Interactive exploration of adverse events and multimorbidity in CKD.

BACKGROUND AND HYPOTHESIS: Persons with chronic kidney disease (CKD) are at increased risk of adverse events, early mortality, and multimorbidity. A detailed overview of adverse event types and rates from a large CKD cohort under regular nephrological care is missing. We generated an interactive tool to enable exploration of adverse events and their combinations in the prospective, observational German CKD (GCKD) study. METHODS: The GCKD study enrolled 5217 participants under regular nephrological care with an estimated glomerular filtration rate of 30-60 or >60 mL/min/1.73m2 and an overt proteinuria. Cardio-, cerebro- and peripheral vascular, kidney, infection, and cancer events, as well as deaths were adjudicated following a standard operation procedure. We summarized these time-to-event data points for exploration in interactive graphs within an R shiny app. Multivariable adjusted Cox models for time to first event were fitted. Cumulative incidence functions, Kaplan-Meier curves and intersection plots were used to display main adverse events and their combinations by sex and CKD etiology. RESULTS: Over a median of 6.5 years, 10 271 events occurred in total and 680 participants (13.0%) died while 2947 participants (56.5%) experienced any event. The new publicly available interactive platform enables readers to scrutinize adverse events and their combinations as well as mortality trends as a gateway to better understand multimorbidity in CKD: incident rates per 1000 patient-years varied by event type, CKD etiology, and baseline characteristics. Incidence rates for the most frequent events and their recurrence were 113.6 (cardiovascular), 75.0 (kidney), and 66.0 (infection). Participants with diabetic kidney disease and men were more prone to experiencing events. CONCLUSION: This comprehensive explorative tool to visualize adverse events (https://gckd.diz.uk-erlangen.de/), their combination, mortality, and multimorbidity among persons with CKD may manifest as a valuable resource for patient care, identification of high-risk groups, health services, and public health policy planning.

SARS-CoV-2 infection in chronic kidney disease patients with pre-existing dialysis: description across different pandemic intervals and effect on disease course (mortality).

PURPOSE: Patients suffering from chronic kidney disease (CKD) are in general at high risk for severe coronavirus disease (COVID-19) but dialysis-dependency (CKD5D) is poorly understood. We aimed to describe CKD5D patients in the different intervals of the pandemic and to evaluate pre-existing dialysis dependency as a potential risk factor for mortality. METHODS: In this multicentre cohort study, data from German study sites of the Lean European Open Survey on SARS-CoV-2-infected patients (LEOSS) were used. We multiply imputed missing data, performed subsequent analyses in each of the imputed data sets and pooled the results. Cases (CKD5D) and controls (CKD not requiring dialysis) were matched 1:1 by propensity-scoring. Effects on fatal outcome were calculated by multivariable logistic regression. RESULTS: The cohort consisted of 207 patients suffering from CKD5D and 964 potential controls. Multivariable regression of the whole cohort identified age (> 85 years adjusted odds ratio (aOR) 7.34, 95% CI 2.45-21.99), chronic heart failure (aOR 1.67, 95% CI 1.25-2.23), coronary artery disease (aOR 1.41, 95% CI 1.05-1.89) and active oncological disease (aOR 1.73, 95% CI 1.07-2.80) as risk factors for fatal outcome. Dialysis-dependency was not associated with a fatal outcome-neither in this analysis (aOR 1.08, 95% CI 0.75-1.54) nor in the conditional multivariable regression after matching (aOR 1.34, 95% CI 0.70-2.59). CONCLUSIONS: In the present multicentre German cohort, dialysis dependency is not linked to fatal outcome in SARS-CoV-2-infected CKD patients. However, the mortality rate of 26% demonstrates that CKD patients are an extreme vulnerable population, irrespective of pre-existing dialysis-dependency.

Interim analysis of the COSA (COVID-19 patients treated with the Seraph® 100 Microbind® Affinity filter) registry.

BACKGROUND: The Seraph® 100 Microbind® Affinity Blood Filter is a haemoperfusion device that is licensed for the reduction of pathogens, including several viruses, in the blood. It received Emergency Use Authorization for the treatment of severe coronavirus disease 2019 (COVID-19) by the Food and Drug Administration (FDA). Several studies have shown that the blood viral load of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) correlates with adverse outcomes and removal of the nucleocapsid of the SARS-CoV-2 virus by the Seraph® 100 has been recently demonstrated. The aim of this registry was to evaluate the safety and efficacy of Seraph® 100 treatment for COVID-19 patients. METHODS: Twelve hospitals from six countries representing two continents documented patient and treatment characteristics as well as outcome parameters without reimbursement. Additionally, mortality and safety results of the device were reported. A total of 102 treatment sessions in 82 patients were documented in the registry. Four patients were excluded from mortality analysis due to incomplete outcome data, which were available in the other 78 patients. RESULTS: Overall, a 30-day mortality rate of 46.2% in the 78 patients with complete follow-up was reported. The median treatment time was 5.00 h (4.00-13.42) and 43.1% of the treatments were performed as haemoperfusion only. Adverse events of the Seraph® 100 treatment were reported in 8.8% of the 102 treatments and represented the premature end of treatment due to circuit failure. Patients who died were treated later in their intensive care unit (ICU) stay and onset of COVID symptoms. They also had higher ferritin levels. Multivariate Cox regression revealed that delayed Seraph® 100 treatment after ICU admission (>60 h), as well as bacterial superinfection, were associated with mortality. While average predicted mortality rate according to Sequential Organ Failure Assessment (SOFA) score in ICU patients was 56.7%, the observed mortality was 50.7%. In non-ICU patients, Coronavirus Clinical Characterisation Consortium (4C) score average predicted a mortality rate of 38.0%, while the observed mortality rate was 11.1%. CONCLUSIONS: The treatment of COVID-19 patients with Seraph® 100 is well tolerated and the circuit failure rate was lower than previously reported for kidney replacement therapy (KRT) in COVID-19 patients. Mortality correlated with late initiation of Seraph treatment after ICU admission and bacterial superinfection. Compared with predicted mortality according to 4C and SOFA scores, mortality of Seraph® 100-treated patients reported in the registry was lower.

Safety and efficacy of the Seraph® 100 Microbind® Affinity Blood Filter to remove bacteria from the blood stream: results of the first in human study.

BACKGROUND: Bacterial burden as well as duration of bacteremia influence the outcome of patients with bloodstream infections. Promptly decreasing bacterial load in the blood by using extracorporeal devices in addition to anti-infective therapy has recently been explored. Preclinical studies with the Seraph® 100 Microbind® Affinity Blood Filter (Seraph® 100), which consists of heparin that is covalently bound to polymer beads, have demonstrated an effective binding of bacteria and viruses. Pathogens adhere to the heparin coated polymer beads in the adsorber as they would normally do to heparan sulfate on cell surfaces. Using this biomimetic principle, the Seraph® 100 could help to decrease bacterial burden in vivo. METHODS: This first in human, prospective, multicenter, non-randomized interventional study included patients with blood culture positive bloodstream infection and the need for kidney replacement therapy as an adjunctive treatment for bloodstream infections. We performed a single four-hour hemoperfusion treatment with the Seraph® 100 in conjunction with a dialysis procedure. Post procedure follow up was 14 days. RESULTS: Fifteen hemodialysis patients (3F/12 M, age 74.0 [68.0-78.5] years, dialysis vintage 28.0 [11.0-45.0] months) were enrolled. Seraph® 100 treatment started 66.4 [45.7-80.6] hours after the initial positive blood culture was drawn. During the treatment with the Seraph® 100 with a median blood flow of 285 [225-300] ml/min no device or treatment related adverse events were reported. Blood pressure and heart rate remained stable while peripheral oxygen saturation improved during the treatment from 98.0 [92.5-98.0] to 99.0 [98.0-99.5] %; p = 0.0184. Four patients still had positive blood culture at the start of Seraph® 100 treatment. In one patient blood cultures turned negative during treatment. The time to positivity (TTP) was increased between inflow and outflow blood cultures by 36 [- 7.2 to 96.3] minutes. However, overall TTP increase was not statistical significant. CONCLUSIONS: Seraph® 100 treatment was well tolerated. Adding Seraph® 100 to antibiotics early in the course of bacteremia might result in a faster resolution of bloodstream infections, which has to be evaluated in further studies. TRAIL REGISTRATION: ClinicalTrials.gov Identifier: NCT02914132 , first posted September 26, 2016.

Fosfomycin single- and multiple-dose pharmacokinetics in patients undergoing prolonged intermittent renal replacement therapy.

BACKGROUND: Fosfomycin is used increasingly in the treatment of MDR bacteria. It is eliminated by renal excretion, but data regarding dosing recommendations for patients undergoing modern means of renal replacement therapies are scarce. OBJECTIVES: Evaluation of the pharmacokinetics (PK) of fosfomycin in patients undergoing prolonged intermittent renal replacement therapy (PIRRT) to guide dosing recommendations. METHODS: Fosfomycin was given in 11 (7 female) patients with severe infections undergoing PIRRT. Plasma levels were measured at several timepoints on the first day of fosfomycin therapy, as well as 5-6 days into therapy, before and after the dialyser, to calculate its clearance. Fosfomycin was measured in the collected spent dialysate. RESULTS: The median (IQR) plasma dialyser clearance for fosfomycin was 183.4 (156.9-214.9) mL/min, eliminating a total amount of 8834 (4556-10 440) mg of fosfomycin, i.e. 73.9% (45.3%-93.5%) of the initial dose. During PIRRT, the fosfomycin half-life was 2.5 (2.2-3.4) h. Data from multiple-dose PK showed an increase in fosfomycin Cmax from 266.8 (166.3-438.1) to 926.1 (446.8-1168.0) mg/L and AUC0-14 from 2540.5 (1815.2-3644.3) to 6714 (4060.6-10612.6) mg·h/L. Dialysis intensity during the study was 1.5 L/h. T>MIC was 100% in all patients. CONCLUSIONS: Patients undergoing PIRRT experience significant fosfomycin elimination, requiring a dose of 5 g/8 h to reach adequate plasma levels. However, drug accumulation may occur, depending on dialysis frequency and intensity.

Clinical course and predictive risk factors for fatal outcome of SARS-CoV-2 infection in patients with chronic kidney disease.

PURPOSE: The ongoing pandemic caused by the novel severe acute respiratory coronavirus 2 (SARS-CoV-2) has stressed health systems worldwide. Patients with chronic kidney disease (CKD) seem to be more prone to a severe course of coronavirus disease (COVID-19) due to comorbidities and an altered immune system. The study's aim was to identify factors predicting mortality among SARS-CoV-2-infected patients with CKD. METHODS: We analyzed 2817 SARS-CoV-2-infected patients enrolled in the Lean European Open Survey on SARS-CoV-2-infected patients and identified 426 patients with pre-existing CKD. Group comparisons were performed via Chi-squared test. Using univariate and multivariable logistic regression, predictive factors for mortality were identified. RESULTS: Comparative analyses to patients without CKD revealed a higher mortality (140/426, 32.9% versus 354/2391, 14.8%). Higher age could be confirmed as a demographic predictor for mortality in CKD patients (> 85 years compared to 15-65 years, adjusted odds ratio (aOR) 6.49, 95% CI 1.27-33.20, p = 0.025). We further identified markedly elevated lactate dehydrogenase (> 2 × upper limit of normal, aOR 23.21, 95% CI 3.66-147.11, p < 0.001), thrombocytopenia (< 120,000/µl, aOR 11.66, 95% CI 2.49-54.70, p = 0.002), anemia (Hb < 10 g/dl, aOR 3.21, 95% CI 1.17-8.82, p = 0.024), and C-reactive protein (≥ 30 mg/l, aOR 3.44, 95% CI 1.13-10.45, p = 0.029) as predictors, while renal replacement therapy was not related to mortality (aOR 1.15, 95% CI 0.68-1.93, p = 0.611). CONCLUSION: The identified predictors include routinely measured and universally available parameters. Their assessment might facilitate risk stratification in this highly vulnerable cohort as early as at initial medical evaluation for SARS-CoV-2.

Heparin 2.0: A New Approach to the Infection Crisis.

In April 2020, the US Food and Drug Administration granted emergency use authorization for certain medical devices to be used in patients with coronavirus disease 2019 (CO-VID-19). This included extracorporeal blood purification devices. This narrative review will give a brief overview regarding some of the extracorporeal devices that could be used to treat COVID-19 patients, including the Seraph® 100 Microbind® Affinity Blood Filter, produced by ExThera Medical (Martinez, CA, USA), first licensed in the European Economic Area in 2019. The Seraph® 100 contains ultrahigh molecular weight polyethylene beads with end point-attached heparin and is approved for the reduction of pathogens from the bloodstream either as a single agent or as an adjunct to conventional anti-infective agents. Bacteria, viruses, fungi, and toxins have been shown to bind to the immobilized heparin in a similar way to the interaction with heparan sulfate on the cell surface. This binding is nonreversible and as such, the pathogens are removed from the bloodstream. In this review, we describe the pathophysiological basis and rationale for using heparin for pathogen removal from the blood as well as exploring the technology behind the adaptation of heparin to deprive it of its systemic anticoagulant activity. In addition, we summarize the in vitro data as well as the available preclinical testing and published clinical reports. Finally, we discuss the enormous potential of this technology in an era of increasing antibiotic resistance and high mortality associated with sepsis and consider the application of this as a possible treatment option for COVID-19.

Using the World Apheresis Association Registry Helps to Improve the Treatment Quality of Therapeutic Apheresis.

Therapeutic apheresis (TA) is prescribed to patients that suffer from a severe progressive disease that is not sufficiently treated by conventional medications. A way to gain more knowledge about this treatment is usually by the local analysis of data. However, the use of large quality assessment registries enables analyses of even rare findings. Here, we report some of the recent data from the World Apheresis Association (WAA) registry. Data from >104,000 procedures were documented, and TA was performed on >15,000 patients. The main indication for TA was the collection of autologous stem cells (45% of patients) as part of therapy for therapy. Collection of stem cells from donors for allogeneic transplantation was performed in 11% of patients. Patients with indications such as neurological diseases underwent plasma exchange (28%). Extracorporeal photochemotherapy, lipid apheresis, and antibody removal were other indications. Side effects recorded in the registry have decreased significantly over the years, with approximately only 10/10,000 procedures being interrupted for medical reasons. CONCLUSION: Collection of data from TA procedures within a multinational and multicenter concept facilitates the improvement of treatment by enabling the analysis of and feedback on indications, procedures, effects, and side effects.

KDIGO Controversies Conference on onco-nephrology: kidney disease in hematological malignancies and the burden of cancer after kidney transplantation.

The bidirectional relationship between cancer and chronic kidney disease (CKD) is complex. Patients with cancer, particularly those with hematological malignancies such as multiple myeloma and lymphoma, are at increased risk of developing acute kidney injury and CKD. On the other hand, emerging evidence from large observational registry analyses have consistently shown that cancer risk is increased by at least 2- to 3-fold in kidney transplant recipients, and the observed increased risk occurs not only in those who have received kidney transplants but also in those on dialysis and with mild- to moderate-stage CKD. The interactions between cancer and CKD have raised major therapeutic and clinical challenges in the management of these patients. Given the magnitude of the problem and uncertainties, and current controversies within the existing evidence, Kidney Disease: Improving Global Outcomes (KDIGO) assembled a global panel of multidisciplinary clinical and scientific expertise for a controversies conference on onco-nephrology to identify key management issues in nephrology relevant to patients with malignancy. This report covers the discussed controversies in kidney disease in hematological malignancies, as well as cancer after kidney transplantation. An overview of future research priorities is also discussed.

KDIGO Controversies Conference on onco-nephrology: understanding kidney impairment and solid-organ malignancies, and managing kidney cancer.

The association between kidney disease and cancer is multifaceted and complex. Persons with chronic kidney disease (CKD) have an increased incidence of cancer, and both cancer and cancer treatments can cause impaired kidney function. Renal issues in the setting of malignancy can worsen patient outcomes and diminish the adequacy of anticancer treatments. In addition, the oncology treatment landscape is changing rapidly, and data on tolerability of novel therapies in patients with CKD are often lacking. Caring for oncology patients has become more specialized and interdisciplinary, currently requiring collaboration among specialists in nephrology, medical oncology, critical care, clinical pharmacology/pharmacy, and palliative care, in addition to surgeons and urologists. To identify key management issues in nephrology relevant to patients with malignancy, KDIGO (Kidney Disease: Improving Global Outcomes) assembled a global panel of multidisciplinary clinical and scientific expertise for a controversies conference on onco-nephrology in December 2018. This report covers issues related to kidney impairment and solid organ malignancies as well as management and treatment of kidney cancer. Knowledge gaps, areas of controversy, and research priorities are described.

Symmetric dimethylarginine in dysfunctional high-density lipoprotein mediates endothelial glycocalyx breakdown in chronic kidney disease.

Dysfunctional high-density lipoprotein (d-HDL) in chronic kidney disease is known to have a change in composition towards an endothelial-damaging phenotype, amongst others, via the accumulation of symmetric dimethylarginine. The endothelial glycocalyx, a carbohydrate-rich layer lining the endothelial luminal surface, is a first line defense against vascular diseases including atherosclerosis. Here we conducted a translational, cross-sectional study to determine the role of symmetric dimethylarginine in d-HDL as a mediator of glycocalyx damage. Using confocal and atomic force microscopy, intact HDL from healthy donors was found to maintain the glycocalyx while isolated HDL from hemodialysis patients and exogenous symmetric dimethylarginine caused significant damage to the glycocalyx in endothelial cells in vitro in a dose-dependent manner. Symmetric dimethylarginine triggered glycocalyx deterioration via molecular pathways mediated by toll-like-receptor 2 and matrix metalloprotease-9. Corresponding intravital microscopy revealed that exogenous symmetric dimethylarginine and d-HDL from hemodialysis patients caused glycocalyx breakdown, which subsequently contributed to alterations in leukocyte rolling. Biologically effective HDL, which estimates the functionality of HDL, was calculated from circulating HDL-cholesterol and symmetric dimethylarginine, as described in the literature. Biologically effective HDL was the only parameter that could independently predict glycocalyx damage in vivo. Thus, our data suggest that symmetric dimethylarginine in d-HDL mediates glycocalyx breakdown in chronic kidney disease.

Drugs linked to plasma homoarginine in chronic kidney disease patients-a cross-sectional analysis of the German Chronic Kidney Disease cohort.

BACKGROUND: Elevated plasma concentrations of symmetric and asymmetric dimethylarginine (SDMA and ADMA, respectively) and a lower plasma concentration of the structurally related homoarginine are commonly observed in patients with chronic kidney disease (CKD) and independently predict total mortality as well as progression of renal disease. We aimed to identify drugs that may alter this adverse metabolite pattern in a favourable fashion. METHODS: Plasma ADMA, SDMA, homoarginine and l-arginine were determined by liquid chromatography-tandem mass spectrometry in 4756 CKD patients ages 18-74 years with an estimated glomerular filtration rate (eGFR) of 30-60 mL/min/1.73 m2 or an eGFR >60 mL/min/1.73 m2 and overt proteinuria who were enrolled in the German Chronic Kidney Disease (GCKD) study. Associations between laboratory, clinical and medication data were assessed. RESULTS: Intake of several commonly used drugs was independently associated with plasma concentrations of homoarginine and/or related metabolites. Among these, the peroxisome proliferator-activated receptor alpha (PPAR-α) agonist fenofibrate was associated with the most profound differences in ADMA, SDMA and homoarginine plasma concentrations: 66 patients taking fenofibrate had a multivariable adjusted odds ratio (OR) of 5.83 [95% confidence interval (CI) 2.82-12.03, P < 0.001] to have a plasma homoarginine concentration above the median. The median homoarginine plasma concentration in patients taking fenofibrate was 2.30 µmol/L versus 1.55 in patients not taking the drug (P < 0.001). In addition, fibrates were significantly associated with lower plasma SDMA and higher l-arginine concentrations. In contrast, glucocorticoids were associated with lower plasma homoarginine, with adjusted ORs of 0.52 (95% CI 0.40-0.67, P < 0.001) and 0.53 (95% CI 0.31-0.90, P = 0.018) for prednisolone and methylprednisolone, respectively. CONCLUSIONS: In a large cohort of CKD patients, intake of fenofibrate and glucocorticoids were independently associated with higher and lower plasma homoarginine concentrations, respectively. Effects on plasma homoarginine and methylarginines warrant further investigation as potential mechanisms mediating beneficial or adverse drug effects.

Management of Hyperuricemia in Patients with Chronic Kidney Disease: a Focus on Renal Protection.

PURPOSE OF REVIEW: In chronic kidney disease (CKD), plasma uric acid levels are increased because of the decrease in glomerular filtration rate. However, in addition to CKD, hyperuricemia is frequently associated with a number of other conditions such as hypertension, type 2 diabetes, obesity, and heart failure, overweight, and cardiovascular disease. RECENT FINDINGS: It is now becoming increasingly clear that, in many clinical conditions, elevated levels of uric acid have a much greater role beyond just causing gout. The present review will summarize current knowledge on the relation between hyperuricemia, CKD, and existing comorbidities, as well as the mechanisms of uric acid-related renal damage. In addition, the role and evidence for urate-lowering therapy in prevention and cardiovascular protection in CKD patients is discussed with a focus on allopurinol and febuxostat. To date, several clinical studies have provided evidence that urate-lowering therapy may help to prevent and delay the decline of renal function in patients with CKD. Use of a xanthine oxidase inhibitor should be considered in patients who are at high renal risk and/or with declining renal function in the presence of hyperuricemia with and without deposition, although additional studies are warranted to define treatment targets. Notwithstanding, the possibility to delay deterioration of renal function in patients with CKD merits consideration.

ADAMTS13 activity is associated with early neurological improvement in acute ischemic stroke patients treated with intravenous thrombolysis.

Although intravenous thrombolysis (IVT) with recombinant tissue-plasminogen-activator represents a highly effective treatment in acute ischemic stroke patients, not every patient benefits. We hypothesized that pretreatment levels of mediators of hemostasis (VWF and ADAMTS13) and dimethylarginines (ADMA and SDMA) are associated with early neurological improvement and outcome after IVT in ischemic stroke. Moreover we aimed to investigate the link between ADAMTS13 and markers of inflammation (CRP, IL-6, MMP-9 and MCP-1). In 43 patients with acute ischemic stroke treated with IVT blood samples for determination of the different markers were strictly taken before treatment, as well as at 24 h, 3, 7 and 90 days after symptom onset. Early neurological improvement was assessed using the shift between National Institutes of Health Stroke Scale (NIHSS) at baseline and at 24 h. Outcome at 90 days was assessed using the modified Rankin Scale. The lowest quartile of ADAMTS13 activity was independently associated with less improvement in NIHSS (baseline-24 h) (OR 1.298, p = 0.050). No independent association of ADMA or SDMA levels at baseline with outcome could be shown. Furthermore, IL-6, MCP-1 and CRP levels at 90 days significantly differed between patients with low and high ADAMTS13 activity. Thus, ADAMTS13 might indicate or even influence efficacy of IVT.

Single- and multiple-dose pharmacokinetics and total removal of colistin in critically ill patients with acute kidney injury undergoing prolonged intermittent renal replacement therapy.

BACKGROUND: Owing to the emerging problem of MDR bacteria, interest in 'old' antibiotics such as colistin has re-emerged. However, research on the dosing of colistin in patients undergoing renal replacement therapy (RRT), such as prolonged intermittent renal replacement therapy (PIRRT), is scarce. OBJECTIVES: The aim of this study was to evaluate single- and multiple-dose pharmacokinetics of colistin and its prodrug colistin methanesulfonate in ICU patients with acute kidney injury (AKI) undergoing PIRRT. METHODS: We performed a prospective clinical pharmacokinetic single- and multiple-dose study. Eight ICU patients with AKI undergoing treatment with PIRRT and receiving intravenous colistin were studied on day 1 and days 5-9 of treatment, depending on the timing of dialysis. Six million IU (MIU) of colistin methanesulfonate was administered 8 h prior to the PIRRT session followed by 3 MIU every 8 h. The study was registered under clinicaltrails.gov (NCT02556190). RESULTS: PIRRT removed a considerable amount of colistin and colistin methanesulfonate with a median dialyser plasma CL of 70.1 mL/min (IQR 36.6-96.2) for colistin and 69.3 mL/min (IQR 56.3-318.7) for colistin methanesulfonate. The median amount of colistin in the total collected dialysate was 154 mg (IQR 105-175), corresponding to about 50% of the daily dose. Median colistin peak concentrations accumulated from 5.79 mg/L (IQR 4.14-8.79) on day 1 to 9.49 mg/L (IQR 8.39-10.41) on days 5-9. Cmax was significantly and inversely correlated with body weight. CONCLUSIONS: PIRRT eliminates about half of the daily administered colistin dose. Even a 6 MIU loading dose of colistin methanesulfonate may not ensure immediate sufficient colistin plasma levels in all critically ill patients. However, we measured significant colistin accumulation, suggesting that the dose of colistin methanesulfonate should be adjusted according to body weight and RRT intensity.

Early therapeutic plasma exchange in septic shock: a prospective open-label nonrandomized pilot study focusing on safety, hemodynamics, vascular barrier function, and biologic markers.

BACKGROUND: Given the pathophysiological key role of the host response to an infection rather than the infection per se, an ideal therapeutic strategy would also target this response. This study was designed to demonstrate safety and feasibility of early therapeutic plasma exchange (TPE) in severely ill individuals with septic shock. METHODS: This was a prospective single center, open-label, nonrandomized pilot study enrolling 20 patients with early septic shock (onset < 12 h) requiring high doses of norepinephrine (NE; > 0.4 µg/kg/min) out of 231 screened septic patients. Clinical and biochemical data were obtained before and after TPE. Plasma samples were taken for ex-vivo stimulation of human umbilical vein endothelial cells (HUVECs) to analyze barrier function (immunocytochemistry and transendothelial electrical resistance (TER)). Cytokines were measured by cytometric bead array (CBA) and enzyme-linked immunosorbent assays (ELISAs). An immediate response was defined as > 20% NE reduction from baseline to the end of TPE. RESULTS: TPE was well tolerated without the occurrence of any adverse events and was associated with a rapid reduction in NE (0.82 (0.61-1.17) vs. 0.56 (0.41-0.78) µg/kg/min, p = 0.002) to maintain mean arterial pressure (MAP) above 65 mmHg. The observed 28-day mortality was 65%. Key proinflammatory cytokines and permeability factors (e.g., interleukin (IL)-6, IL-1b, and angiopoietin-2) were significantly reduced after TPE, while the protective antipermeability factor angiopoietin-1 was not changed. Ex-vivo stimulation of HUVECs with plasma obtained before TPE induced substantial cellular hyperpermeability, which was completely abolished with plasma obtained after TPE. CONCLUSIONS: Inclusion of early septic shock patients with high doses of vasopressors was feasible and TPE was safe. Rapid hemodynamic improvement and favorable changes in the cytokine profile in patients with septic shock were observed. It has yet to be determined whether early TPE also improves outcomes in this patient cohort. An appropriately powered multicenter randomized controlled trial is desirable. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03065751 . Retrospectively registered on 28 February 2017.

Therapeutic plasma exchange in a tertiary care center: 185 patients undergoing 912 treatments - a one-year retrospective analysis.

BACKGROUND: Therapeutic plasma exchange (TPE) is increasingly used throughout the world. Although the procedure itself is fairly standardized, it is yet unknown how the underlying disease entities influence the key coordinates of the treatment. METHODS: Retrospective chart review. The treatment indications were clustered into four categories. Data are presented as median and interquartile (25-75%) range [IQR]. RESULTS: Within 1 year, 912 TPE treatments were performed in 185 patients (90 female, 48.6%). The distribution of the treatment numbers to the pre-specified disease categories were as follows: transplantation (35.7%), neurology (31.9%), vasculitis and immunological disease (17.3%), and others including thrombotic microangiopathy (8.1%), critical care related diseases (5.4%), hematology [multiple myeloma] (1.1%), and endocrine disorders (0.5%). The calculated plasma volume was significantly higher in patients with vasculitis and immunological diseases (3984 [3433-4439] ml) as compared to patients treated for transplant related indications (3194 [2545-3658] ml; p = 0.0003) and neurological diseases (3058 [2533-3359] ml; p < 0.0001). This was mainly due to the differences in the hematocrit which was 30.5 [27.0-33.6] % in the vasculitis/immunological disease patients and 40.2 [37.5-42.9] % in the neurological patients; p < 0.0001. Interestingly, treatment time using a membrane based technology was significantly longer than TPE using a centrifugal device 135.0 [125.0-140.0] min vs. 120.0 [112.5-135.0] min. Furthermore, the relative exchanged plasma volume was significantly lower in the treatment of vasculitis and immunological diseases as compared to treatments of transplant related indications and neurological diseases. CONCLUSION: Patients with low hematocrit and high body weight do not receive the minimum recommended dose of exchange volume. Centrifugal TPE allowed faster plasma exchange than membrane TPE.

Dimethylarginines in patients with intracerebral hemorrhage: association with outcome, hematoma enlargement, and edema.

BACKGROUND: Asymmetric dimethylarginine (ADMA)--the most potent endogenous NO-synthase inhibitor, has been regarded as mediator of endothelial dysfunction and oxidative stress. Considering experimental data, levels of ADMA and its structural isomer symmetric dimethylarginine (SDMA) might be elevated after intracerebral hemorrhage (ICH) and associated with clinical outcome and secondary brain injury. METHODS: Blood samples from 20 patients with acute ICH were taken at ≤ 24 h and 3 and 7 days after the event. Nine patients had favorable (modified Rankin Scale (mRS) at 90 days 0-2) outcome, and 11 patients unfavorable outcome (mRS 3-6). Patients' serum ADMA, SDMA, and L-arginine levels were determined by high-performance liquid chromatography-tandem mass spectrometry. Levels were compared to those of 30 control subjects without ICH. For further analysis, patients were grouped according to outcome, hematoma and perihematomal edema volumes, occurrence of hematoma enlargement, and cytotoxic edema as measured by computed tomography and serial magnetic resonance imaging. RESULTS: Levels of ADMA--but not SDMA and L-arginine--were elevated in ICH patients compared to controls (binary logistic regression analysis: ADMA ≤ 24 h, p = 0.003; 3 days p = 0.005; 7 days p = 0.004). If patients were grouped according to outcome, dimethylarginines were increased in patients with unfavorable outcome. The binary logistic regression analysis confirmed an association of SDMA levels ≤ 24 h (p = 0.048) and at 3 days (p = 0.028) with unfavorable outcome. ADMA ≤ 24 h was increased in patients with hematoma enlargement (p = 0.003), while SDMA ≤ 24 h was increased in patients with large hematoma (p = 0.029) and perihematomal edema volume (p = 0.023). CONCLUSIONS: Our data demonstrate an association between dimethylarginines and outcome of ICH. However, further studies are needed to confirm this relationship and elucidate the mechanisms behind.