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Klein J.,French Institute of Health and Medical Research | Klein J.,University Paul Sabatier | Lacroix C.,University Paul Sabatier | Lacroix C.,CNRS Institute of Pharmacology and Structural Biology | And 23 more authors.
Science Translational Medicine | Year: 2013

Bilateral congenital abnormalities of the kidney and urinary tract (CAKUT), although are individually rare diseases, remain the main cause of chronic kidney disease in infants worldwide. Bilateral CAKUT display a wide spectrum of pre- and postnatal outcomes ranging from death in utero to normal postnatal renal function. Methods to predict these outcomes in utero are controversial and, in several cases, lead to unjustified termination of pregnancy. Using capillary electrophoresis coupled with mass spectrometry, we have analyzed the urinary proteome of fetuses with posterior urethral valves (PUV), the prototypic bilateral CAKUT, for the presence of biomarkers predicting postnatal renal function. Among more than 4000 fetal urinary peptide candidates, 26 peptides were identified that were specifically associated with PUV in 13 patients with early end-stage renal disease (ESRD) compared to 15 patients with absence of ESRD before the age of 2. A classifier based on these peptides correctly predicted postnatal renal function with 88% sensitivity and 95% specificity in an independent blinded validation cohort of 38 PUV patients, outperforming classical methods, including fetal urine biochemistry and fetal ultrasound. This study demonstrates that fetal urine is an important pool of peptides that can predict postnatal renal function and thus be used to make clinical decisions regarding pregnancy. Copyright © 2013, American Association for the Advancement of Science.


Dakna M.,Mosaiques diagnostics and therapeutics | Harris K.,University of Glasgow | Kalousis A.,University of Geneva | Carpentier S.,Catholic University of Leuven | And 9 more authors.
BMC Bioinformatics | Year: 2010

Background: The purpose of this manuscript is to provide, based on an extensive analysis of a proteomic data set, suggestions for proper statistical analysis for the discovery of sets of clinically relevant biomarkers. As tractable example we define the measurable proteomic differences between apparently healthy adult males and females. We choose urine as body-fluid of interest and CE-MS, a thoroughly validated platform technology, allowing for routine analysis of a large number of samples. The second urine of the morning was collected from apparently healthy male and female volunteers (aged 21-40) in the course of the routine medical check-up before recruitment at the Hannover Medical School.Results: We found that the Wilcoxon-test is best suited for the definition of potential biomarkers. Adjustment for multiple testing is necessary. Sample size estimation can be performed based on a small number of observations via resampling from pilot data. Machine learning algorithms appear ideally suited to generate classifiers. Assessment of any results in an independent test-set is essential.Conclusions: Valid proteomic biomarkers for diagnosis and prognosis only can be defined by applying proper statistical data mining procedures. In particular, a justification of the sample size should be part of the study design. © 2010 Dakna et al; licensee BioMed Central Ltd.


Klein J.,French Institute of Health and Medical Research | Klein J.,University Paul Sabatier | Bascands J.-L.,French Institute of Health and Medical Research | Bascands J.-L.,University Paul Sabatier | And 4 more authors.
Kidney International | Year: 2016

Urinary peptidomics focuses on endogenous urinary peptide content. Many studies now show the usefulness of this approach for the discovery and validation of biomarkers in kidney diseases that are as varied as chronic kidney disease, acute kidney injury, congenital anomalies of the kidney and the urinary tract, and polycystic kidney disease. Most studies focus on chronic kidney disease and demonstrate that urinary peptidome analysis can substantially contribute to early detection and stratification of patients with chronic kidney disease. A number of multicenter studies are ongoing that aim further validation in a clinical setting and broaden the applicability of urinary peptides. The association of urinary peptides with kidney disease also starts to deliver information on the pathophysiology of kidney disease with emphasis on extracellular matrix remodeling. Bioinformatic peptide centric tools have been developed that allow to model the changes in protease activity involved in kidney disease, based on the urinary peptidome content. A novel application of urinary peptidome analysis is the back-translation of results obtained in humans to animals for animal model validation and improvement of readout in these preclinical models. In conclusion, urinary peptidomics not only contribute to detection and stratification of kidney disease in the clinic, but might also create a new impulse in drug discovery through better insight in the pathophysiology of disease and optimized translatability of animal models. © 2016 International Society of Nephrology.


Zapf A.,University of Gottingen | Gwinner W.,Hannover Medical School | Karch A.,Hannover Medical School | Metzger J.,Mosaiques Diagnostics and Therapeutics | And 2 more authors.
BMC Nephrology | Year: 2015

Background: Reliable and timely detection of acute rejection in renal transplant patients is important to preserve the allograft function and to prevent premature allograft failure. The current gold standard for the rejection diagnosis is an allograft biopsy which is usually performed upon an unexplained decline in allograft function. Because of the invasiveness of the biopsy, non-invasive tests have been suggested to diagnose acute rejection including mass spectrometry analysis of urine samples. Design and methods: The aim of this study is to examine the diagnostic accuracy of mass spectrometry analysis in urine for the diagnosis of acute rejections using the biopsy as gold-standard. The study is an ongoing prospective, single-arm, multicentre, phase 3 diagnostic accuracy study. It started in October 2011 and will be concluded in December 2015. Patient within the first year after transplantation who are scheduled for a biopsy to clarify unexplained impairment of the allograft are consecutively recruited into the study. The overall sample size (n∈=∈600) was calculated to demonstrate a sensitivity of 83 % and a specificity of 70 % for a one-sided type one error of 2.5 % and a power of 80 % per hypothesis. Biopsy evaluation and mass spectrometry analysis of urine samples (obtained immediately before biopsy) are performed independently by different readers without knowledge from the respective other assessment. The follow-up observation period is 6 months. For the primary analysis, the lower limits of the two-sided 95 % Wald confidence intervals for sensitivity and specificity will be compared with the pre-specified thresholds (83 % for sensitivity and 70 % for specificity). In secondary analyses the predictive values, the diagnostic measures in subgroups, and the clinical course will be assessed. Discussion: Previous phase 2 diagnostic accuracy studies (in small selected study populations) provided sufficient evidence to suggest mass spectrometry on urine samples as a promising approach to detect acute rejections. This study determines the diagnostic performance of the test in the routine setting of post-transplant patient care, compared to the biopsy-based rejection diagnosis. The next step would be a randomized trial to compare the two diagnostic strategies (including the urine test or not) in relation to patient relevant endpoints. Trial registration: NCT01315067; March 14, 2011 © 2015 Zapf et al.


PubMed | Hannover Medical School, Mosaiques Diagnostics and Therapeutics and University of Gottingen
Type: | Journal: BMC nephrology | Year: 2015

Reliable and timely detection of acute rejection in renal transplant patients is important to preserve the allograft function and to prevent premature allograft failure. The current gold standard for the rejection diagnosis is an allograft biopsy which is usually performed upon an unexplained decline in allograft function. Because of the invasiveness of the biopsy, non-invasive tests have been suggested to diagnose acute rejection including mass spectrometry analysis of urine samples.The aim of this study is to examine the diagnostic accuracy of mass spectrometry analysis in urine for the diagnosis of acute rejections using the biopsy as gold-standard. The study is an ongoing prospective, single-arm, multicentre, phase 3 diagnostic accuracy study. It started in October 2011 and will be concluded in December 2015. Patient within the first year after transplantation who are scheduled for a biopsy to clarify unexplained impairment of the allograft are consecutively recruited into the study. The overall sample size (n=600) was calculated to demonstrate a sensitivity of 83% and a specificity of 70% for a one-sided type one error of 2.5% and a power of 80% per hypothesis. Biopsy evaluation and mass spectrometry analysis of urine samples (obtained immediately before biopsy) are performed independently by different readers without knowledge from the respective other assessment. The follow-up observation period is 6months. For the primary analysis, the lower limits of the two-sided 95% Wald confidence intervals for sensitivity and specificity will be compared with the pre-specified thresholds (83% for sensitivity and 70% for specificity). In secondary analyses the predictive values, the diagnostic measures in subgroups, and the clinical course will be assessed.Previous phase 2 diagnostic accuracy studies (in small selected study populations) provided sufficient evidence to suggest mass spectrometry on urine samples as a promising approach to detect acute rejections. This study determines the diagnostic performance of the test in the routine setting of post-transplant patient care, compared to the biopsy-based rejection diagnosis. The next step would be a randomized trial to compare the two diagnostic strategies (including the urine test or not) in relation to patient relevant endpoints.NCT01315067 ; March 14, 2011.


Klein J.,Mosaiques Diagnostics and Therapeutics | Buffin-Meyer B.,French Institute of Health and Medical Research | Buffin-Meyer B.,University Paul Sabatier | Mullen W.,University of Glasgow | And 11 more authors.
Expert Review of Proteomics | Year: 2014

Clinical proteomics has been applied to the identification of biomarkers of obstetric and neonatal disease. We will discuss a number of encouraging studies that have led to potentially valid biomarkers in the context of Down's syndrome, preterm birth, amniotic infections, preeclampsia, intrauterine growth restriction and obstructive uropathies. Obtaining noninvasive biomarkers (e.g., from the maternal circulation, urine or cervicovaginal fluid) may be more feasible for obstetric diseases than for diseases of the fetus, for which invasive methods are required (e.g., amniotic fluid, fetal urine). However, studies providing validated proteomics-identified biomarkers are limited. Efforts should be made to save well-characterized samples of these invasive body fluids so that many valid biomarkers of pregnancy-related diseases will be identified in the coming years using proteomics based analysis upon adoption of 'clinical proteomics guidelines'. © 2014 Informa UK, Ltd.


Jankowski J.,RWTH Aachen | Schanstra J.P.,French Institute of Health and Medical Research | Schanstra J.P.,University Paul Sabatier | Mischak H.,Mosaiques Diagnostics and Therapeutics | Mischak H.,University of Glasgow
Nephrology Dialysis Transplantation | Year: 2015

Body fluid protein-based biomarkers carry the hope of improving patient management in diabetes by enabling more accurate and earlier detection of diabetic kidney disease (DKD), but also of defining the most suitable therapeutic targets. We present the data on some of the best studied individual protein markers in body fluids and conclude that their potential in clinical application for assessing DKD is moderate. Proteome-based approaches aiming at the identification of panels of body fluid biomarkers might be a valid alternative. We discuss the past (first) clinical proteomics studies in DKD, stressing their drawbacks but also the lessons that could be learned from them, as well as the more recent studies that have a potential for actual clinical implementation. We also highlight relevant issues and current problems associated with clinical proteomics from discovery towards application, and give suggestions for solutions that may help guiding proteomic studies, thereby removing some of the current hurdles for implementation of potentially beneficial results. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.


Schanstra J.P.,French Institute of Health and Medical Research | Schanstra J.P.,University Paul Sabatier | Mischak H.,Mosaiques Diagnostics and Therapeutics | Mischak H.,University of Glasgow
Pediatric Nephrology | Year: 2014

Biomarkers hold the promise of significantly improving health care by enabling prognosis and diagnosis with improved accuracy, and at earlier points in time. Previous results have indicated that single biomarkers are not suitable to describe complex diseases such as kidney disease. Here we provide an update on the progress of urinary proteomics-based studies and strategies to develop biomarker-based classifiers that tolerate instability and inconsistency of individual biomarkers. The examples focus on two major fields in nephrology: chronic kidney disease in the adult population and obstructive nephropathies in the pediatric population. When employed adequately, urinary proteomics demonstrates a clear value in kidney disease, indicating that the current status quo ruling for decades now could be changed by applying modern "omics" approaches. However, while research is able to deliver these useful tools for patient management, the issues associated with implementation are not yet solved. Active engagement of the relevant clinical professional societies, as well as patient's organizations, might help to implement these omics approaches that have shown a clear benefit for the patient. © 2014 IPNA.


Albalat A.,University of Glasgow | Franke J.,Mosaiques Diagnostics and Therapeutics | Gonzalez J.,University of Glasgow | Mischak H.,University of Glasgow | Zurbig P.,Mosaiques Diagnostics and Therapeutics
Methods in Molecular Biology | Year: 2013

Urine is an excellent sample source in the proteomic study of diseases. It is available in large quantities, is relatively stable, is not contaminated by cells or lipids, and has shown to provide information not only on the organs in contact with the urinary tract but also of more remote organs and tissues. In addition to these qualities, it can be collected by untrained personnel. For these reasons, urinary proteomic studies have escalated in recent years with the aim of identifying biomarkers that could be use for diagnosis or to predict the outcome of renal pathologies. In this chapter, we present one of the analytical platforms that has been successfully used in a number of studies for the identification and validation of biomarkers in kidney diseases. This technique is capillary electrophoresis coupled online to an electrospray ionization time-of-flight mass spectrometer (CE-MS). This technology has proven to be highly reproducible, sensitive with a quick analysis time, important features when analytical platforms have to be used in a clinical setting. © 2013 Springer Science+Business Media, LLC.


Albalat A.,Institute of Cardiovascular and Medical science | Bitsika V.,Academy of Athens | Zurbig P.,Mosaiques Diagnostics and Therapeutics | Siwy J.,Mosaiques Diagnostics and Therapeutics | Mullen W.,Institute of Cardiovascular and Medical science
Methods in Molecular Biology | Year: 2013

The analysis of proteins and peptides in biological fluids is becoming more important as they are potential sources of diagnostic biomarkers of disease. The complexity of body fluids is such that no single technique can both identify and quantify all the constituents present. It therefore requires pre-concentration of the compounds of interest and hyphenated techniques like capillary electrophoresis (CE) or high-performance liquid chromatography (HPLC) coupled to a mass spectrometer (MS) to provide the separation, identification, and quantification of the proteins and peptides under investigation. Here we provide protocols for sample preparation of various body fluids, namely, urine, plasma, and cerebrospinal fluid, and how to obtain maximum sensitivity and selectivity of the small proteins and peptides under investigation by CE-MS. © Springer Science+Business Media, LLC 2013.

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