Publications by authors named "Hung-Chun Chen"

266 Publications

Low serum iron is associated with anemia in CKD stage 1-4 patients with normal transferrin saturations.

Sci Rep 2021 Apr 16;11(1):8343. Epub 2021 Apr 16.

Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou First Road, San-Ming District, Kaohsiung, 807, Taiwan.

Low transferrin saturation (TSAT), calculated by serum iron divided by total iron-binding capacity (TIBC), indicates iron deficiency. Because malnutrition and inflammation are associated with low TIBC in chronic kidney disease (CKD), TSAT might not reflect iron status or risk for anemia. We examined whether low serum iron was a risk factor for anemia in CKD patients with normal TSAT. Thus we compare the risk for anemia in 2500 CKD stage 1-4 patients divided by TSAT (cutoff: 20%) and serum iron (cutoff: 70 μg/dL in men, 60 μg/dL in women). Our results confirmed low TIBC (< 200 μg/dL) was associated with hypoalbuminemia and high C-reactive protein. In fully-adjusted logistic regression, both "normal TSAT low iron" and "low TSAT low iron" groups were associated with baseline anemia (hemoglobin < 11 g/dL) (odds ratios (OR) 1.56; 95% confidence interval (CI) 1.13-2.16 and OR 2.36; 95% CI 1.76-3.18, respectively) compared with the reference group (normal TSAT normal iron). Sensitivity tests with different cutoffs for TSAT and iron also showed similar results. In patients without anemia, both groups were associated with anemia after 1 year (OR 1.69; 95% CI 1.00-2.83 and OR 1.94; 95% CI 1.11-3.40, respectively). In conclusion, CKD stage 1-4 patients with normal TSAT but low serum iron are still at risk for anemia.
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http://dx.doi.org/10.1038/s41598-021-87401-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052429PMC
April 2021

Discovery of Novel Protein Biomarkers in Urine for Diagnosis of Urothelial Cancer Using iTRAQ Proteomics.

J Proteome Res 2021 May 29;20(5):2953-2963. Epub 2021 Mar 29.

Division of Nephrology and the Kidney Institute, Department of Internal Medicine, China Medical University and Hospitals, Taichung 404332, Taiwan.

Urothelial carcinoma (UC) is the ninth most prevalent malignancy worldwide. Noninvasive and efficient biomarkers with high accuracy are imperative for the surveillance and diagnosis of UC. CKD patients were enrolled as a control group in this study for the discovery of highly specific urinary protein markers of UC. An iTRAQ-labeled quantitative proteomic approach was used to discover novel potential markers. These markers were further validated with 501 samples by ELISA assay, and their diagnostic accuracies were compared to those of other reported UC markers. BRDT, CYBP, GARS, and HDGF were identified as novel urinary UC biomarkers with a high discrimination ability in a population comprising CKD and healthy subjects. The diagnostic values of the four novel UC markers were better than that of a panel of well-known or FDA-approved urinary protein markers CYFR21.1, Midkine, and NUMA1. Three of our discovered markers (BRDT, HDGF, GARS) and one well-known marker (CYFR21.1) were finally selected and combined as a marker panel having AUC values of 0.962 (95% CI, 0.94-0.98) and 0.860 (95% CI, 0.83-0.89) for the discrimination between UC and normal groups and UC and control (healthy + CKD) groups, respectively.
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http://dx.doi.org/10.1021/acs.jproteome.1c00164DOI Listing
May 2021

Association of digoxin with mortality in patients with advanced chronic kidney disease: A population-based cohort study.

PLoS One 2021 15;16(1):e0245620. Epub 2021 Jan 15.

Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.

Digoxin is commonly prescribed for heart failure and atrial fibrillation, but there is limited data on its safety in patients with chronic kidney disease (CKD). We conducted a population-based cohort study using the pre-end stage renal disease (ESRD) care program registry and the National Health Insurance Research Database in Taiwan. Of advanced CKD patient cohort (N = 31,933), we identified the digoxin user group (N = 400) matched with age and sex non-user group (N = 2,220). Multivariable Cox proportional hazards and sub-distribution hazards models were used to evaluate the association between digoxin use and the risk of death, cardiovascular events (acute coronary syndrome, ischemic stroke, or hemorrhagic stroke) and renal outcomes (ESRD, rapid decline in estimated glomerular filtration rate-eGFR, or acute kidney injury). Results showed that all-cause mortality was higher in the digoxin user group than in the non-user group, after adjusting for covariates (adjusted hazard ratio, aHR 1.63; 95% CI 1.23-2.17). The risk for acute coronary syndrome (sub-distribution hazard ratio, sHR 1.18; 95% CI 0.75-1.86), ischemic stroke (sHR 1.42; 95% CI 0.85-2.37), and rapid eGFR decline (sHR 1.00 95% CI 0.78-1.27) was not significantly different between two groups. In conclusion, our study demonstrated that digoxin use was associated with increased mortality, but not cardiovascular events or renal function decline in advanced CKD patients. This finding warns the safety of prescribing digoxin in this population. Future prospective studies are needed to overcome the limitations of cohort study design.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245620PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810292PMC
January 2021

The interaction between self-care behavior and disease knowledge on the decline in renal function in chronic kidney disease.

Sci Rep 2021 Jan 11;11(1):401. Epub 2021 Jan 11.

Department of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 TzYou 1st Road, Kaohsiung, 807, Taiwan.

Multidisciplinary care can improve the outcomes of chronic kidney disease (CKD), however the contribution of self-care behavior and knowledge about CKD is unclear. This study enrolled 454 participants with CKD stages 1-5 not on dialysis. Structured questionnaires were used to evaluate self-care behavior and kidney disease knowledge. Rapid decline in renal function was defined as the decline in estimated filtration rate > 3 ml/min per 1.73 m/year within 1-year prior to enrollment. The mean age of all study participants was 65.8 ± 12.1 years and 55.9% were male. The elderly had better self-care behavior while younger participants had better disease knowledge. Both high self-care and high disease knowledge scores were significantly associated with and had a synergistic effect on decreasing the risk of rapid decline in renal function. CKD patients with better self-care behavior and better kidney disease knowledge had lower risk of rapid decline in renal function.
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http://dx.doi.org/10.1038/s41598-020-79873-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801646PMC
January 2021

Lung Cancer Cell-Derived Secretome Mediates Paraneoplastic Inflammation and Fibrosis in Kidney in Mice.

Cancers (Basel) 2020 Nov 28;12(12). Epub 2020 Nov 28.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.

Kidney failure is a possible but rare complication in lung cancer patients that may be caused by massive tumor lysis or a paraneoplastic effect. Clinical case reports have documented pathological characteristics of paraneoplastic syndrome in glomeruli, but are short of molecular details. When Lewis lung carcinoma 1 (LLC1) cells were implanted in mice lungs to establish lung cancer, renal failure was frequently observed two weeks post orthotopic xenograft. The high urinary albumin-to-creatinine ratio (ACR) was diagnosed as paraneoplastic nephrotic syndrome in those lung cancer mice. Profiling the secretome of the lung cancer cells revealed that the secretory proteins were potentially nephrotoxic. The nephrotoxicity of lung cancer-derived secretory proteins was tested by examining the pathogenic effects of 1 × 10, 2 × 10, and 5 × 10 LLC1 cell xenografts on the pathogenic progression in kidneys. Severe albuminuria was present in the mice that received 5 × 10 LLC1 cells implantation, whereas 10 cell and 2 × 10 cell-implanted mice have slightly increased albuminuria. Pathological examinations revealed that the glomeruli had capillary loop collapse, tumor antigen deposition in glomeruli, and renal intratubular casts. Since IL-6 and MCP-1 are pathologic markers of glomerulopathy, their distributions were examined in the kidneys of the lung cancer mice. Moderate to severe inflammation in the kidneys was correlated with increases in the number of cells implanted in the mice, which was reflected by renal IL-6 and MCP-1 levels, and urine ACR. TGF-β signaling-engaged renal fibrosis was validated in the lung cancer mice. These results indicated that lung cancer cells could provoke inflammation and activate renal fibrosis.
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http://dx.doi.org/10.3390/cancers12123561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760555PMC
November 2020

Study comparing the efficacy and renal safety for patients with diabetes switching from dapagliflozin to empagliflozin.

Int J Clin Pharm 2020 Nov 30. Epub 2020 Nov 30.

Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China.

Background Previously, dapagliflozin was limited to patients with an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m, while empagliflozin can be used for those with an eGFR ≥ 45 mL/min/1.73 m. Therefore dapagliflozin was switched to empagliflozin in many patients when eGFR decreased. However, the clinical efficacy and safety of these switcfhes are not clear. Objective In this study, we compared the efficacy and renal safety between patients switching from dapagliflozin to empagliflozin in patients. Setting This is a retrospective study of adult patients (aged ≥ 20 years) who had attended the Kaohsiung Medical University Hospital. Method This retrospective observational study included patients who were switched from dapagliflozin to empagliflozin. To assess the effect of other hypoglycemic drugs on efficacy, the types and dose alterations of other hypoglycemic drugs were classified on the defined daily dose (DDD). Main outcome measure The primary outcome measure was the change in hemoglobin A1c (HbA1c) level after 6 months. Patients with HbA1c levels at or lower than the baseline value after 6 months were defined as effective and patients with levels higher than the baseline were defined as invalid. Safety was evaluated by comparing the difference of eGFR between the baseline value and 6 months after treatment. Results Overall, 111 patients were enrolled in the study. Six months after switching from dapagliflozin to empagliflozin, HbA1c significantly reduced, with no statistically significant difference observed in eGFR. In our study, 78 patients were assigned to the effective group (70.3%) and 33 patients were invalid (29.7%). When the other hypoglycemic drugs were grouped by total dosage, fasting plasma glucose and HbA1c only decreased significantly in the "DDD decrease" and "DDD increase" groups. Conclusion Our study showed that switching from dapagliflozin to empagliflozin in patients with type 2 diabetes was effective for blood glucose maintenance and caused no significant changes in renal function. In addition, compared to similar sodium-glucose co-transporter-2 inhibitors, other hypoglycemic drugs may be factors that influence the efficacy of sugar-lowering treatments.
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http://dx.doi.org/10.1007/s11096-020-01210-1DOI Listing
November 2020

Pyuria, urinary tract infection and renal outcome in patients with chronic kidney disease stage 3-5.

Sci Rep 2020 11 10;10(1):19460. Epub 2020 Nov 10.

Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100 Tzyou First Road, Kaohsiung, 807, Taiwan.

Pyuria is common in chronic kidney disease (CKD), which could be due to either urinary tract infection (UTI) or renal parenchymal inflammation. Only little is known regarding the association of pyuria or UTI with renal outcomes. We investigated 3226 patients with stage 3-5 CKD. Pyuria was defined as ≥ 50 WBC per high-power field (hpf) and was correlated to old age, female, diabetes, hypoalbuminemia, lower eGFR, and higher inflammation status. In Cox regression, patients with more than one episode of pyuria in the first year (11.8%) had increased risks for end-stage renal disease (ESRD) [hazard ratio (95% CI): 1.90 (1.58-2.28); p < 0.001], rapid renal function progression [odds ratio (95% CI): 1.49 (1.13-1.95); p = 0.001], and all-cause mortality [hazard ratio: 1.63 (1.29-2.05); p < 0.001], compared to those without pyuria. In a subgroup analysis, the risk of pyuria for ESRD was modified by CKD stages. We investigated the effects of UTI (urinary symptoms and treated by antibiotics) and pyuria without UTI (urine WBC < 50 to ≥ 10/hpf without any episodes of ≥ 50 WBC/hpf or UTI), while both groups were associated with clinical outcomes. In conclusion, CKD stage 3-5 patients with frequent pyuria or UTI episodes have increased risks of renal outcomes.
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http://dx.doi.org/10.1038/s41598-020-76520-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655801PMC
November 2020

Urine phthalate metabolites are associated with urothelial cancer in chronic kidney disease patients.

Chemosphere 2021 Jun 3;273:127834. Epub 2020 Sep 3.

Division of Nephrology and Kidney Institute, Department of Internal Medicine, China Medical University and Hospitals, Taichung, Taiwan; College of Medicine, China Medical University, Taichung, Taiwan. Electronic address:

Background: Di(2-ethylhexyl) phthalate (DEHP) is one of the most widely used phthalates and is associated with breast cancer. Ths association between DEHP and other types of cancer is not clear. DEHP may increase matrix metalloproteinase-9 that is critical for the development of urothelial cancer (UC). We examined the association between urinary phthalate metabolites and UC. CKD patients were selected as a control group because CKD patients are more at risk of UC than the general population.

Methods: In this cross-sectional study, we measured seven urinary phthalate metabolites that are abundant and can be measured using HPLC-MS/MS in Taiwan CKD patients between Jul 2013 and Dec 2015. MiBP (a urinary metabolite of Dibutyl phthalates[DBP]) and MEHHP (a urinary metabolite of DEHP) were described because they are the most abundant phthalate metabolites. The association of phthalate (log-transformed) and UC were analyzed using logistic regression with adjustments for age, gender, renal function, use of traditional Chinese medicine, toxins (dye, organic solvent), and non-steroidal anti-inflammatory drugs.

Results: We measured the urinary MEHHP and MiBP of 496 patients (224 UC and 272 CKD patients). The urinary MEHHP was associated with UC but MiBP was not. Medical history including the use of non-steroid anti-inflammatory drugs, exposure to environmental toxins (dye, paint, and organic solvent), and the use of traditional Chinese medicine was independently associated with UC. The adjusted odds ratio of MEHHP was 1.42 (95% confidence interval: 1.21-1.68).

Conclusion: Phthalate urinary metabolite(MEHHP) may be associated with UC in CKD patients and the association is independent of well-known risk factors of UC.
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http://dx.doi.org/10.1016/j.chemosphere.2020.127834DOI Listing
June 2021

Hyperuricemia Is Associated with Left Ventricular Dysfunction and Inappropriate Left Ventricular Mass in Chronic Kidney Disease.

Diagnostics (Basel) 2020 Jul 24;10(8). Epub 2020 Jul 24.

Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

Background: Hyperuricemia is common in patients with chronic kidney disease (CKD), and this may lead to poor cardiovascular (CV) outcomes. The aim of this cross-sectional study was to assess associations among serum uric acid (UA) and echocardiographic parameters, ankle-brachial index (ABI), and brachial-ankle pulse wave velocity (baPWV) in patients with CKD.

Methods: A total of 418 patients with CKD were included. The echocardiographic measurements included left atrial diameter (LAD), left ventricular ejection fraction (LVEF) and the ratio of observed to predict left ventricular mass (LVM). ABI, baPWV and medical records were obtained.

Results: Multivariable forward logistic regression analysis showed that a high UA level was significantly associated with LAD > 47 mm (odds ratio [OR], 1.329; = 0.002), observed/predicted LVM > 128% (OR, 1.198; = 0.008) and LVEF < 50% (OR, 1.316; = 0.002). No significant associations were found between UA and ABI < 0.9 or baPWV > 1822 cm/s. Multivariate stepwise linear regression analysis showed that a high UA level correlated with high LAD (unstandardized coefficient β, 0.767; < 0.001), high observed/predicted LVM (unstandardized coefficient β, 4.791; < 0.001) and low LVEF (unstandardized coefficient β, -1.126; = 0.001). No significant associations between UA and low ABI and high baPWV were found.

Conclusion: A high serum UA level was associated with a high LAD, high observed/predicted LVM and low LVEF in the patients with CKD. A high serum UA level may be correlated with abnormal echocardiographic parameters in patients with stage 3-5 CKD.
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http://dx.doi.org/10.3390/diagnostics10080514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460446PMC
July 2020

Progression of Aortic Arch Calcification Is Associated with Overall and Cardiovascular Mortality in Hemodialysis.

Dis Markers 2020 20;2020:6293185. Epub 2020 Jun 20.

Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.

Background: Vascular calcification is common and associated with unfavorable outcomes among patients with end-stage renal disease (ESRD). Nevertheless, little is known whether the progression of vascular calcification outweighs the baseline calcification in association with overall and cardiovascular (CV) mortality in hemodialysis (HD) patients.

Methods: This study included 140 maintenance HD patients. Vascular calcification was assessed using the aortic arch calcification (AoAC) score measured from chest radiographs at the baseline and the second year of follow-up. Progression of vascular calcification (AoAC) was defined as the difference between the two measurements of AoAC. The association of AoAC with overall and CV mortality was evaluated using multivariate Cox regression analysis.

Results: During the mean follow-up period of 5.8 years, there were 49 (35%) overall mortality and 27 (19.3%) CV mortality. High brachial-ankle pulse wave velocity was positively correlated with AoAC, whereas old age was negatively correlated with AoAC. In multivariate adjusted Cox analysis, increased AoAC (per 1 unit), but not baseline AoAC, was significantly associated with overall mortality (HR, 1.183; 95% CI, 1.056-1.327; = 0.004) and CV mortality (HR, 1.194; 95% CI, 1.019-1.398; = 0.028).

Conclusion: Progression of AoAC outperformed the baseline AoAC in association with increased risk of overall and CV mortality in HD patients. A regular follow-up of chest radiograph and AoAC score assessments are simple and cost-effective to identify the high-risk individuals of unfavorable outcomes in maintenance HD patients.
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http://dx.doi.org/10.1155/2020/6293185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330648PMC
June 2020

Associations of Small Fiber Neuropathy with Geriatric Nutritional Risk Index and Arterial Stiffness in Hemodialysis.

Dis Markers 2020 19;2020:1694218. Epub 2020 May 19.

Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.

Background: Peripheral neuropathy is a common neurological complication in uremic patients, and quantitative sensory testing (QST) is effective for diagnosis of small fiber neuropathy. Malnutrition and arterial stiffness are prevalent in patients undergoing hemodialysis (HD). The associations of small fiber neuropathy with nutritional status and arterial stiffness remain uncertain in maintenance HD patients.

Methods: A total of 152 HD patients were included. Geriatric nutritional risk index (GNRI), an indicator of nutritional status, was calculated by serum albumin and actual and ideal body weight. Arterial stiffness was defined as brachial-ankle pulse wave velocity (baPWV) > 1400 cm/s. Small fiber neuropathy was assessed by an abnormal QST threshold of cold and warm sensation in patients' hands or feet. Multivariate forward logistic regression analysis was performed to examine the associations among abnormal QST threshold, GNRI, and arterial stiffness.

Results: baPWV and prevalence of abnormal QST threshold were significantly higher in diabetic patients. Multivariate logistic analyses revealed that older age (OR, 1.081; 95% CI, 1.026-1.139, = 0.003) and male gender (OR, 4.450; 95% CI, 1.250-15.836, = 0.021) were associated with abnormal warm threshold of hands. Furthermore, diabetes (OR, 3.966; 95% CI, 1.351-11.819, = 0.012) and lower GNRI (per 1 unit increase, OR, 0.935, 95% CI, 0.887-0.985, = 0.012) were associated with abnormal cold threshold of feet. Arterial stiffness (OR, 5.479, 95% CI, 1.132-22.870, = 0.020) and higher calcium-phosphorus product (OR, 1.071, 95% CI, 1.013-1.132, = 0.015) were associated with abnormal warm threshold of feet.

Conclusions: Lower GNRI and arterial stiffness were significantly associated with small fiber neuropathy in patients undergoing HD. Malnutrition risk and vascular factors might play important roles in small fiber neuropathy among patients undergoing HD.
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http://dx.doi.org/10.1155/2020/1694218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254095PMC
April 2021

Macrophage migration inhibitory factor regulates integrin-β1 and cyclin D1 expression via ERK pathway in podocytes.

Biomed Pharmacother 2020 Apr 24;124:109892. Epub 2020 Jan 24.

Department of Nephrology, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.

Aims: Macrophage migration inhibitory factor (MIF) is found to increase in proliferative glomerulonephritis. MIF binds to the MIF receptor (CD74) that activates MAP kinase (ERK and p38). Integrins and cyclinD1 regulate cell proliferation, differentiation and adhesion. This study evaluates whether MIF can regulate integrin-β1/cyclin D1 expression and cell adhesion of podocytes.

Main Methods: Expression of integrin-β1 mRNA/protein and cyclin D1 mRNA under stimulation of MIF was evaluated by real-time PCR and Western blotting. MIF receptor (CD74) and MAP kinase under MIF treatment were examined to determine which pathway regulated integrin-β1 and cyclin D1 expression. Cell adhesion was evaluated under MIF treatment and/or anti-integrin-β1 antibody by cell adhesion assay.

Key Findings: Protein levels of integrin-β1 were up-regulated under MIF treatment in a dosage-dependent manner. CD74 protein levels were not changed after MIF treatment. Integrin-β1 and cyclin D1 mRNA levels were up-regulated after MIF 100 ng/ml treatment. ERK inhibitor U0126 reduced MIF-induced the increase in integrin-β1 mRNA and protein expression following MIF stimulation. However, p38 inhibitor SB 203580 did not inhibit MIF-induced increase in integrin-β1 mRNA and protein expression following MIF stimulation. MIF-induced increase in cyclin D1 mRNA level also was inhibited only by U0126 following MIF stimulation. Podocyte adhesion was increased after MIF treatment, but, anti-integrin-β1 antibody decreased MIF-enhanced podocyte adhesion.

Significance: MIF increases integrin-β1 and cyclin D1 expression through the ERK pathway in podocytes, and the up-regulated expression of integrin-β1 increases podocyte adhesion. These results provide further understanding for the role of MIF in developing proliferative glomerulonephritis.
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http://dx.doi.org/10.1016/j.biopha.2020.109892DOI Listing
April 2020

Blood pressure modifies outcomes in patients with stage 3 to 5 chronic kidney disease.

Kidney Int 2020 02 7;97(2):402-413. Epub 2019 Nov 7.

Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Observational studies have demonstrated that low blood pressure is related to poor clinical outcomes in patients with chronic kidney disease (CKD). Subgroup analyses from the SPRINT trial showed that targeting systolic blood pressure under 120 mmHg is less beneficial for patients with CKD. Although malnutrition and inflammation are common in patients with advanced CKD, such patients are usually excluded from clinical trials. Therefore, we hypothesized that malnutrition-inflammation-cachexia syndrome could explain this J-shaped relationship. To test this, we studied 2441 patients with CKD stages 3-5 who received anti-hypertensive treatment for at least one year. Averaged blood pressures of the first year were used in the analyses. Fine-Gray competing risks regression showed a J-shaped relationship between continuous systolic blood pressure and end-stage kidney disease (ESKD) with a nadir risk at a systolic blood pressure of 120 mmHg. Adjusted sub-distribution hazard ratios of categorical systolic blood pressure 100-109 and 110-119 mmHg were 2.17 (95% confidence interval: 1.21-3.89) and 1.37 (0.94-1.99) for ESKD, respectively, compared with systolic blood pressures of 120-129 mmHg. Cox regression also showed J-shaped relationships between continuous systolic or diastolic blood pressures, and the composite outcomes of cardiovascular events and all-cause mortality. Logistic regression demonstrated the odds ratios of blood pressure components for Malnutrition-Inflammation Scores over 4 were J-shaped. Sub-distribution hazard ratios of systolic blood pressure 100-119 mmHg for ESKD was higher in those with a Malnutrition-Inflammation Score over 4, compared to 0.93 (0.53-1.63) in those with a score of 4 or under with significant interaction. Thus, malnutrition-inflammation-cachexia syndrome is associated with low blood pressure and modifies the J-shaped relationship in patients with advanced CKD.
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http://dx.doi.org/10.1016/j.kint.2019.10.021DOI Listing
February 2020

Investigation of Acoustic Cardiographic Parameters before and after Hemodialysis.

Dis Markers 2019 5;2019:5270159. Epub 2019 Nov 5.

Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.

Patients with end-stage renal disease are at an increased risk of cardiovascular diseases and associated mortality. Acoustic cardiography is a technique in which cardiac acoustic data is synchronized with electric information to detect and characterize heart sounds and detect heart failure early. The aim of this study was to investigate acoustic cardiographic parameters before and after hemodialysis (HD) and their correlations with ankle-brachial index (ABI), brachial-ankle pulse wave velocity (baPWV), and ratio of brachial preejection period to ejection time (bPEP/bET) obtained from an ABI-form device in HD patients. This study enrolled 162 HD patients between October 2016 and April 2018. Demographic, medical, and laboratory data were collected. Acoustic cardiography was performed before and after HD to assess parameters including third heart sound (S3), fourth heart sound (S4), systolic dysfunction index (SDI), electromechanical activation time (EMAT), and left ventricular systolic time (LVST). The mean age of the enrolled patients was 60.4 ± 10.9 years, and 86 (53.1%) patients were male. S4 ( < 0.001) and LVST ( < 0.001) significantly decreased after HD, but EMAT ( < 0.001) increased. Multivariate forward linear regression analysis showed that EMAT/LVST before HD was negatively associated with albumin (unstandardized coefficient = -0.076; = 0.004) and ABI (unstandardized coefficient = -0.115; = 0.011) and positively associated with bPEP/bET (unstandardized coefficient = 0.278; = 0.003). Screening HD patients with acoustic cardiography may help to identify patients at a high risk of malnutrition, peripheral artery disease, and left ventricular systolic dysfunction.
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http://dx.doi.org/10.1155/2019/5270159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874870PMC
April 2020

Dialysis Care and Dialysis Funding in Asia.

Am J Kidney Dis 2020 05 5;75(5):772-781. Epub 2019 Nov 5.

The George Institute for Global Health, New Delhi, India; The George Institute for Global Health, University of Oxford, Oxford, United Kingdom; Department of Medicine, University of New South Wales, Sydney, Australia; Manipal Academy of Higher Education, Manipal, India.

Asia is the largest and most populated continent in the world, with a high burden of kidney failure. In this Policy Forum article, we explore dialysis care and dialysis funding in 17 countries in Asia, describing conditions in both developed and developing nations across the region. In 13 of the 17 countries surveyed, diabetes is the most common cause of kidney failure. Due to great variation in gross domestic product per capita across Asian countries, disparities in the provision of kidney replacement therapy (KRT) exist both within and between countries. A number of Asian nations have satisfactory access to KRT and have comprehensive KRT registries to help inform practices, but some do not, particularly among low- and low-to-middle-income countries. Given these differences, we describe the economic status, burden of kidney failure, and cost of KRT across the different modalities to both governments and patients and how changes in health policy over time affect outcomes. Emerging trends suggest that more affluent nations and those with universal health care or access to insurance have much higher prevalent dialysis and transplantation rates, while in less affluent nations, dialysis access may be limited and when available, provided less frequently than optimal. These trends are also reflected by an association between nephrologist prevalence and individual nations' incomes and a disparity in the number of nephrologists per million population and per thousand KRT patients.
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http://dx.doi.org/10.1053/j.ajkd.2019.08.005DOI Listing
May 2020

Ratio of Early Mitral Inflow Velocity to the Global Diastolic Strain Rate and Global Left Ventricular Longitudinal Systolic Strain Predict Overall Mortality and Major Adverse Cardiovascular Events in Hemodialysis Patients.

Dis Markers 2019 5;2019:7512805. Epub 2019 Sep 5.

Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.

Background: The ratio of early mitral inflow velocity to the global diastolic strain rate (E/E'sr) and global longitudinal systolic strain (GLS) of the left ventricle (LV) are emerging indices of diastolic and systolic functions, respectively, for the LV. Their prognostic significance in the prediction of mortality and cardiovascular (CV) outcomes remains underexplored in hemodialysis (HD) patients.

Methods: This prospective study included 190 maintenance HD patients. The E/E'sr ratio and GLS were assessed using two-dimensional speckle tracking echocardiography. The clinical outcomes included overall mortality, CV mortality, and major adverse cardiovascular events (MACE). The associations between the E/E'sr ratio, GLS, and clinical outcomes were evaluated using multivariate Cox regression analysis. The incremental values of the E/E'sr ratio and GLS in outcome prediction were assessed by changes in Cox models.

Results: Over a median follow-up period of 3.7 years, there were 35 overall deaths, 16 CV deaths, and 45 MACE. Impaired diastolic function with a higher E/E'sr ratio was associated with overall mortality (HR, 1.484; 95% CI, 1.201-1.834; < 0.001), CV mortality (HR, 1.584; 95% CI, 1.058-2.371; = 0.025), and MACE (HR, 1.205; 95% CI, 1.040-1.397; = 0.013) in multivariate adjusted Cox analysis. Worsening GLS was associated with overall mortality (HR, 1.276; 95% CI, 1.101-1.480; = 0.001), CV mortality (HR, 1.513; 95% CI, 1.088-2.104; = 0.014), and MACE (HR, 1.214; 95% CI, 1.103-1.337; < 0.001). The E/E'sr ratio and GLS had better outcome prediction than the E to early diastolic mitral annular velocity (E/E') ratio and left ventricular ejection fraction (LVEF). Moreover, adding the E/E'sr ratio and GLS to Cox models containing relevant clinical and conventional echocardiographic parameters improved the prediction of overall mortality ( < 0.001), CV mortality ( < 0.001), and MACE ( < 0.001).

Conclusion: The E/E'sr ratio and GLS, as emerging indices of LV diastolic and systolic functions, significantly predict mortality and CV outcomes and outperform conventional echocardiographic parameters in outcome prediction in HD patients.
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http://dx.doi.org/10.1155/2019/7512805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748193PMC
February 2020

Effect of differences in serum creatinine estimation methodologies on estimated glomerular filtration rate.

Singapore Med J 2019 Sep;60(9):468-473

Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.

Introduction: Serum creatinine is crucial in glomerular filtration rate (GFR) estimation. Various methods of measuring GFR have been developed, which vary in their ability to estimate the prevalence of chronic kidney disease (CKD) and predict consequences associated with CKD. The use of different laboratory devices also results in uncertainty in estimated GFR (eGFR). The purpose of our study was to discuss the effect of differences in laboratory devices on eGFR when performing serum creatinine measurements.

Methods: 163 participants aged 51.22 ± 18.66 years were enrolled during a community health screening programme conducted on 18 June 2011. Samples were sent to four different hospitals using four different devices to check serum creatinine by the Jaffe and enzymatic creatinine methods.

Results: Using Roche Cobas Integra 400, Beckman LX20, Hitachi 7180 and Toshiba TBA - c8000, the proportion of the population with eGFR < 60 mL/min/1.73 m was 11.04%, 6.75%, 20.25% and 20.86%, respectively. Moreover, 3.68% of the participants had eGFR < 60 mL/min/1.73 m in the laboratory when Roche Cobas Integra 400 was used with the enzymatic creatinine method and compensated Jaffe method.

Conclusion: Although standardisation of serum creatinine measurement has been achieved by using isotope dilution mass spectrometry, differences in measurement devices still cause substantial bias in the overall results. This affects the application of GFR in the estimation of CKD progression and outcomes associated with CKD.
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http://dx.doi.org/10.11622/smedj.2019115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911078PMC
September 2019

A Low Ankle-Brachial Index and High Brachial-Ankle Pulse Wave Velocity Are Associated with Poor Cognitive Function in Patients Undergoing Hemodialysis.

Dis Markers 2019 19;2019:9421352. Epub 2019 Aug 19.

Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.

Patients with end-stage renal disease (ESRD) have an increased risk of both impaired cognitive function and peripheral artery disease (PAD) than the general population. The association between PAD and dementia is recognized, but there are limited studies in patients with ESRD. The aim of this study was to evaluate the relationship between ankle-brachial index (ABI) and brachial-ankle pulse wave velocity (baPWV) and cognitive impairment in patients receiving hemodialysis (HD). We enrolled 136 prevalent HD patients (mean age 59.3 ± 10.5 years, 55.9% male). Cognitive performance was measured using the Montreal Cognitive Assessment (MoCA) and Cognitive Abilities Screening Instrument (CASI) by trained psychiatrists. Associations between the cognitive function and ABI and baPWV were assessed using multiple linear regression analysis. Compared with HD patients with ABI ≥ 0.9, patients with ABI < 0.9 had lower MoCA score ( = 0.027) and lower CASI score but did not achieve significant level ( = 0.056). In the multivariate stepwise linear regression analysis, ABI (per 0.1) was independently positively associated with the MoCA score ( coefficient = 0.62, = 0.011) and the CASI score ( coefficient = 1.43, = 0.026). There is a negative association between baPWV (per 100 cm/s) and CASI ( coefficient = -0.70, = 0.009). In conclusion, a low ABI or high baPWV was associated with a lower cognitive function in HD patients.
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http://dx.doi.org/10.1155/2019/9421352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721107PMC
February 2020

Urinary Melamine Levels and Progression of CKD.

Clin J Am Soc Nephrol 2019 08 23;14(8):1133-1141. Epub 2019 Jul 23.

Research Center for Environmental Medicine,

Background And Objectives: CKD is a global public health problem. Some cross-sectional studies have associated environmental melamine exposure with kidney diseases, but evidence is limited.

Design, Setting, Participants, & Measurements: We conducted this prospective cohort study to enroll patients with eGFR≥30 ml/min per 1.73 m in 2006-2010. Urinary corrected melamine levels (ratio of urinary melamine to urinary creatinine) were measured by liquid chromatography/tandem mass spectrometry at enrollment. Kidney outcomes included doubling of serum creatinine levels, eGFR decline >3 ml/min per 1.73 m per year, and 30% decline in eGFR in the first 2 years. Subjects were followed until targeted kidney outcomes, cancer, death, last contact, or the end of observation in December 2016.

Results: In a total of 293 subjects, the median urinary corrected melamine level was 0.97 (interquartile range, 0.43-2.08) g/mmol. Over a median follow-up period of 7.0 years, serum creatinine levels doubled in 80 subjects (27%). Subjects in the highest tertile of urinary melamine level 12.70 g/mmol) had a 2.30 (95% confidence interval, 1.25 to 4.23; <0.01) hazard risk for doubling of serum creatinine compared with those in the lowest tertile (0.02-0.58 g/mmol). Similar significant dose-response results were found in eGFR decline >3 ml/min per 1.73 m per year and 30% decline in eGFR in the first 2 years.

Conclusions: Urinary melamine level is significantly associated with kidney function deterioration in patients with early-stage CKD.
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http://dx.doi.org/10.2215/CJN.01740219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682811PMC
August 2019

The association of adiponectin with metabolic syndrome and clinical outcome in patients with non-diabetic chronic kidney disease.

PLoS One 2019 19;14(7):e0220158. Epub 2019 Jul 19.

Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.

Adiponectin is the most abundant circulating adipokine, and it has insulin-sensitizing and anti-inflammatory properties. Although it has been speculated that kidney function decline associated with elevated adiponectin is attributable to decreased renal clearance and compensatory responses to adiponectin resistance, it is unclear how elevated adiponectin affects clinical outcomes in chronic kidney disease (CKD) patients and whether the effects are the same as those in the general population. Therefore, the aim of this study is to examine whether the association between serum adiponectin levels and clinical outcomes in non-diabetic CKD patients is independent of adiposity and metabolic syndrome. We enrolled 196 non-diabetic CKD patients with eGFR ranging between 10 and 60 mL/min/1.73 m2, these patients were divided into two groups based on the presence of metabolic syndrome. The primary endpoint was all-cause mortality or renal events (renal failure requiring renal replacement therapy [RRT] or 50% reduction in eGFR). During the mean follow-up period of 5 years, 48 (24.5%) incident cases of end-stage renal disease (ESRD) were observed, and 33 (16.8%) deaths occurred. The mean eGFR was 29.8 ± 12.8 mL/min/1.73m2. The baseline median adiponectin concentration in the cohort was 29.4(interquartile range, 13.3-108.7) μg/ml. Adiponectin levels were inversely related to body mass index (BMI) (r = -0.29; P < 0.001) and waist circumference (r = -0.35; P < 0.001). In the fully adjusted Cox regression model, the hazard ratios (HRs) were 2.08 (95% confidence interval [CI], 1.08-4.02; P = 0.03) for RRT and 1.66 (95% CI, 1.03-2.65; P = 0.04) for composite renal outcome. The risks remained consistent within different subgroups. However, no association was observed with mortality risk. In conclusion, higher adiponectin levels are associated with a higher risk of ESRD independent of conventional risk factors, BMI, and metabolic syndrome components.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220158PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6641197PMC
March 2020

Effects of Sustained-Release Beraprost in Patients With Primary Glomerular Disease or Nephrosclerosis: CASSIOPEIR Study Results.

Ther Apher Dial 2020 Feb 28;24(1):42-55. Epub 2019 Jul 28.

The University of Tokyo, Tokyo, Japan.

TRK-100STP, a sustained-release preparation of the orally active prostacyclin analogue beraprost sodium, targets renal hypoxia. This study aimed to show the superiority of TRK-100STP over placebos in patients with chronic kidney disease (with either primary glomerular disease or nephrosclerosis) to determine the recommended dose. CASSIOPEIR (Chronic Renal Failure Asian Study with Oral PGI Derivative for Evaluating Improvement of Renal Function) was a randomized, double-blind, placebo-controlled study conducted at 160 sites in seven Asia-Pacific countries and regions. Eligible patients (n = 892) were randomized to TRK-100STP 120, 240 μg, or placebo for a treatment period of up to 4 years. The primary efficacy endpoint was time to first occurrence of a renal composite: doubling of serum creatinine or occurrence of end-stage renal disease. No significant differences were observed in composite endpoints between TRK-100STP and placebo (P = 0.5674). Hazard ratios (95% CI) in the TRK-100STP 120 and 240 μg vs. placebo groups were 0.98 (0.78, 1.22) and 0.91 (0.72, 1.14), respectively. The overall incidence of adverse events and adverse drug reactions was comparable between treatment arms.
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http://dx.doi.org/10.1111/1744-9987.12840DOI Listing
February 2020

Associations among Geriatric Nutrition Risk Index, bone mineral density, body composition and handgrip strength in patients receiving hemodialysis.

Nutrition 2019 09 26;65:6-12. Epub 2019 Feb 26.

Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Objectives: Malnutrition occurs as a complication of hemodialysis (HD) and has been identified as a risk factor for osteoporosis, sarcopenia, and low physical performance. The aim of this study was to assess the associations among nutrition, bone mineral density (BMD), body composition, and handgrip strength (HGS) in patients receiving HD.

Methods: We enrolled 164 patients receiving HD who have undergone the dual energy x-ray absorptiometry (DXA) examination, categorized according to baseline Geriatric Nutritional Risk Index (GNRI) values calculated by serum albumin levels and body weight index. GNRI was used to evaluate nutritional status, and DXA to investigate BMD and body composition. Additionally, HGS test was performed. Multiple stepwise linear regression analysis was used to identify the factors associated with BMD, T-score, and HGS.

Results: Compared with patients with tertile 1 of GNRI, those with tertile 3 of GNRI tend to have higher lumbar spine BMD and T-score, higher femoral neck BMD, higher total hip BMD, higher left distal mid-third radius BMD and T-score, higher fat mass index, higher android-to-gynoid ratio, higher lean mass index, and higher HGS. An increase in GNRI tertile was associated with an increase of BMD and a decrease of osteoporosis prevalence. The GNRI was positively correlated with BMD and T-score, body composition, and HGS. Low lean mass index and high parathyroid hormone were significantly associated with low BMD and T-score. Additionally, high GNRI and high left distal mid-third radius BMD were significantly associated with high HGS.

Conclusions: The present study demonstrated that good nutrition, indicated as high GNRI, resulted in higher BMD and T-score, lean mass index, and HGS in patients receiving HD. Using GNRI to evaluate nutritional status and using DXA to investigate BMD and body composition in patients receiving HD is important to bone health and physical performance.
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http://dx.doi.org/10.1016/j.nut.2019.02.013DOI Listing
September 2019

Increased Aortic Arch Calcification and Cardiomegaly is Associated with Rapid Renal Progression and Increased Cardiovascular Mortality in Chronic Kidney Disease.

Sci Rep 2019 03 29;9(1):5354. Epub 2019 Mar 29.

Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.

Vascular calcification and cardiomegaly are highly prevalent in chronic kidney disease (CKD) patients. However, the association of the combination of aortic arch calcification (AoAC) and cardio-thoracic ratio (CTR) with clinical outcomes in patients with CKD is not well investigated. This study investigated whether the combination of AoAC and CTR is associated with poor clinical outcomes in CKD stages 3-5 patients. We enrolled 568 CKD patients, and AoAC and CTR were determined by chest radiography at enrollment. Rapid renal progression was defined as estimated glomerular filtration rate (eGFR) decline over 3 ml/min/1.73 m per year. Both AoAC score and CTR were significantly associated with rapid renal progression. High CTR was correlated with increased risk for cardiovascular mortality. We stratified the patients into four groups according to the median AoAC score of 4 and CTR of 50%. Those with AoAC ≥ 4 and CTR ≥ 50% (vs. AoAC score < 4 and CTR < 50%) were associated with eGFR decline over 3 ml/min/1.73 m/year and cardiovascular mortality. AoAC and CTR were independently associated with eGFR slope. In conclusion, the combination of increased AoAC and cardiomegaly was associated with rapid renal progression and increased cardiovascular mortality in patients with CKD stage 3-5 patients. We suggest that evaluating AoAC and CTR on chest plain radiography may be a simple and inexpensive method for detecting CKD patients at high risk for adverse clinical outcomes.
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http://dx.doi.org/10.1038/s41598-019-41841-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441024PMC
March 2019

Development and validation of a nomogram for urothelial cancer in patients with chronic kidney disease.

Sci Rep 2019 03 5;9(1):3473. Epub 2019 Mar 5.

Division of Nephrology and Kidney Institute, Department of Internal Medicine, China Medical University and Hospital, Taichung, Taiwan.

Urothelial cancer (UC) is a common kidney cancer in Taiwan and patients with chronic kidney disease (CKD) are more at risk for UC than the general population. The diagnostic value of urine analysis and urine cytology is limited, especially in CKD patients. The aim of the study is to develop a nomogram to predict the risk of UC in CKD patients. We enrolled 169 UC patients and 1383 CKD patients from 9 hospitals in Taiwan between 2012 and 2015. CA125, HE4, clinical characteristics, and medical history were analyzed using multivariable logistic regression for its association with UC. A nomogram was developed to predict the risk of UC and was validated using Bootstrap. CA125 was associated with UC in CKD patients (OR: 5.91, 95% CI: 3.24-10.77) but HE4 was not (OR: 1.29, 95% CI: 0.67-2.35). A nomogram based on patients' age, estimated glomerular filtration rate, CA125 (log transformed), smoking, exposure of environmental toxin, use of nonsteroid anti-inflammatory drugs, and use of traditional Chinese medicine was conducted. The AUC of the nomogram was 0.90 (95% CI: 0.86-0.92, p < 0.01). Serum CA125 may identify UC patients from CKD patients but has limited diagnostic value due to low sensitivity. The diagnostic value of serum CA125 level can be improved by the combination with clinical characteristics including age, renal function, and medical history.
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http://dx.doi.org/10.1038/s41598-019-40276-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401318PMC
March 2019

Primary cardiac manifestation of autosomal dominant polycystic kidney disease revealed by patient induced pluripotent stem cell-derived cardiomyocytes.

EBioMedicine 2019 Feb 11;40:675-684. Epub 2019 Jan 11.

Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; Cellular and Molecular Arrhythmia Research Program, University of Wisconsin-Madison, Madison, WI, United States; Department of Medicine, University of Wisconsin-Madison, Madison, WI, United States. Electronic address:

Background: Mutations in PKD1 or PKD2 gene lead to autosomal dominant polycystic kidney disease (ADPKD). The mechanism of ADPKD progression and its link to increased cardiovascular mortality is still elusive.

Methods: We differentiated ADPKD patient induced pluripotent stem cells (iPSCs) to cardiomyocytes (CMs). The electrophysiological properties at the cellular level were analyzed by calcium imaging and whole cell patch clamping.

Findings: The ADPKD patient iPSC-CMs had decreased sarcoplasmic reticulum calcium content compared with Control-CMs. Spontaneous action potential of the PKD2 mutation line-derived CMs demonstrated slower beating rate and longer action potential duration. The PKD1 mutation line-derived CMs showed a comparable dose-dependent shortening of phase II repolarization with the Control-CMs, but a significant increase in beating frequency in response to L-type calcium channel blocker. The PKD1-mutant iPSC-CMs also showed a relatively unstable baseline as a greater percentage of cells exhibited delayed afterdepolarizations (DADs). Both the ADPKD patient iPSC-CMs showed more β-adrenergic agonist-elicited DADs compared with Control-CMs.

Interpretation: Characterization of ADPKD patient iPSC-CMs provides new insights into the increased clinical risk of arrhythmias, and the results enable disease modeling and drug screening for cardiac manifestations of ADPKD. FUND: Ministry of Science and Technology, National Health Research Institutes, Academia Sinica Program for Technology Supporting Platform Axis Scheme, Thematic Research Program and Summit Research Program, and Kaohsiung Medical University Hospital, Taiwan.
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http://dx.doi.org/10.1016/j.ebiom.2019.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413318PMC
February 2019

The Interaction of miR-378i-Skp2 Regulates Cell Senescence in Diabetic Nephropathy.

J Clin Med 2018 Nov 22;7(12). Epub 2018 Nov 22.

Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

Diabetic nephropathy (DN) is the major cause of end stage renal disease. Proximal tubular epithelial cell (PTEC) injury occurs early in diabetic kidney, and it is correlated with consequent renal failure. Cellular senescence participates in the pathophysiology of DN, but its role remains unclear. We conducted a cross-disciplinary study, including human, in vivo, and in vitro studies, to explore the novel molecular mechanisms of PTEC senescence in DN. We found that HG induced cell senescence in PTECs, supported by enhanced β-galactosidase staining, p53 and p27 expression, and reduced cyclin E levels. Transcriptome analysis of PTECs from a type 2 diabetic patient and a normal individual using next generation sequencing (NGS) and systematic bioinformatics analyses indicated that miR-378i and its downstream target S-phase kinase protein 2 (Skp2) contribute to HG-induced senescence in PTECs. High glucose (HG) elevated miR-378i expression in PTECs, and miR-378i transfection reduced Skp2 expression. Urinary miR-378i levels were elevated in both db/db mice and type 2 diabetic patients, whereas decreased Skp2 levels were shown in proximal tubule of db/db mice and human DN. Moreover, urinary miR-378i levels were positively correlated with urinary senescence-associated secretory phenotype cytokines and renal function in in vivo and human study. This study demonstrates that the interaction between miR-378i and Skp2 regulates PTEC senescence of DN. miR-378i has the potential to predict renal injury in DN. These findings suggest future applications in both therapy and in predicting renal dysfunction of DN.
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http://dx.doi.org/10.3390/jcm7120468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306775PMC
November 2018

Association between albumin and C-reactive protein and ankle-brachial index in haemodialysis.

Nephrology (Carlton) 2018 Oct;23 Suppl 4:5-10

Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.

Aim: Peripheral artery occlusive disease (PAOD) is associated with increased rates of cardiovascular mortality, morbidity and hospitalization in patients undergoing dialysis. An ankle-brachial index (ABI) less than 0.9 has been used to diagnose PAOD. The aim of this study was to evaluate associations among inflammation, malnutrition and their interactions on the risk of PAOD.

Methods: Two hundred and twenty-two haemodialysis patients (mean age 61.0 ± 11.7 years, 56.8% men) were enrolled and stratified into four groups according to median values of albumin (3.87 g/dL) and logarithm of C-reactive protein (CRP) (0.48 mg/L). Associations between the study groups and an ABI less than 0.9 were assessed using multiple logistic regression analysis. Receiver operating characteristic curves were constructed to predict an ABI less than 0.9.

Results: A lower level of albumin and higher level of CRP were significantly associated with an ABI less than 0.9 in multivariate analysis (odds ratio, 5.688; 95% confidence interval, 1.369-23.626; P = 0.017) after adjusting for demographic, clinical, biochemical and medication data. The interaction between albumin and CRP in relation to an ABI less than 0.9 was significant in multivariate analysis (odds ratio, 1.797; 95% confidence interval, 1.258-2.568; P = 0.001). The areas under the curve for albumin, CRP and albumin + CRP for the prediction of ABI less than 0.9 were 0.311, 0.654 and 0.733, respectively.

Conclusion: Patients undergoing haemodialysis with a lower albumin level and higher CRP level have an increased risk of PAOD. A combination of malnutrition and inflammation may be associated with PAOD in haemodialysis patients.
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http://dx.doi.org/10.1111/nep.13455DOI Listing
October 2018

Hematuria and Renal Outcomes in Patients With Diabetic Chronic KidneyDisease.

Am J Med Sci 2018 09 12;356(3):268-276. Epub 2018 Jun 12.

Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address:

Background: Hematuria may indicate nondiabetic renal disease in diabetic chronic kidney disease (CKD). However, some studies have reported that hematuria is noted in diabetic nephropathy and is associated with albuminuria. Hematuria is a risk factor for end-stage renal disease in glomerulonephritis, but its prognostic value in diabetic CKD is unknown. We investigated the factors associated with hematuria and the prognostic value of hematuria in patients with diabetic CKD.

Material And Methods: We included 1958 patients with type 2 diabetes and CKD stages 1-5, and 111 patients underwent renal biopsy. Patients in the biopsied cohort were younger and had more severe proteinuria, compared with those in the total cohort; hematuria was associated with nondiabetic renal disease.

Results: In the total cohort, hematuria was observed in 15.0% of the patients and was associated with young age, a lower estimated glomerular filtration rate, proteinuria, high blood pressure and short diabetes duration. Hematuria was significantly associated with an increased risk (hazard ratio 1.39, 95% CI: 1.10-1.76, P < 0.001) of end-stage renal disease, particularly in patients with CKD stages 1-3 or a urine protein-to-creatinine ratio of <1,500mg/g (P for interaction < 0.05). The odds ratio of hematuria for rapid renal progression was 1.81 (95% CI: 1.29-2.53, P < 0.001).

Conclusions: Hematuria is associated with nondiabetic renal disease in biopsied patients with diabetic CKD and is associated with an increased risk of end-stage renal disease in patients with early diabetic CKD.
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http://dx.doi.org/10.1016/j.amjms.2018.06.005DOI Listing
September 2018

Risk factors for thyroid surgery-related unilateral vocal fold paralysis.

Laryngoscope 2019 01 3;129(1):275-283. Epub 2018 Oct 3.

From the Department of Otolaryngology-Head and Neck Surgery, Taoyuan, Taiwan.

Objectives/hypothesis: We aimed to identify the risk factors for iatrogenic unilateral vocal fold paralysis (UVFP) caused by thyroid surgery, to allow the identification of patients requiring nerve-protection procedures and monitoring technologies.

Study Design: Retrospective case study in a medical center.

Methods: Patients who underwent thyroid surgery from April 2011 to February 2016 and who were diagnosed with UVFP by laryngoscopy and laryngeal electromyography were included. Patient demographics, types of surgery, and characteristics of the thyroid lesions were analyzed.

Results: Sixty (2.1%) of 2,815 patients who received thyroid surgery developed UVFP. The risk of UVFP was higher in patients over 60 years old (odds ratio, 1.89; 95% confidence interval, 1.01-3.26; P = .01). Involvement of the external branch of superior laryngeal nerve (EBSLN) occurred in 19 (31.7%) of the 60 UVFP patients, and was more likely to occurr in patients with diabetes mellitus (odds ratio, 14.19; 95% confidence interval, 3.80-52.94; P < .001). The incidence of UVFP and involvement of the EBSLN differed among surgery types, and was the highest among patients undergoing total thyroidectomy with neck dissection (TTND) (10/158, 6.3% and 5/158, 3.2%, respectively).

Conclusions: The risk of thyroid surgery-related UVFP is higher in older patients. EBSLN involvement is more likely in patients with diabetes mellitus. TTND is associated with higher risks of UVFP and EBSLN injury than other types of surgery, implying the need of intraoperative nerve monitoring in these high-risk characteristics.

Level Of Evidence: 4 Laryngoscope, 129:275-283, 2019.
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http://dx.doi.org/10.1002/lary.27336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585753PMC
January 2019

Prognostic Cardiovascular Markers in Chronic Kidney Disease.

Kidney Blood Press Res 2018 28;43(4):1388-1407. Epub 2018 Aug 28.

Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.

Chronic kidney disease (CKD), including end-stage renal disease (ESRD), is a public health issue worldwide, and is associated with high rates of morbidity and mortality. In addition, cardiovascular disease is a major cause of mortality in these patients. Both traditional and nontraditional risk factors associated with CKD can lead to remodeling of the myocardium and blood vessels, thereby resulting in cardiomyopathy, atherosclerosis and arterial stiffness. This can subsequently lead to ischemic heart disease, heart failure, cardiovascular death, rapid renal progression and progression to ESRD. Identifying these risk factors to allow for aggressive preventive and interventional strategies is important for the management of patients with CKD. This aim of this review was to survey the clinical outcomes of CKD using cardiac and vascular markers including echocardiographic parameters, systolic time intervals, electrocardiography, heart rate variability, ankle-brachial index, pulse wave velocity, differences between interarm and interankle blood pressure, and vascular calcification.
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http://dx.doi.org/10.1159/000492953DOI Listing
November 2018