Acute kidney injury prediction in cardiac surgery patients by a urinary peptide pattern: a case-control validation study

Background Acute kidney injury (AKI) is a prominent problem in hospitalized patients and associated with increased morbidity and mortality. Clinical medicine is currently hampered by the lack of accurate and early biomarkers for diagnosis of AKI and the evaluation of the severity of the disease. In 2010, we established a multivariate peptide marker pattern consisting of 20 naturally occurring urinary peptides to screen patients for early signs of renal failure. The current study now aims to evaluate if, in a different study population and potentially various AKI causes, AKI can be detected early and accurately by proteome analysis. Methods Urine samples from 60 patients who developed AKI after cardiac surgery were analyzed by capillary electrophoresis-mass spectrometry (CE-MS). The obtained peptide profiles were screened by the AKI peptide marker panel for early signs of AKI. Accuracy of the proteomic model in this patient collective was compared to that based on urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) ELISA levels. Sixty patients who did not develop AKI served as negative controls. Results From the 120 patients, 110 were successfully analyzed by CE-MS (59 with AKI, 51 controls). Application of the AKI panel demonstrated an AUC in receiver operating characteristics (ROC) analysis of 0.81 (95 % confidence interval: 0.72–0.88). Compared to the proteomic model, ROC analysis revealed poorer classification accuracy of NGAL and KIM-1 with the respective AUC values being outside the statistical significant range (0.63 for NGAL and 0.57 for KIM-1)

Translational development of ABCB5+ dermal mesenchymal stem cells for therapeutic induction of angiogenesis in non-healing diabetic foot ulcers

Background While rapid healing of diabetic foot ulcers (DFUs) is highly desirable to avoid infections, amputations and life-threatening complications, DFUs often respond poorly to standard treatment. GMP-manufactured skin-derived ABCB5+ mesenchymal stem cells (MSCs) might provide a new adjunctive DFU treatment, based on their remarkable skin wound homing and engraftment potential, their ability to adaptively respond to inflammatory signals, and their wound healing-promoting efficacy in mouse wound models and human chronic venous ulcers. Methods The angiogenic potential of ABCB5+ MSCs was characterized with respect to angiogenic factor expression at the mRNA and protein level, in vitro endothelial trans-differentiation and tube formation potential, and perfusion-restoring capacity in a mouse hindlimb ischemia model. Finally, the efficacy and safety of ABCB5+ MSCs for topical adjunctive treatment of chronic, standard therapy-refractory, neuropathic plantar DFUs were assessed in an open-label single-arm clinical trial. Results Hypoxic incubation of ABCB5+ MSCs led to posttranslational stabilization of the hypoxia-inducible transcription factor 1α (HIF-1α) and upregulation of HIF-1α mRNA levels. HIF-1α pathway activation was accompanied by upregulation of vascular endothelial growth factor (VEGF) transcription and increase in VEGF protein secretion. Upon culture in growth factor-supplemented medium, ABCB5+ MSCs expressed the endothelial-lineage marker CD31, and after seeding on gel matrix, ABCB5+ MSCs demonstrated formation of capillary-like structures comparable with human umbilical vein endothelial cells. Intramuscularly injected ABCB5+ MSCs to mice with surgically induced hindlimb ischemia accelerated perfusion recovery as measured by laser Doppler blood perfusion imaging and enhanced capillary proliferation and vascularization in the ischemic muscles. Adjunctive topical application of ABCB5+ MSCs onto therapy-refractory DFUs elicited median wound surface area reductions from baseline of 59 % (full analysis set, n = 23), 64 % (per-protocol set, n = 20) and 67 % (subgroup of responders, n = 17) at week 12, while no treatment-related adverse events were observed. Conclusions The present observations identify GMP-manufactured ABCB5+ dermal MSCs as a potential, safe candidate for adjunctive therapy of otherwise incurable DFUs and justify the conduct of a larger, randomized controlled trial to validate the clinical efficacy. Trial registration ClinicalTrials.gov, NCT03267784, Registered 30 August 2017, https://clinicaltrials.gov/ct2/show/NCT0326778

Impact of Renal Replacement Therapy on Mortality in Critically Ill Patients—The Nephrologist’s View within an Interdisciplinary Intensive Care Team

Acute kidney injury (AKI) is a common complication in critically ill patients with an incidence of up to 50% in intensive care patients. The mortality of patients with AKI requiring dialysis in the intensive care unit is up to 50%, especially in the context of sepsis. Different approaches have been undertaken to reduce this high mortality by changing modalities and techniques of renal replacement therapy: an early versus a late start of dialysis, high versus low dialysate flows, intermittent versus continuous dialysis, anticoagulation with citrate or heparin, the use of adsorber or special filters in case of sepsis. Although in smaller studies some of these approaches seemed to have a positive impact on the reduction of mortality, in larger studies these effects could not been reproduced. This raises the question of whether there exists any impact of renal replacement therapy on mortality in critically ill patients—beyond an undeniable impact on uremia, hyperkalemia and/or hypervolemia. Indeed, this is one of the essential challenges of a nephrologist within an interdisciplinary intensive care team: according to the individual situation of a critically ill patient the main indication of dialysis has to be identified and all parameters of dialysis have to be individually chosen with respect to the patient’s situation and targeting the main dialysis indication. Such an interdisciplinary and individual approach would probably be able to reduce mortality in critically ill patients with dialysis requiring AKI

Improved Pt-utilization efficiency of low Pt-loading PEM fuel cell electrodes using direct membrane deposition

Direct membrane deposition was used to produce record platinum catalyst utilization efficiency polymer electrolyte membrane fuel cells. The novel membrane fabrication technique was applied to gas diffusion electrodes with low Pt-loadings of 0.102 and 0.029 mg/cm2. Under oxygen atmosphere and 300 kPaabs total pressure, 88 kW/gPt cathodic catalyst utilization efficiency with a symmetrical Pt-loading of 0.029 mg/cm2 on the anode and cathode side was achieved. This is 2.3 times higher than the Pt-utilization efficiency of a reference fuel cell prepared using a commercial Nafion N-211 membrane and identical catalyst layers, emphasizing that the improvement is purely attributable to the novel membrane fabrication technique. This value represents the highest Pt-utilization efficiency reported in literature. The results strongly motivate the application of employing direct membrane deposition techniques to prepare low resistance polymer electrolyte thin films in order to compensate for kinetic losses introduced when using low catalyst loadings

The reasons for the high power density of fuel cells fabricated with directly deposited membranes

In a previous study, we reported that polymer electrolyte fuel cells prepared by direct membrane deposition (DMD) produced power densities in excess of 4 W/cm2. In this study, the underlying origins that give rise to these high power densities are investigated and reported. The membranes of high power, DMD-fabricated fuel cells are relatively thin (12 μm) compared to typical benchmark, commercially available membranes. Electrochemical impedance spectroscopy, at high current densities (2.2 A/cm2) reveals that mass transport resistance was half that of reference, catalyst-coated-membranes (CCM). This is attributed to an improved oxygen supply in the cathode catalyst layer by way of a reduced propensity of flooding, and which is facilitated by an enhancement in the back diffusion of water from cathode to anode through the thin directly deposited membrane. DMD-fabricated membrane-electrode-assemblies possess 50% reduction in ionic resistance (15 mΩcm2) compared to conventional CCMs, with contributions of 9 mΩcm2 for the membrane resistance and 6 mΩcm2 for the contact resistance of the membrane and catalyst layer ionomer. The improved mass transport is responsible for 90% of the increase in power density of the DMD fuel cell, while the reduced ionic resistance accounts for a 10% of the improvement

Electrospun sulfonated poly(ether ketone) nanofibers as proton conductive reinforcement for durable Nafion composite membranes

We show that the combination of direct membrane deposition with proton conductive nanofiber reinforcement yields highly durable and high power density fuel cells. Sulfonated poly(ether ketone) (SPEK) was directly electrospun onto gas diffusion electrodes and then filled with Nafion by inkjet-printing resulting in a 12 μm thin membrane. The ionic membrane resistance (30 mΩ*cm2) was well below that of a directly deposited membrane reinforced with chemically inert (PVDF-HFP) nanofibers (47 mΩ*cm2) of comparable thickness. The power density of the fuel cell with SPEK reinforced membrane (2.04 W/cm2) is 30% higher than that of the PVDF-HFP reinforced reference sample (1.57 W/cm2). During humidity cycling and open circuit voltage (OCV) hold, the SPEK reinforced Nafion membrane showed no measurable degradation in terms of H2 crossover current density, thus fulfilling the target of 2 mA/cm2 of the DOE after degradation. The chemical accelerated stress test (100 h OCV hold at 90 °C, 30% RH, H2/air, 50/50 kPa) revealed a degradation rate of about 0.8 mV/h for the fuel cell with SPEK reinforced membrane, compared to 1.0 mV/h for the PVDF-HFP reinforced membrane

Effects of through-plane ionomer gradients in PEMFC cathode catalyst layers

The production of components in polymer electrolyte membrane fuel cells is a widely researched topic and still has a lot of potential for optimization. Especially the reduction of used materials like ionomer and platinum in fuel cell electrodes and the improvement of their performance are highly desired. In this study we discuss the potential of structured cathode catalyst layers by introducing a through plane ionomer gradient. For this purpose different catalyst layers with a platinum loading of 0.25 mg/cm2 have been produced by screen printing, followed by extensive In-Situ characterization in a fuel cell test bench. The results show that combining high amounts of ionomer at the membrane/electrode interface, and decreasing amounts towards the gas diffusion layer enable a good protonic connection of the catalyst layer to the membrane while improving the performance in the high current area due to lower diffusion resistance. This trend was also supported by limiting current measurements, showing increasing diffusion resistances with higher ionomer contents at the gas diffusion layer interface

The gap between calculated and actual calcium substitution during citrate anticoagulation in an immobilised patient on renal replacement therapy reflects the extent of bone loss – a case report

BACKGROUND: Demineralisation and bone density loss during immobilisation are known phenomena. However information concerning the extent of calcium loss during immobilisation remains inconsistent within literature. This may explain why treatment of bone loss and prevention of further demineralisation is often initiated only when spontaneous bone fracture occurred. Continuous renal replacement therapy is commonly utilised in critically ill patients with acute kidney injury requiring RRT. Regional anticoagulation with citrate for CRRT is well-established within the intensive care setting. Due to calcium free dialysate, calcium is eliminated directly as well as indirectly via citrate binding necessitating calcium substitution. In anuric patients declining calcium requirements over time reflect bone calcium liberation secondary to immobilisation. The difference between the expected and actual need for calcium infusion corresponds to calcium release from bone which is particularly impressive in patients exposed to long-term immobilisation and CRRT. We report a dialysis period in excess of 250 days with continuous renal replacement therapy and anticoagulation with citrate. CASE PRESENTATION: We present a 30-year old male with prolonged multisystem organ failure after bilateral lung transplantation, in whom during a period of 254 days the cumulative difference between expected and actual need for calcium infusion was 14.25 mol, representing an estimated calcium loss of about 571 g. Comparison of computed tomographic imaging of the lower thoracic vertebrae over this period depicts a radiographically discernible decrease in bone density from 238 to 52 Hounsfield Units. The first spontaneous fracture occurred after 6 months of immobilisation. Despite subsequent treatment with bisphosphonates and androgen therapy resulting in an increase in bone density to 90 HU a further fracture occurred. CONCLUSION: In immobilised patients receiving CRRT and anticoagulation with citrate, decreasing need for calcium substitution reflects the degree of bone demineralisation corresponding with radiographic assessment of declining bone mineral density. Such a declining need for calcium substitution could be useful in clinical practice highlighting relevant bone loss which results in spontaneous fractures in immobilised critically ill patients