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Amornpan Lertrit,1 Suchin Worawichawong,2 Somlak Vanavanan,2 Anchalee Chittamma,2 Dittapol Muntham,3 Piyanuch Radinahamed,1 Aumporn Nampoon,4 Chagriya Kitiyakara1 1Department of Medicine, 2Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, 3Section for Mathematics, Faculty of Science and Technology, Rajamangala University of Technology Suvarnabhumi, Phranakhon Si Ayutthaya, 4Research Center, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand Abstract: The degree of interstitial fibrosis and tubular atrophy (IFTA) is one of the strongest prognostic factors in glomerulonephritis (GN). In experimental models, high serum uric acid (UA) could contribute to IFTA through direct effects on the renal tubules, but the significance of this process has not been evaluated in patients. Urine neutrophil gelatinase–associated lipocalin (NGAL) is produced by renal tubules following acute or chronic damage. We investigated the relationship between UA and NGAL excretion in primary GN and tested whether these biomarkers are independently associated with IFTA. Urine and blood were collected from patients on the day of kidney biopsy. IFTA was assessed semi-quantitatively. Fifty-one patients with primary GN were enrolled. NGAL/creatinine correlated significantly with proteinuria but not with glomerular filtration rate (GFR). By contrast, UA correlated with GFR but not with proteinuria. NGAL/creatinine did not correlate with UA. Both NGAL/creatinine and UA increased with the severity of IFTA. By multivariate analysis, GFR, NGAL/creatinine, and UA were independently associated with moderate-to-severe IFTA. Combining UA and NGAL/creatinine with classical predictors (proteinuria and GFR) tended to improve discrimination for moderate-to-severe IFTA. Findings that UA was unrelated to urinary NGAL excretion suggest that the two biomarkers reflect different pathways related to the development of IFTA in primary GN. Both NGAL/creatinine and UA were independently associated with moderate-to-severe IFTA. Keywords: biomarker, fibrosis, glomerulonephritis, kidney, neutrophil gelatinase–associated lipocalin, uric acid

The disadvantaged populations eGFR (estimated glomerular filtration rate) epidemiology (DEGREE) study was designed to gain insight into the burden of chronic kidney disease (CKD) of undetermined cause (CKDu) using standard protocols to estimate the general-population prevalence of low eGFR internationally. We estimated the age-standardised prevalence of eGFR<60ml/min/1.73m 2 in adults aged 18-60, excluding participants with commonly known causes of CKD, i.e., ACR>300mg/g or equivalent, or self-reported or measured hypertension or diabetes (eGFR<60 [absent HT,DM,high ACR] ), and stratified by sex and location. We included population-representative surveys conducted around the world that were either designed to estimate CKDu burden or were re-analyses of large surveys. There were 60 964 participants from 43 areas across 14 countries, with data collected during 2007-2023. The highest prevalence was seen in rural men in Uddanam, India (14%) and Northwest Nicaragua (14%). Prevalence above 5% was generally only observed in rural men, with exceptions for rural women in Ecuador (6%) and parts of Uddanam (6-8%), and for urban men in Leon, Nicaragua (7%). Outside of Central America and South Asia, prevalence was below 2%. These observations represent the first attempts to estimate the prevalence of eGFR<60 [absent HT,DM,high ACR] around the world, as an estimate of CKDu burden, and provide a starting point for global monitoring. It is not yet clear what drives the differences, but available evidence to date supports a high general-population burden of CKDu in multiple areas within Central America and South Asia, although the possibility that unidentified clusters of disease may exist elsewhere cannot be excluded.

Background: The effectiveness of tixagevimab-cilgavimab as pre-exposure prophylaxis (PrEP) against breakthrough coronavirus disease 2019 (COVID-19) in dialysis patients remains uncertain due to limited data., Methods: In this multicenter prospective study, we enrolled vaccinated dialysis patients and divided them into two groups: a tixagevimab-cilgavimab group (received a 150 mg/150 mg intramuscular dose of tixagevimab-cilgavimab) and a control group (age-matched patients not receiving tixagevimab-cilgavimab). The primary outcome was the breakthrough COVID-19 rate at 6 months, whereas secondary outcomes included COVID-19-related hospitalization, intensive care unit admission, endotracheal intubation and mortality. The safety of tixagevimab-cilgavimab was assessed., Results: Two hundred participants were enrolled, with equal numbers in each group ( n  = 100 each). Baseline characteristics were comparable between groups, except for a higher number of COVID-19 vaccine doses in the tixagevimab-cilgavimab group [median (IQR) 4 (3-5) vs. 3 (3-4); P  = .01]. At 6 months, the breakthrough COVID-19 rates were comparable between the tixagevimab-cilgavimab (17%) and control (15%) groups ( P  = .66). However, the median (IQR) time to diagnosis of breakthrough infections tended to be longer in the tixagevimab-cilgavimab group [4.49 (2.81-4.98) vs 1.96 (1.65-2.91) months; P  = .08]. Tixagevimab-cilgavimab significantly reduced COVID-19-related hospitalization rates (5.9% vs 40.0%; P  = .02) among participants with breakthrough infections. All tixagevimab-cilgavimab-related adverse events were mild., Conclusion: The use of tixagevimab-cilgavimab as PrEP in vaccinated dialysis patients during the Omicron surge did not prevent breakthrough infections but significantly reduced COVID-19-related hospitalizations. Further research should prioritize alternative strategies., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Increased protein-bound uremic toxins (PBUTs) in patients with chronic kidney disease (CKD) are associated with cardiovascular diseases (CVDs); however, whether retention of PBUTs causes CVD remains unclear. Previous studies assessing the impacts of PBUTs on the vasculature have relied on 2D cell cultures lacking in vivo microenvironments. Here, we investigated the impact of various PBUTs (p-cresol (PC), indoxyl sulfate (IS), and p-cresyl sulfate (PCS)) on microvascular function using an organ-on-a-chip (OOC). Human umbilical vein endothelial cells were used to develop 3D vessels. Chronic exposure to PC resulted in significant vascular leakage compared with controls, whereas IS or PCS treatment did not alter the permeability of 3D vessels. Increased permeability induced by PC was correlated with derangement of cell adherens junction complex, vascular endothelial (VE)-cadherin and filamentous (F)-actin. Additionally, PC decreased endothelial viability in a concentration-dependent manner with a lower IC 50 in 3D vessels than in 2D cultures. IS slightly decreased cell viability, while PCS did not affect viability. PC induced inflammatory responses by increasing monocyte adhesion to endothelial surfaces of 3D vessels and IL-6 production. In conclusion, this study leveraged an OOC to determine the diverse effects of PBUTs, demonstrating that PC accumulation is detrimental to ECs during kidney insufficiency., (© 2024. The Author(s).)

The cardio-ankle vascular index (CAVI) is a noninvasive parameter reflecting vascular stiffness. CAVI correlates with the burden of atherosclerosis and future cardiovascular events. Mitochondria of peripheral blood mononuclear cells (PBMCs) have been identified as a noninvasive source for assessing systemic mitochondrial bioenergetics. This study aimed to investigate the relationship between CAVI values and mitochondrial bioenergetics of PBMCs in the older adults.. This cross-sectional study enrolled participants from the Electricity Generating Authority of Thailand between 2017 and 2018. A total of 1 640 participants with an ankle-brachial index greater than 0.9 were included in this study. All participants were stratified into 3 groups based on their CAVI values as high (CAVI ≥ 9), moderate (9 > CAVI ≥ 8), and low (CAVI < 8), in which each group comprised 702, 507, and 431 participants, respectively. The extracellular flux analyzer was used to measure mitochondrial respiration of isolated PBMCs. The mean age of the participants was 67.9 years, and 69.6% of them were male. After adjusted with potential confounders including age, sex, smoking status, body mass index, diabetes, dyslipidemia, hypertension, and creatinine clearance, participants with high CAVI values were independently associated with impaired mitochondrial bioenergetics, including decreased basal respiration, maximal respiration, and spare respiratory capacity, as well as increased mitochondrial reactive oxygen species. This study demonstrated that CAVI measurement reflects the underlying impairment of cellular mitochondrial bioenergetics in PBMCs. Further longitudinal studies are necessary to establish both a causal relationship between CAVI measurement and underlying cellular dysfunction., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The collision cross-sections (CCS) measurement using ion mobility spectrometry (IMS) in combination with mass spectrometry (MS) offers a great opportunity to increase confidence in metabolite identification. However, owing to the lack of sensitivity and resolution, IMS has an analytical challenge in studying the CCS values of very low-molecular-weight metabolites (VLMs ≤ 250 Da). Here, we describe an analytical method using ultrahigh-performance liquid chromatography (UPLC) coupled to a traveling wave ion mobility-quadrupole-time-of-flight mass spectrometer optimized for the measurement of VLMs in human urine samples. The experimental CCS values, along with mass spectral properties, were reported for the 174 metabolites. The experimental data included the mass-to-charge ratio ( m / z ), retention time (RT), tandem MS (MS/MS) spectra, and CCS values. Among the studied metabolites, 263 traveling wave ion mobility spectrometry (TWIMS)-derived CCS values ( TW CCS N2 ) were reported for the first time, and more than 70% of these were CCS values of VLMs. The TW CCS N2 values were highly repeatable, with inter-day variations of <1% relative standard deviation (RSD). The developed method revealed excellent TW CCS N2 accuracy with a CCS difference (ΔCCS) within ±2% of the reported drift tube IMS (DTIMS) and TWIMS CCS values. The complexity of the urine matrix did not affect the precision of the method, as evidenced by ΔCCS within ±1.92%. According to the Metabolomics Standards Initiative, 55 urinary metabolites were identified with a confidence level of 1. Among these 55 metabolites, 53 (96%) were VLMs. The larger number of confirmed compounds found in this study was a result of the addition of TW CCS N2 values, which clearly increased metabolite identification confidence., Competing Interests: The authors declare that there are no conflicts of interest., (© 2023 The Author(s).)

Kidney transplant recipients (KTRs) are at increased risk of developing de novo post-transplant malignancies (PTMs), with regional differences in types with excess risk compared to the general population. A single-center, population-controlled, retrospective cohort study was conducted at a tertiary care center in Thailand among all adults who underwent their first kidney transplant from 1986 to 2018. Standardized incidence ratios (SIRs) of malignancy by age, sex, and place of residence were obtained using data from the National Cancer Registry of Thailand as population control. There were 2,024 KTRs [mean age, 42.4 years (SD 11.4); female patients, 38.6%] during 16,495 person-years at risk. Of these, 125 patients (6.2%) developed 133 de novo PTMs. The SIR for all PTMs was 3.85 (95% CI 3.22, 4.56), and for pooled solid and hematologic PTMs, it was 3.32 (95% CI 2.73, 3.99). Urothelial malignancies had the largest excess risk, especially in women [female SIR 114.7 (95% CI 66.8, 183.6); male SIR 17.5 (95% CI 8.72, 31.2)]. The next two most common cancers were non-Hodgkin's lymphoma and skin cancer [SIR 20.3 (95% CI 13.6, 29.1) and 24.7 (95% CI 15.3-37.8), respectively]. Future studies are needed to identify the risk factors and assess the need for systematic screening among PTMs with excess risk in KTRs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Srisuwarn, Sutharattanapong, Disthabanchong, Kantachuvesiri, Kitiyakara, Phakdeekitcharoen, Ingsathit and Sumethkul.)

Death and end-stage kidney disease (ESKD) are major outcomes of glomerular disease. (GD) The years of potential life lost (YLL) may provide additional insight into the disease burden beyond death rates. There is limited data on premature mortality in GD. In this retrospective observational cohort study, we evaluated the mortality, ESKD rates, and YLL in Thais with biopsy-proven GD. The mortality and combined outcome rates were determined by log-rank test and ESKD by using a competing risk model. YLL and premature life lost before age 60 were calculated for different GD based on the life expectancy of the Thai population. Patients with GD (n = 949) were followed for 5237 patient years. The death rate and ESKD rates (95%CI) were 4.2 (3.7-4.9) and 3.3 (2.9-3.9) per 100 patient-years, respectively. Paraprotein-related kidney disease had the highest death rate, and diabetic nephropathy had the highest ESKD rate. Despite not having the highest death rate, lupus nephritis (LN) had the highest YLL (41% of all GD) and premature loss of life before age 60. In conclusion, YLL provided a different disease burden assessment compared to mortality rates and identified LN as the major cause of premature death due to GD in a Southeast Asian cohort., (© 2023. The Author(s).)

Introduction: Despite recognized geographic and sex-based differences in hemoglobin in the general population, these factors are typically ignored in patients with chronic kidney disease (CKD) in whom a single therapeutic range for hemoglobin is recommended. We sought to compare the distribution of hemoglobin across international nondialysis CKD populations and evaluate predictors of hemoglobin., Methods: In this cross-sectional study, hemoglobin distribution was evaluated in each cohort overall and stratified by sex and estimated glomerular filtration rate (eGFR). Relationships between candidate predictors and hemoglobin were assessed from linear regression models in each cohort. Estimates were subsequently pooled in a random effects model., Results: A total of 58,613 participants from 21 adult cohorts (median eGFR range of 17-49 ml/min) and 3 pediatric cohorts (median eGFR range of 26-45 ml/min) were included with broad geographic representation. Hemoglobin values varied substantially among the cohorts, overall and within eGFR categories, with particularly low mean hemoglobin observed in women from Asian and African cohorts. Across the eGFR range, women had a lower hemoglobin compared to men, even at an eGFR of 15 ml/min (mean difference 5.3 g/l, 95% confidence interval [CI] 3.7-6.9). Lower eGFR, female sex, older age, lower body mass index, and diabetic kidney disease were all independent predictors of a lower hemoglobin value; however, this only explained a minority of variance (R 2 7%-44% across cohorts)., Conclusion: There are substantial regional differences in hemoglobin distribution among individuals with CKD, and the majority of variance is unexplained by demographics, eGFR, or comorbidities. These findings call for a renewed interest in improving our understanding of hemoglobin determinants in specific CKD populations., (© 2023 Published by Elsevier, Inc., on behalf of the International Society of Nephrology.)

MicroRNAs (miRNAs) are a family of conserved small noncoding RNAs whose expression is associated with many diseases, including cancer. Salivary miRNAs are gaining popularity as noninvasive diagnostic biomarkers for cancer and other systemic disorders, but their use is limited by their low abundance and complicated detection procedure. Herein, we present a novel self-assembly approach based on rolling circle amplification (RCA) and graphene oxide (GO) for the ultrasensitive detection of miRNA21 and miRNA16 (miRNA oral cancer biomarkers in human saliva). First, target miRNA hybridizes with the RCA template. In the presence of DNA polymerase, the RCA reaction is induced and sequences matching the template are generated. Then, a nicking enzyme cuts the long ssDNA product into tiny pieces to obtain the amplified products. The DNA-decorated GO sensor was fabricated by preabsorbing the ssDNA fluorescence-labeled probe on the GO surface, resulting in fluorescence quenching. The DNA-decorated GO sensor could detect the amplified product via the self-assembly of dsDNA, leading to the desorption and recovery of the fluorescence-labeled probe. Under optimal conditions, the proposed system exhibited ultrasensitive detection; the detection limits of miRNA16 and miRNA21 were 8.81 and 3.85 fM, respectively. It showed a wide range of detection between 10 fM and 100 pM for miRNA16 and between 10 fM and 1 nM for miRNA16. It demonstrated high selectivity, distinguishing between 1- and 3-mismatch nucleotides in target miRNA. Overall, our proposed DNA-decorated GO sensor can accurately detect the salivary miRNAs and may potentially be used for the diagnosis and screening of early-stage oral cancer., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Mitochondrial dysfunction is a factor potentially contributing to the Aging process. However, evidence surrounding changes in mitochondrial function and aging is still limited; therefore, this study aimed to investigate further the association between them. Possible confounding factors were included in the statistical analysis to explore the possibility of any independent associations. One thousand seven hundred and sixty-nine participants (619 middle-aged adults [age < 65] and 1,150 older adults [age ≥ 65]) from the Electricity Generating Authority of Thailand were enrolled in the study. The clinical characteristics and medical history were collected. Peripheral blood mononuclear cells (PBMCs) were isolated from venous blood and used for analysis of mitochondrial function. Several parameters pertinent to mitochondrial respiration including non-mitochondrial respiration, basal respiration, maximal respiration, proton leak, and spare respiratory capacity were found to be two to three times lower in the mitochondria isolated from the cells of older adults. Interestingly, the mitochondrial ATP production was only slightly reduced, and the percentage of coupling efficiency of PBMC mitochondria was significantly higher in the older adult group. The mitochondrial mass and oxidative stress were significantly reduced in older adult participants; however, the ratio of oxidative stress to mass was significantly increased. The association of these parameters with age was still shown to be the same from the outcome of the multivariate analyses. The mitochondrial functions and mitochondrial mass in PBMCs were shown to decline in association with age. However, the upregulation of mitochondrial oxidative stress production and mitochondrial coupling efficiency might indicate a compensatory response in mitochondria during aging., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Higher residential greenness is associated with a lower risk of chronic kidney disease, but evidence on the association between greenness exposure and kidney function has not been conducted. Using cohort data from Electricity Generating Authority of Thailand (EGAT) employees, we investigated the association between long-term exposure to greenness and kidney function using estimated glomerular filtration rate (eGFR) in Bangkok Metropolitan Region (BMR), Thailand. We analyzed data from 2022 EGAT workers (aged 25-55 years at baseline) from 2009 to 2019. The level of greenness was calculated using the satellite-derived Enhanced Vegetation Index (EVI) and Normalized Difference Vegetation Index (NDVI). From 2008 to 2019, the average concentration of each air pollutant (PM 10 , O 3 , NO 2 , SO 2 , and CO) at the sub-district level in BMR was generated using the Kriging method. Long-term exposure for each participant was defined as the 1-year average concentrations before the date of the physical examination in 2009, 2014, and 2019. We employed linear mixed effects models to evaluate associations of NDVI and EVI with eGFR. The robustness of the results was also tested by including air pollutants in the models. After relevant confounders were controlled, the interquartile range increase in NDVI was associated with higher eGFR [1.03% (95%CI: 0.33, 1.74)]. After PM 10 and SO 2 were included in the models, the associations between NDVI and eGFR became weaker. The additions of O 3 , NO 2 , and CO strengthened the associations between them. In contrast, we did not find any association between EVI and eGFR. In conclusion, there was a positive association between NDVI and eGFR, but not for EVI. Air pollutants had a significant impact on the relationship between NDVI and eGFR. Additional research is needed to duplicate this result in various settings and populations to confirm our findings., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: Universal health coverage can decrease the magnitude of the individual patient's financial burden of chronic kidney disease (CKD), but the residual financial hardship from the patients' perspective has not been well-studied in low and middle-income countries (LMICs). This study aimed to evaluate the residual financial burden in patients with CKD stage 3 to dialysis in the "PD First Policy" under Universal Coverage Scheme (UCS) in Thailand., Methods: This multicenter nationwide cross-sectional study in Thailand enrolled 1,224 patients with pre-dialysis CKD, hemodialysis (HD), and peritoneal dialysis (PD) covered by UCS and other health schemes for employees and civil servants. We interviewed patients to estimate the proportion with catastrophic health expenditure (CHE) and medical impoverishment. The risk factors associated with CHE were analyzed by multivariable logistic regression., Results: Under UCS, the total out-of-pocket expenditure in HD was over two times higher than PD and nearly six times higher than CKD stages 3-4. HD suffered significantly more CHE and medical impoverishment than PD and pre-dialysis CKD [CHE: 8.5, 9.3, 19.5, 50.0% ( p < 0.001) and medical impoverishment: 8.0, 3.1, 11.5, 31.6% ( p < 0.001) for CKD Stages 3-4, Stage 5, PD, and HD, respectively]. In the poorest quintile of UCS, medical impoverishment was present in all HD and two-thirds of PD patients. Travel cost was the main driver of CHE in HD. In UCS, the adjusted risk of CHE increased in PD and HD (OR: 3.5 and 16.3, respectively) compared to CKD stage 3., Conclusions: Despite universal coverage, the residual financial burden remained high in patients with kidney failure. CHE was considerably lower in PD than HD, although the rates remained alarmingly high in the poor. The "PD First' program" could serve as a model for other LMICs. However, strategies to minimize financial distress should be further developed, especially for the poor., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sangthawan, Klyprayong, Geater, Tanvejsilp, Anutrakulchai, Boongird, Gojaseni, Kuhiran, Lorvinitnun, Noppakun, Parapiboon, Sirilak, Tankee, Taruangsri, Sangsupawanich, Sritara, Chaiyakunapruk and Kitiyakara.)

Two dimensional GC (GC × GC)-time-of-flight mass spectrometry (TOFMS) has been used to improve accurate metabolite identification in the chemical industry, but this method has not been applied as readily in biomedical research. Here, we evaluated and validated the performance of high resolution GC × GC-TOFMS against that of GC-TOFMS for metabolomics analysis of two different plasma matrices, from healthy controls (CON) and diabetes mellitus (DM) patients with kidney failure (DM with KF). We found GC × GC-TOFMS outperformed traditional GC-TOFMS in terms of separation performance and metabolite coverage. Several metabolites from both the CON and DM with KF matrices, such as carbohydrates and carbohydrate-conjugate metabolites, were exclusively detected using GC × GC-TOFMS. Additionally, we applied this method to characterize significant metabolites in the DM with KF group, with focused analysis of four metabolite groups: sugars, sugar alcohols, amino acids, and free fatty acids. Our plasma metabolomics results revealed 35 significant metabolites (12 unique and 23 concentration-dependent metabolites) in the DM with KF group, as compared with those in the CON and DM groups (N = 20 for each group). Interestingly, we determined 17 of the 35 (14/17 verified with reference standards) significant metabolites identified from both the analyses were metabolites from the sugar and sugar alcohol groups, with significantly higher concentrations in the DM with KF group than in the CON and DM groups. Enrichment analysis of these 14 metabolites also revealed that alterations in galactose metabolism and the polyol pathway are related to DM with KF. Overall, our application of GC × GC-TOFMS identified key metabolites in complex plasma matrices., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Two-dimensional gas chromatography-time-of-flight mass spectrometry (GC × GC-TOFMS) provides a large amount of molecular information from biological samples. However, the lack of a comprehensive compound library or customizable bioinformatics tool is currently a challenge in GC × GC-TOFMS data analysis. We present an open-source deep learning (DL) software called contour regions of interest (ROI) identification, simulation and untargeted metabolomics profiler (CRISP). CRISP integrates multiple customizable deep neural network architectures for assisting the semi-automated identification of ROIs, contour synthesis, resolution enhancement and classification of GC × GC-TOFMS-based contour images. The approach includes the novel aggregate feature representative contour (AFRC) construction and stacked ROIs. This generates an unbiased contour image dataset that enhances the contrasting characteristics between different test groups and can be suitable for small sample sizes. The utility of the generative models and the accuracy and efficacy of the platform were demonstrated using a dataset of GC × GC-TOFMS contour images from patients with late-stage diabetic nephropathy and healthy control groups. CRISP successfully constructed AFRC images and identified over five ROIs to create a deepstacked dataset. The high fidelity, 512 × 512-pixels generative model was trained as a generator with a Fréchet inception distance of <47.00. The trained classifier achieved an AUROC of >0.96 and a classification accuracy of >95.00% for datasets with and without column bleed. Overall, CRISP demonstrates good potential as a DL-based approach for the rapid analysis of 4-D GC × GC-TOFMS untargeted metabolite profiles by directly implementing contour images. CRISP is available at https://github.com/vivekmathema/GCxGC-CRISP., (© The Author(s) 2022. Published by Oxford University Press.)

Introduction: There is a need for sensitive and specific biomarkers to predict kidney damage and therapeutic response in lupus nephritis (LN). Monocyte chemoattractant protein-1 (MCP-1) and epidermal growth factor (EGF) are cytokines with divergent roles. EGF or EGF/MCP1 ratio have been shown to correlate with prognosis in primary glomerulonephritis, but there is limited information in lupus nephritis (LN). This study evaluated the roles of MCP-1, EGF or their ratio as biomarkers of histopathology and response to treatment in LN., Methods: This was a cross-sectional and observational study. Baseline urine MCP-1 and EGF levels in systemic lupus erythematosus (SLE) patients and controls (total n = 101) were compared, and levels were correlated with clinicopathological findings and subsequent response to treatment., Results: MCP-1 was higher in active LN (n = 69) compared to other SLE groups and controls, whereas EGF was not different. MCP-1 correlated with disease activity (proteinuria, renal SLEDAI, classes III/IV/V, and high activity index.) By contrast, EGF correlated with eGFR, but not with proteinuria, activity index, or class III/IV/V. MCP-1 was higher, and EGF was lower in high chronicity index. EGF/MCP-1 decreased with greater clinicopathological severity. In a subgroup with proliferative LN who completed six months of induction therapy (n = 41), EGF at baseline was lower in non-responders compared to responders, whereas MCP-1 was similar. By multivariable analysis, baseline EGF was independently associated with subsequent treatment response. Area under the curve for EGF to predict response was 0.80 (0.66-0.95). EGF ≥ 65.6 ng/ mgCr demonstrated 85% sensitivity and 71% specificity for response. EGF/MCP-1 did not improve the prediction for response compared to EGF alone., Conclusion: MCP-1 increased with disease activity, whereas EGF decreased with low GFR and chronic damage. Urine EGF may be a promising biomarker to predict therapeutic response in LN. EGF/MCP-1 did not improve the prediction of response., Competing Interests: The authors have declared that no competing interests exist.

Background: Urine tissue inhibitor of metalloproteinases-2/insulin-like growth factor-binding protein 7 (TIMP-2/IGFBP7) (NephroCheck, Ortho Clinical Diagnostics, Raritan, NJ, USA) is a US Food and Drug Administration-approved biomarker for risk assessment of acute kidney injury (AKI) in critically ill adult patients in intensive care units; however, its clinical impact in the emergency department (ED) remains unproven. We evaluated the utility of NephroCheck for predicting AKI development and short-term mortality in the ED., Methods: This was a prospective, observational, five-center international study. We consecutively enrolled ED patients admitted with ≥30% risk of AKI development (assessed by ED physician: ED score) or acute diseases. Serum creatinine was tested on ED arrival (T0), day 1, and day 2 (T48); urine for NephroCheck was collected at T0 and T48. We performed ROC curve and reclassification analyses., Results: Among the 529 patients enrolled (213 females; median age, 65 years), AKI developed in 59 (11.2%) patients. The T0 NephroCheck value was higher in the AKI group than in the non-AKI group (median 0.77 vs. 0.29 (ng/m) 2 /1,000, P=0.001), and better predicted AKI development than the ED score (area under the curve [AUC], 0.64 vs. 0.53; P =0.04). In reclassification analyses, adding NephroCheck to the ED score improved the prediction of AKI development ( P <0.05). The T0 NephroCheck value predicted 30-day mortality (AUC, 0.68; P <0.001)., Conclusions: NephroCheck can predict both AKI development and short-term mortality in at-risk ED patients. NephroCheck would be a useful biomarker for early ruling-in or ruling-out of AKI in the ED.

Background: Kidney dysfunction is considered a cardiovascular risk factor. However, few longitudinal studies have examined the effects of air pollution on kidney function. We evaluated associations between long-term air pollution exposure and estimated glomerular filtration rate (eGFR) using data from a cohort of the Electricity Generating Authority of Thailand (EGAT) study in Bangkok Metropolitan Region, Thailand., Methods: This longitudinal study included 1839 subjects (aged 52-71 years in 2002) from the EGAT1 cohort study during 2002-2012. eGFR, based on creatinine, was measured in 2002, 2007, and 2012. Annual mean concentrations of air pollutants (i.e., particulate matter with an aerodynamic diameter ≤10 μm (PM 10 ), ozone (O 3 ), nitrogen dioxide (NO 2 ), sulfur dioxide (SO 2 ), and carbon monoxide (CO)) prior to a measurement of creatinine were assessed with the ordinary kriging method. Mixed-effect linear regression models were used to assess associations between air pollutants and eGFR, while controlling for potential covariates. eGFR values are expressed as percent change per interquartile range (IQR) increments of each pollutant., Results: Lower eGFR was associated with higher concentrations of PM 10 (-1.99%, 95% confidence interval (CI): -3.33, -0.63), SO 2 (-4.89%, 95%CI: -6.69, -3.07), and CO (-0.97%, 95%CI: -1.96, 0.03). However, after adjusting for temperature, relative humidity, PM 10 , and SO 2 , no significant association was observed between CO and eGFR., Conclusions: Our findings support the hypothesis that long-term exposure to high concentrations of PM 10 and SO 2 is associated with the progression of kidney dysfunction in subjects of the EGAT cohort study., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

There are limited data on chronic kidney disease of unknown etiology (CKDu) from Southeast Asia. Initially described in working age men, a common approach to detect CKDu that includes all adults has recently been proposed. We determined the prevalence, and risk factors for CKDu using data from a cross-sectional, nationally representative survey of the adult population of Thailand. We used a proxy for CKDu as age < 70 with impaired kidney function (eGFR < 60) in the absence of diabetes and hypertension (CKDu1) and heavy proteinuria (CKDu2). Prevalence estimates were probability-weighted for the Thai population. The associations between risk factors and CKDu or elderly subjects with eGFR < 60 without traditional causes were assessed by multivariable logistic regression. Of 17,329 subjects, the prevalence were: eGFR < 60, 5.3%; CKDu1 0.78%; CKDu2, 0.75%. CKDu differed by 4.3-folds between regions. Women, farmers/laborers, older age, gout, painkillers, rural area, and stones were independent risk factors for CKDu. Women, age, rural, gout, painkillers were significant risk factors for both CKDu and elderly subjects. These data collected using standardized methodology showed that the prevalence of CKDu in Thailand was low overall, although some regions had higher risk. Unlike other countries, Thai women had a two-fold higher risk of CKDu., (© 2021. The Author(s).)

The current gold standard for classifying lupus nephritis (LN) progression is a renal biopsy, which is an invasive procedure. Undergoing a series of biopsies for monitoring disease progression and treatments is unlikely suitable for patients with LN. Thus, there is an urgent need for non-invasive alternative biomarkers that can facilitate LN class diagnosis. Such biomarkers will be very useful in guiding intervention strategies to mitigate or treat patients with LN. Urine samples were collected from two independent cohorts. Patients with LN were classified into proliferative (class III/IV) and membranous (class V) by kidney histopathology. Metabolomics was performed to identify potential metabolites, which could be specific for the classification of membranous LN. The ratio of picolinic acid (Pic) to tryptophan (Trp) ([Pic/Trp] ratio) was found to be a promising candidate for LN diagnostic and membranous classification. It has high potential as an alternative biomarker for the non-invasive diagnosis of LN., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Background: Dialysis patients have an increased risk of mortality. Recently treatment with haemodiafiltration (HDF) has been reported to reduce mortality, particularly cardiovascular mortality, compared to standard high-flux haemodialysis (HD). However, why HDF may offer a survival advantage remains to be determined. So, we conducted a pilot study to explore differences in middle-molecules, inflammation and markers of vascular disease in patients treated by HD and HDF., Methods: Observational cross-sectional study measuring serum β2-microglobulin (β2M), Advanced Glycosylation End Products (AGEs) by skin autofluorescence (SAF), oxidative stress with ischaemia modified albumin ratio (IMAR) and peripheral vascular disease assessment using Ankle-Brachial Index (ABI), and arterial stiffness using Cardio-Ankle Vascular Index (CAVI)., Results: We studied 196 patients, mean age 69.1 ± 12.4 years, 172 (87.8%) treated by HD and 24 (12.2%) by HDF. Age, body mass index, co-morbidity and dialysis vintage were not different between HD and HDF groups. Middle molecules; β2M (31±9.9 vs 31.2±10 ug/mL) and SAF (2.99±0.72 vs 3.0±0.84 AU), ABI (1.06±0.05 vs 1.07±0.10) and CAVI (9.34±1.55 vs 9.35±1.23) were not different, but IMAR was higher in the HD patients (38.4±14.8 vs 31.3 ± 17.4, P = 0.035)., Conclusions: In this pilot observational study, we found patients treated by HDF had lower oxidative stress as measured by IMAR, with no differences in middle molecules. Lower oxidative stress would be expected to have diverse protective effects on the cardiovascular system Although we found no differences in ABI and CAVI, future studies are required to determine whether reduced oxidative stress translates into clinically relevant differences over time., Competing Interests: The authors have declared that no competing interests exist.

Mesangial C4d deposits have been associated with worse outcomes in Western patients with IgA nephropathy (IgAN), but there is limited data in Asians. Previously, a high proportion of stained glomeruli was often required for the classification of C4d positive (C4d+ve). Positive staining in lower proportion of staining would be classified as C4d-ve. This retrospective study evaluated the prognostic value of C4d+ve using a less stringent definition (one C4d+ve glomerulus) in Thai patients with IgAN (n = 120). Baseline findings and outcomes were compared between those with more extensive C4d staining patterns and those with more restricted staining. Clinico-pathologic parameters and risk for kidney outcomes (kidney failure or decline GFR50%) were compared between C4d+ve versus C4d-ve, and between different patterns: Focal (< 50%) versus Diffuse (≥ 50% of glomeruli); or Global (≥ 50) versus Segmental (< 50% of mesangial area). The hazard ratios were estimated using Cox proportional hazard models for Model 1 (Oxford score+ C4d) and Model 2 (Model 1+ clinical factors). C4d+ve (n = 81) had lower eGFR, more global sclerosis, and interstitial fibrosis than C4d-ve at baseline. The 5-year kidney survival for C4d+ve was lower (53.7%) than C4d-ve (89.7%); P = 0.0255. By univariate analysis, T1, T2, C4d+ve, eGFR<60, proteinuria were predictors of kidney outcome. By multivariate analysis, proteinuria, T1, T2 and C4d+ve were independent predictors (Model 2 HR (95% CI) C4d+ve: 3.24 (1.09-9.58), p = 0.034). Segmental had lower eGFR, higher tubulointerstitial fibrosis, and segmental sclerosis compared to Global pattern. Clinicopathological parameters were not different between Focal and Diffuse patterns. Outcomes were similar between staining patterns. In conclusion, C4d staining may be a valuable marker of poor prognosis in Asian patients with IgAN. Less stringent criteria for C4d+ve should be considered as no differences in outcomes were observed between more extensive staining with less extensive patterns. More studies are needed to identify the optimum criteria for C4d+ve., Competing Interests: The authors have declared that no competing interests exist.

Background: Pretransplant desensitization protocols, including plasmapheresis, intravenous immunoglobulin, induction antibody therapy, and intensive maintenance immunosuppression, are generally employed in kidney transplant recipients who have positive status for donor-specific anti-HLA antibody (DSA). To avoid serious infectious complications, the authors designed a novel low-dose protocol in Thai patients undergoing DSA+ living-related kidney transplantation (LRKT)., Methods: A retrospective cohort study of the patients who underwent DSA+ LRKT was conducted. The novel protocol consisted of 3 to 5 sessions of pretransplant double-filtration plasmapheresis (DFPP) with or without low-dose intravenous immunoglobulin together with low-dose anti-thymocyte globulin (ATG) induction (1-1.5 mg/kg/d for 3-4 days) and low-dose tacrolimus (Tac) (trough level 5-10 ng/mL), mycophenolate, and prednisolone., Results: The study included 17 patients. The lymphocyte crossmatch via complement-dependent cytotoxicity was negative in 12 patients and positive for B cell immunoglobulin M in 5 patients. The novel desensitization protocol resulted in a decrease of at least 50% of DSA mean fluorescence intensity from baseline (from 4320 ± 549 before DFPP to 1601 ± 350 before transplantation, P < .005) and successful kidney transplantation with good allograft function in all cases. Early DSA rebound was observed in 3 patients after transplantation, and kidney biopsy revealed subclinical antibody-mediated rejection in 1 patient and diffuse C4d staining without cell infiltration in 2 patients. There were good long-term outcomes in patient and graft survival (100% and 94.1%, respectively). Only 1 allograft loss occurred because of nonadherence. The majority of patients have stable allograft function with serum creatinine less than 1.5 mg/dL. However, infections, including CMV and other organisms, were commonly observed., Conclusions: Desensitization protocol with DFPP, low-dose ATG, and Tac provides excellent outcomes in living donor kidney transplantation in highly sensitized Asian populations., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Cognitive impairment is commonly found in the elderly population. Evidence suggests that mitochondrial function in lymphocytes are potential biomarkers in the progression of neurodegeneration, as peripheral mitochondrial function is associated with mild cognitive impairment (MCI) in the elderly population. Therefore, we hypothesize that impaired mitochondrial ATP production and oxidative stress in peripheral blood mononuclear cells (PBMCs) are associated with cognitive impairment in the elderly population. Data were collected from 897 participants from the EGAT (The Electricity Generating Authority of Thailand) cohort. The participants were classified to be in the normal cognition group (n = 428) or mild cognitive impairment group (n = 469), according to their MoCA score. The association of mitochondrial function and cognitive status was analyzed by binary logistic regression analysis. MCI participants had higher age, systolic blood pressure, waist/hip ratio, and lower plasma high- and low-density lipoprotein cholesterol levels, when compared to the normal cognition group. In addition, estimated glomerular filtration rate were lower in the MCI group than those in the normal cognition group. Collectively, MCI is associated with mitochondrial dysfunction in PBMCs as indicated by decreasing mitochondrial ATP production, increasing proton leak, and oxidative stress, in the elderly population, independently of the possible confounding factors in this study.

Background: There is limited information on the role of low socioeconomic status (SES) in the development of new chronic kidney disease (CKD) in the general population, especially from developing countries. This study will test the hypothesis that low SES increases the risk of incidence of decreased glomerular filtration rate (GFR, used as an estimate for CKD) in a Thai worker cohort., Method: In this prospective, longitudinal observational study, we evaluated the association of income and educational attainment on incident decreased GFR ( iGFR <60 mL/min/1.73 m 2 ) over a 27-year period in employees of Electricity Generating Authority of Thailand. In 1985, subjects participated in a health survey and were re-examined in 1997, 2002, 2007 and 2012. Education was classified into three categories: low, 0-8th grade; medium, 9-12th grade; and high, >12th grade. Income was categorised as follows: low <10 000 Thai Baht (THB)/month; medium, 10 000-20 000 THB/month; and high, >20 000 THB/month. HRs of iGFR <60 mL/min/1.73 m 2 were estimated using Cox interval-censored models with high income or education as the reference groups after adjustments for clinical risk factors., Results: Participants (n=3334) were followed for 23 (15, 27) years. When evaluated separately, both education and income were risk factors for iGFR <60 mL/min/1.73 m 2 (adjusted HR education: medium-1.26 (95% CI 1.13 to1.42) and low-1.57 (95% CI 1.36 to 1.81) and adjusted HR income: medium-1.21 (95% CI 0.97 to 1.50) and low-1.47 (95% CI 1.18 to 1.82)). When both income and education were included together, low and medium education remained independently associated with iGFR <60 mL/min/1.73 m 2 ., Conclusions: Low education was independently associated with increased risk of decreased GFR in a Thai worker population. Strategies to identify risk factors among low SES may be useful to prevent early CKD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Peri-procedural i.v. fluid administration is important for the prevention of contrast-induced acute kidney injury (CI-AKI). However, standardized fluid management protocols may not be suitable for all patients. We therefore wished to determine whether an individualized fluid administration protocol guided by measuring extracellular water (ECW) using bioimpedance analysis (BIA) would be safe and would reduce the incidence CI-AKI compared to a standardized fluid administration prescription., Methods: In this pilot, randomized, parallel-group, single-blind, controlled trial, we compared the effect of BIA-guided isotonic bicarbonate administration according to the ratio of ECW to total body water (ECW/TBW) to our standard isotonic bicarbonate protocol in regard to the safety and efficacy of preventing CI-AKI in chronic kidney disease patients undergoing elective cardiac angiography. Our primary outcome was the incidence of CI-AKI, which was defined as a ≥0.3 mg/dl or 150% increase in serum creatinine concentration within 48 to 72 hours after cardiac angiography ., Results: We studied 61 patients, 30 in the bioimpedance group and 31 in the control group. Age was similar (72.5 ± 7 vs. 71.4 ± 7.9 years), as were body mass index (25.5 vs. 25.8 kg/m 2 ) and baseline serum creatinine (1.3 ± 0.3 vs. 1.4 ± 0.4 mg/dl). The peri-procedural fluid volume administered was significantly greater in the BIA-guided hydration group (899.0 ± 252.7 ml vs. 594.4 ± 125.9 ml, P  < .01). The incidence of CI-AKI was 3.3% in BIA-guided hydration group and 6.5% in the control group (relative risk = 0.52, 95% confidence interval = 0.05-5.40, P  = 1.00). Adverse events reported were comparable between groups (6.7% vs. 6.5%, P  = 1.00)., Conclusions: The overall incidence of CI-AKI after cardiac angiography in our patients with mild-to-moderate renal insufficiency was lower than anticipated. Isotonic bicarbonate administration guided by bioimpedance measurements was safe, and probably led to a lower incidence of CI-AKI, although this not reach statistical significance., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)

Diabetic nephropathy, a major complication of diabetes mellitus (DM), is increasing worldwide and the large majority of patients have type 2 DM. Microalbuminuria has been used as a diagnostic marker of diabetic nephropathy. But owing to its insufficient sensitivity and specificity, other biomarkers are being sought. In addition, the pathophysiology of diabetic nephropathy is not fully understood and declines in renal function occur even without microalbuminuria. In this study, we investigated urinary proteins from three study groups (controls, and type 2 diabetic subjects with or without microalbuminuria). Non-targeted label-free Nano-LC QTOF analysis was conducted to discover underlying mechanisms and protein networks, and targeted label-free Nano-LC QTOF with SWATH was performed to qualify discovered protein candidates. Twenty-eight proteins were identified as candidates and functionally analyzed via String DB, gene ontology and pathway analysis. Four predictive mechanisms were analyzed: i) response to stimulus, ii) platelet activation, signaling and aggregation, iii) ECM-receptor interaction, and iv) angiogenesis. These mechanisms can provoke kidney dysfunction in type 2 diabetic patients via endothelial cell damage and glomerulus structural alteration. Based on these analyses, three proteins (kininogen-1, basement membrane-specific heparan sulfate proteoglycan core protein, and roundabout homolog 4) were proposed for further study as potential biomarkers. Our findings provide insights that may improve methods for both prevention and diagnosis of diabetic nephropathy., (Copyright © 2020 Na Nakorn et al.)