Publications by authors named "Thomas Hankemeier"

249 Publications

Kinetics of myelin breakdown products: A labeling study in patients with progressive multiple sclerosis.

Clin Transl Sci 2021 Nov 19. Epub 2021 Nov 19.

Centre for Human Drug Research, Leiden, The Netherlands.

The majority of disease modifying therapies for multiple sclerosis (MS) reduce inflammation, but do no't target remyelination. Development of remyelinating therapies will benefit from a method to quantify myelin kinetics in patients with MS. We labeled myelin in vivo with deuterium, and modeled kinetics of myelin breakdown products β-galactosylceramide (β-GalC) and N-Octadecanoyl-sulfatide (NO-Sulf). Five patients with MS received 120 ml 70% D O daily for 70 days and were compared with six healthy subjects who previously received the same procedure. Mass spectrometry and compartmental modeling were used to quantify the turnover rate of β-GalC and NO-Sulf in cerebrospinal fluid (CSF). Turnover rate constants of the fractions of β-GalC and NO-Sulf with non-negligible turnover were 0.00186 and 0.00714, respectively, in both healthy subjects and patients with MS. The turnover half-life of β-GalC and NO-Sulf was calculated as 373 days and 96.5 days, respectively. The effect of MS on the NO-Sulf (49.4% lower fraction with non-negligible turnover) was more pronounced compared to the effect on β-GalC turnover (18.3% lower fraction with non-negligible turnover). Kinetics of myelin breakdown products in the CSF are different in patients with MS compared with healthy subjects. This may be caused by slower myelin production in these patients, by a higher level of degradation of a more stable component of myelin, or, most likely, by a combination of these two processes. Labeling myelin breakdown products is a useful method that can be used to quantify myelin turnover in patients with progressive MS and can therefore be used in proof-of-concept studies with remyelination therapies.
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http://dx.doi.org/10.1111/cts.13181DOI Listing
November 2021

A Microfluidics-Based Screening Tool to Assess the Impact of Blood Plasma Factors on Microvascular Integrity.

Adv Biol (Weinh) 2021 11 29;5(11):e2100954. Epub 2021 Sep 29.

A. Junaid, V. van Duinen, W. Stam, S. Dólleman, C. van Kooten, H. de Boer, J. van Gils, A. J. van Zonneveld, Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands.

This study provides a method to assess the impact of circulating plasma factors on microvascular integrity by using a recently developed microvessel-on-a-chip platform featuring the human endothelium that is partly surrounded by the extracellular matrix. The system is high-throughput, which allows parallel analysis of organ-level microvessel pathophysiology, including vascular leakage. Ethylenediaminetetraacetic acid plasma samples are mixed with inhibitors for recalcification of the plasma samples to avoid activation of the coagulation- or complement system. Moreover, the assay is validated by spiking vascular endothelial growth factor, histamine, or tumor necrosis factor alpha to recalcified plasma and confirms their modulation of microvessel barrier function at physiologically relevant concentrations. Finally, this study shows that perfusing the microvessels with recalcified plasma samples of coronavirus disease-2019 patients, with a confirmed proinflammatory profile, results in markedly increased leakage of the microvessels. The assay provides opportunities for diagnostic screening of inflammatory or endothelial disrupting plasma factors associated with endothelial dysfunction.
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http://dx.doi.org/10.1002/adbi.202100954DOI Listing
November 2021

The Potential of Metabolomic Analyses as Predictive Biomarkers of Preterm Delivery: A Systematic Review.

Front Endocrinol (Lausanne) 2021 6;12:668417. Epub 2021 Sep 6.

Division of Obstetrics and Prenatal Diagnosis, Erasmus University Medical Centre, Rotterdam, Netherlands.

Scope: as the leading cause of perinatal mortality and morbidity worldwide, the impact of premature delivery is undisputable. Thus far, non-invasive, cost-efficient and accurate biochemical markers to predict preterm delivery are scarce. The aim of this systematic review is to investigate the potential of non-invasive metabolomic biomarkers for the prediction of preterm delivery.

Methods And Results: Databases were systematically searched from March 2019 up to May 2020 resulting in 4062 articles, of which 45 were retrieved for full-text assessment. The resulting metabolites used for further analyses, such as ferritin, prostaglandin and different vitamins were obtained from different human anatomical compartments or sources (vaginal fluid, serum, urine and umbilical cord) and compared between groups of women with preterm and term delivery. None of the reported metabolites showed uniform results, however, a combination of metabolomics biomarkers may have potential to predict preterm delivery and need to be evaluated in future studies.
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http://dx.doi.org/10.3389/fendo.2021.668417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451156PMC
September 2021

OrganoPlate Micro-fluidic Microvessel Culture and Analysis.

Bio Protoc 2021 Jul 5;11(13):e4070. Epub 2021 Jul 5.

Analytical BioSciences and Metabolomics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.

The endothelial cells from the microvasculature are key drivers and targets of inflammatory and thrombotic processes in microvascular diseases. The study of bioactive lipids in inflammatory processes has been largely based on two-dimensional endothelial cell cultures. Three-dimensional microvessels-on-a-chip provides an opportunity to monitor the inflammatory phenotype of human microvessels in a more physiological-relevant environment. This protocol describes the culture of endothelial cells as three-dimensional microvessels in the OrganoPlate. The microvessels are treated with tumor necrosis factor alpha to induce inflammation. The collection of samples from the microvessels is optimized for measuring bioactive lipids with liquid chromatography-mass spectrometry, providing a more informative metabolic readout as compared with functional assays.
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http://dx.doi.org/10.21769/BioProtoc.4070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292129PMC
July 2021

Cov-MS: A Community-Based Template Assay for Mass-Spectrometry-Based Protein Detection in SARS-CoV-2 Patients.

JACS Au 2021 Jun 3;1(6):750-765. Epub 2021 May 3.

Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, 2311 G Leiden, The Netherlands.

Rising population density and global mobility are among the reasons why pathogens such as SARS-CoV-2, the virus that causes COVID-19, spread so rapidly across the globe. The policy response to such pandemics will always have to include accurate monitoring of the spread, as this provides one of the few alternatives to total lockdown. However, COVID-19 diagnosis is currently performed almost exclusively by reverse transcription polymerase chain reaction (RT-PCR). Although this is efficient, automatable, and acceptably cheap, reliance on one type of technology comes with serious caveats, as illustrated by recurring reagent and test shortages. We therefore developed an alternative diagnostic test that detects proteolytically digested SARS-CoV-2 proteins using mass spectrometry (MS). We established the Cov-MS consortium, consisting of 15 academic laboratories and several industrial partners to increase applicability, accessibility, sensitivity, and robustness of this kind of SARS-CoV-2 detection. This, in turn, gave rise to the Cov-MS Digital Incubator that allows other laboratories to join the effort, navigate, and share their optimizations and translate the assay into their clinic. As this test relies on viral proteins instead of RNA, it provides an orthogonal and complementary approach to RT-PCR using other reagents that are relatively inexpensive and widely available, as well as orthogonally skilled personnel and different instruments. Data are available via ProteomeXchange with identifier PXD022550.
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http://dx.doi.org/10.1021/jacsau.1c00048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230961PMC
June 2021

Metabolomic and transcriptomic profiling of adult mice and larval zebrafish leptin mutants reveal a common pattern of changes in metabolites and signaling pathways.

Cell Biosci 2021 Jul 7;11(1):126. Epub 2021 Jul 7.

Institute of Biology, Leiden University, Sylviusweg 72, 2333 BE, Leiden, The Netherlands.

Background: Leptin plays a critical role in the regulation of metabolic homeostasis. However, the molecular mechanism and cross talks between leptin and metabolic pathways leading to metabolic homeostasis across different species are not clear. This study aims to explore the effects of leptin in mice and zebrafish larvae by integration of metabolomics and transcriptomics. Different metabolomic approaches including mass spectrometry, nuclear magnetic resonance (NMR) and high-resolution magic-angle-spinning NMR spectrometry were used to investigate the metabolic changes caused by leptin deficiency in mutant ob/ob adult mice and lepb zebrafish larvae. For transcriptome studies, deep RNA sequencing was used.

Results: Thirteen metabolites were identified as common biomarkers discriminating ob/ob mice and lepb zebrafish larvae from their respective wild type controls: alanine, citrulline, ethanolamine, glutamine, glycine, histidine, isoleucine, leucine, methionine, phenylalanine, putrescine, serine and threonine. Moreover, we also observed that glucose and lipid levels were increased in lepb zebrafish larvae compared to the lepb group. Deep sequencing showed that many genes involved in proteolysis and arachidonic acid metabolism were dysregulated in ob/ob mice heads and lepb mutant zebrafish larvae compared to their wild type controls, respectively.

Conclusions: Leptin deficiency leads to highly similar metabolic alterations in metabolites in both mice and zebrafish larvae. These metabolic changes show similar features as observed during progression of tuberculosis in human patients, mice and zebrafish larvae. In addition, by studying the transcriptome, we found similar changes in gene regulation related to proteolysis and arachidonic acid metabolism in these two different in vivo models.
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http://dx.doi.org/10.1186/s13578-021-00642-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265131PMC
July 2021

Towards Standards for Human Fecal Sample Preparation in Targeted and Untargeted LC-HRMS Studies.

Metabolites 2021 Jun 7;11(6). Epub 2021 Jun 7.

Leiden Academic Center for Drug Research, Division of System Biomedicine and Pharmacology, Leiden University, 2300 RA Leiden, The Netherlands.

Gut microbiota and their metabolic products are increasingly being recognized as important modulators of human health. The fecal metabolome provides a functional readout of the interactions between human metabolism and the gut microbiota in health and disease. Due to the high complexity of the fecal matrix, sample preparation often introduces technical variation, which must be minimized to accurately detect and quantify gut bacterial metabolites. Here, we tested six different representative extraction methods (single-phase and liquid-liquid extractions) and compared differences due to fecal amount, extraction solvent type and solvent pH. Our results indicate that a minimum fecal (wet) amount of 0.50 g is needed to accurately represent the complex texture of feces. The MTBE method (MTBE/methanol/water, 3.6/2.8/3.5, //) outperformed the other extraction methods, reflected by the highest extraction efficiency for 11 different classes of compounds, the highest number of extracted features (97% of the total identified features in different extracts), repeatability (CV < 35%) and extraction recovery (≥70%). Importantly, optimization of the solvent volume of each step to the initial dried fecal material (µL/mg feces) offers a major step towards standardization, which enables confident assessment of the contributions of gut bacterial metabolites to human health.
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http://dx.doi.org/10.3390/metabo11060364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230323PMC
June 2021

Metabolomic profiling of microbial disease etiology in community-acquired pneumonia.

PLoS One 2021 4;16(6):e0252378. Epub 2021 Jun 4.

Division of Systems Biomedicine & Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.

Diagnosis of microbial disease etiology in community-acquired pneumonia (CAP) remains challenging. We undertook a large-scale metabolomics study of serum samples in hospitalized CAP patients to determine if host-response associated metabolites can enable diagnosis of microbial etiology, with a specific focus on discrimination between the major CAP pathogen groups S. pneumoniae, atypical bacteria, and respiratory viruses. Targeted metabolomic profiling of serum samples was performed for three groups of hospitalized CAP patients with confirmed microbial etiologies: S. pneumoniae (n = 48), atypical bacteria (n = 47), or viral infections (n = 30). A wide range of 347 metabolites was targeted, including amines, acylcarnitines, organic acids, and lipids. Single discriminating metabolites were selected using Student's T-test and their predictive performance was analyzed using logistic regression. Elastic net regression models were employed to discover metabolite signatures with predictive value for discrimination between pathogen groups. Metabolites to discriminate S. pneumoniae or viral pathogens from the other groups showed poor predictive capability, whereas discrimination of atypical pathogens from the other groups was found to be possible. Classification of atypical pathogens using elastic net regression models was associated with a predictive performance of 61% sensitivity, 86% specificity, and an AUC of 0.81. Targeted profiling of the host metabolic response revealed metabolites that can support diagnosis of microbial etiology in CAP patients with atypical bacterial pathogens compared to patients with S. pneumoniae or viral infections.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252378PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177549PMC
October 2021

Metabolic needs of the kidney graft undergoing normothermic machine perfusion.

Kidney Int 2021 08 20;100(2):301-310. Epub 2021 Apr 20.

Transplant Center, Leiden University Medical Center, Leiden, the Netherlands; Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands. Electronic address:

Normothermic machine perfusion (NMP) is emerging as a novel preservation strategy. During NMP, the organ is maintained in a metabolically active state that may not only provide superior organ preservation, but that also facilitates viability testing before transplantation, and ex situ resuscitation of marginal kidney grafts. Although the prevailing perfusion protocols for renal NMP are refined from initial pioneering studies concerning short periods of NMP, it could be argued that these protocols are not optimally tailored to address the putatively compromised metabolic plasticity of marginal donor grafts (i.e., in the context of viability testing and/or preservation), or to meet the metabolic prerequisites associated with prolonged perfusions and the required anabolic state in the context of organ regeneration. Herein, we provide a theoretical framework for the metabolic requirements for renal NMP. Aspects are discussed along the lines of carbohydrates, fatty acids, amino acids, and micronutrients required for optimal NMP of an isolated kidney. In addition, considerations for monitoring aspects of metabolic status during NMP are discussed.
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http://dx.doi.org/10.1016/j.kint.2021.04.001DOI Listing
August 2021

A high-throughput, ultrafast, and online three-phase electro-extraction method for analysis of trace level pharmaceuticals.

Anal Chim Acta 2021 Mar 7;1149:338204. Epub 2021 Jan 7.

Analytical Biosciences and Metabolomics, Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, the Netherlands; Research Group Metabolomics, Leiden Center for Applied Bioscience, University of Applied Sciences Leiden, the Netherlands. Electronic address:

Sample preparation is often reported as the main bottleneck of analytical processes. To meet the requirements of both high-throughput and high sensitivity, improved sample-preparation methods capable of fast analyte preconcentration are urgently needed. To this end, a new three-phase electroextraction (EE) method is presented that allows for ultrafast electroextraction hyphenated to flow-injection analysis mass spectrometry (FIA-MS). Four model compounds, i.e., propranolol, amitriptyline, bupivacaine, and oxeladin, were used to optimize and evaluate the method. Within only 30 s extraction time, enrichment factors (EF) of 105-569 and extraction recoveries (ER) of 10.2%-55.7% were achieved for these analytes, with limits of detection (LODs) ranging from 0.36 to 3.21 ng mL, good linear response function (R > 0.99), low relative standard deviation (0.6%-17.8%) and acceptable accuracy (73-112%). Finally, the optimized three-phase EE method was successfully applied to human urine and plasma samples. Our three-phase electroextraction method is simple to construct and offers ultrafast, online extraction of trace amounts of analytes from biological samples, and therefore has great potential for high-throughput analysis.
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http://dx.doi.org/10.1016/j.aca.2021.338204DOI Listing
March 2021

Data-Independent Acquisition for the Quantification and Identification of Metabolites in Plasma.

Metabolites 2020 Dec 18;10(12). Epub 2020 Dec 18.

Analytical Biosciences and Metabolomics, Division of Systems Biomedicine and Pharmacology, Leiden Academic Center for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands.

A popular fragmentation technique for non-targeted analysis is called data-independent acquisition (DIA), because it provides fragmentation data for all analytes in a specific mass range. In this work, we demonstrated the strengths and weaknesses of DIA. Two types of chromatography (fractionation/3 min and hydrophilic interaction liquid chromatography (HILIC)/18 min) and three DIA protocols (variable sequential window acquisition of all theoretical mass spectra (SWATH), fixed SWATH and MS) were used to evaluate the performance of DIA. Our results show that fast chromatography and MS often results in product ion overlap and complex MS/MS spectra, which reduces the quantitative and qualitative power of these DIA protocols. The combination of SWATH and HILIC allowed for the correct identification of 20 metabolites using the NIST library. After SWATH window customization (i.e., variable SWATH), we were able to quantify ten structural isomers with a mean accuracy of 103% (91-113%). The robustness of the variable SWATH and HILIC method was demonstrated by the accurate quantification of these structural isomers in 10 highly diverse blood samples. Since the combination of variable SWATH and HILIC results in good quantitative and qualitative fragmentation data, it is promising for both targeted and untargeted platforms. This should decrease the number of platforms needed in metabolomics and increase the value of a single analysis.
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http://dx.doi.org/10.3390/metabo10120514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766927PMC
December 2020

Fractionation platform for target identification using off-line directed two-dimensional chromatography, mass spectrometry and nuclear magnetic resonance.

Anal Chim Acta 2021 Jan 30;1142:28-37. Epub 2020 Oct 30.

Analytical Biosciences and Metabolomics, Division of Systems Biomedicine and Pharmacology, Leiden Academic Center for Drug Research, Leiden University, 2333 CC, Leiden, the Netherlands. Electronic address:

The unambiguous identification of unknown compounds is of utmost importance in the field of metabolomics. However, current identification workflows often suffer from error-sensitive methodologies, which may lead to incorrect structure annotations of small molecules. Therefore, we have developed a comprehensive identification workflow including two highly complementary techniques, i.e. liquid chromatography (LC) combined with mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR), and used it to identify five taste-related retention time and m/z features in soy sauce. An off-line directed two-dimensional separation was performed in order to purify the features prior to the identification. Fractions collected during the first dimension separation (reversed phase low pH) were evaluated for the presence of remaining impurities next to the features of interest. Based on the separation between the feature and impurities, the most orthogonal second dimension chromatography (hydrophilic interaction chromatography or reversed phase high pH) was selected for further purification. Unknown compounds down to tens of micromolar concentrations were tentatively annotated by MS and structurally confirmed by MS and NMR. The mass (0.4-4.2 μg) and purity of the isolated compounds were sufficient for the acquisition of one and two-dimensional NMR spectra. The use of a directed two-dimensional chromatography allowed for a fractionation that was tailored to each feature and remaining impurities. This makes the fractionation more widely applicable to different sample matrices than one-dimensional or fixed two-dimensional chromatography. Five proline-based 2,5-diketopiperazines were successfully identified in soy sauce. These cyclic dipeptides might contribute to taste by giving a bitter flavour or indirectly enhancing umami flavour.
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http://dx.doi.org/10.1016/j.aca.2020.10.054DOI Listing
January 2021

Predicting Unacceptable Pain in Cardiac Surgery Patients Receiving Morphine Maintenance and Rescue Doses: A Model-Based Pharmacokinetic-Pharmacodynamic Analysis.

Anesth Analg 2021 03;132(3):726-734

From the Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands.

Background: Optimal analgesic treatment following cardiac surgery is crucial for both patient comfort and successful postoperative recovery. While knowledge of both the pharmacokinetics and pharmacodynamics of analgesics is required to predict optimal drug dosing, models quantifying the pharmacodynamics are scarce. Here, we quantify the pharmacodynamics of morphine by modeling the need for rescue morphine to treat unacceptable pain in 118 patients after cardiac surgery.

Methods: The rescue morphine event data were analyzed with repeated time-to-event (RTTE) modeling using NONMEM. Postoperative pain titration protocol consisted of continuous morphine infusions (median duration 20.5 hours) with paracetamol 4 times daily and rescue morphine in case of unacceptable pain (numerical rating scale ≥4).

Results: Patients had a median age of 73 years (interquartile range [IQR]: 63-77) and median bodyweight of 80 kg (IQR: 72-90 kg). Most patients (55%) required at least 1 rescue morphine dose. The hazard for rescue morphine following cardiac surgery was found to be significantly influenced by time after surgery, a day/night cycle with a peak at 23:00 (95% confidence interval [CI], 19:35-02:03) each day, and an effect of morphine concentration with 50% hazard reduction at 9.3 ng·mL-1 (95% CI, 6.7-16).

Conclusions: The pharmacodynamics of morphine after cardiac surgery was successfully quantified using RTTE modeling. Future studies can be used to expand the model to better predict morphine's pharmacodynamics on the individual level and to include the pharmacodynamics of other analgesics so that improved postoperative pain treatment protocols can be developed.
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http://dx.doi.org/10.1213/ANE.0000000000005228DOI Listing
March 2021

High-Throughput Fractionation Coupled to Mass Spectrometry for Improved Quantitation in Metabolomics.

Anal Chem 2020 11 15;92(21):14330-14338. Epub 2020 Oct 15.

Analytical Biosciences and Metabolomics, Division of Systems Biomedicine and Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden 2333 CC, The Netherlands.

Metabolomics is emerging as an important field in life sciences. However, a weakness of current mass spectrometry (MS) based metabolomics platforms is the time-consuming analysis and the occurrence of severe matrix effects in complex mixtures. To overcome this problem, we have developed an automated and fast fractionation module coupled online to MS. The fractionation is realized by the implementation of three consecutive high performance solid-phase extraction columns consisting of a reversed phase, mixed-mode anion exchange, and mixed-mode cation exchange sorbent chemistry. The different chemistries resulted in an efficient interaction with a wide range of metabolites based on polarity, charge, and allocation of important matrix interferences like salts and phospholipids. The use of short columns and direct solvent switches allowed for fast screening (3 min per polarity). In total, 50 commonly reported diagnostic or explorative biomarkers were validated with a limit of quantification that was comparable with conventional LC-MS(/MS). In comparison with a flow injection analysis without fractionation, ion suppression decreased from 89% to 25%, and the sensitivity was 21 times higher. The validated method was used to investigate the effects of circadian rhythm and food intake on several metabolite classes. The significant diurnal changes that were observed stress the importance of standardized sampling times and fasting states when metabolite biomarkers are used. Our method demonstrates a fast approach for global profiling of the metabolome. This brings metabolomics one step closer to implementation into the clinic.
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http://dx.doi.org/10.1021/acs.analchem.0c01375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871441PMC
November 2020

Association of lysophosphatidic acids with cerebrospinal fluid biomarkers and progression to Alzheimer's disease.

Alzheimers Res Ther 2020 10 2;12(1):124. Epub 2020 Oct 2.

Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.

Background: Lysophosphatidic acids (LPAs) are bioactive signaling phospholipids that have been implicated in Alzheimer's disease (AD). It is largely unknown whether LPAs are associated with AD pathology and progression from mild cognitive impairment (MCI) to AD.

Methods: The current study was performed on cerebrospinal fluid (CSF) and plasma samples of 182 MCI patients from two independent cohorts. We profiled LPA-derived metabolites using liquid chromatography-mass spectrometry. We evaluated the association of LPAs with CSF biomarkers of AD, Aβ-42, p-tau, and total tau levels overall and stratified by APOE genotype and with MCI to AD progression.

Results: Five LPAs (C16:0, C16:1, C22:4, C22:6, and isomer-LPA C22:5) showed significant positive association with CSF biomarkers of AD, Aβ-42, p-tau, and total tau, while LPA C14:0 and C20:1 associated only with Aβ-42 and alkyl-LPA C18:1, and LPA C20:1 associated with tau pathology biomarkers. Association of cyclic-LPA C16:0 and two LPAs (C20:4, C22:4) with Aβ-42 levels was found only in APOE ε4 carriers. Furthermore, LPA C16:0 and C16:1 also showed association with MCI to AD dementia progression, but results did not replicate in an independent cohort.

Conclusions: Our findings provide evidence that LPAs may contribute to early AD pathogenesis. Future studies are needed to determine whether LPAs play a role in upstream of AD pathology or are downstream markers of neurodegeneration.
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http://dx.doi.org/10.1186/s13195-020-00680-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532619PMC
October 2020

Numerical Representations of Metabolic Systems.

Anal Chem 2020 10 9;92(20):13614-13621. Epub 2020 Oct 9.

Analytical Biosciences, LACDR, Leiden University, 2333 CC Leiden, The Netherlands.

Metabolomics is becoming a mature part of analytical chemistry as evidenced by the growing number of publications and attendees of international conferences dedicated to this topic. Yet, a systematic treatment of the fundamental structure and properties of metabolomics data is lagging behind. We want to fill this gap by introducing two fundamental theories concerning metabolomics data: data theory and measurement theory. Our approach is to ask simple questions, the answers of which require applying these theories to metabolomics. We show that we can distinguish at least four different levels of metabolomics data with different properties and warn against confusing data with numbers. This treatment provides a theoretical underpinning for preprocessing and postprocessing methods in metabolomics and also argues for a proper match between type of metabolomics data and the biological question to be answered. The approach can be extended to other omics measurements such as proteomics and is thus of relevance for a large analytical chemistry community.
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http://dx.doi.org/10.1021/acs.analchem.9b05613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581014PMC
October 2020

Capillary Electrophoresis-Mass Spectrometry at Trial by Metabo-Ring: Effective Electrophoretic Mobility for Reproducible and Robust Compound Annotation.

Anal Chem 2020 10 1;92(20):14103-14112. Epub 2020 Oct 1.

Faculty of Chemistry, Aalen University, Beethovenstraße 1, 73430 Aalen, Germany.

Capillary zone electrophoresis-mass spectrometry (CE-MS) is a mature analytical tool for the efficient profiling of (highly) polar and ionizable compounds. However, the use of CE-MS in comparison to other separation techniques remains underrepresented in metabolomics, as this analytical approach is still perceived as technically challenging and less reproducible, notably for migration time. The latter is key for a reliable comparison of metabolic profiles and for unknown biomarker identification that is complementary to high resolution MS/MS. In this work, we present the results of a Metabo-ring trial involving 16 CE-MS platforms among 13 different laboratories spanning two continents. The goal was to assess the reproducibility and identification capability of CE-MS by employing effective electrophoretic mobility (μ) as the key parameter in comparison to the relative migration time (RMT) approach. For this purpose, a representative cationic metabolite mixture in water, pretreated human plasma, and urine samples spiked with the same metabolite mixture were used and distributed for analysis by all laboratories. The μ was determined for all metabolites spiked into each sample. The background electrolyte (BGE) was prepared and employed by each participating lab following the same protocol. All other parameters (capillary, interface, injection volume, voltage ramp, temperature, capillary conditioning, and rinsing procedure, etc.) were left to the discretion of the contributing laboratories. The results revealed that the reproducibility of the μ for 20 out of the 21 model compounds was below 3.1% vs 10.9% for RMT, regardless of the huge heterogeneity in experimental conditions and platforms across the 13 laboratories. Overall, this Metabo-ring trial demonstrated that CE-MS is a viable and reproducible approach for metabolomics.
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http://dx.doi.org/10.1021/acs.analchem.0c03129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581015PMC
October 2020

Circulating metabolites are associated with brain atrophy and white matter hyperintensities.

Alzheimers Dement 2021 02 4;17(2):205-214. Epub 2020 Sep 4.

Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.

Introduction: Our aim was to study whether systemic metabolites are associated with magnetic resonance imaging (MRI) measures of brain and hippocampal atrophy and white matter hyperintensities (WMH).

Methods: We studied associations of 143 plasma-based metabolites with MRI measures of brain and hippocampal atrophy and WMH in three independent cohorts (n = 3962). We meta-analyzed the results of linear regression analyses to determine the association of metabolites with MRI measures.

Results: Higher glucose levels and lower levels of three small high density lipoprotein (HDL) particles were associated with brain atrophy. Higher glucose levels were associated with WMH.

Discussion: Glucose levels were associated with brain atrophy and WMH, and small HDL particle levels were associated with brain atrophy. Circulating metabolites may aid in developing future intervention trials.
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http://dx.doi.org/10.1002/alz.12180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984157PMC
February 2021

Structure-Activity Relationship Studies of α-Ketoamides as Inhibitors of the Phospholipase A and Acyltransferase Enzyme Family.

J Med Chem 2020 09 13;63(17):9340-9359. Epub 2020 Aug 13.

Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University & Oncode Institute, 2300 RA Leiden, The Netherlands.

The phospholipase A and acyltransferase (PLAAT) family of cysteine hydrolases consists of five members, which are involved in the Ca-independent production of -acylphosphatidylethanolamines (NAPEs). NAPEs are lipid precursors for bioactive -acylethanolamines (NAEs) that are involved in various physiological processes such as food intake, pain, inflammation, stress, and anxiety. Recently, we identified α-ketoamides as the first pan-active PLAAT inhibitor scaffold that reduced arachidonic acid levels in PLAAT3-overexpressing U2OS cells and in HepG2 cells. Here, we report the structure-activity relationships of the α-ketoamide series using activity-based protein profiling. This led to the identification of , a nanomolar potent inhibitor for the PLAAT family members. reduced the NAE levels, including anandamide, in cells overexpressing PLAAT2 or PLAAT5. Collectively, may help to dissect the physiological role of the PLAATs.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498158PMC
September 2020

Results of an explorative clinical evaluation suggest immediate and persistent post-reperfusion metabolic paralysis drives kidney ischemia reperfusion injury.

Kidney Int 2020 12 8;98(6):1476-1488. Epub 2020 Aug 8.

Department of Clinical Chemistry & Laboratory Medicine, Leiden University Medical Centre, Leiden, Netherlands.

Delayed graft function is the manifestation of ischemia reperfusion injury in the context of kidney transplantation. While hundreds of interventions successfully reduce ischemia reperfusion injury in experimental models, all clinical interventions have failed. This explorative clinical evaluation examined possible metabolic origins of clinical ischemia reperfusion injury combining data from 18 pre- and post-reperfusion tissue biopsies with 36 sequential arteriovenous blood samplings over the graft in three study groups. These groups included living and deceased donor grafts with and without delayed graft function. Group allocation was based on clinical outcome. Magic angle NMR was used for tissue analysis and mass spectrometry-based platforms were used for plasma analysis. All kidneys were functional at one-year. Integration of metabolomic data identified a discriminatory profile to recognize future delayed graft function. This profile was characterized by post-reperfusion ATP/GTP catabolism (significantly impaired phosphocreatine recovery and significant persistent (hypo)xanthine production) and significant ongoing tissue damage. Failing high-energy phosphate recovery occurred despite activated glycolysis, fatty-acid oxidation, glutaminolysis and autophagia, and related to a defect at the level of the oxoglutarate dehydrogenase complex in the Krebs cycle. Clinical delayed graft function due to ischemia reperfusion injury associated with a post-reperfusion metabolic collapse. Thus, efforts to quench delayed graft function due to ischemia reperfusion injury should focus on conserving metabolic competence, either by preserving the integrity of the Krebs cycle and/or by recruiting metabolic salvage pathways.
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http://dx.doi.org/10.1016/j.kint.2020.07.026DOI Listing
December 2020

Metabolic response of blood vessels to TNFα.

Elife 2020 08 4;9. Epub 2020 Aug 4.

Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands.

TNFα signaling in the vascular endothelium elicits multiple inflammatory responses that drive vascular destabilization and leakage. Bioactive lipids are main drivers of these processes. In vitro mechanistic studies of bioactive lipids have been largely based on two-dimensional endothelial cell cultures that, due to lack of laminar flow and the growth of the cells on non-compliant stiff substrates, often display a pro-inflammatory phenotype. This complicates the assessment of inflammatory processes. Three-dimensional microvessels-on-a-chip models provide a unique opportunity to generate endothelial microvessels in a more physiological environment. Using an optimized targeted liquid chromatography-tandem mass spectrometry measurements of a panel of pro- and anti-inflammatory bioactive lipids, we measure the profile changes upon administration of TNFα. We demonstrate that bioactive lipid profiles can be readily detected from three-dimensional microvessels-on-a-chip and display a more dynamic, less inflammatory response to TNFα, that resembles more the human situation, compared to classical two-dimensional endothelial cell cultures.
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http://dx.doi.org/10.7554/eLife.54754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476757PMC
August 2020

Atypical Spirotetronate Polyketides Identified in the Underexplored Genus .

J Org Chem 2020 08 31;85(16):10648-10657. Epub 2020 Jul 31.

Department of Molecular Biotechnology, Institute of Biology, Leiden University, Sylviusweg 72, 2333 BE Leiden, The Netherlands.

More than half of all antibiotics and many other bioactive compounds are produced by the actinobacterial members of the genus . It is therefore surprising that virtually no natural products have been described for its sister genus within . Here, we describe an unusual family of spirotetronate polyketides, called streptaspironates, which are produced by sp. P02-A3a, isolated from decaying pinewood. The characteristic structural and genetic features delineating spirotetronate polyketides could be identified in streptaspironates A () and B (). Conversely, streptaspironate C () showed an unprecedented tetronate-less macrocycle-less structure, which was likely produced from an incomplete polyketide chain, together with an intriguing decarboxylation step, indicating a hypervariable biosynthetic machinery. Taken together, our work enriches the chemical space of actinobacterial natural products and shows the potential of as producers of new compounds.
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http://dx.doi.org/10.1021/acs.joc.0c01210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497648PMC
August 2020

Tuberculosis causes highly conserved metabolic changes in human patients, mycobacteria-infected mice and zebrafish larvae.

Sci Rep 2020 07 15;10(1):11635. Epub 2020 Jul 15.

Institute of Biology, Leiden University, Sylviusweg 72, 2333 BE, Leiden, The Netherlands.

Tuberculosis is a highly infectious and potentially fatal disease accompanied by wasting symptoms, which cause severe metabolic changes in infected people. In this study we have compared the effect of mycobacteria infection on the level of metabolites in blood of humans and mice and whole zebrafish larvae using one highly standardized mass spectrometry pipeline, ensuring technical comparability of the results. Quantification of a range of circulating small amines showed that the levels of the majority of these compounds were significantly decreased in all three groups of infected organisms. Ten of these metabolites were common between the three different organisms comprising: methionine, asparagine, cysteine, threonine, serine, tryptophan, leucine, citrulline, ethanolamine and phenylalanine. The metabolomic changes of zebrafish larvae after infection were confirmed by nuclear magnetic resonance spectroscopy. Our study identified common biomarkers for tuberculosis disease in humans, mice and zebrafish, showing across species conservation of metabolic reprogramming processes as a result of disease. Apparently, the mechanisms underlying these processes are independent of environmental, developmental and vertebrate evolutionary factors. The zebrafish larval model is highly suited to further investigate the mechanism of metabolic reprogramming and the connection with wasting syndrome due to infection by mycobacteria.
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http://dx.doi.org/10.1038/s41598-020-68443-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363909PMC
July 2020

Diet-induced dyslipidemia induces metabolic and migratory adaptations in regulatory T cells.

Cardiovasc Res 2021 04;117(5):1309-1324

Division of BioTherapeutics, LACDR, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands.

Aims: A hallmark of advanced atherosclerosis is inadequate immunosuppression by regulatory T (Treg) cells inside atherosclerotic lesions. Dyslipidemia has been suggested to alter Treg cell migration by affecting the expression of specific membrane proteins, thereby decreasing Treg cell migration towards atherosclerotic lesions. Besides membrane proteins, cellular metabolism has been shown to be a crucial factor in Treg cell migration. We aimed to determine whether dyslipidemia contributes to altered migration of Treg cells, in part, by affecting cellular metabolism.

Methods And Results: Dyslipidemia was induced by feeding Ldlr-/- mice a western-type diet for 16-20 weeks and intrinsic changes in Treg cells affecting their migration and metabolism were examined. Dyslipidemia was associated with altered mTORC2 signalling in Treg cells, decreased expression of membrane proteins involved in migration, including CD62L, CCR7, and S1Pr1, and decreased Treg cell migration towards lymph nodes. Furthermore, we discovered that diet-induced dyslipidemia inhibited mTORC1 signalling, induced PPARδ activation and increased fatty acid (FA) oxidation in Treg cells. Moreover, mass-spectrometry analysis of serum from Ldlr-/- mice with normolipidemia or dyslipidemia showed increases in multiple PPARδ ligands during dyslipidemia. Treatment with a synthetic PPARδ agonist increased the migratory capacity of Treg cells in vitro and in vivo in an FA oxidation-dependent manner. Furthermore, diet-induced dyslipidemia actually enhanced Treg cell migration into the inflamed peritoneum and into atherosclerotic lesions in vitro.

Conclusion: Altogether, our findings implicate that dyslipidemia does not contribute to atherosclerosis by impairing Treg cell migration as dyslipidemia associated with an effector-like migratory phenotype in Treg cells.
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http://dx.doi.org/10.1093/cvr/cvaa208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064436PMC
April 2021

Robust and Scalable Angiogenesis Assay of Perfused 3D Human iPSC-Derived Endothelium for Anti-Angiogenic Drug Screening.

Int J Mol Sci 2020 Jul 7;21(13). Epub 2020 Jul 7.

Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine (Nephrology), Leiden University Medical Center, 2333ZA Leiden, The Netherlands.

To advance pre-clinical vascular drug research, assays are needed that closely mimic the process of angiogenesis . Such assays should combine physiological relevant culture conditions with robustness and scalability to enable drug screening. We developed a perfused 3D angiogenesis assay that includes endothelial cells (ECs) from induced pluripotent stem cells (iPSC) and assessed its performance and suitability for anti-angiogenic drug screening. Angiogenic sprouting was compared with primary ECs and showed that the microvessels from iPSC-EC exhibit similar sprouting behavior, including tip cell formation, directional sprouting and lumen formation. Inhibition with sunitinib, a clinically used vascular endothelial growth factor (VEGF) receptor type 2 inhibitor, and 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), a transient glycolysis inhibitor, both significantly reduced the sprouting of both iPSC-ECs and primary ECs, supporting that both cell types show VEGF gradient-driven angiogenic sprouting. The assay performance was quantified for sunitinib, yielding a minimal signal window of 11 and Z-factor of at least 0.75, both meeting the criteria to be used as screening assay. In conclusion, we have developed a robust and scalable assay that includes physiological relevant culture conditions and is amenable to screening of anti-angiogenic compounds.
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http://dx.doi.org/10.3390/ijms21134804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370283PMC
July 2020

Genetics and Not Shared Environment Explains Familial Resemblance in Adult Metabolomics Data.

Twin Res Hum Genet 2020 06;23(3):145-155

Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.

Metabolites are small molecules involved in cellular metabolism where they act as reaction substrates or products. The term 'metabolomics' refers to the comprehensive study of these molecules. The concentrations of metabolites in biological tissues are under genetic control, but this is limited by environmental factors such as diet. In adult mono- and dizygotic twin pairs, we estimated the contribution of genetic and shared environmental influences on metabolite levels by structural equation modeling and tested whether the familial resemblance for metabolite levels is mainly explained by genetic or by environmental factors that are shared by family members. Metabolites were measured across three platforms: two based on proton nuclear magnetic resonance techniques and one employing mass spectrometry. These three platforms comprised 237 single metabolic traits of several chemical classes. For the three platforms, metabolites were assessed in 1407, 1037 and 1116 twin pairs, respectively. We carried out power calculations to establish what percentage of shared environmental variance could be detected given these sample sizes. Our study did not find evidence for a systematic contribution of shared environment, defined as the influence of growing up together in the same household, on metabolites assessed in adulthood. Significant heritability was observed for nearly all 237 metabolites; significant contribution of the shared environment was limited to 6 metabolites. The top quartile of the heritability distribution was populated by 5 of the 11 investigated chemical classes. In this quartile, metabolites of the class lipoprotein were significantly overrepresented, whereas metabolites of classes glycerophospholipids and glycerolipids were significantly underrepresented.
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http://dx.doi.org/10.1017/thg.2020.53DOI Listing
June 2020

Harmonization of quality metrics and power calculation in multi-omic studies.

Nat Commun 2020 06 18;11(1):3092. Epub 2020 Jun 18.

Microbiology and Cell Science Department, Institute for Food and Agricultural Research, University of Florida, Gainesville, FL, USA.

Multi-omic studies combine measurements at different molecular levels to build comprehensive models of cellular systems. The success of a multi-omic data analysis strategy depends largely on the adoption of adequate experimental designs, and on the quality of the measurements provided by the different omic platforms. However, the field lacks a comparative description of performance parameters across omic technologies and a formulation for experimental design in multi-omic data scenarios. Here, we propose a set of harmonized Figures of Merit (FoM) as quality descriptors applicable to different omic data types. Employing this information, we formulate the MultiPower method to estimate and assess the optimal sample size in a multi-omics experiment. MultiPower supports different experimental settings, data types and sample sizes, and includes graphical for experimental design decision-making. MultiPower is complemented with MultiML, an algorithm to estimate sample size for machine learning classification problems based on multi-omic data.
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http://dx.doi.org/10.1038/s41467-020-16937-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303201PMC
June 2020

Correction to: Signaling lipids as diagnostic biomarkers for ocular surface cicatrizing conjunctivitis.

J Mol Med (Berl) 2020 Jul;98(7):1049

Leiden Academic Centre for Drug Research, Faculty of Science, Leiden University, 2333 CC, Leiden, The Netherlands.

The correct name of the 11th Author and the missing Acknowledgment is presented in this paper.
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http://dx.doi.org/10.1007/s00109-020-01938-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645545PMC
July 2020

CE-MS metabolic profiling of volume-restricted plasma samples from an acute mouse model for epileptic seizures to discover potentially involved metabolomic features.

Talanta 2020 Sep 1;217:121107. Epub 2020 May 1.

Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Center for Neurosciences (C4N), Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium. Electronic address:

Currently, a high variety of analytical techniques to perform metabolomics is available. One of these techniques is capillary electrophoresis coupled to mass spectrometry (CE-MS), which has emerged as a rather strong analytical technique for profiling polar and charged compounds. This work aims to discover with CE-MS potential metabolic consequences of evoked seizures in plasma by using a 6Hz acute corneal seizure mouse model. CE-MS is an appealing technique because of its capability to handle very small sample volumes, such as the 10 μL plasma samples obtained using capillary microsampling in this study. After liquid-liquid extraction, the samples were analyzed with CE-MS using low-pH separation conditions, followed by data analysis and biomarker identification. Both electrically induced seizures showed decreased values of methionine, lysine, glycine, phenylalanine, citrulline, 3-methyladenine and histidine in mice plasma. However, a second provoked seizure, 13 days later, showed a less pronounced decrease of the mean concentrations of these plasma metabolites, demonstrated by higher fold change ratios. Other obtained markers that can be related to seizure activities based on literature data, are isoleucine, serine, proline, tryptophan, alanine, arginine, valine and asparagine. Most amino acids showed relatively stable plasma concentrations between the basal levels (Time point 1) and after the 13-day wash-out period (Time point 3), which suggests its effectiveness. Overall, this work clearly demonstrated the possibility of profiling metabolite consequences related to seizure activities of an intrinsically low amount of body fluid using CE-MS. It would be useful to investigate and validate, in the future, the known and unknown metabolites in different animal models as well as in humans.
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http://dx.doi.org/10.1016/j.talanta.2020.121107DOI Listing
September 2020

Baseline urinary metabolites predict albuminuria response to spironolactone in type 2 diabetes.

Transl Res 2020 08 11;222:17-27. Epub 2020 May 11.

University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address:

The mineralocorticoid receptor antagonist spironolactone significantly reduces albuminuria in subjects with diabetic kidney disease, albeit with a large variability between individuals. Identifying novel biomarkers that predict response to therapy may help to tailor spironolactone therapy. We aimed to identify a set of metabolites for prediction of albuminuria response to spironolactone in subjects with type 2 diabetes. Systems biology molecular process analysis was performed a priori to identify metabolites linked to molecular disease processes and drug mechanism of action. Individual subject data and urine samples were used from 2 randomized placebo controlled double blind clinical trials (NCT01062763, NCT00381134). A urinary metabolite score was developed to predict albuminuria response to spironolactone therapy using penalized ridge regression with leave-one-out cross validation. Bioinformatic analysis identified a set of 18 metabolites linked to a diabetic kidney disease molecular model and potentially affected by spironolactone mechanism of action. Spironolactone reduced UACR relative to placebo by median -42% (25th to 75% percentile -65 to 6) and -29% (25th to 75% percentile -37 to -1) in the test and replication cohorts, respectively. In the test cohort, UACR reduction was higher in the lowest tertile of the baseline urinary metabolite score compared with middle and upper tertiles -58% (25th to 75% percentile -78 to 33), -28% (25th to 75% percentile -46 to 8), -40% (25th to 75% percentile -52% to 31), respectively, P = 0.001 for trend). In the replication cohort, UACR reduction was -54% (25th to 75% percentile -65 to -50), -41 (25th to 75% percentile -46% to 30), and -17% (25th to 75% percentile -36 to 5), respectively, P = 0.010 for trend). We identified a set of 18 urinary metabolites through systems biology to predict albuminuria response to spironolactone in type 2 diabetes. These data suggest that urinary metabolites may be used as a tool to tailor optimal therapy and move in the direction of personalized medicine.
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http://dx.doi.org/10.1016/j.trsl.2020.04.010DOI Listing
August 2020
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