Obernburg am Main, Germany
Obernburg am Main, Germany

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The present invention relates to methods for diagnosing and/or monitoring the onset or progression of chronic kidney disease (CKD) in a patient by the analysis of post-translational modification of plasma proteins. The present invention provides improved means for diagnosing chronic kidney disease (CKD), and especially for the early recognition of CKD.


Grant
Agency: European Commission | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2012-ITN | Award Amount: 3.79M | Year: 2012

Renal and liver diseases are global public health problems, with the incidences of end-stage renal disease (ESRD) and end-stage liver disease (ESLD) rising annually. Due to the lack of donor kidneys, most of ESRD patients depend on dialysis treatment using either an artificial kidney or the peritoneal membrane. Both modes are inefficient in removing uremic waste molecules and inadequately remove excess body fluids, potassium and phosphate contributing significantly to severe patient health problems, poor life quality and high mortality (15-20% per year). The impairment of liver functions has also serious implications and it is responsible for high rates of patient morbidity and mortality. Presently, liver transplantation remains the treatment of choice for ESLD patients but it is limited by both the high costs and severe shortage of donor organs. BIOART ITN will provide state-of-the-art multidisciplinary training for a cohort of 16 young researchers in order to equip them with the skills required to make a significant impact in the treatment of kidney and liver diseases. For this, BIOART ITN will develop: - A prototype artificial kidney devices enabling prolonged / continuous removal of uremic toxins - A prototype bioartificial kidney device that utilizes human renal epithelial cells for removal of uremic toxins. - Prototype bioreactor devices to ensure viability and functions of hepatocyte cells. In fact, BIOART ITN will provide the European Union with specific multidisciplinary expertise in the area of (bio)artificial organs for treatment of kidney and liver diseases. This will be achieved through the training of highly educated researchers able to understand and eventually to manage all scientific, industrial and clinical aspects of these (bio)artificial organs. Fourteen individual RTD Projects will be performed and thirty five scientific training courses will be offered by the host organizations to the recruited young researchers. During four years, the re


Desjardins L.,French Institute of Health and Medical Research | Desjardins L.,Amiens University Medical Center and the Jules Verne | Liabeuf S.,French Institute of Health and Medical Research | Liabeuf S.,Amiens University Medical Center and the Jules Verne | And 10 more authors.
Osteoporosis International | Year: 2012

Summary The hormone fibroblast growth factor 23 (FGF23) is involved in mineral homeostasis but may also have a role in vascular calcification and bone mineralization. In a cohort of 142 patients with CKD stages 2-5D, plasma FGF23 was independently associated with aortic calcification but not with pulse wave velocity or bone mineral density. Introduction FGF23 is involved in mineral homeostasis but may also have a role in vascular calcification and bone mineralization. Previous studies related to FGF23 and vascular and bone outcomes have been restricted to dialysis patients. The aim of the present study was to establish whether or not plasma FGF23 is associated with aortic and coronary calcification, arterial stiffness, and bone mineral density in patients with early as well as late stages of CKD. Methods In a cohort of 142 patients with CKD stages 2-5D, we made routine biochemistry and intact FGF23 determinations, and assessed aortic and coronary calcification, bone mineral density (BMD), and arterial stiffness by multislice spiral computed tomography and automated pulse wave velocity (PWV). Results Plasma intact FGF23 levels were elevated in CKD patients; the elevation preceded that of serum phosphate in early-stage CKD. Patients with elevated FGF23 levels had higher aortic and coronary calcification scores than patients with lower FGF23 levels. Multivariate linear regression analysis indicated that only age (p<0.001) and FGF23 (p=0.008) were independently associated with aortic calcification score. Plasma FGF23 was neither associated with PWV nor with BMD. Conclusion Our data suggest that plasma FGF23 is an independent biomarker of vascular calcification in patients with various CKD stages including early stages. The association between vascular calcification and FGF23 levels appears to be independent of BMD. It remains to be seen whether this association is independent of bone turnover and bone mass. © 2012 International Osteoporosis Foundation and National Osteoporosis Foundation.


Krieter D.H.,University of Würzburg | Hackl A.,University of Würzburg | Rodriguez A.,Montpellier University | Chenine L.,Montpellier University | And 4 more authors.
Nephrology Dialysis Transplantation | Year: 2010

Background. The accumulation of larger and protein-bound toxins is involved in the uraemic syndrome but their elimination by dialysis therapy remains difficult. In the present study, the impact of the albumin permeability of recently introduced advanced high-flux dialysis membranes on the removal of such substances was tested in haemodialysis and online post-dilution haemodiafiltration.Methods. Two types of polyethersulfone membranes only differing in albumin permeability (referred as PU- and PU+) were compared in eight patients on maintenance dialysis in a prospective cross-over manner. Treatment settings were identical for individual patients: time 229 ± 22 min; blood flow rate 378 ± 33 mLmin; dialysate flow rate 500 mLmin; substitution flow rate in haemodiafiltration 94 ± 9 mLmin. Removal of the protein-bound compounds p-cresyl sulfate (pCS) and indoxyl sulfate (IS) was determined by reduction ratios (RRs), dialytic clearances and mass in continuously collected dialysate. In addition, the elimination of the low-molecular weight (LMW) proteins beta2-microglobulin, cystatin c, myoglobin (myo), free retinol-binding protein (rbp) and albumin was measured.Results. Plasma levels of the protein-bound toxins were significantly decreased by all treatment forms. However, the decreases were comparable between dialysis membranes and between haemodialysis and haemodiafiltration. The RRs of total pCS ranged between 40.4 ± 25.3 and 47.8 ± 10.3 and of total IS between 50.4 ± 2.6 and 54.6 ± 8.7. Elimination of free protein-bound toxins as assessed by their mass in dialysate closely correlated positively with the pre-treatment plasma concentrations being r = 0.920 (P < 0.001) for total pCS and r = 0.906 (P < 0.001) for total IS, respectively. Compared to haemodialysis, much higher removal of all LMW proteins was found in haemodiafiltration. Dialysis membrane differences were only obvious in haemodialysis for the larger LMW proteins myo and rbp yielding significantly higher RRs for PU+ (myo 46 ± 9 versus 37 ± 9; rbp 18 ± 5 versus 15 ± 5; P < 0.05). Additionally, the albumin loss varied between membranes and treatment modes being undetectable with PU- in haemodialysis and highest with PU+ in haemodiafiltration (1430 ± 566 mg).Conclusions. The elimination of protein-bound compounds into dialysate is predicted by the level of pre-treatment plasma concentrations and depends particularly on diffusion. Lacking enhanced removal in online post-dilution haemodiafiltration emphasizes the minor significance of convection for the clearance of these solutes. Compared to LMW proteins, the highly protein-bound toxins pCS and IS are less effectively eliminated with all treatment forms. For a sustained decrease of pCS and IS plasma levels, alternative strategies promise to be more efficient therapy forms.


Devine E.,EXcorLab GmbH | Krieter D.H.,University of Würzburg | Ruth M.,EXcorLab GmbH | Jankovski J.,Charité - Medical University of Berlin | Lemke H.-D.,EXcorLab GmbH
Toxins | Year: 2014

Protein binding prevents uremic toxins from removal by conventional extracorporeal therapies leading to accumulation in maintenance dialysis patients. Weakening of the protein binding may enhance the dialytic elimination of these toxins. In ultrafiltration and equilibrium dialysis experiments, different measures to modify the plasma binding affinity and capacity were tested: (i), increasing the sodium chloride (NaCl) concentration to achieve a higher ionic strength; (ii), increasing the temperature; and (iii), dilution. The effects on the dissociation constant KD and the protein bound fraction of the prototypical uremic toxin indoxyl sulfate (IS) in plasma of healthy and uremic individuals were studied. Binding of IS corresponded to one site binding in normal plasma. KD increased linearly with the NaCl concentration between 0.15 (KD = 13.2 ± 3.7 μM) and 0.75 M (KD = 56.2 ± 2.0 μM). Plasma dilution further reduced the protein bound toxin fraction by lowering the protein binding capacity of the plasma. Higher temperatures also decreased the protein bound fraction of IS in human plasma. Increasing the NaCl concentration was effective to weaken the binding of IS also in uremic plasma: the protein bound fraction decreased from 89% ± 3% to 81% ± 3% at 0.15 and 0.75 M NaCl, respectively. Dilution and increasing the ionic strength and temperature enhance the free fraction of IS allowing better removal of the substance during dialysis. Applied during clinical dialysis, this may have beneficial effects on the long-term outcome of maintenance dialysis patients. © 2014 by the authors; licensee MDPI, Basel, Switzerland.


Barreto D.V.,French Institute of Health and Medical Research | Barreto D.V.,University of Picardie Jules Verne | Barreto F.C.,French Institute of Health and Medical Research | Barreto F.C.,University of Picardie Jules Verne | And 12 more authors.
Kidney International | Year: 2010

Chronic inflammation associated with chronic kidney disease predicts all-cause and cardiovascular mortality in hemodialysis patients. Here we sought to evaluate the association between plasma levels of the inflammatory mediator interleukin-6 (IL-6) and mortality and aortic calcification/stiffness in 125 patients at different stages (2-5D) of chronic kidney disease. Using multivariate linear regression, we found that plasma IL-6 was independently associated with C-reactive protein, albumin and the stage of chronic kidney disease, but not the aortic calcification score or pulse wave velocity. During follow-up studies (median of 829 days), 38 patients died, 22 from cardiovascular events. Plasma IL-6 significantly predicted overall and cardiovascular mortality; this association persisted after multiple adjustments or restricting the analysis to pre-dialysis patients. Moreover, IL-6 was a significantly better predictor of mortality than C-reactive protein, albumin or tumor necrosis factor-α. Hence, plasma IL-6 independently predicted overall and cardiovascular mortality in patients at different stages of chronic kidney disease; however, whether lowering plasma IL-6 will affect the outcome of chronic kidney disease will require more direct evaluation. © 2010 International Society of Nephrology.


Liabeuf S.,French Institute of Health and Medical Research | Liabeuf S.,Amiens University Hospital | Liabeuf S.,University of Picardie Jules Verne | Lenglet A.,French Institute of Health and Medical Research | And 16 more authors.
Kidney International | Year: 2012

Since beta-2 microglobulin (B2M) is a surrogate marker for middle molecular weight uremic toxins and the major protein component in dialysis-related amyloidosis, it has been frequently studied in dialysis patients. It is not known, however, whether B2M has an impact in patients with chronic kidney disease (CKD) not yet on dialysis. Here we studied the relationship of plasma B2M levels to clinical and cardiovascular outcomes in 142 patients (mean age of 67 years) at different stages of CKD. B2M levels increased with CKD stage and thus were highest in hemodialysis patients. Baseline B2M levels were associated with vascular calcification but not with arterial stiffness or bone density. During a mean follow-up of 969 days, 44 patients died and 49 suffered a cardiovascular event. Higher B2M levels were independently associated with overall and cardiovascular mortality and cardiovascular events in the whole cohort and with cardiovascular events in the predialysis cohort. Moreover, B2M appeared to be a better predictor than well-established factors associated with outcomes in this population, such as estimated glomerular filtration rate ((eGFR), only for predialysis patients), inflammation biomarkers, and other factors included in a propensity score. Thus, we confirm the strong relationship between B2M levels and eGFR and confirm the power of B2M to predict overall and cardiovascular mortality and cardiovascular events in patients at different stages of CKD. © 2012 International Society of Nephrology.


The present invention relates to methods for diagnosing and/or monitoring the onset or progression of chronic kidney disease (CKD) in a patient by the analysis of post-translational modification of plasma proteins. The present invention provides improved means for diagnosing chronic kidney disease (CKD) especially for the early recognition of CKD.


PubMed | EXcorLab GmbH, Aachen University, University of Hyderabad and Helmholtz Center Geesthacht
Type: | Journal: Clinical hemorheology and microcirculation | Year: 2016

Accumulated uremic toxins like indoxyl sulphate, hippuric acid and p-cresyl sulphates in renal failure patients stimulate proinflammatory effects, and consequently kidney and cardiovascular diseases. Low clearance rate of these uremic toxins from the blood of uremic patients by convention techniques like hemodialysis is due to their strong covalent albumin binding (greater than 95%) and hydrophobic nature, which led to alternatives like usage of hydrophobic adsorbers in removing these toxins from the plasma of kidney patients. Usage of biodegradable synthetic polymers as hydrophobic adsorbers has taken centre stage for their wide range of biomedical applications in the form of medical devices. Applications of polymers range from tissue engineering to drug delivery, abundance and special features like tissue engineering provided a great boon for their valuable therapeutic applications. Polymers like polyethylene, polyurethane, polymethylmethacrylate, cellophane and polytetrafluoroethylene were already in use as substitutes for metal devices as dialysis membranes. Among new crop of synthetic polymers, one such ideal adsorbed material are highly porous micro particles of poly(etherimide) (PEI) with an average diameter of 50-180 m and porosity around 88 2% prepared by spraying and coagulation process.It is essential to make sure that these synthetic polymers should not evoke any inflammatory or apoptotic response during dialysis. Therefore in our study we evaluated in vitro effect of PEI microparticle extracts in HAECs concerning toxicity, inflammation and apoptosis. No cell toxicity was observed when HAECs were treated with PEI extracts and inflammatory/apoptotic markers were not upregulated in presence of PEI extracts. Our results ensures biocompatibility of PEI particles and further hemocompatibility of particles will be tested.


PubMed | EXcorLab GmbH, Aachen University, University of Hyderabad and Helmholtz Center Geesthacht
Type: Journal Article | Journal: Clinical hemorheology and microcirculation | Year: 2016

Current haemodialysis techniques are not capable to remove efficiently low molecular weight hydrophobic uremic toxins from the blood of patients suffering from chronic renal failure. With respect to the hydrophobic characteristics and the high level of protein binding of these uremic toxins, hydrophobic adsorber materials might be an alternative to remove these substances from the plasma of the chronic kidney disease (CKD) patients. Here nanoporous microparticles prepared from poly(ether imide) (PEI) with an average diameter of 90 30 m and a porosity around 88 2% prepared by a spraying/coagulation process are considered as candidate adsorber materials. A prerequisite for the clinical application of such particles is their biocompatibility, which can be examined i.e. indirectly in cell culture experiments with the particles extracts. In this work we studied the effects of aqueous extracts of PEI microparticles on the viability of THP-1 cells, a human leukemia monocytic cell line, as well as their macrophage differentiation, reactive oxygen species (ROS) generation and inflammation.A high cell viability of around 99 18% and 99 5% was observed when THP-1 cells were cultured in the presence of aqueous extracts of the PEI microparticles in medium A and medium B respectively. The obtained microscopic data suggested that PEI particle extracts have no significant effect on cell death, oxidative stress or differentiation to macrophages. It was further found that the investigated proinflammatory markers in THP-1 cells were not up-regulated. These results are promising with regard to the biocompatibility of PEI microparticles and in a next step the hemocompatibility of the microparticles will be examined.

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