Non-adherence to cardiometabolic medication as assessed by LC-MS/MS in urine and its association with kidney and cardiovascular outcomes in type 2 diabetes mellitus.

AIMS/HYPOTHESIS: Non-adherence to medication is a frequent barrier in the treatment of patients with type 2 diabetes mellitus, potentially limiting the effectiveness of evidence-based treatments. Previous studies have mostly relied on indirect adherence measures to analyse outcomes based on adherence. The aim of this study was to use LC-MS/MS in urine-a non-invasive, direct and objective measure-to assess non-adherence to cardiometabolic drugs and analyse its association with kidney and cardiovascular outcomes. METHODS: This cohort study includes 1125 participants from the PROVALID study, which follows patients with type 2 diabetes mellitus at the primary care level. Baseline urine samples were tested for 79 cardiometabolic drugs and metabolites thereof via LC-MS/MS. An individual was classified as totally adherent if markers for all drugs were detected, partially non-adherent when at least one marker for one drug was detected, and totally non-adherent if no markers for any drugs were detected. Non-adherence was then analysed in the context of cardiovascular (composite of myocardial infarction, stroke and cardiovascular death) and kidney (composite of sustained 40% decline in eGFR, sustained progression of albuminuria, kidney replacement therapy and death from kidney failure) outcomes. RESULTS: Of the participants, 56.3% were totally adherent, 42.0% were partially non-adherent, and 1.7% were totally non-adherent to screened cardiometabolic drugs. Adherence was highest to antiplatelet and glucose-lowering agents and lowest to lipid-lowering agents. Over a median (IQR) follow-up time of 5.10 (4.12-6.12) years, worse cardiovascular outcomes were observed with non-adherence to antiplatelet drugs (HR 10.13 [95% CI 3.06, 33.56]) and worse kidney outcomes were observed with non-adherence to antihypertensive drugs (HR 1.98 [95% CI 1.37, 2.86]). CONCLUSIONS/INTERPRETATION: This analysis shows that non-adherence to cardiometabolic drug regimens is common in type 2 diabetes mellitus and negatively affects kidney and cardiovascular outcomes.

International Variability of Renal and Cardiovascular Outcomes and Mortality in Patients with Type 2 Diabetes Mellitus in Europe.

INTRODUCTION: Type 2 diabetes and its complications represent a huge burden to public health. With this prospective, observational cohort study, we aimed to estimate and to compare the incidence rate (IR) of renal and cardiovascular outcomes and all-cause mortality in patients with type 2 diabetes in different European countries. METHODS: The renal endpoint was a composite of a sustained decline in estimated GFR of at least 40%, a sustained increase in albuminuria of at least 30% including a transition in albuminuria class, progression to kidney failure with replacement therapy, or death from renal causes. The cardiovascular endpoint was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. RESULTS: 3,131 participants from four European countries (Austria, Hungary, The Netherlands, and Scotland) with a median follow-up time of 4.4 years were included. IRs were adjusted for several risk factors including sex, age, estimated GFR, albuminuria, HbA1c, blood pressure, and duration of type 2 diabetes. Across countries, the adjusted IR for the renal endpoint was significantly higher in Hungary and Austria, and the adjusted IR for the cardiovascular endpoint was significantly higher in Scotland and Austria. All-cause mortality was significantly higher in Scotland compared to all other countries. CONCLUSION: Our findings show how the longitudinal outcome of patients with type 2 diabetes varies significantly across European countries even after accounting for the distribution of underlying risk factors.

Pneumoperitoneum and Acute Kidney Injury-An Integrative Clinical Concept Review.

An increased intraabdominal pressure, particularly when occurring during periods of hemodynamic instability or fluid overload, is regarded as a major contributor to acute kidney injury (AKI) in intensive care units. During abdominal laparoscopic procedures, intraoperative insufflation pressures up to 15 mmHg are applied, to enable visualization and surgical manipulation but with the potential to compromise net renal perfusion. Despite the widely acknowledged renal arterial autoregulation, net arterial perfusion pressure is known to be narrow, and the effective renal medullary perfusion is disproportionately impacted by venous and lymphatic congestion. At present, the potential risk factors, mitigators and risk-stratification of AKI during surgical pneumoperitoneum formation received relatively limited attention among nephrologists and represent an opportunity to look beyond mere blood pressure and intake-output balances. Careful charting and reporting duration and extent of surgical pneumoperitoneum represents an opportunity for anesthesia teams to better communicate intraoperative factors affecting renal outcomes for the postoperative clinical teams. In this current article, the authors are integrating preclinical data and clinical experience to provide a better understanding to optimize renal perfusion during surgeries. Future studies should carefully consider intrabdominal insufflation pressure as a key variable when assessing outcomes and blood pressure goals in these settings.

Susceptibility to kidney fibrosis in mice is associated with early growth response-2 protein and tissue inhibitor of metalloproteinase-1 expression.

Patients with chronic kidney disease and experimental animal models of kidney fibrosis manifest diverse progression rates. Genetic susceptibility may contribute to this diversity, but the causes remain largely unknown. We have previously described kidney fibrosis with a mild or severe phenotype in mice expressing transforming growth factor-beta1 (TGF-ß1) under the control of a mouse albumin promoter (Alb/TGF-ß1), on a mixed genetic background with CBAxC57Bl6 mice. Here, we aimed to examine how genetic background may influence kidney fibrosis in TGF-ß1 transgenic mice, and in the unilateral ureteral obstruction (UUO) and subtotal nephrectomy (SNX) mouse models. Congenic C57Bl6(B6)-TGFß and CBAxB6-TGFß (F1) transgenic mice were generated and survival, proteinuria, kidney histology, transcriptome and protein expressions were analyzed. We investigated the kidneys of B6 and CBA mice subjected to UUO and SNX, and the effects of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) neutralization on the fibrotic process. CBAxB6-TGFß mice developed severe kidney fibrosis and premature death, while B6-TGF-ß mice had mild fibrosis and prolonged survival. Kidney early growth response factor-2 (EGR2) and TIMP-1 expression were induced only in CBAxB6-TGFß mice. Similar strain-dependent early changes in EGR2 and TIMP-1 of mice subjected to UUO or SNX were observed. TIMP-1 neutralization in vivo hindered fibrosis both in transgenic mice and the SNX model. EGR2 over-expression in cultured HEK293 cells induced TIMP-1 while EGR2 silencing hindered TGF-ß induced TIMP-1 production in HK-2 cells and ureteral obstructed kidneys. Finally, EGR2 and TIMP1 was increased in human kidneys manifesting focal segmental glomerulosclerosis suggesting a correlation between animal studies and patient clinical settings. Thus, our observations demonstrate a strong relationship between genetic background and the progression of kidney fibrosis, which might involve early altered EGR2 and TIMP-1 response, but the relationship to patient genetics remains to be explored.

Clonal Hematopoiesis of Indeterminate Potential and Diabetic Kidney Disease: A Nested Case-Control Study.

Introduction: The disease trajectory of diabetic kidney disease (DKD) shows a high interindividual variability not sufficiently explained by conventional risk factors. Clonal hematopoiesis of indeterminate potential (CHIP) is a proposed novel cardiovascular risk factor. Increased kidney fibrosis and glomerulosclerosis were described in mouse models of CHIP. Here, we aim to analyze whether CHIP affects the incidence or progression of DKD. Methods: A total of 1419 eligible participants of the PROVALID Study were the basis for a nested case-control (NCC) design. A total of 64 participants who reached a prespecified composite endpoint within the observation period (initiation of kidney replacement therapy, death from kidney failure, sustained 40% decline in estimated glomerular filtration rate or sustained progression to macroalbuminuria) were identified and matched to 4 controls resulting in an NCC sample of 294 individuals. CHIP was assessed via targeted amplicon sequencing of 46 genes in peripheral blood. Furthermore, inflammatory cytokines were analyzed in plasma via a multiplex assay. Results: The estimated prevalence of CHIP was 28.91% (95% CI 22.91%-34.91%). In contrast to other known risk factors (albuminuria, hemoglobin A1c, heart failure, and smoking) and elevated microinflammation, CHIP was not associated with incident or progressive DKD (hazard ratio [HR] 1.06 [95% CI 0.57-1.96]). Conclusions: In this NCC study, common risk factors as well as elevated microinflammation but not CHIP were associated with kidney function decline in type 2 diabetes mellitus.

A porcine model of hemodialyzer reactions: roles of complement activation and rinsing back of extracorporeal blood.

Hemodialysis reactions (HDRs) resemble complement-activation-related pseudoallergy (CARPA) to certain i.v. drugs, for which pigs provide a sensitive model. On this basis, to better understand the mechanism of human HDRs, we subjected pigs to hemodialysis using polysulfone (FX CorDiax 40, Fresenius) or cellulose triacetate (SureFlux-15UX, Nipro) dialyzers, or Dialysis exchange-set without membranes, as control. Experimental endpoints included typical biomarkers of porcine CARPA; pulmonary arterial pressure (PAP), blood cell counts, plasma sC5b-9 and thromboxane-B2 levels. Hemodialysis (60 min) was followed by reinfusion of extracorporeal blood into the circulation, and finally, an intravenous bolus injection of the complement activator zymosan. The data indicated low-extent steady rise of sC5b-9 along with transient leukopenia, secondary leukocytosis and thrombocytopenia in the two dialyzer groups, consistent with moderate complement activation. Surprisingly, small changes in baseline PAP and plasma thromboxane-B2 levels during hemodialysis switched into 30%-70% sharp rises in all three groups resulting in synchronous spikes within minutes after blood reinfusion. These observations suggest limited complement activation by dialyzer membranes, on which a membrane-independent second immune stimulus was superimposed, and caused pathophysiological changes also characteristic of HDRs. Thus, the porcine CARPA model raises the hypothesis that a second "hit" on anaphylatoxin-sensitized immune cells may be a key contributor to HDRs.

Impact of the first wave of COVID-19 pandemic on the Hungarian university students' social and health behaviour.

BACKGROUND: The COVID-19 pandemic brought quick, severe and unexpected changes to our everyday life and also changed the traditional education pattern of Semmelweis University in the middle of academic year 2019-2020. We explored adaptive changes in Hungarian students' behaviour and their time-budget in order to determine whether quarantine and/or fear of infection were responsible for these changes. METHODS: A self-administered online questionnaire was distributed to all students in the Hungarian language program (N = 7436) of Semmelweis University. Information was collected on basic demographic data, knowledge and attitude about COVID-19, methods of prevention as well as the students' behaviour before, during and after the first wave of the pandemic. Statistical analyses were processed using the IBM-SPSS 25.0 software package. RESULTS: The overall response rate was 11% (N = 816). Only complete responses were processed (55%, N = 447). Among these responders, 83% did not fear the pandemic. Those who greatly feared COVID-19 infection strictly kept all regulations. The number of non-smokers increased by the end of the first wave. The nutrition of 100 students (21%) became healthier and the lockdown reduced the level of physical activity. CONCLUSION: Social and health-related behaviour of medical students changed basically during the first wave of the pandemic and some changes remained after it in tobacco smoking, nutrition and sleeping habits. Time-budget of students changed significantly during the pandemic and did not return to the baseline values. Results of this study justify future multiple systematic research to analyse and better understand the short- and long-term effects of the current crisis.

Intra-individual variability of eGFR trajectories in early diabetic kidney disease and lack of performance of prognostic biomarkers.

Studies reporting on biomarkers aiming to predict adverse renal outcomes in patients with type 2 diabetes and kidney disease (DKD) conventionally define a surrogate endpoint either as a percentage of decrease of eGFR (e.g. ≥ 30%) or an absolute decline (e.g. ≥ 5 ml/min/year). The application of those study results in clinical practise however relies on the assumption of a linear and intra-individually stable progression of DKD. We studied 860 patients of the PROVALID study and 178 of an independent population with a relatively preserved eGFR at baseline and at least 5 years of follow up. Individuals with a detrimental prognosis were identified using various thresholds of a percentage or absolute decline of eGFR after each year of follow up. Next, we determined how many of the patients met the same criteria at other points in time. Interindividual eGFR decline was highly variable but in addition intra-individual eGFR trajectories also were frequently non-linear. For example, of all subjects reaching an endpoint defined as a decrease of eGFR by ≥ 30% between baseline and 3 years of follow up, only 60.3 and 45.2% lost at least the same amount between baseline and year 4 or 5. The results were similar when only patients on stable medication or subpopulations based on baseline eGFR or albuminuria status were analyzed or an eGFR decline of ≥ 5 ml/min/1.73m2/year was used. Identification of reliable biomarkers predicting adverse prognosis is a strong clinical need given the large interindividual variability of DKD progression. However, it is conceptually challenging in early DKD because of non-linear intra-individual eGFR trajectories. As a result, the performance of a prognostic biomarker may be accurate after a specific time of follow-up in a single population only.

Safety and efficacy of placement of tunneled hemodialysis catheter without the use of fluoroscopy.

INTRODUCTION: The implantation of acute or chronic vascular accesses for hemodialysis (HD) in end-stage kidney disease patients is a critical skill procedure for nephrologists, with an impact on short- and long-term outcomes of the modality and patient survival. Placement circumstances, however, may depend on the availability of technological support and will likely vary across the world. MATERIALS AND METHODS: We retrospectively reviewed our local experience with ultrasound-guided tunneled dialysis catheter (TDC) insertions but without access to fluoroscopic guidance. Data were available for 63 patients with TDCs placed by faculty nephrologists at the dialysis unit procedure rooms between March 2015 and February 2018. We reviewed circumstances of TDC placement, patient characteristics, and procedural outcomes. RESULTS: The mean age was 62 (± 41) years, and 46% of the patients were male. All TDC placements were technically successful and no major complications occurred. Most TDCs (52.8%) were a de novo placement. In the de novo patient group, there were 27 right-sided internal jugular vein (IJV) and 6 left-sided IJV cannulations. Blood pump flow was 284.6 (± 58) mL/min via the temporary catheter 1 month before and 316.7 (± 46) mL/min 1 month after TDC placement (p < 0.0001). The majority of catheter tips (63%) reached the right atrial placement position successfully. DISCUSSION: Technologically successful TDC placement can be performed without fluoroscopic tip guidance and result in improved access flows and dialysis efficacy when compared to temporary hemodialysis catheters.

All together to Fight COVID-19.

Novel coronavirus disease (COVID-19), named a pandemic by the WHO, is the current global health crisis. National and international collaboration are indispensable for combating COVID-19 and other similar potential outbreaks. International efforts to tackle this complex problem have led to remarkable scientific advances. Yet, as a global society, we can and must take additional measures to fight this pandemic. Undoubtedly, our approach toward COVID-19 was not perfect, and testing has not been deployed fast enough to arrest the epidemic early on. It is critical that we revise our approaches to be more prepared for pandemics as a united body by promoting global cooperation and commitment.

Can chlorine dioxide prevent the spreading of coronavirus or other viral infections? Medical hypotheses.

Motivation: Viruses have caused many epidemics throughout human history. The novel coronavirus [10] is just the latest example. A new viral outbreak can be unpredictable, and development of specific defense tools and countermeasures against the new virus remains time-consuming even in today's era of modern medical science and technology. In the lack of effective and specific medication or vaccination, it would be desirable to have a nonspecific protocol or substance to render the virus inactive, a substance/protocol, which could be applied whenever a new viral outbreak occurs. This is especially important in cases when the emerging new virus is as infectious as SARS-CoV-2 [4]. Aims and structure of the present communication: In this editorial, we propose to consider the possibility of developing and implementing antiviral protocols by applying high purity aqueous chlorine dioxide (ClO2) solutions. The aim of this proposal is to initiate research that could lead to the introduction of practical and effective antiviral protocols. To this end, we first discuss some important properties of the ClO2 molecule, which make it an advantageous antiviral agent, then some earlier results of ClO2 gas application against viruses will be reviewed. Finally, we hypothesize on methods to control the spread of viral infections using aqueous ClO2 solutions.

Integrative analysis of prognostic biomarkers derived from multiomics panels helps discrimination of chronic kidney disease trajectories in people with type 2 diabetes.

Clinical risk factors explain only a fraction of the variability of estimated glomerular filtration rate (eGFR) decline in people with type 2 diabetes. Cross-omics technologies by virtue of a wide spectrum screening of plasma samples have the potential to identify biomarkers for the refinement of prognosis in addition to clinical variables. Here we utilized proteomics, metabolomics and lipidomics panel assay measurements in baseline plasma samples from the multinational PROVALID study (PROspective cohort study in patients with type 2 diabetes mellitus for VALIDation of biomarkers) of patients with incident or early chronic kidney disease (median follow-up 35 months, median baseline eGFR 84 mL/min/1.73 m2, urine albumin-to-creatinine ratio 8.1 mg/g). In an accelerated case-control study, 258 individuals with a stable eGFR course (median eGFR change 0.1 mL/min/year) were compared to 223 individuals with a rapid eGFR decline (median eGFR decline -6.75 mL/min/year) using Bayesian multivariable logistic regression models to assess the discrimination of eGFR trajectories. The analysis included 402 candidate predictors and showed two protein markers (KIM-1, NTproBNP) to be relevant predictors of the eGFR trajectory with baseline eGFR being an important clinical covariate. The inclusion of metabolomic and lipidomic platforms did not improve discrimination substantially. Predictions using all available variables were statistically indistinguishable from predictions using only KIM-1 and baseline eGFR (area under the receiver operating characteristic curve 0.63). Thus, the discrimination of eGFR trajectories in patients with incident or early diabetic kidney disease and maintained baseline eGFR was modest and the protein marker KIM-1 was the most important predictor.

Complement Activation-Related Pathophysiological Changes in Anesthetized Rats: Activator-Dependent Variations of Symptoms and Mediators of Pseudoallergy.

Complement (C) activation can underlie the infusion reactions to liposomes and other nanoparticle-based medicines, a hypersensitivity syndrome that can be partially reproduced in animal models. However, the sensitivities and manifestations substantially differ in different species, and C activation may not be the only cause of pathophysiological changes. In order to map the species variation of C-dependent and -independent pseudoallergy (CARPA/CIPA), here we used known C activators and C activator liposomes to compare their acute hemodynamic, hematological, and biochemical effects in rats. These C activators were cobra venom factor (CVF), zymosan, AmBisome (at 2 doses), its amphotericin B-free vehicle (AmBisombo), and a PEGylated cholesterol-containing liposome (PEG-2000-chol), all having different powers to activate C in rat blood. The pathophysiological endpoints measured were blood pressure, leukocyte and platelet counts, and plasma thromboxane B2, while C activation was assessed by C3 consumption using the Pan-Specific C3 assay. The results showed strong linear correlation between C activation and systemic hypotension, pointing to a causal role of C activation in the hemodynamic changes. The observed thrombocytopenia and leukopenia followed by leukocytosis also correlated with C3 conversion in case of C activators, but not necessarily with C activation by liposomes. These findings are consistent with the double hit hypothesis of hypersensitivity reactions (HSRs), inasmuch as strong C activation can fully account for all symptoms of HSRs, but in case of no-, or weak C activators, the pathophysiological response, if any, is likely to involve other activation pathways.

Liposome-induced hypersensitivity reactions: Risk reduction by design of safe infusion protocols in pigs.

Intravenous administration of liposomal drugs can entail infusion reactions, also known as hypersensitivity reactions (HSRs), that can be severe and sometimes life-threatening in a small portion of patients. One empirical approach to prevent these reactions consists of lowering the infusion speed and extending the infusion time of the drug. However, different liposomal drugs have different levels of reactogenicity, which means that the optimal protocol for each liposomal drug may differ and should be identified and evaluated to make the treatment as safe and convenient as possible. The goal of the present study was to explore the use of pigs for the above purpose, using PEGylated liposomal prednisolone (PLP) as a model drug. We compared the reactogenicities of bolus versus infusion protocols involving 2-, 3- and 4-step dose escalations for a clinically relevant total dose, also varying the duration of infusions. The strength of HSRs was measured via continuous recording of hemodynamic parameters and blood thromboxane B2 levels. We showed that bolus administration or rapid infusion of PLP caused transient changes in systemic and pulmonary blood pressure and heart rate, most notably pulmonary hypertension with paralleling rises in plasma thromboxane B2. These adverse responses could be significantly reduced or eliminated by slow infusion of PLP, with the 3-h 3-step dose escalation protocol being the least reactogenic. These data suggest that the pig model enables the development of safe infusion protocols for reactogenic nanomedicines.

Pseudo-anaphylaxis to Polyethylene Glycol (PEG)-Coated Liposomes: Roles of Anti-PEG IgM and Complement Activation in a Porcine Model of Human Infusion Reactions.

Polyethylene glycol (PEG)-coated nanopharmaceuticals can cause mild to severe hypersensitivity reactions (HSRs), which can occasionally be life threatening or even lethal. The phenomenon represents an unsolved immune barrier to the use of these drugs, yet its mechanism is poorly understood. This study showed that a single i.v. injection in pigs of a low dose of PEGylated liposomes (Doxebo) induced a massive rise of anti-PEG IgM in blood, peaking at days 7-9 and declining over 6 weeks. Bolus injections of PEG-liposomes during seroconversion resulted in anaphylactoid shock (pseudo-anaphylaxis) within 2-3 min, although similar treatments of naïve animals led to only mild hemodynamic disturbance. Parallel measurement of pulmonary arterial pressure (PAP) and sC5b-9 in blood, taken as measures of HSR and complement activation, respectively, showed a concordant rise of the two variables within 3 min and a decline within 15 min, suggesting a causal relationship between complement activation and pulmonary hypertension. We also observed a rapid decline of anti-PEG IgM in the blood within minutes, increased binding of PEGylated liposomes to IgM+ B cells in the spleen of immunized animals compared to control, and increased C3 conversion by PEGylated liposomes in the serum of immunized pigs. These observations taken together suggest rapid binding of anti-PEG IgM to PEGylated liposomes, leading to complement activation via the classical pathway, entailing anaphylactoid shock and accelerated blood clearance of liposome-IgM complexes. These data suggest that complement activation plays a causal role in severe HSRs to PEGylated nanomedicines and that pigs can be used as a hazard identification model to assess the risk of HSRs in preclinical safety studies.

The association of overhydration with megafistulas in hemodialysis patients.

Objectives: Diffuse enlargements of arteriovenous dialysis fistulas customarily attributed to either excessive arterial inflow or central outflow stenosis. The relationship between volume status and clinically enlarged (arteriovenous) fistula (CEF) formation in end-stage renal disease (ESRD) patients is not well understood. Methods: We assessed the pre-dialysis bioimpedance spectroscopy-measured percentage of overhydration (OH%) in 13 prevalent dialysis patients with CEF development and negative angiography and compared the results with those of 52 control dialysis patients (CONTR). All patients were prevalent ESRD patients receiving thrice-weekly maintenance hemodiafiltration at an academic outpatient dialysis unit. Results: 10/13 CEF patients had OH% ≥15% as compared to 20/52 control patients (Chi square p: .02). The degree of OH% was 20.2 ± 7.4% among the CEF vs. 14.4 ± 7.1% in the control group (Student's t-test p: .01), representing 4.2 ± 3.2 vs. 2.8 ± 1.6 L of excess fluid pre-dialysis (p: .03). Patients with CEF development took an average of 1.7 ± 1.4 vs. 0.8 ± 0.8 (p: .002) antihypertensive medications compared to the CONTR patients, yet their blood pressure was higher: 156/91 vs. 141/78 mmHg (systolic/diastolic p: .03<.0001). We found no difference in fistula vintage, body mass index, age, diabetes status, or diuretic use. The odds ratio of having a CEF in patients with ≥15% OH status was 5.3 (95% CI: 1.3-21.7; p: .01), the Number Needed to Harm with overhydration was 4. Conclusions: There is an association between bioimpedance spectroscopy-measured overhydrated clinical state and the presence of CEF; either as an increased volume capacitance or as a potential cause.

Bedside placement of peritoneal dialysis catheters - a single-center experience from Hungary.

Objectives: The successful implantation of peritoneal dialysis (PD) catheters is a critical skill procedure with the potential to impact both the short- and long-term success of renal replacement therapy and the patients' survival. Methods: We retrospectively reviewed our single-center experience with nephrologist-placed minimally invasive, double-cuffed PD catheters (PDCs). Results: The recruitment period was March 2014 through December 2015. The follow-up period lasted until 2016. The mean age of the subjects was 60 ± 18 years and indications for the PD were diuretic resistant acutely decompensated chronic heart failure in seven patients (47%) and end-stage renal disease in eight (53%) patients. Comorbid conditions included diabetes (27%), ischemic heart disease (47%), advanced liver failure (27%), and a history of hypertension (73%). The cohort had a high mortality with five subjects only in severe heart failure group (33%) passing away during the index hospitalization; of the rest, two (13%) had heart transplantation, three (20%) changed modality to hemodialysis, and only five (33%) continued with maintenance PD beyond 1 month. Acute technical complications within the first month were infrequent: one catheter (6%) had drainage problems and one (6%) was lost due to extrusion. There were no serious complications (e.g., organ damage, peritonitis, etc.). Conclusions: In selected cases, particularly in severe diuretic refractory heart failure, PDC placement placed by a nephrologist is feasible with a low rate of complications even in a low-volume center setting. The catheters we placed were all functioning with only minor complications and PD could be started immediately.

Therapeutic Targeting of Fibrotic Epithelial-Mesenchymal Transition-An Outstanding Challenge.

Back in 1995, a landmark paper was published, which shaped the fibrosis literature for many years to come. During the characterization of a fibroblast-specific marker (FSP1) in the kidneys, an observation was made, which gave rise to the hypothesis that "fibroblasts in some cases arise from the local conversion of epithelium." In the following years, epithelial-mesenchymal transition was in the spotlight of fibrosis research, especially in the kidney. However, the hypothesis came under scrutiny following some discouraging findings from lineage tracing experiments and clinical observations. In this review, we provide a timely overview of the current position of the epithelial-mesenchymal transition hypothesis in the context of fibrosis (with a certain focus on renal fibrosis) and highlight some of the potential hurdles and pitfalls preventing therapeutic breakthroughs targeting fibrotic epithelial-mesenchymal transition.

The association of overhydration with chronic inflammation in chronic maintenance hemodiafiltration patients.

INTRODUCTION: Achieving euvolemia is one of the major challenges when treating end-stage renal disease (ESRD) patients receiving maintenance renal replacement therapy. Fluid overload is recognized as an independent predictor of mortality in ESRD, but its association with chronic inflammation is less well explored especially in chronic maintenance hemodiafiltration. METHODS: We performed a cross-sectional study of 87 prevalent ESRD patients receiving chronic maintenance hemodiafiltration (vintage 66.5 ± 57.1 months) with bioimpedance analysis to characterize the degree of percent overhydration (OH%). We also compared the levels of inflammatory markers, including C-reactive protein (CRP), serum albumin, neutrophil/lymphocyte ratio (NLR), and hemoglobin red cell distribution width (RDW) for the overhydrated (OH% ≥ 15%) versus euvolemic (OH% < 15%) groups. Linear regression analysis was performed to explore relationships between the degree of OH and inflammatory indicators. FINDINGS: The cohort represented an all-European population with a mean age of 60.9 ± 14.7 years and prevalence of diabetes mellitus of 27%. The entire cohort's OH% was 14.9% ± 5.1% (range -11.1% to 39.0%); further, the <15% group of patients' OH% was 8.0% ± 8.5% versus 20.9% ± 5.1% in the OH% ≥ 15% group (P < 0.0001). Forty-seven patients (53%) were overhydrated by traditional criteria (OH% ≥15%) and 20 patients (23%) were severely overhydrated (OH% > 20%). The euvolemic (OH% <15%) versus severely overhydrated (OH% > 20%) groups had significant differences in markers of inflammation: CRP (9.8 ± 10.6 vs. 21.5 ± 21.6 mg/L, P < 0.006), serum albumin (37.6 ± 02.9 vs. 34.5 ± 5.3 g/L, P < 0.004), and NLR (3.06 ± 1.25 vs. 3.92 ± 2.04; P < 0.004). On linear regression, significant correlations were found between OH% and CRP (r = 0.2899, P < 0.006), serum albumin (r = -0.3670; P < 0.0005), RDW (r = 0.2992; P < 0.005), and NLR (r = 0.2900; P < 0.006). DISCUSSION: In a prevalent hemodiafiltration cohort, OH was common and correlated with several inflammatory markers.

Acute physiological changes caused by complement activators and amphotericin B-containing liposomes in mice.

PURPOSE: Undesirable complement (C) activation by nanomedicines can entail an adverse immune reaction known as C activation-related pseudoallergy (CARPA) in sensitive patients. The syndrome includes cardiopulmonary, hemodynamic, and a variety of other physiological changes that have been well described in man, pigs, dogs, and rats. However, the information on CARPA is scarce and ambiguous in mice, a species widely used in preclinical studies. The present study aimed to fill this gap by exploring signs of CARPA in mice following i.v. administration of AmBisome and Abelcet, which are nano-formulations of Amphotericin B with high risk to cause CARPA. MATERIALS AND METHODS: Anesthetized NMRI mice were intravenously injected with liposomal amphotericin B (Abelcet and AmBisome; 30-300 mg phospholipid/kg), drug-free high cholesterol multilamellar vesicles (HC-MLV), and positive controls, cobra venom factor (CVF) and zymosan, followed by the measurement of blood pressure (BP), heart rate, white blood cell, and platelet counts and plasma thromboxane B2 (TXB2) levels. C activation was assessed by C3a ELISA, a C3 consumption assay (PAN-C3) and a modified sheep red blood cell hemolytic assay. RESULTS: All test agents, except HC-MLV, caused transient hypertension, thrombocytopenia, and elevation of plasma TXB2, which were paralleled by significant rises of plasma C3a in CVF and zymosan-treated animals, wherein the initial hypertension turned into hypotension and shock. Abelcet and AmBisome caused minor, delayed rise of C3a that was not associated with hypertension. The C3a receptor inhibitor SB-290157 attenuated the hypertension caused by Abelcet and decreased the BP thereafter. CONCLUSION: The parallelism between C3a anaphylatoxin production and severity of physiological changes caused by the different agents is consistent with CARPA underlying these changes. Although the reactive dose of liposomal phospholipids was substantially higher than that in other species (pigs, dogs), the mouse seems suitable for studying the mechanism of hypersensitivity reactions to liposomal formulations of amphotericin B, a frequent side effect of these drugs.