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Acute kidney injury (AKI) is a common syndrome that has a significant impact on prognosis in various clinical settings. To evaluate whether new evidence supports changing the current definition/classification/staging systems for AKI suggested by the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guideline, the Taiwan AKI-TASK Force, composed of 64 experts in various disciplines, systematically reviewed the literature and proposed recommendations about the current nomenclature and diagnostic criteria for AKI. The Taiwan Acute Kidney Injury (TW-AKI) Consensus 2020 was established following the principles of evidence-based medicine to investigate topics covered in AKI guidelines. The Taiwan AKI-TASK Force determined that patients with AKI have a higher risk of developing chronic kidney disease, end-stage renal disease, and death. After a comprehensive review, the TASK Force recommended using novel biomarkers, imaging examinations, renal biopsy, and body fluid assessment in the diagnosis of AKI. Clinical issues with regards to the definitions of baseline serum creatinine (sCr) level and renal recovery, as well as the use of biomarkers to predict renal recovery are also discussed in this consensus. Although the present classification systems using sCr and urine output for the diagnosis of AKI are not perfect, there is not enough evidence to change the current criteria in clinical practice. Future research should investigate and clarify the roles of the aforementioned tools in clinical practice for AKI.

HIC1 and RassF1A methylation, which cause loss of gene function, are found in various cancers, including renal cell carcinoma (RCC), and could alter cell stiffness and the content of extracellular vesicles (EVs). These physiological changes may provide a tumoral survival advantage and thus could serve as cellular biomarkers for monitoring cell transformation, although direct associations between these changes and cell transformation remain to be established. As we found HIC1 and RassF1A methylation and expression changes in RCC samples, we examined the effects of gain and loss of HIC1 and RassF1A expression on cell DNA content, cytoskeletal structure, and Piwi-interacting RNA (piRNA) expression in EVs. We found HIC1 and RassF1A hypermethylation and abnormal expression in RCC patient samples was independent of the somatic mutations found in publicly available data. Cell stiffness was reduced in accordance with disrupted cytoskeleton conformation after knockdown of HIC1 or RassF1A. Gain or loss of HIC1 expression induced instability in genomic content, abnormal RassF1A expression disturbed cytoskeletal structure, and the abnormal expression of either gene altered piRNA content in EVs. These results suggest a causal relationship between abnormal tumor suppressor gene expression, cell stiffness, and piRNA expression.

Chronic kidney disease (CKD) is a global burden in the world. Low protein diet (LPD) recommendation is suggested in CKD patients to avoid or defer dialysis initiation and slow down CKD progression. However, nutritional imbalance and protein energy wasting represent key worries. The amino acid-based metabolic profile may provide a sensitive biomarker to evaluate CKD patients' nutrition status with LPD recommendations.We conducted a cross-sectional study in CKD stage 3-5 patients who had received LPD recommendation to evaluate the association between LPD and traditional markers (including plasma levels of albumin, pre-albumin, transferrin, total iron-binding capacity), inflammation markers (including peripheral leukocyte count and plasma levels of high-sensitivity C-reactive protein), body composition, muscle strength, and physical function, and novel nutrition markers (including amino acid-based metabolic profile) in CKD stage 3-5 patients.In our study CKD stage 3-5 patients with the total number of 73, the mean age was around 71 ± 10 years old. The mean daily protein intake (DPI) was around 0.9 ± 0.3 g/kg/day and 25 (34%) patients met the recommended goal of DPI0.8 g/kg/day. The mean daily calorie intake (DCI) was around 23 ± 6 kcal/kg/day, with only 11 (15%) patients met the recommend DCI with 30-35 kcal/kg/day. Compared to CKD patients with non-LPD, patients with LPD had significantly lower hemoglobin and albumin levels, shorter 6-min walking distance (6MWD), and lower leucine levels. Multivariable analysis found that lower hemoglobin and leucine levels, and shorter 6MWD were negatively and independently associated with LPD (all p 0.05). Then ROC curve analysis found that the optimal cut-off value of leucine plasma levels was 95.5 μM with 60% sensitivity and 71% specificity to predict those CKD patients with LPD with the area under the curve of 0.646 (95% CI: 0.512-0.780).LPD attainment was noted in 34% patients and most of CKD stage 3-5 patients (around 85%) had inadequate daily calorie intake although receiving standard dietary counseling routinely. A low protein diet and inadequate daily calorie intake in CKD patients were associated with shorter 6MWD, and lower hemoglobin and leucine levels. Plasma leucine levels lower than 95.5 μM may be a herald for muscle wasting and malnutrition in these CKD stage 3-5 patients with inadequate calorie intake.

Background: The Coronavirus -19 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 ( SARS-CoV-2 ) is an ongoing world-wide plague The viral spike (S) coat protein of SARS-CoV-2 engages the human angiotensin-converting enzyme 2 (ACE2) cell surface receptor to infect the host cells Thus, concerns arose regarding theoretically higher risk for COVID-19 in patients taking angiotensin-converting enzyme inhibitors (ACEI)/ angiotensin II type 1 receptor antagonists (ARBs) Methods: We systematically assessed case-population and cohort studies from MEDLINE (Ovid), Cochrane Database of Systematic Reviews PubMed, Embase, medRXIV, the World Health Organization data-base of COVID-19 publications and ClinicalTrials gov through Jun 1, 2020, with planned ongoing surveillance We rated the certainty of evidence according to Cochrane methods and the GRADE approach This study has been registered with PROSPERO, CRD42020190666 Findings: 14,921 ACEi users and 149,163 non-users were included In the eligible studies, 2,756 ACEi users tested positive among a total of 22,114 patients of SARS-CoV-2 infection 22,685 ARBs users and 141,399 non-users were included In the eligible studies, 3,352 ARBs users tested positive among 22,114 patients of SARS-CoV-2 infection After pooling the adjusted odds ratios (aOR), no significant increase was noted in the risk of SARS-CoV-2 infection by ACEi (aOR, 0 95;95% CI, 0 86-1 05) or ARBs (aOR, 1 05;95% CI, 0 97-1 14) users However, the random-effects meta-regression revealed that age may modify the SARS-CoV-2 infection risk in subjects with ARBs usage (coefficient, -0 006;95% CI, -0 016 to 0 004)-i e : the use of ARBs, as opposed to ACEi, specifically augmented the risk of SARS-CoV-2 infection in subjects 60 years-old In the COVID-19 outcome analysis, neither ACEi (aOR, 1 00;95% CI, 0 80-1 26) nor ARBs (aOR, 0 99;95% CI, 0 83-1 18) usage aggravated disease severity or mortality of COVID-19 Interpretation: ACEi usage might not increase the susceptibility of SARS-CoV-2 infection, severity of disease and mortality in case-population and cohort studies Additionally, we found for the first time that the usage of ARBs, as opposed to ACEi, specifically augmented the risk of SARS-CoV-2 infection in younger subjects;without obvious effects on COVID-19 outcomes Funding Statement: This study was supported by Taiwan National Science Council (grants NSC 101- 2314-B-002-132-MY3, NSC100-2314-B-002-119, NSC 101-2314-B-002-085-MY3, MOST 104-2314-B-002 -125 -MY3) and NTUH 100-N1776, 101-M1953, 102- S2097 Declaration of Interests: The authors declare that they have no competing interest

Summary: Background: Renal replacement therapy (RRT) is an effective rescue therapy for Type 1 cardiorenal syndrome (CRS). Previous studies have demonstrated that type 1 CRS patients with severe renal dysfunction were susceptible to sepsis, and that serum lactate has been correlated with the risk of mortality in patients with sepsis. However, the association between serum lactate level and the prognosis of type 1 CRS patients requiring RRT is unknown. Methods: An inception cohort of 500 type 1 CRS patients who received RRT in a tertiary-care referral hospital in Taiwan from August 2011 to January 2018 were enrolled. The outcomes of interest were dialysis withdrawal and 90-day mortality. The results were further externally validated using sampling data of type 1 CRS patients requiring dialysis from multiple tertiary-care centers. Findings: The 90-day mortality rate was 52.8% and the incidence rate of dialysis withdrawal was 34.8%. Lower pre-dialysis lactate was correlated with a higher rate of dialysis withdrawal and lower rate of mortality. Generalized additive model showed that 4.2 mmol/L was an adequate cut-off value of lactate to predict mortality. Taking mortality as a competing risk, Fine-Gray subdistribution hazard analysis further indicated that a low lactate level (≦ 4.2 mmol/L) was an independent predictor for the possibility of dialysis withdrawal, as also shown in external validation. The interaction of quick Sequential Organ Failure Assessment score and lactate was associated with dialysis dependence in a disease severity-dependent manner. Furthermore, the associations between hyperlactatemia and dialysis dependence were consistent in the patients with and without sepsis. Interpretation: Serum lactate level is accurate and capable of forecasting the prognosis along with qSOFA severity for clinical decision-making for treating type 1 CRS patients. Further studies are needed to validate our results. Funding: This study was supported by grants from Taiwan National Science Council [104–2314-B-002–125-MY3,106–2314-B-002–166-MY3,107–2314-B-002–026-MY3], National Taiwan University Hospital [106-FTN20,106-P02,UN106–014,106-S3582,107-S3809,107-T02,PC1246,VN109–09,109-S4634,UN109–041], Ministry of Science and Technology of the Republic of China [MOST106–2321-B-182–002,106-2314-B-182A-064,MOST107–2321-B-182–004,MOST107-2314-B-182A-138, MOST108–2321-B-182–003,MOST109–2321-B-182–001, MOST108-2314-B-182A-027], Chang Gung Memorial Hospital [CMRPG-2G0361,CMRPG-2H0161,CMRPG-2J0261, CMRPG-2K0091], and Ministry of Health and Welfare of the Republic of China [PMRPG-2L0011].

Highlights • 6-Mercaptopurine and 6-thioguanine are competitive inhibitors of SARS-CoV and MERS-CoV papain-like proteases. • Mycophenolic acid can noncompetitively inhibit papain-like protease of MERS-CoV, while cannot inhibit that of SARS-CoV. • 6-Mercaptopurine/6-thioguanine and mycophenolic acid synergistically inhibit MERS-CoV papain-like protease. • The three drugs with inhibitory effect for MERS-CoV papain-like protease can be used as lead compounds for drug development., Middle East respiratory syndrome coronavirus (MERS-CoV) is a new highly pathogenic human coronaviruses that emerged in Jeddah and Saudi Arabia and has quickly spread to other countries in Middle East, Europe and North Africa since 2012. Up to 17 December 2014, it has infected at least 938 people with a fatality rate of about 36% globally. This has resulted in an urgent need to identify antiviral drugs that are active against MERS-CoV. The papain-like protease (PLpro) of MERS-CoV represents an important antiviral target as it is not only essential for viral maturation, but also antagonizes interferon stimulation of the host via its deubiquitination activity. Here, we report the discovery that two SARS-CoV PLpro inhibitors, 6-mercaptopurine (6MP) and 6-thioguanine (6TG), as well as the immunosuppressive drug mycophenolic acid, are able to inhibit MERS-CoV PLpro. Their inhibition mechanisms and mutually binding synergistic effect were also investigated. Our results identify for the first time three inhibitors targeting MERS-CoV PLpro and these can now be used as lead compounds for further antiviral drug development.

The Klotho gene functions as an aging suppressor gene. Evidence from animal models suggests that induction of Klotho expression may be a potential treatment for age-associated diseases. However, the molecular mechanism involved in regulating renal Klotho gene expression remains unclear. In this study, we determined that resveratrol, a natural polyphenol, induced renal Klotho expression both in vivo and in vitro. In the mouse kidney, resveratrol administration markedly increased both Klotho mRNA and protein expression. In resveratrol-treated NRK-52E cells, increased Klotho expression was accompanied by the upregulation and nuclear translocation of activating transcription factor 3 (ATF3) and c-Jun. ATF3 or c-Jun overexpression enhanced the transcriptional activation of Klotho. Conversely, resveratrol-induced Klotho expression was attenuated in the presence of dominant-negative ATF3 or c-Jun. Coimmunoprecipitation and a chromatin immunoprecipitation assay revealed that ATF3 physically interacted with c-Jun and that the ATF3/c-Jun complex directly bound to the Klotho promoter through ATF3- and AP-1-binding elements. c-Jun cotransfection augmented the effects of ATF3 on Klotho transcription in vitro. Although Sirtuin 1 mRNA expression was induced by resveratrol and involved in regulating Klotho mRNA expression, it was not the primary cause for the aforementioned ATF3/c-Jun pathway. In summary, resveratrol enhances the renal expression of the anti-aging Klotho gene, and the transcriptional factors ATF3 and c-Jun functionally interact and coordinately regulate the resveratrol-mediated transcriptional activation of Klotho.

Objective The incidence of chronic kidney disease (CKD) is on the rise. CKD patients are at high risk of cardiovascular (CVD) and all-cause mortality. CKD patients have several endocrine disorders, including low levels of dehydroepiandrosterone sulfate (DHEA-S). In the general population, low levels of DHEA-S are associated with high CVD and all-cause mortality. The aim of this study was to analyze the prognostic value of plasma DHEA-S on the survival of CKD patients on hemodialysis. Method This was a single-center prospective cohort study on two hundred CKD patients on hemodialysis, which assessed the prognostic value of plasma DHEA-S on their survival. Result We found that plasma DHEA-S levels were negatively associated with age, and positively associated with dialysis duration and plasma creatinine, albumin, and phosphate levels in hemodialysis men. Elderly patients with co-morbidities (i.e. diabetes mellitus, congestive heart failure, and chronic obstructive pulmonary disease), poorer fluid control which was evaluated by higher cardiothoracic ratio, and low plasma creatinine and albumin levels seemed to have poor prognosis in hemodialysis men. Furthermore, low plasma DHEA-S levels were significantly associated with CVD-related [hazard ratio (HR) = 3.877; P = 0.021], non-CVD-related (HR = 3.522; P = 0.016), and all-cause mortality (HR = 3.667; P = 0.001) in hemodialysis men. But low plasma DHEA-S levels were not significantly associated with CVD-related, non-CVD-related, and all-cause mortality in hemodialysis women. Multivariate Cox regression analysis suggested that low plasma DHEA-S levels are significantly and independently associated with all-cause mortality in hemodialysis men (HR = 2.933; P = 0.033). Conclusion The study suggested that low plasma DHEA-S was independently and significantly associated with all-cause mortality in CKD hemodialysis men.

The expression of the renoprotective antiaging gene Klotho is decreased in uremia. Recent studies suggest that Klotho may be a tumor suppressor, and its expression may be repressed by DNA hypermethylation in cancer cells. Here we investigated the effects and possible mechanisms by which Klotho expression is regulated during uremia in uninephrectomized B-6 mice given the uremic toxins indoxyl sulfate or p -cresyl sulfate. Cultured human renal tubular HK2 cells treated with these toxins were used as an in vitro model. Injections of indoxyl sulfate or p -cresyl sulfate increased their serum concentrations, kidney fibrosis, CpG hypermethylation of the Klotho gene, and decreased Klotho expression in renal tubules of these mice. The expression of DNA methyltransferases 1, 3a, and 3b isoforms in HK2 cells treated with indoxyl sulfate or p -cresyl sulfate was significantly increased. Specific inhibition of DNA methyltransferase isoform 1 by 5-aza-2′-deoxycytidine caused demethylation of the Klotho gene and increased Klotho expression in vitro . Thus, inhibition of Klotho gene expression by uremic toxins correlates with gene hypermethylation, suggesting that epigenetic modification of specific genes by uremic toxins may be an important pathological mechanism of disease.

Objective Depression is common in hemodialysis patients. Reduced DHEA-S levels have been shown to be associated with depression in general population. Abnormalities in hormone production and metabolism are found in hemodialysis patients. However, the association between DHEA-S levels and depression in hemodialysis patients has not been established. Method We conducted a cross-sectional study, in which 80 patients under regular hemodialysis were studied, and their serum DHEA-S levels were analyzed. Results The prevalence of depression in our studied hemodialysis population is 37.5% (30/80). The DHEA-S level was 1138.1 ± 1216.9 ng/mL in male patients and 502.1 ± 389.4 ng/mL in female patients. The levels were not significantly different between patients with or without depression (910.8 ± 1127.1 ng/mL vs. 769.3 ± 848.3 ng/mL, P = 0.533). As compared to the non-depressed patients, the depressed patients were more likely to be male, with lower body mass index, consuming more alcohol, and with more co-morbidity. The prevalence of depression was not associated with age, educational background, smoking, duration of dialysis, hemoglobin, albumin, CRP, ferritin, and urea clearance (Kt/V and URR). The serum DHEA-S levels exhibited significant and independent associations with age, gender, diabetes mellitus, and the levels of serum albumin. Conclusion The study suggested a lack of association between plasma DHEA-S levels and depression in hemodialysis patients.

a Division of Nephrology, Chang Gung Memorial Hospital, Keelung, Taiwan b Graduate Institute of Clinical Medical Sciences, Chang Gung University Medical College, Taoyuan School of Medicine, Taiwan c Chang Gung University, Taipei, Taiwan d Department of Pediatrics, Taipei Medical University Hospital, Taipei, Taiwan e Division of Psychiatry, Chang Gung Memorial Hospital, Keelung, Taiwan f Laboratory of Epidemiology, Department of Health Care Management, Chang Gung University, Taipei, Taiwan g Division of Nephrology, Taipei Medical University Hospital, Taipei, Taiwan h Department of Internal Medicine, Taipei Medical University, Taipei, Taiwan

Background Depression and suicide are well established as prevalent mental health problems for patients on hemodialysis. Objective The authors examined the demographic and psychological factors associated with depression among hemodialysis patients and elucidated the relationships between depression, anxiety, fatigue, poor health-related quality of life, and increased suicide risk. Method This cross-sectional study enrolled 200 end-stage renal disease patients age ≥18 years on hemodialysis. Psychological characteristics were assessed with the Mini-International Neuropsychiatric Interview, the Hospital Anxiety and Depression Scale, the short-form Health-Related Quality of Life Scale, and Chalder Fatigue Scale, and structural equation modeling was used to analyze the models and the strength of relationships between variables and suicidal ideation. Results Of the 200 patients, 70 (35.0%) had depression symptoms, and 43 (21.5%) had had suicidal ideation in the previous month. Depression was significantly correlated with a low body mass index (BMI) and the number of comorbid physical illnesses. Depressed patients had greater levels of fatigue and anxiety, more common suicidal ideation, and poorer quality of life than nondepressed patients. Results revealed a significant direct effect for depression and anxiety on suicidal ideation. Conclusion Among hemodialysis patients, depression was associated with a low BMI and an increased number of comorbid physical illnesses. Depression and anxiety were robust indicators of suicidal ideation. A prospective study would prove helpful in determining whether early detection and early intervention of comorbid depression and anxiety among hemodialysis patients would reduce suicide risk.