Towards Metabolic Biomarkers for the Diagnosis and Prognosis of CKD

Chronic kidney disease, the gradual loss of renal function, is an increasingly recognized burden for patients and health care systems; globally, it has a high and rapidly growing prevalence, a significant mortality, and causes disproportionately high costs, particularly for hemodialysis and kidney transplantations. Yet, the available diagnostic tools are either impractical in clinical routine or have serious shortcomings preventing a well-informed disease management, although optimized treatment strategies with impressive benefits for patients have been established. Advances in bioanalytics have facilitated the identification of many genomic, proteomic, and metabolic biomarker candidates, some of which have been validated in independent cohorts. Summarizing the markers discovered so far, this chapter focuses on compounds or pathways, for which quantitative data, substantiating evidence from translational research, and a mechanistic understanding is available. Also, multiparametric marker panels have been suggested with promising diagnostic and prognostic performance in initial analyses, although the data basis from prospective trials is very limited. Large-scale studies, however, are underway and will validate certain sets of parameters and discard others. Finally, the path from clinical research to routine application is discussed, focusing on potential obstacles such as the use of mass spectrometry, and the feasibility of obtaining regulatory approval for metabolomics assays

Targeted Metabolomics for Clinical Biomarker Discovery in Multifactorial Diseases

Diseases & disorder

Assessment of metabolomic and proteomic biomarkers in detection and prognosis of progression of renal function in chronic kidney disease

Chronic kidney disease (CKD) is part of a number of systemic and renal diseases and may reach epidemic proportions over the next decade. Efforts have been made to improve diagnosis and management of CKD. We hypothesised that combining metabolomic and proteomic approaches could generate a more systemic and complete view of the disease mechanisms. To test this approach, we examined samples from a cohort of 49 patients representing different stages of CKD. Urine samples were analysed for proteomic changes using capillary electrophoresis-mass spectrometry and urine and plasma samples for metabolomic changes using different mass spectrometry-based techniques. The training set included 20 CKD patients selected according to their estimated glomerular filtration rate (eGFR) at mild (59.9±16.5 mL/min/1.73 m2; n = 10) or advanced (8.9±4.5 mL/min/1.73 m2; n = 10) CKD and the remaining 29 patients left for the test set. We identified a panel of 76 statistically significant metabolites and peptides that correlated with CKD in the training set. We combined these biomarkers in different classifiers and then performed correlation analyses with eGFR at baseline and follow-up after 2.8±0.8 years in the test set. A solely plasma metabolite biomarker-based classifier significantly correlated with the loss of kidney function in the test set at baseline and follow-up (ρ = −0.8031; p<0.0001 and ρ = −0.6009; p = 0.0019, respectively). Similarly, a urinary metabolite biomarker-based classifier did reveal significant association to kidney function (ρ = −0.6557; p = 0.0001 and ρ = −0.6574; p = 0.0005). A classifier utilising 46 identified urinary peptide biomarkers performed statistically equivalent to the urinary and plasma metabolite classifier (ρ = −0.7752; p<0.0001 and ρ = −0.8400; p<0.0001). The combination of both urinary proteomic and urinary and plasma metabolic biomarkers did not improve the correlation with eGFR. In conclusion, we found excellent association of plasma and urinary metabolites and urinary peptides with kidney function, and disease progression, but no added value in combining the different biomarkers data

Amelioration of systemic inflammation via the display of two different decoy protein receptors on extracellular vesicles

Extracellular vesicles (EVs) can be functionalized to display specific protein receptors on their surface. However, surface-display technology typically labels only a small fraction of the EV population. Here, we show that the joint display of two different therapeutically relevant protein receptors on EVs can be optimized by systematically screening EV-loading protein moieties. We used cytokine-binding domains derived from tumour necrosis factor receptor 1 (TNFR1) and interleukin-6 signal transducer (IL-6ST), which can act as decoy receptors for the pro-inflammatory cytokines tumour necrosis factor alpha (TNF-α) and IL-6, respectively. We found that the genetic engineering of EV-producing cells to express oligomerized exosomal sorting domains and the N-terminal fragment of syntenin (a cytosolic adaptor of the single transmembrane domain protein syndecan) increased the display efficiency and inhibitory activity of TNFR1 and IL-6ST and facilitated their joint display on EVs. In mouse models of systemic inflammation, neuroinflammation and intestinal inflammation, EVs displaying the cytokine decoys ameliorated the disease phenotypes with higher efficacy as compared with clinically approved biopharmaceutical agents targeting the TNF-α and IL-6 pathways.International Society for Advancement of Cytometry Marylou Ingram Scholar 2019-2023H2020 EXPERTSwedish foundation of Strategic Research (SSF-IRC; FormulaEx)ERC CoG (DELIVER)Swedish Medical Research CouncilAccepte

Riskbedömning för att förutse komplikationer hos äldre patienter vid kolorektal kirurgi.

SAMMANFATTNING Bakgrund: Det skulle vara värdefullt att ha ett riskbedömningsinstrument för att identifiera äldre patienter som är i risk för komplikationer efter kolorektal kirurgi. Syfte: Att undersöka förekomst av postoperativa komplikationer hos äldre kolorektalpatienter och om riskbedömningsinstrument eller andra faktorer kan förutse dessa. Metod: En prospektiv studie med kvantitativ ansats och deskriptiv design. Urvalskriterier var patienter, män och kvinnor, ≥ 70 år, elektiv kirurgi för kolorektaltumör. Datainsamling gjordes före kirurgi genom intervju med standardiserade frågeformulär och test. Journalgranskning genomfördes 30 dagar efter kirurgi. Resultat: Trettiosex procent av patienterna utvecklade någon form av komplikation. Vanligaste komplikationerna var sårinfektion och urinvägsinfektion. Riskpoäng på riskbedömningsinstrumenten GFI, VES-13 och "Upp och gå" testet hade inget samband med komplikationer i denna patientgrupp. Patienter som var undernärda eller i risk för undernäring, hade hjärt- och kärlsjukdom som komorbiditet samt att lång operationstid fick signifikant fler komplikationer. Slutsats: Det var många patienter som utvecklade någon form av komplikation. Riskbedömningsinstrumenten GFI, VES-13 och "Upp och gå" testet kunde inte identifiera patienter i risk för komplikationer. Tre faktorer som bör beaktas för dessa patienter är undernäring, hjärt- och kärlsjukdom och operationens längd. Viktigt att identifiera dessa patienter då det kan vara ett sätt att minska komplikationerna efter kolorektal kirurgi. Nyckelord: preoperativ, riskbedömning, äldre, kolorektal kirurgi, komplikationABSTRACT Background: It would be valuable to have a riskestimate instrument to identify elderly patients who are at risk for complications after colorectal surgery. Aim: Investigate the prevalence of postoperative complications in older patients with colorectal tumor and if riskestimate instruments or other factors could predict these. Method: A prospective study with quantitative approach and a descriptive design. Inclusion criteria were patients, men and women, aged ≥ 70 years, undergoing elective surgery for colorectaltumor. Data was collected before surgery through interviews with a standardized questionnaire and test. Audit of patient records was conducted 30 days after surgery. Results: Thirtysix procent of the patients developed complications. The most common complications were wound infections and urinary infections. Riskestimate instruments as GFI, VES-13 and "Up and go" test could not predict complications. Patients who were malnourished or at risk for malnutrition had cardiovascular comorbidity and long operation time developed significant more complications. Conclusion: Many patients developed complications. The riskestimate instruments GFI, VES-13 and "Up and go" test could not identify patients in risk for complications. Three factors should be considered are malnutrition, caridiovascular illness and long operation time in surgery. Important to identify these patients because this can lead to complication after colorectal surgery. Keywords: preoperative, riskestimation, elderly, colorectal surgery, complicatio

Biomarker Discovery in Diabetic Nephropathy by Targeted Metabolomics

Diabetic nephropathy is a chronic kidney disease and one of the more severe complications from diabetes mellitus type 2. The glomerular and tubular dysfunctions usually lead to end stage renal disease and the treatments of these patients (dialysis, kidney transplants) are a huge economic burden for the society. Due to an epidemiologic increase of type 2 diabetes, conventional diagnostic markers like creatinine and albumin are not sufficient, since they are only able to identify already existing kidney damage. With targeted metabolomics, the analysis of small molecules produced from metabolism, this project aimed at finding novel and more sensitive metabolic biomarkers from several different classes of metabolites. The different assays were performed with flow injection analysis, high performance liquid chromatography, gas chromatography and mass spectrometry, and with principal component analysis and discriminant analysis, up-and down-regulated metabolites could be identified and their respective biochemical pathways, if possible, explained. In diabetics significantly elevated concentrations of very long chain fatty acids (impaired peroxisomal β-oxidation), urinary sugars and acylcarnitines in plasma could be recognized. Markers indicating kidney damage included significantly increased plasma concentrations of asymmetric dimethylarginine (inhibition of nitric oxide synthase resulting in decreased endothelial functionality) and histamine (indication of uremic pruritus). Oxidative stress was also found to be a potential prognostic marker as indicated by the raised methionine-sulfoxide to methionine ratio in nephrotic patients. To summarize, this project succeeded in identifying metabolic biomarkers both for diabetes type 2 and nephropathy, which in the future might become important tools in slowing down progression or diagnosing these diseases

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Validerat; 20101217 (root

Riskbedömning för att förutse komplikationer hos äldre patienter vid kolorektal kirurgi.

SAMMANFATTNING Bakgrund: Det skulle vara värdefullt att ha ett riskbedömningsinstrument för att identifiera äldre patienter som är i risk för komplikationer efter kolorektal kirurgi. Syfte: Att undersöka förekomst av postoperativa komplikationer hos äldre kolorektalpatienter och om riskbedömningsinstrument eller andra faktorer kan förutse dessa. Metod: En prospektiv studie med kvantitativ ansats och deskriptiv design. Urvalskriterier var patienter, män och kvinnor, ≥ 70 år, elektiv kirurgi för kolorektaltumör. Datainsamling gjordes före kirurgi genom intervju med standardiserade frågeformulär och test. Journalgranskning genomfördes 30 dagar efter kirurgi. Resultat: Trettiosex procent av patienterna utvecklade någon form av komplikation. Vanligaste komplikationerna var sårinfektion och urinvägsinfektion. Riskpoäng på riskbedömningsinstrumenten GFI, VES-13 och "Upp och gå" testet hade inget samband med komplikationer i denna patientgrupp. Patienter som var undernärda eller i risk för undernäring, hade hjärt- och kärlsjukdom som komorbiditet samt att lång operationstid fick signifikant fler komplikationer. Slutsats: Det var många patienter som utvecklade någon form av komplikation. Riskbedömningsinstrumenten GFI, VES-13 och "Upp och gå" testet kunde inte identifiera patienter i risk för komplikationer. Tre faktorer som bör beaktas för dessa patienter är undernäring, hjärt- och kärlsjukdom och operationens längd. Viktigt att identifiera dessa patienter då det kan vara ett sätt att minska komplikationerna efter kolorektal kirurgi. Nyckelord: preoperativ, riskbedömning, äldre, kolorektal kirurgi, komplikationABSTRACT Background: It would be valuable to have a riskestimate instrument to identify elderly patients who are at risk for complications after colorectal surgery. Aim: Investigate the prevalence of postoperative complications in older patients with colorectal tumor and if riskestimate instruments or other factors could predict these. Method: A prospective study with quantitative approach and a descriptive design. Inclusion criteria were patients, men and women, aged ≥ 70 years, undergoing elective surgery for colorectaltumor. Data was collected before surgery through interviews with a standardized questionnaire and test. Audit of patient records was conducted 30 days after surgery. Results: Thirtysix procent of the patients developed complications. The most common complications were wound infections and urinary infections. Riskestimate instruments as GFI, VES-13 and "Up and go" test could not predict complications. Patients who were malnourished or at risk for malnutrition had cardiovascular comorbidity and long operation time developed significant more complications. Conclusion: Many patients developed complications. The riskestimate instruments GFI, VES-13 and "Up and go" test could not identify patients in risk for complications. Three factors should be considered are malnutrition, caridiovascular illness and long operation time in surgery. Important to identify these patients because this can lead to complication after colorectal surgery. Keywords: preoperative, riskestimation, elderly, colorectal surgery, complicatio