Therapeutic apheresis within immune-mediated neurological disorders: dosing and its effectiveness

Plasma exchange (PE) and immunoadsorption (IA) are standard therapeutic options of immune-mediated neurological disorders. This study evaluates the relation of the relative quantity of applied dose of PE and/ or IA and its achieved therapeutic effectiveness within the treated underlying neurological disorders. In a retrospective study, we evaluated data from PE and IA carried out 09/2009-06/2014 in neurological patients at the University-Hospital of Saarland, Germany. Apheresis dose was defined as the ratio of the extracorporeal treated plasma volume to the patient's plasma volume. Effectiveness was assessed through disease-specific tests and scores by the attending neurologist(s); results were classified into response or no response. 1101 apheresis (PE:238, IA:863), in 153 hospital-stays were carried out, averaged, 7.0 treatments per patients, 82% responded, 18% not. Mean applied apheresis dose per treatment was 0.91 with mean doses of 1.16 for PE and 0.81 for IA. The totally applied mean dose per stay was 5.6 (PE:5.01, IA:5.81). No correlation was seen between apheresis dosing and treatment effectiveness (PE:R2 = 0.074, IA:R2 = 0.0023). PE and IA in therapy-refractory immune-mediated neurological disorders majorly achieved a measurable severity improvement - without correlation to the applied dose. Moreover, our data rather suggest, that effectiveness may be given with volumes below currently recommended volumes

Carbamylated low-density lipoprotein induces endothelial dysfunction

Aims Cardiovascular events remain the leading cause of death in Western world. Atherosclerosis is the most common underlying complication driven by low-density lipoproteins (LDL) disturbing vascular integrity. Carbamylation of lysine residues, occurring primarily in the presence of chronic kidney disease (CKD), may affect functional properties of lipoproteins; however, its effect on endothelial function is unknown. Methods and results Low-density lipoprotein from healthy donors was isolated and carbamylated. Vascular reactivity after treatment with native LDL (nLDL) or carbamylated LDL (cLDL) was examined in organ chambers for isometric tension recording using aortic rings of wild-type or lectin-like-oxidized LDL receptor-1 (LOX-1) transgenic mice. Reactive oxygen species (ROS) and nitric oxide (NO) production were determined using electron spin resonance spectroscopy. The effect of LDL-carbamyl-lysine levels on cardiovascular outcomes was determined in patients with CKD during a median follow-up of 4.7 years. Carbamylated LDL impaired endothelium-dependent relaxation to acetylcholine or calcium-ionophore A23187, but not endothelium-independent relaxation to sodium nitroprusside. In contrast, nLDL had no effect. Carbamylated LDL enhanced aortic ROS production by activating NADPH-oxidase. Carbamylated LDL stimulated endothelial NO synthase (eNOS) uncoupling at least partially by promoting S-glutathionylation of eNOS. Carbamylated LDL-induced endothelial dysfunction was enhanced in LOX-1 transgenic mice. In patients with CKD, LDL-carbamyl-lysine levels were significant predictors for cardiovascular events and all-cause mortality. Conclusions Carbamylation of LDL induces endothelial dysfunction via LOX-1 activation and increased ROS production leading to eNOS uncoupling. This indicates a novel mechanism in the pathogenesis of atherosclerotic disease which may be pathogenic and prognostic in patients with CKD and high plasma levels of cLD

Association of Homocysteine, S-Adenosylhomocysteine and S-Adenosylmethionine with Cardiovascular Events in Chronic Kidney Disease

Background: Patients suffering from chronic kidney disease (CKD) have a high risk of premature cardiovascular morbidity and mortality. It has been suggested that elevated homocysteine (Hcy) or disturbances in the transmethylation pathway may contribute to this high cardiovascular risk burden due to epigenetic mechanisms. The objective of this study was to explore the prognostic value of Hcy, S-adenosylhomocysteine (SAH) and Sadenosylmethionine (SAM) (one-carbon (C1)-metabolites) among patients with CKD. Methods: Plasma concentrations of Hcy, SAM and SAH were measured among 297 participants with CKD (KDIGO GFR category G2–G5). The predefined endpoint was the occurrence of major cardiovascular events (MACE), defined as carotid, coronary and peripheral arterial revascularization, stroke, acute myocardial infarction, major amputation, cardiovascular death and all-cause mortality during a median (IQR) follow-up period of 4.0 [3.2; 4.3] years. Results: Among all participants, the median (IQR) of plasma Hcy, SAH, and SAM levels were 16.6 [13.5; 21.2] µmol/L, 41.5 [26.6; 63.9] nmol/L, 183.4 [151.1; 223.5] nmol/L, respectively. Estimated glomerular filtration rate (eGFR) correlated more strongly with plasma SAH (r = −0.588) than with SAM (r = −0.497) and Hcy (r = −0.424). During the follow-up period, 55 participants experienced MACE. In a univariate Kaplan Meier analysis, all three C1-metabolites were significantly associated with the occurrence of the primary outcome. In a Cox-regression analysis, the association between Hcy and MACE was not significant after adjustment for age and sex (hazard ratio (HR) and 95% confidence intervals (95% CI) for the 3rd vs. 1st tertile = 1.804 (0.868–3.974)). Both SAH and SAM were not associated with MACE after adjustment for age, sex and additionally for renal function markers (SAH: HR 3rd vs. 1st tertile 1.645 95% (0.654–4.411); SAM: HR 3rd vs. 1st tertile 1.920 95% CI (0.764–5.138)). Conclusions: In people with CKD, plasma Hcy, SAH and SAM were not independent predictors of MACE after adjustment for age, sex and renal function. Disturbed renal function may explain elevated C1-metabolites and disturbed transmethylation, while this pathway is not likely to be an appropriate access point to modify the risk of cardiovascular events in CKD patients

Once-Monthly Continuous Erythropoietin Receptor Activator (C.E.R.A.) in Patients with Hemodialysis-Dependent Chronic Kidney Disease: Pooled Data from Phase III Trials

INTRODUCTION: Erythropoiesis-stimulating agents and iron are commonly used in patients with chronic kidney disease with the aim of correcting anemia and maintaining stable hemoglobin levels. We analyzed pooled data from 13 studies with similar designs included in the Umbrella Continuous Erythropoietin Receptor Activator (C.E.R.A.) program to investigate the effects of continuous erythropoiesis receptor activator in clinically relevant subgroups of patients with chronic kidney disease and to determine whether the efficacy and safety outcomes demonstrated in the overall chronic kidney disease population are maintained in specific subgroups. METHODS: Data from 13 Phase III trials set up with similar design were retrospectively pooled for this analysis. Patients with chronic kidney disease who had previously been receiving epoetin or darbepoetin were switched to continuous erythropoiesis receptor activator once-monthly after a 4- to 8-week screening period. Patients entered a 16-week continuous erythropoiesis receptor activator dose-titration period followed by an 8-week evaluation period. In total, 2060 patients were included in the analysis. Subgroups were defined based on: hemoglobin target range [lower (10.0–12.0 g/dL)/upper (10.5–13.0 g/dL)], gender (female/male), age (<65/≥65), baseline N-terminal pro-B-type natriuretic peptide levels (<5000/≥5000), cardiovascular risk factors (diabetes/cardiac/vascular/none). RESULTS: Across all subgroups analyzed, switching from shorter-acting erythropoiesis-stimulating agents to continuous erythropoiesis receptor activator once-monthly maintained stable hemoglobin concentrations in a high proportion of patients (78%), with only moderate hemoglobin fluctuations and a low number of dose changes. The safety profile across subgroups was as expected based on pre-existing risk factors; observed increases in adverse events were attributable to underlying risk factors rather than study drug. CONCLUSIONS: This retrospective analysis of 13 trials showed that continuous erythropoiesis receptor activator once-monthly maintained stable hemoglobin levels across a number of clinically relevant patient subgroups, including those with higher inherent cardiovascular risk. The safety profile was consistent with that previously established in the chronic kidney disease population. CLINICALTRIALS.GOV IDENTIFIERS: NCT00413894/NCT00545571/NCT00517413/NCT00560404/NCT00882713/NCT00550680/NCT00576303/NCT00660023/NCT00717821/NCT00642850/NCT00605293/NCT00661505/NCT00699348. FUNDING: F. Hoffmann-La Roche Ltd, Basel, Switzerland. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12325-016-0309-6) contains supplementary material, which is available to authorized users

Total-to-ionized calcium ratio predicts mortality in continuous renal replacement therapy with citrate anticoagulation in critically ill patients

INTRODUCTION: Regional citrate anticoagulation is safe, feasible and increasingly used in critically ill patients on continuous renal replacement therapy (CRRT). However, in patients with hepatic or multi-organ dysfunction, citrate accumulation may lead to an imbalance of calcium homeostasis. The study aimed at evaluating the incidence and prognostic relevance of an increased total to ionized calcium ratio (T/I Ca(2+ )ratio) and its association to hepatic dysfunction. METHODS: We performed a prospective observational study on n = 208 critically ill patients with acute kidney injury (AKI) and necessity for CRRT with regional citrate anticoagulation (CRRT-citrate) between September 2009 and September 2011. Critical illness was estimated by Simplified Acute Physiology Score II; hepatic function was measured with indocyanine green plasma disappearance rate. After achieving a steady state of calcium homeostasis patients were classified into tertiles according to the T/I Ca(2+ )ratio (<2.0 versus 2.0 - 2.39 versus ≥2.4). RESULTS: The T/I Ca(2+ )ratio was determined as an independent predictor for 28-day mortality in critically ill patients with AKI on CRRT-citrate confirmed by receiver operating characteristics and multivariate analysis (Area under the curve 0.94 ± 0.02; p<0.001). A T/I Ca(2+ )ratio ≥2.4 independently predicted a 33.5-fold (p<0.001) increase in 28-day mortality-rate. There was a significant correlation between the T/I Ca(2+ )ratio and the hepatic clearance (p<0.001) and the severity of critical illness (p<0.001). The efficacy and safety of citrate anticoagulation, determined by blood urea nitrogen, mean filter patency and bleeding episodes, were not significantly different between the tertiles. CONCLUSIONS: In patients on CRRT-citrate T/I Ca(2+ )ratio is closely related to the clinical outcome and emerged as an independent predictor of 28-day mortality. Larger studies are required to define the cut-off and predictive value for the T/I Ca(2+ )ratio. This ratio is associated with hepatic and/or multi-organ dysfunction and therefore an important therapeutic target

Calcineurin inhibitors differentially alter the circadian rhythm of T-cell functionality in transplant recipients

Background: Graft survival in transplant recipients depends on pharmacokinetics and on individual susceptibility towards immunosuppressive drugs. Nevertheless, pharmacodynamic changes in T-cell functionality in response to drugs and in relation to pharmacokinetics are poorly characterized. We therefore investigated the immunosuppressive effect of calcineurin inhibitors and steroids on general T-cell functionality after polyclonal stimulation of whole blood samples. Methods: General T-cell functionality in the absence or presence of immunosuppressive drugs was determined in vitro directly from whole blood based on cytokine induction after stimulation with the polyclonal stimulus Staphylococcus aureus enterotoxin B. In addition, diurnal changes in leukocyte and lymphocyte subsets, and on T-cell function after intake of immunosuppressive drugs were analyzed in 19 patients during one day and compared to respective kinetics in six immunocompetent controls. Statistical analysis was performed using non-parametric and parametric tests. Results: Susceptibility towards calcineurin inhibitors showed interindividual differences. When combined with steroids, tacrolimus led to more pronounced increase in the inhibitory activity as compared to cyclosporine A. While circadian alterations in leukocyte subpopulations and T-cell function in controls were related to endogenous cortisol levels, T-cell functionality in transplant recipients decreased after intake of the morning medication, which was more pronounced in patients with higher drug-dosages. Interestingly, calcineurin inhibitors differentially affected circadian rhythm of T-cell function, as patients on cyclosporine A showed a biphasic decrease in T-cell reactivity after drug-intake in the morning and evening, whereas T-cell reactivity in patients on tacrolimus remained rather stable. Conclusions: The whole blood assay allows assessment of the inhibitory activity of immunosuppressive drugs in clinically relevant concentrations. Circadian alterations in T-cell function are determined by dose and type of immunosuppressive drugs and show distinct differences between cyclosporine A and tacrolimus. In future these findings may have practical implications to estimate the net immunosuppressive effect of a given drug-regimen that daily acts in an individual patient, and may contribute to individualize immunosuppressio

Calcineurin inhibitors differentially alter the circadian rhythm of T-cell functionality in transplant recipients

Background: Graft survival in transplant recipients depends on pharmacokinetics and on individual susceptibility towards immunosuppressive drugs. Nevertheless, pharmacodynamic changes in T-cell functionality in response to drugs and in relation to pharmacokinetics are poorly characterized. We therefore investigated the immunosuppressive effect of calcineurin inhibitors and steroids on general T-cell functionality after polyclonal stimulation of whole blood samples. Methods: General T-cell functionality in the absence or presence of immunosuppressive drugs was determined in vitro directly from whole blood based on cytokine induction after stimulation with the polyclonal stimulus Staphylococcus aureus enterotoxin B. In addition, diurnal changes in leukocyte and lymphocyte subsets, and on T-cell function after intake of immunosuppressive drugs were analyzed in 19 patients during one day and compared to respective kinetics in six immunocompetent controls. Statistical analysis was performed using non-parametric and parametric tests. Results: Susceptibility towards calcineurin inhibitors showed interindividual differences. When combined with steroids, tacrolimus led to more pronounced increase in the inhibitory activity as compared to cyclosporine A. While circadian alterations in leukocyte subpopulations and T-cell function in controls were related to endogenous cortisol levels, T-cell functionality in transplant recipients decreased after intake of the morning medication, which was more pronounced in patients with higher drug-dosages. Interestingly, calcineurin inhibitors differentially affected circadian rhythm of T-cell function, as patients on cyclosporine A showed a biphasic decrease in T-cell reactivity after drug-intake in the morning and evening, whereas T-cell reactivity in patients on tacrolimus remained rather stable. Conclusions: The whole blood assay allows assessment of the inhibitory activity of immunosuppressive drugs in clinically relevant concentrations. Circadian alterations in T-cell function are determined by dose and type of immunosuppressive drugs and show distinct differences between cyclosporine A and tacrolimus. In future these findings may have practical implications to estimate the net immunosuppressive effect of a given drug-regimen that daily acts in an individual patient, and may contribute to individualize immunosuppressio

What should European nephrology do with the new CKD-EPI equation?

Nephrology; CKD-EPI equationNefrologia; Equació CKD-EPINefrología; Ecuación CKD-EP

Plasma biomarkers outperform echocardiographic measurements for cardiovascular risk prediction in kidney transplant recipients: results of the HOME ALONE study

Background Since kidney transplant recipients (KTRs) have a high cardiovascular disease burden, adequate risk prediction is of importance. Whether echocardiographic parameters and plasma biomarkers, natriuretic peptides [N-terminal pro-B-type natriuretic peptide (NT-proBNP)] and troponin T provide complementary or overlapping prognostic information on cardiovascular events remains uncertain. Methods The prospective Heterogeneity of Monocytes and Echocardiography Among Allograft Recipients in Nephrology (HOME ALONE) study followed 177 KTRs for 5.4 ± 1.7 years. Predefined endpoints were hospitalization for acute decompensated heart failure or all-cause death (HF/D) and major atherosclerotic cardiovascular events or all-cause death (MACE/D). At baseline, plasma NT-proBNP, plasma troponin T and echocardiographic parameters [left atrial volume index, left ventricular (LV) mass index, LV ejection fraction, and LV filling pressure] were assessed. Results Among all echocardiographic and plasma biomarkers measured, only NT-proBNP was consistently associated with HF/D in univariate and multivariate {third versus first tertile: hazard ratio [HR] 4.20 [95% confidence interval (CI) 1.02–17.27]} analysis, and only troponin T was consistently associated with MACE/D in univariate and multivariate [third versus first tertile: HR 8.15 (95% CI 2.75–24.18)] analysis. Conclusion Our data suggest that plasma biomarkers are robust and independent predictors of heart failure and atherosclerotic cardiovascular events after kidney transplantation, whereas standard echocardiographic follow-up does not add to risk prediction