CKDNET, a quality improvement project for prevention and reduction of chronic kidney disease in the Northeast Thailand.

BACKGROUND: The incidence of chronic kidney disease (CKD) is high in the Northeast Thailand compared to other parts of the country. Therefore, a broad program applying all levels of care is inevitable. This paper describes the results of the first year trial of the Chronic Kidney Disease Prevention in the Northeast Thailand (CKDNET), a quality improvement project collaboratively established to curb CKD. METHODS: We have covered general population, high risk persons and all stages of CKD patients with expansive strategies such as early screening, effective CKD registry, prevention and CKD comprehensive care models including cost effectiveness analysis. RESULTS: The preliminary results from CKD screening in general population of two rural sub-districts show that 26.8% of the screened population has CKD and 28.9% of CKD patients are of unknown etiology. We have established the CKD registry that has enlisted a total of 10.4 million individuals till date, of which 0.13 million are confirmed to have CKD. Pamphlets, posters, brochures and other media of 94 different types in the total number of 478,450 has been distributed for CKD education and awareness at the community level. A CKD guideline that suits for local situation has been formulated to deal the problem effectively and improve care. Moreover, our multidisciplinary intervention and self-management supports were effective in improving glomerular filtration rate (49.57 versus 46.23 ml/min/1.73 m2; p < 0.05), blood pressure (129.6/76.1 versus 135.8/83.6 mmHg) and quality of life of CKD patients included in the program compared to those of the patients under conventional care. The cost effectiveness analysis revealed that lifetime cost for the comprehensive health services under the CKDNET program was 486,898 Baht compared to that of the usual care of 479,386 Baht, resulting in an incremental-cost effectiveness ratio of 18,702 Baht per quality-adjusted life years gained. CONCLUSION: CKDNET, a quality improvement project of the holistic approach is currently applying to the population in the Northeast Thailand which will facilitate curtailing of CKD burden in the region.

Overexpression of the peroxin Pex34p suppresses impaired acetate utilization in yeast lacking the mitochondrial aspartate/glutamate carrier Agc1p.

PEX34, encoding a peroxisomal protein implicated in regulating peroxisome numbers, was identified as a high copy suppressor, capable of bypassing impaired acetate utilization of agc1∆ yeast. However, improved growth of agc1∆ yeast on acetate is not mediated through peroxisome proliferation. Instead, stress to the endoplasmic reticulum and mitochondria from PEX34 overexpression appears to contribute to enhanced acetate utilization of agc1∆ yeast. The citrate/2-oxoglutarate carrier Yhm2p is required for PEX34 stimulated growth of agc1∆ yeast on acetate medium, suggesting that the suppressor effect is mediated through increased activity of a redox shuttle involving mitochondrial citrate export. Metabolomic analysis also revealed redirection of acetyl-coenzyme A (CoA) from synthetic reactions for amino acids in PEX34 overexpressing yeast. We propose a model in which increased formation of products from the glyoxylate shunt, together with enhanced utilization of acetyl-CoA, promotes the activity of an alternative mitochondrial redox shuttle, partially substituting for loss of yeast AGC1.

Increase of MAL-II Binding Alpha2,3-Sialylated Glycan Is Associated with 5-FU Resistance and Short Survival of Cholangiocarcinoma Patients.

BACKGROUND AND OBJECTIVES: Sialylation plays important roles in tumor progression. Our present study aimed to demonstrate the alteration of sialylation and its role in cholangiocarcinoma (CCA). MATERIALS AND METHODS: The α2,3- and α2,6-sialylation in CCA tissue was analyzed by lectin-histochemistry using Maackia amurensis lectin-II (MAL-II) and Sambucus nigra agglutinin (SNA). CCA cell lines were treated with the pan-sialylation inhibitor 3Fax-peracetyl-Neu5Ac (3F-Sia) followed by proliferation and chemosensitivity assays. RESULTS: MAL-II binding α2,3-Sialylated Glycan (MAL-SG) and SNA binding α2,6-Sialylated Glycan (SNA-SG) were both elevated in CCA compared with hyperplastic/dysplastic (HP/DP) and normal bile ducts (NBD). The positive staining for MAL-SG or SNA-SG were found in 82% (61/74) of the CCA cases. Higher expression of MAL-SG in CCA was associated with shorter survival of the patients. The median survival of patients with high and low MAL-SG were 167 and 308 days, respectively, with overall survival of 233 days, suggesting the involvement of MAL-SG in CCA progression. MAL-SG expression of CCA cell lines was markedly decreased after treatment with 3F-Sia for 48 to 72 h. While proliferation of CCA cells were not affected by 3F-Sia treatment, their susceptibility to 5-fluorouracil (5-FU) was significantly enhanced. These results suggest that sialylation is involved in the development of 5-FU resistance and the sialylation inhibitor 3F-Sia can be used as a chemosensitizer for CCA. CONCLUSIONS: Sialylation is critically involved in the development of chemoresistance of CCA, and sialylation inhibitors may be used as a chemosensitizer in CCA treatment.

Metagenomics and metaproteomics alterations are associated with kidney disease in opisthorchiasis hamsters fed a high-fat and high-fructose diet.

BACKGROUND: Opisthorchis viverrini (O. viverrini, Ov) infection and consumption of high-fat and high-fructose (HFF) diet exacerbate liver and kidney disease. Here, we investigated the effects of a combination of O. viverrini infection and HFF diet on kidney pathology via changes in the gut microbiome and host proteome in hamsters. METHODOLOGY/PRINCIPAL FINDINGS: Twenty animals were divided into four groups; 1) fed a normal diet not infected with O. viverrini (normal group), 2) fed an HFF diet and not infected with O. viverrini (HFF), 3) fed a normal diet and infected with O. viverrini (Ov), and 4) fed an HFF diet and infected with O. viverrini (HFFOv). DNA was extracted from fecal samples and the V3-V4 region of the bacterial 16S rRNA gene sequenced on an Illumina MiSeq sequencing platform. In addition, LC/MS-MS analysis was done. Histopathological studies and biochemical assays were also conducted. The results indicated that the HFFOv group exhibited the most severe kidney injury, manifested as elevated KIM-1 expression and accumulation of fibrosis in kidney tissue. The microbiome of the HFFOv group was more diverse than in the HFF group: there were increased numbers of Ruminococcaceae, Lachnospiraceae, Desulfovibrionaceae and Akkermansiaceae, but fewer Eggerthellaceae. In total, 243 host proteins were identified across all groups. Analysis using STITCH predicted that host proteome changes may lead to leaking of the gut, allowing molecules such as soluble CD14 and p-cresol to pass through to promote kidney disease. In addition, differential expression of TGF-beta-activated kinase 1 and MAP3K7-binding protein 2 (Tab2, involving renal inflammation and injury) are predicted to be associated with kidney disease. CONCLUSIONS/SIGNIFICANCE: The combination of HFF diet and O. viverrini infection may promote kidney injury through alterations in the gut microbiome and host proteome. This knowledge may suggest an effective strategy to prevent kidney disease beyond the early stages.

Integrated Care Model by the Village Health Volunteers to Prevent and Slow down Progression of Chronic Kidney Disease in a Rural Community, Thailand.

INTRODUCTION: Chronic kidney disease (CKD) is a major health problem in Thailand and health behaviors are central to its risk and progression. Because of the shortage of healthcare personnel, village health volunteers (VHVs) have been collaborating in the primary health care system. However, the contribution of VHVs to CKD reduction has not been evaluated yet. This study aimed to evaluate the efficacy of the VHV-integrated model in preventing and slowing down CKD and its risk factors. METHODS: The population-based cohort study was conducted in a rural community of Thailand between 2017 and 2019. Baseline clinical and behavioral characteristics including CKD, diabetes, hypertension, and other high-risk factors of the participants were collected. The integrated care model was initiated by the multidisciplinary care team that facilitated, empowered, and trained VHVs targeting risk factors of CKD, health literacy, and health promotion. Then the participants were educated and trained for lifestyle modification and were monitored continuously for 18 months by VHVs. Changes in the CKD risk factors, and kidney functions before and after the application of integrated care model were compared. RESULTS: A total of 831 subjects participated in the study with an average age of 57.5 years, and 69.5% were female. Among them, 222 participants (26.7%) were diagnosed as having CKD, the vast majority (95%) of which were in the early stages (G1-G3 and A1-A2). CKD risk factors such as high salt intake, smoking, alcohol consumption, self-NSAID (non-steroidal anti-inflammatory drugs) use were significantly decreased after application of the care model. Also, hemoglobin A1c was significantly reduced in diabetic patients, and blood pressure was controlled better than before in the hypertensive patients. Most importantly, a decline of estimated glomerular filtration rate of the CKD group was improved and lower than the non-CKD group. CONCLUSION: The integrated care model through VHV significantly attenuated the risk factors associated with CKD in the general and high-risk population and effectively slowed down the progression of CKD.

Genetic Analysis of Peroxisomal Genes Required for Longevity in a Yeast Model of Citrin Deficiency.

Citrin is a liver-specific mitochondrial aspartate-glutamate carrier encoded by SLC25A13. Citrin deficiency caused by SLC25A13 mutation results in carbohydrate toxicity, citrullinemia type II, and fatty liver diseases, the mechanisms of some of which remain unknown. Citrin shows a functional homolog in yeast aspartate-glutamate carrier (Agc1p) and agc1Δ yeasts are used as a model organism of citrin deficiency. Here, we found that agc1Δ yeasts decreased fat utilization, impaired NADH balance in peroxisomes, and decreased chronological lifespan. The activation of GPD1-mediated NAD+ regeneration in peroxisomes by GPD1 over-expression or activation of the malate-oxaloacetate NADH peroxisomal shuttle, by increasing flux in this NADH shuttle and over-expression of MDH3, resulted in lifespan extension of agc1Δ yeasts. In addition, over-expression of PEX34 restored longevity of agc1Δ yeasts as well as wild-type cells. The effect of PEX34-mediated longevity required the presence of the GPD1-mediated NADH peroxisomal shuttle, which was independent of the presence of the peroxisomal malate-oxaloacetate NADH shuttle and PEX34-induced peroxisome proliferation. These data confirm that impaired NAD+ regeneration in peroxisomes is a key defect in the yeast model of citrin deficiency, and enhancing peroxisome function or inducing NAD+ regeneration in peroxisomes is suggested for further study in patients' hepatocytes.