest tertile of TG/HDL-C ratio was an independent factor associated with increased risk of MACEs (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.26-1.93; p<0.001). Then we performed subgroup analyses according to renal function. In patients with normal renal function (eGFR ≥ 90 ml/min/1.73m2) and mild renal dysfunction (eGFR ≥ 60 to < 90ml/min/1.73m2), a higher TG/HDL-C ratio was significantly associated with increased risk of MACEs (HR, 1.64; 95% CI, 1.04-2.60; p = 0.035; and HR, 1.56; 95% CI, 1.14-2.12; p = 0.005, respectively). However, in patients with moderate renal dysfunction (eGFR < 60 ml/min/1.73m2), TG/HDL-C ratio lost its predictive value on the risk of MACEs (HR, 1.23; 95% CI, 0.82-1.83; p = 0.317). CONCLUSIONS: In patients with AMI, TG/HDL-C ratio is a useful independent predictor of 12-month MACEs. However, this ratio does not have predictive power in patients with moderate renal dysfunction.

Significant Association between Toll-Like Receptor Gene Polymorphisms and Posttransplantation Diabetes Mellitus.

BACKGROUND: Posttransplantation diabetes mellitus (PTDM) is an important metabolic complication after renal transplantation. Activation of the innate immune system via toll-like receptors (TLRs) is implicated in the pathogenesis of insulin resistance and deficiency. Although links between diabetes, dysregulated innate immune responses, and the TLR signaling pathway have been reported, no study so far has investigated their associations with PTDM. In this study, we ascertained whether single nucleotide polymorphisms (SNPs) in TLRs are associated with PTDM in the Korea population. METHODS: A total of 305 patients who received renal transplants without previously diagnosed diabetes were included. We analyzed the association between PTDM development and 6 SNPs within 2 genes of TLR2, 1 gene of TLR4, and 3 genes of TRL6. RESULTS: Of 305 patients, PTDM developed in 51 patients (16.6%). Patients in the PTDM group were older than those in the non-PTDM group (45.56 ± 1.28 vs. 38.28 ± 0.71 years). Patients with PTDM had significantly higher allele frequency compared to those without PTDM for the TLR4 rs1927914*T, TLR6 rs3775073*A, TLR6 rs3821985*C, and TLR6 rs1039559*C alleles. Of the 6 SNPs, rs1927914 in the TLR4 gene and rs1039559 in the TLR6 gene were significantly associated with the development of PTDM after adjustment for age, gender, and tacrolimus usage. CONCLUSIONS: Our study demonstrates a significant association between SNPs rs1927914 in TLR4 and rs1039559 in TLR6 and PTDM in the renal transplantation recipient group. These data suggest that the activation of the innate immune system and inflammation via TLR activation might have an essential role in the pathogenesis of PTDM in renal transplantation.

Birth statistics of high birth weight infants (macrosomia) in Korea.

PURPOSE: The authors analyzed the trend from the birth-related statistics of high birth weight infants (HBWIs) over 50 years in Korea from 1960 to 2010. METHODS: We used 2 data sources, namely, the hospital units (1960's to 1990's) and Statistics Korea (1993 to 2010). The analyses include the incidence of HBWIs, birth weight distribution, sex ratio, and the relationship of HBWI to maternal age. RESULTS: The hospital unit data indicated the incidence of HBWI as 3 to 7% in the 1960's and 1970's and 4 to 7% in the 1980's and 1990's. Data from Statistics Korea indicated the percentages of HBWIs among total live births decreased over the years: 6.7% (1993), 6.3% (1995), 5.1% (2000), 4.5% (2000), and 3.5% (2010). In HBWIs, the birth weight rages and percentage of incidence in infants' were 4.0 to 4.4 kg (90.3%), 4.5 to 4.9 kg (8.8%), 5.0 to 5.4 kg (0.8%), 5.5 to 5.9 kg (0.1%), and >6.0 kg (0.0%) in 2000 but were 92.2%, 7.2%, 0.6%, 0.0%, and 0.0% in 2009. The male to female ratio of HBWIs was 1.89 in 1993 and 1.84 in 2010. In 2010, the mother's age distribution correlated with low (4.9%), normal (91.0%), and high birth weights (3.6%): an increase in mother's age resulted in an increase in the frequency of low birth weight infants (LBWIs) and HBWIs. CONCLUSION: The incidence of HBWIs for the past 50 years has been dropping in Korea. The older the mother, the higher was the risk of a HBWI and LBWI. We hope that these findings would be utilized as basic data that will aid those managing HBWIs.

Polymorphisms of the CTLA4 gene and kidney transplant rejection in Korean patients.

Cytotoxic T-lymphocyte-associated protein 4 (CTLA4) is a member of the immunoglobulin superfamily. CTLA4, which binds to B7 molecules on antigen- presenting cells, is expressed on activated T cells, thereby delivering negative signals that down-regulate T-cell proliferation and cytokine production. Consequently, CTLA4 may be a good candidate gene to evaluate in kidney transplantation rejection. In this study, we investigated whether polymorphisms of the CTLA4 gene were associated with susceptibility to kidney transplantation rejection. We genotyped three selected SNPs in the CTLA4 gene using direct sequencing in 325 renal transplant recipients. Of the SNPs examined, one (rs231775) showed a statistical association with late acute rejection (p=0.026, odds ratio (OR)=0.48, 95% confidence interval (CI)=0.23-0.93 in the dominant model). Also, the frequency of the G allele (rs231775) was higher in late acute rejection patients (p=0.013, OR=2.02, 95% CI=1.15-3.52). One CTLA4 gene polymorphism was associated with susceptibility to late acute rejection in kidney transplantation in Korean patients.