The Warburg Effect in Diabetic Kidney Disease
2018; Elsevier BV; Volume: 38; Issue: 2 Linguagem: Inglês
10.1016/j.semnephrol.2018.01.002
ISSN1558-4488
AutoresGuanshi Zhang, Manjula Darshi, Kumar Sharma,
Tópico(s)Adipose Tissue and Metabolism
ResumoSummary: Diabetic kidney disease (DKD) is the leading cause of morbidity and mortality in diabetic patients. Defining risk factors for DKD using a reductionist approach has proven challenging. Integrative omics-based systems biology tools have shed new insights in our understanding of DKD and have provided several key breakthroughs for identifying novel predictive and diagnostic biomarkers. In this review, we highlight the role of the Warburg effect in DKD and potential regulating factors such as sphingomyelin, fumarate, and pyruvate kinase muscle isozyme M2 in shifting glucose flux from complete oxidation in mitochondria to the glycolytic pathway and its principal branches. With the development of highly sensitive instruments and more advanced automatic bioinformatics tools, we believe that omics analyses and imaging techniques will focus more on singular-cell-level studies, which will allow in-depth understanding of DKD and pave the path for personalized kidney precision medicine. Summary: Diabetic kidney disease (DKD) is the leading cause of morbidity and mortality in diabetic patients. Defining risk factors for DKD using a reductionist approach has proven challenging. Integrative omics-based systems biology tools have shed new insights in our understanding of DKD and have provided several key breakthroughs for identifying novel predictive and diagnostic biomarkers. In this review, we highlight the role of the Warburg effect in DKD and potential regulating factors such as sphingomyelin, fumarate, and pyruvate kinase muscle isozyme M2 in shifting glucose flux from complete oxidation in mitochondria to the glycolytic pathway and its principal branches. With the development of highly sensitive instruments and more advanced automatic bioinformatics tools, we believe that omics analyses and imaging techniques will focus more on singular-cell-level studies, which will allow in-depth understanding of DKD and pave the path for personalized kidney precision medicine. Diabetic kidney disease (DKD) develops in approximately 40% of patients with diabetes and is the leading cause of chronic kidney disease worldwide.1Alicic R.Z. Rooney M.T. Tuttle K.R. Diabetic kidney disease: challenges, progress, and possibilities.Clin J Am Soc Nephrol. 2017; 12: 2032-2045Crossref PubMed Scopus (1020) Google Scholar Metabolic alterations associated with diabetes lead to renal pathologic changes including tubulointerstitial inflammation and fibrosis, glomerular hypertrophy, and glomerulosclerosis.1Alicic R.Z. Rooney M.T. Tuttle K.R. Diabetic kidney disease: challenges, progress, and possibilities.Clin J Am Soc Nephrol. 2017; 12: 2032-2045Crossref PubMed Scopus (1020) Google Scholar However, because only less than 10% of patients with diabetes ultimately reach end-stage renal disease, there must be something missing in our understanding of the pathophysiology of DKD. Genetic studies have not identified a major genetic contribution,2Shimazaki A. Kawamura Y. Kanazawa A. Sekine A. Saito S. Tsunoda T. et al.Genetic variations in the gene encoding ELMO1 are associated with susceptibility to diabetic nephropathy.Diabetes. 2005; 54: 1171-1178Crossref PubMed Scopus (171) Google Scholar, 3Kottgen A. Glazer N.L. Dehghan A. Hwang S.J. Katz R. Li M. et al.Multiple loci associated with indices of renal function and chronic kidney disease.Nat Genet. 2009; 41: 712-717Crossref PubMed Scopus (476) Google Scholar although it is likely that there are important genetic determinants.4Thomas M.C. Brownlee M. Susztak K. Sharma K. Jandeleit-Dahm K.A. Zoungas S. et al.Diabetic kidney disease.Nat Rev Dis Primers. 2015; 1: 15018Crossref PubMed Scopus (374) Google Scholar, 5Hallan S. Sharma K. The role of mitochondria in diabetic kidney disease.Curr Diab Rep. 2016; 16: 61Crossref PubMed Scopus (60) Google Scholar As part of the International Society of Nephrology Forefronts Symposium of Systems Biology, the application of systems biology tools to understanding DKD was a major topic. Detailed roles of mitochondria in DKD has been reviewed previously.5Hallan S. Sharma K. The role of mitochondria in diabetic kidney disease.Curr Diab Rep. 2016; 16: 61Crossref PubMed Scopus (60) Google Scholar, 6Sharma K. Mitochondrial dysfunction in the diabetic kidney.Adv Exp Med Biol. 2017; 982: 553-562Crossref PubMed Scopus (28) Google Scholar, 7Bhargava P. Schnellmann R.G. 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Gonzalo H. et al.Cellular dysfunction in diabetes as maladaptive response to mitochondrial oxidative stress.Exp Diabetes Res. 2012; 2012: 696215Crossref PubMed Scopus (83) Google Scholar Activation of the earlier-mentioned pathways was reported to be associated with diabetic complications, either by causing oxidative stress, inflammation, fibrosis, DNA damage, and vascular changes, or by resulting in pathologic gene expression.5Hallan S. Sharma K. The role of mitochondria in diabetic kidney disease.Curr Diab Rep. 2016; 16: 61Crossref PubMed Scopus (60) Google Scholar Overproduction of superoxide in mitochondria might play a unifying role for the activation of the aforementioned metabolic pathways.15Brownlee M. The pathobiology of diabetic complications - a unifying mechanism.Diabetes. 2005; 54: 1615-1625Crossref PubMed Scopus (3975) Google Scholar New evidence indicates that alternative pathways such as enhanced fatty acid oxidation in mitochondria are involved in diabetic complications.15Brownlee M. The pathobiology of diabetic complications - a unifying mechanism.Diabetes. 2005; 54: 1615-1625Crossref PubMed Scopus (3975) Google Scholar, 16Sas K.M. Kayampilly P. Byun J. Nair V. Hinder L.M. Hur J. et al.Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications.JCI Insight. 2016; 1: e86976Crossref PubMed Scopus (142) Google Scholar However, it still is unclear whether mitochondrial dysfunction in DKD results in altered glycolysis flux, or if glycolysis flux/accumulation of glycolytic intermediates in DKD drives the metabolic flux into the five pathways discussed earlier, leading to impaired mitochondrial function, or if a bidirectional causality exists. The current review highlights the diabetes-induced metabolic switch from oxidative phosphorylation to glycolysis and the potential link to downstream effects on kidney function and disease progression. The Warburg effect or aerobic glycolysis, first observed in 1924 by Otto Warburg, has had a profound influence on cancer metabolism.17Warburg O. Posener K. Negelein E. On the metabolism of carcinoma cells.Biochem Z. 1924; 152: 309-344Google Scholar Warburg proposed that, independent of cellular oxygen, tumor cells synthesize adenosine triphosphate (ATP) through glycolysis and a metabolic state involving enhanced glucose uptake leads to local acidification through enhanced lactate production. Although Warburg's18Warburg O. On the origin of cancer cells.Science. 1956; 123: 309-314Crossref PubMed Scopus (9557) Google Scholar studies suggested that mitochondrial dysfunction is the root of aerobic glycolysis, subsequent studies and technical advances have since shown that mitochondria in cancer are indeed functional and that genetic or environmental cues may contribute to this metabolic shift to the glycolysis in tumor cells.19Crabtree H.G. Observations on the carbohydrate metabolism of tumours.Biochem J. 1929; 23: 536-545Crossref PubMed Google Scholar Although enhanced glucose entry and glycolysis has been observed in diabetic tissues, the Warburg effect has not been proposed as a major feature in diabetic complications. Recent omic studies in diabetes and diabetes kidney disease have provided unbiased evidence that both mitochondrial dysfunction and the Warburg effect play pivotal roles in the development of DKD.16Sas K.M. Kayampilly P. Byun J. Nair V. Hinder L.M. Hur J. et al.Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications.JCI Insight. 2016; 1: e86976Crossref PubMed Scopus (142) Google Scholar, 20Sharma K. Karl B. Mathew A.V. Gangoiti J.A. Wassel C.L. Saito R. et al.Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease.J Am Soc Nephrol. 2013; 24: 1901-1912Crossref PubMed Scopus (378) Google Scholar, 21Qi W. Keenan H.A. Li Q. Ishikado A. Kannt A. Sadowski T. et al.Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction.Nat Med. 2017; 23: 753-762Crossref PubMed Scopus (255) Google Scholar Several groups now have found that reduced mitochondrial function plays a key role in DKD both in mouse models and in patients with DKD.20Sharma K. Karl B. Mathew A.V. Gangoiti J.A. Wassel C.L. Saito R. et al.Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease.J Am Soc Nephrol. 2013; 24: 1901-1912Crossref PubMed Scopus (378) Google Scholar, 22You Y.H. Quach T. Saito R. Pham J. Sharma K. Metabolomics reveals a key role for fumarate in mediating the effects of NADPH oxidase 4 in diabetic kidney disease.J Am Soc Nephrol. 2016; 27: 466-481Crossref PubMed Scopus (127) Google Scholar, 23Dugan L.L. You Y.H. Ali S.S. Diamond-Stanic M. Miyamoto S. DeCleves A.E. et al.AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function.J Clin Invest. 2013; 123: 4888-4899Crossref PubMed Scopus (325) Google Scholar By using transcriptomic, metabolomics, and flux approaches, Sas et al16Sas K.M. Kayampilly P. Byun J. Nair V. Hinder L.M. Hur J. et al.Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications.JCI Insight. 2016; 1: e86976Crossref PubMed Scopus (142) Google Scholar reported significantly increased glycolytic intermediates and enzymes in kidney cortex, along with a significant reduction in mitochondrial function in a type 2 diabetic mouse model. Interestingly, in a very recent study, Qi et al21Qi W. Keenan H.A. Li Q. Ishikado A. Kannt A. Sadowski T. et al.Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction.Nat Med. 2017; 23: 753-762Crossref PubMed Scopus (255) Google Scholar reported that enhanced pyruvate kinase II (PKM2) activity may preserve mitochondrial function by increasing glucose flux through glycolysis in podocytes and alleviate the progression of DKD in patients with diabetes. To understand how the Warburg effect may play a role in DKD, here we review the major metabolic pathways and associated enzymes and intermediates that are involved in DKD pathometabolism. Compared with mitochondrial respiration, aerobic glycolysis is an inefficient pathway of generating ATP per unit of glucose.24Heiden M.G.V. Cantley L.C. Thompson C.B. Understanding the Warburg effect: the metabolic requirements of cell proliferation.Science. 2009; 324: 1029-1033Crossref PubMed Scopus (10144) Google Scholar Although complete oxidation of one molecule of glucose via pyruvate within the tricarboxylic acid (TCA) cycle in the presence of oxygen generates 38 molecules of ATP, the glycolysis, the first step of glucose oxidation process that occurs in cytosol, generates only two molecules of ATP, leading to pyruvate as a final product. However, the rate of glucose metabolism through aerobic glycolysis is much higher (10-100 times faster) than the complete oxidation of glucose through the TCA cycle and oxidative phosphorylation in the mitochondria. Therefore, in diabetic patients, activation of aerobic glycolysis might help metabolize glucose rapidly from systemic circulation. In addition, with the evidence of mitochondrial dysfunction including low peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) levels, abnormalities in electron transport chain complex assembly/activity, alterations in pyruvate dehydrogenase complex (PDH) phosphorylation, and altered TCA cycle intermediates in DKD,20Sharma K. Karl B. Mathew A.V. Gangoiti J.A. Wassel C.L. Saito R. et al.Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease.J Am Soc Nephrol. 2013; 24: 1901-1912Crossref PubMed Scopus (378) Google Scholar, 25Qi H.Y. Casalena G. Shi S.L. Yu L.P. Ebefors K. Sun Y.Z. et al.Glomerular endothelial mitochondrial dysfunction is essential and characteristic of diabetic kidney disease susceptibility.Diabetes. 2017; 66: 763-778Crossref PubMed Scopus (122) Google Scholar it is not surprising that the glucose oxidation through glycolysis is a more favorable process toward ATP synthesis. Recent omics studies in diabetes and DKD have provided unbiased evidence that both mitochondrial dysfunction and the Warburg effect play pivotal roles in the development of DKD.16Sas K.M. Kayampilly P. Byun J. Nair V. Hinder L.M. Hur J. et al.Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications.JCI Insight. 2016; 1: e86976Crossref PubMed Scopus (142) Google Scholar, 20Sharma K. Karl B. Mathew A.V. Gangoiti J.A. Wassel C.L. Saito R. et al.Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease.J Am Soc Nephrol. 2013; 24: 1901-1912Crossref PubMed Scopus (378) Google Scholar, 21Qi W. Keenan H.A. Li Q. Ishikado A. Kannt A. Sadowski T. et al.Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction.Nat Med. 2017; 23: 753-762Crossref PubMed Scopus (255) Google Scholar By using targeted metabolomics and systems biology tools we reported that human DKD is associated with mitochondrial dysfunction. Gas chromatography-mass spectrometry–based targeted metabolomics were performed and 94 urinary metabolites were quantified in patients with established DKD and compared with healthy controls.20Sharma K. Karl B. Mathew A.V. Gangoiti J.A. Wassel C.L. Saito R. et al.Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease.J Am Soc Nephrol. 2013; 24: 1901-1912Crossref PubMed Scopus (378) Google Scholar Results indicated a marked reduction in organic anions, the TCA cycle, and amino acid metabolites. We established a 13–urinary metabolite biomarker signature of DKD, all of which were decreased significantly. Correlation analysis between each of 13 metabolites and common biomarkers of DKD showed that five of the metabolites (ie, 3-hydroxy isovalerate, aconitic acid, citric acid, glycolic acid, and uracil) were correlated significantly with estimated glomerular filtration rate, and another three metabolites (ie, 2-methyl acetoacetate, 3-methyl crotonyl glycine, and 3-methyl adipic acid) were associated with albuminuria.20Sharma K. Karl B. Mathew A.V. Gangoiti J.A. Wassel C.L. Saito R. et al.Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease.J Am Soc Nephrol. 2013; 24: 1901-1912Crossref PubMed Scopus (378) Google Scholar In particular, 12 of the 13 metabolites are associated with mitochondrial metabolism, the metabolites are either generated within the TCA cycle or regulated by the mitochondrial enzymes (Table 1), suggesting suppressed mitochondrial activity in DKD.20Sharma K. Karl B. Mathew A.V. Gangoiti J.A. Wassel C.L. Saito R. et al.Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease.J Am Soc Nephrol. 2013; 24: 1901-1912Crossref PubMed Scopus (378) Google Scholar Further analysis of kidney biopsy samples and urinary exosomes showed a significant reduction in PGC-1α, mitochondrial proteins, and mitochondrial DNA levels in diabetic nephropathy patients as compared with healthy controls. These findings suggest an overall reduction in mitochondrial biogenesis in the kidney of DKD patients, contributing to a reduction in the TCA cycle metabolites and a potential shift to glycolysis.Table 1Thirteen Urinary Metabolite Biomarkers for DKD and Their Associated Enzymes and PathwaysMetabolite Decreased in DKDHMDB ID of MetaboliteFunction in Intermediary MetabolismEnzyme(s) Producing the MetaboliteSubcellular location of Enzymes3-Hydroxyisovaleric acidHMDB00754Leu metabolite3-methylglutaconyl CoA hydrataseMitochondriaGlycolic acidHMDB00115Gly (peroxisomes) and 4-hydroxyproline (mitochondria)NADPH-glyoxylate reductasePeroxisomes, mitochondriaCitric acidHMDB00094The TCA cycle and lipid synthesisCitrate synthaseMitochondria2-Ethylhydracrylic acidHMDB00396Ile metaboliteFrom R-pathway of Ile metabolism (with 2MBDH deficiency)MitochondriaUracilHMDB00300Pyrimidine synthesisCoenzyme Q10: dihydroorotate dehydrogenase, UMPSMitochondria3-Hydroxyisobutyric acidHMDB00023Val metabolite3HIBCHMitochondriaAconitic acidHMDB00072The TCA cycleAconitaseMitochondria3-Methyladipic acidHMDB00555Indicates incomplete BCFA oxidationFrom decreased intake of phytanic acid or increased α-oxidation of BAFAMitochondriaTiglylglycineHMDB00959Ile metaboliteFAD and 2MBDHMitochondria3-MethylcrotonylglycineHMDB00459Leu metaboliteFAD and IVDMitochondria2-Methylacetoacetic acidHMDB03771Ile metaboliteNAD+ and MHBDMitochondriaHomovanillic acidHMDB00118Dopamine metaboliteCOMT and MAOCytosol, MitochondriaHydroxypropionic acidHMDB00700Ile, Val, Thr, and Met metabolite2MAACT (Ile), NAD+ and MMSDH (Val), NAD+ and 2KBDH (Thr and Met)MitochondriaAbbreviations: 2MAACT, 2-methylacetoacetyl Coa thiolase; 2MBDH, 2-methylbutyryl-CoA dehydrogenase; 2KBDH, 2-ketobutyrate dehydrogenase; 3HIBCH, 3-hydroxyisobutryl-CoA hydrolase; BAFA, branched-chain fatty acids; COMT, catechol-O-methyl transferase; FAD, flavin adenine dinucleotide; Gly, glycine; Ile, isoleucine; IVD, isovaleryl-CoA dehydrogenase; Leu, leucine; MAO, monoamine oxidase; Met, methionine; MHBD, 2-methyl-3-hydroxybutyryl CoA dehydrogenase; MMSDH, methylmalonate semialdehyde dehydrogenase; NAD+, nicotinamide adenine dinucleotide; Thr, threonine; UMPS, uridine monophosphate synthetase; Val, valine.Adapted with permission from Sharma et al.20Sharma K. Karl B. Mathew A.V. Gangoiti J.A. Wassel C.L. Saito R. et al.Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease.J Am Soc Nephrol. 2013; 24: 1901-1912Crossref PubMed Scopus (378) Google Scholar Open table in a new tab Abbreviations: 2MAACT, 2-methylacetoacetyl Coa thiolase; 2MBDH, 2-methylbutyryl-CoA dehydrogenase; 2KBDH, 2-ketobutyrate dehydrogenase; 3HIBCH, 3-hydroxyisobutryl-CoA hydrolase; BAFA, branched-chain fatty acids; COMT, catechol-O-methyl transferase; FAD, flavin adenine dinucleotide; Gly, glycine; Ile, isoleucine; IVD, isovaleryl-CoA dehydrogenase; Leu, leucine; MAO, monoamine oxidase; Met, methionine; MHBD, 2-methyl-3-hydroxybutyryl CoA dehydrogenase; MMSDH, methylmalonate semialdehyde dehydrogenase; NAD+, nicotinamide adenine dinucleotide; Thr, threonine; UMPS, uridine monophosphate synthetase; Val, valine. Adapted with permission from Sharma et al.20Sharma K. Karl B. Mathew A.V. Gangoiti J.A. Wassel C.L. Saito R. et al.Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease.J Am Soc Nephrol. 2013; 24: 1901-1912Crossref PubMed Scopus (378) Google Scholar The mechanisms of mitochondrial dysfunction and reduction in TCA metabolites in DKD are not fully understood. It is unclear if low TCA cycle metabolite flux is the causal or consequence of the mitochondrial dysfunction. Recent studies by Sas et al16Sas K.M. Kayampilly P. Byun J. Nair V. Hinder L.M. Hur J. et al.Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications.JCI Insight. 2016; 1: e86976Crossref PubMed Scopus (142) Google Scholar using a systems-based approach combining transcriptomic, metabolomic, and metabolomic flux in a mouse model of type 2 diabetic (db/db) kidney cortex and in type 2 diabetic human patients identified enhanced metabolic flux into glycolysis, fatty acid oxidation, and TCA cycle pathways. Several of the glycolytic enzyme transcripts including hexokinase, phosphofructokinase, and pyruvate kinase were increased significantly in glomeruli-depleted kidney cortex of the db/db mice as compared with the control db/m mice. No significant changes were observed in the expression of TCA cycle pathway-related genes, suggesting a diabetes-induced metabolic shift to glycolysis. This was confirmed further by metabolomic analysis of kidney cortex, urine, plasma, and isolated mitochondria. Several glycolytic metabolites were up-regulated in the diabetic mouse kidney and urine at both 12 and 24 weeks. Likewise, several of the TCA cycle metabolites and acylcarnitines were increased in kidney cortex, isolated mitochondria, and urine samples of the diabetic mice, suggesting that mitochondrial metabolic alterations in the kidney cortex are reflective of whole-body metabolism. The TCA cycle metabolites and acylcarnitines were increased significantly in the mitochondria from kidney cortex of 24-week-old compared with 12-week-old mice, indicating a progressive increase in metabolism in the mitochondria with disease progression in DKD. Metabolomic flux analysis using [U-13C6]glucose, [2,3-13C2]pyruvate, and [13C16]palmitate were performed to assess flux through glycolysis, the TCA cycle, and fatty acid oxidation, respectively. Results from these studies showed that db/db kidney tissues had significantly increased flux of all three metabolic pathways, although there were no changes in corresponding ATP. Analysis of oxygen consumption of isolated mitochondria from kidney cortex further identified that the db/db kidney mitochondria have reduced state 3 respiration (ADP-stimulated respiration) and enhanced proton leaking, suggesting uncoupling of electron transport chain from ATP synthesisoccurs. 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Decleves A.E. et al.Mass spectrometry imaging reveals elevated glomerular ATP/AMP in diabetes/obesity and identifies sphingomyelin as a possible mediator.EBioMedicine. 2016; 7: 121-134Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar We applied matrix-assisted laser desorption/ionization (MALDI)-MSI to localize and quantify renal nucleotides.33Miyamoto S. Hsu C.C. Hamm G. Darshi M. Diamond-Stanic M. Decleves A.E. et al.Mass spectrometry imaging reveals elevated glomerular ATP/AMP in diabetes/obesity and identifies sphingomyelin as a possible mediator.EBioMedicine. 2016; 7: 121-134Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar MALDI-MSI at 70-μmol/L resolution identified ATP, adenosine diphosphate, and AMP widely distributed throughout the kidney and showed a significant increase in ATP and decrease in AMP, leading to significantly increased ATP/AMP in glomeruli of diabetic mice when compared with nondiabetic ones. Furthermore, biochemical analysis of freshly extracted nucleotides from total kidney cortex showed a similar increase in total ATP levels in db/db diabetic mice compared with the db/m controls. To identify analytes that may regulate ATP production in the diabetic kidney, we used untargeted high spatial resolution (25-μmol/L resolution) MALDI-MSI to analyze both human and mouse kidney sections. Particularly, three peaks (ie, m/z values) of analytes were distributed mainly in mouse and human glomeruli compared with the nearby regions. Based on high accuracy measurements of parent m/z's using high resolving power Fourier transform ion cyclotron resonance mass spectrometry and their subsequent tandem mass spectrometry analysis, three m/z values, 703.578 (+H+), 725.558 (+Na+), and 741.534 (+K+), were annotated as a specific sphingomyelin (ie, SM [d18:1/16:0]) in METLIN and LIPID MAPS databases.34Smith C.A. O'Maille G. Want E.J. Qin C. Trauger S.A. 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