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Lymphoma-associated Hemophagocytic lymphohistiocytosis (HLH) represents a severe complication of disease progression, mediated through cytokine release from the lymphoma cells. Cytokine adsorption may contribute as a supportive treatment to stabilize organ function by reduction of cytokine levels. So far, no experiences of cytokine adsorption and simultaneous stem cell transplantation were published. We report the case of a patient with aggressive lymphoma secondary to chronic lymphocytic leukemia with rapidly progressive HLH (Richter’s transformation) upon conditioning chemotherapy prior to allogeneic stem cell transplantation (ASCT). Continuous hemodiafiltration was initiated in the treatment of shock with acute renal failure, lactacidosis and need for high-dose catecholamine therapy, integrating an additional cytokine-adsorbing filter (CytoSorb®) to reduce cytokine levels. This was followed by scheduled allogenic stem cell transplantation. We observed a marked decrease in interleukin-6 plasma levels, associated with a reduced need for vasopressor therapy and organ function stabilization. Hematopoietic engraftment was present at day 14 post-ASCT, leading to disease-free discharge at day 100 post-transplantation. Cytokine adsorption may serve as a safe adjunct to HLH/sepsis treatment during allogeneic stem cell transplantation. Clinical studies are required to make future treatment recommendations.

Endpoints of large-scale trials in chronic heart failure have mostly been defined to evaluate treatments with regard to hospitalizations and mortality. However, patients with heart failure are also affected by very severe reductions in exercise capacity and quality of life. We aimed to evaluate the effects of heart failure treatments on these endpoints using available evidence from randomized trials. Interventions with evidence for improvements in exercise capacity include physical exercise, intravenous iron supplementation in patients with iron deficiency, and - with less certainty - testosterone in highly selected patients. Erythropoiesis-stimulating agents have been reported to improve exercise capacity in anaemic patients with heart failure. Sinus rhythm may have some advantage when compared with atrial fibrillation, particularly in patients undergoing pulmonary vein isolation. Studies assessing treatments for heart failure co-morbidities such as sleep-disordered breathing, diabetes mellitus, chronic kidney disease and depression have reported improvements of exercise capacity and quality of life; however, the available data are limited and not always consistent. The available evidence for positive effects of pharmacologic interventions using angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and mineralocorticoid receptor antagonists on exercise capacity and quality of life is limited. Studies with ivabradine and with sacubitril/valsartan suggest beneficial effects at improving quality of life; however, the evidence base is limited in particular for exercise capacity. The data for heart failure with preserved ejection fraction are even less positive, only sacubitril/valsartan and spironolactone have shown some effectiveness at improving quality of life. In conclusion, the evidence for state-of-the-art heart failure treatments with regard to exercise capacity and quality of life is limited and appears not robust enough to permit recommendations for heart failure. The treatment of co-morbidities may be important for these patient-related outcomes. Additional studies on functional capacity and quality of life in heart failure are required.

Background Risk of kidney function decline in immunoglobulin A (IgA) nephropathy (IgAN) is significant and may not be predicted by available clinical and histological tools. To serve this unmet need, we aimed at developing a urinary biomarker-based algorithm that predicts rapid disease progression in IgAN, thus enabling a personalized risk stratification. Methods In this multicentre study, urine samples were collected in 209 patients with biopsy-proven IgAN. Progression was defined by tertiles of the annual change of estimated glomerular filtration rate (eGFR) during follow-up. Urine samples were analysed using capillary electrophoresis coupled mass spectrometry. The area under the receiver operating characteristic curve (AUC) was used to evaluate the risk prediction models. Results Of the 209 patients, 64% were male. Mean age was 42 years, mean eGFR was 63 mL/min/1.73 m2 and median proteinuria was 1.2 g/day. We identified 237 urine peptides showing significant difference in abundance according to the tertile of eGFR change. These included fragments of apolipoprotein C-III, alpha-1 antitrypsin, different collagens, fibrinogen alpha and beta, titin, haemoglobin subunits, sodium/potassium-transporting ATPase subunit gamma, uromodulin, mucin-2, fractalkine, polymeric Ig receptor and insulin. An algorithm based on these protein fragments (IgAN237) showed a significant added value for the prediction of IgAN progression [AUC 0.89; 95% confidence interval (CI) 0.83–0.95], as compared with the clinical parameters (age, gender, proteinuria, eGFR and mean arterial pressure) alone (0.72; 95% CI 0.64–0.81). Conclusions A urinary peptide classifier predicts progressive loss of kidney function in patients with IgAN significantly better than clinical parameters alone., Graphical Abstract Graphical Abstract

OBJECTIVES Football as the most popular sport could improve insufficient physical activity in patients with cardiovascular risk factors. A modified 'healthy' football training format could motivate hypertensive patients to return to sport and improve risk factors. METHODS The 3F study: 'Fit and Fun with Football' a prospective interventional study with 1 year follow-up. Football group: n = 103, structured 'health'-football training (1×/week, 90 min) led by Deutscher Fusball Bund-licensed football coaches. Hypertensive patients at least 45 years who have not exercised for several years were compared with a control group (n = 105). PRIMARY STUDY OBJECTIVE Reduction of office (OBP) and/or 24-h ambulatory blood pressure (BP) monitoring (ABPM) and/or reduction of number or dosage of antihypertensive medication. MAIN RESULTS OBP values decreased significantly in the football group from 142.6/87.9 to 130.8/81.8 mmHg (P

Background Due to rising vascular comorbidities of patients undergoing dialysis, the prevalence of permanent hemodialysis catheters as hemodialysis access is increasing. However, infection is a major complication of these catheters. Therefore, identification of potential predicting risk factors leading to early infection related complications is valuable, in particular the significance the CRP (C-reactive protein)-value is of interest. Methods In this retrospective study 151 permanent hemodialysis catheters implanted in 130 patients were examined. The following data were collected at the time of catheter implantation: CRP-value, history of catheter-related infection, microbiological status, immunosuppression and diabetes mellitus. The primary outcomes were recorded over the 3 months following the implantation: catheter-related infection, days of hospital stay and death. Catheter removal or revision, rehospitalization and use of antibiotics were identified as secondary outcomes. Results We identified a total of 27 (17.9%) infections (systemic infection: 2.26 episodes/ 1000 catheter days, local infection: 0.6 episodes/ 1000 catheter days). The development of an infection was independent of the CRP-value (p = 0.66) as well as the presence of diabetes mellitus (p = 0.64) or immunosuppression (p = 0.71). Univariate analysis revealed that infection was more frequent in patients with MRSA-carriage (p

In addition to the early detection of an acute kidney injury (AKI), several problems or questions have to be addressed. These include the identification of the etiology, the severity (functional or structural), the prognosis (recovery or transition to chronic renal failure), the course of the disease (dialysis or not), and the identification of specific treatment options for AKI. The following article provides an overview of established and new AKI biomarkers as well as an outlook on the potential of future biomarker-associated models of AKI.

Twenty-four patients with bi-allelic familial hypercholesterolemia commencing chronic lipoprotein apheresis (LA) at a mean age of 8.5 ± 3.1 years were analysed retrospectively and in part prospectively with a mean follow-up of 17.2 ± 5.6 years. Mean age at diagnosis was 6.3 ± 3.4 years. Untreated mean LDL-C concentrations were 752 mg/dl ± 193 mg/dl (19.5 mmol/l ± 5.0 mmol/l). Multimodal lipid lowering therapy including LA resulted in a mean LDL-C concentration of 184 mg/dl (4.8 mmol/l), which represents a 75.5% mean reduction. Proprotein convertase subtilisin/kexin type 9-antibodies contributed in 3 patients to LDL-C lowering with 5 patients remaining to be tested. After commencing chronic LA, 16 patients (67%) remained clinically stable with only subclinical findings of atherosclerotic cardiovascular disease (ASCVD), and neither cardiovascular events, nor need for vascular interventions or surgery. In 19 patients (79%), pathologic findings were detected at the aortic valve (AV), which in the majority were mild. AV replacement was required in 2 patients. Mean Lipoprotein(a) concentration was 42.4 mg/dl, 38% had >50 mg/dl. There was no overt correlation of AV pathologies with other ASCVD complications, or Lipoprotein(a) concentration. Physicochemical elimination of LDL particles by LA appears indispensable for patients with bi-allelic familial hypercholesterolemia and severe hypercholesterolemia to maximize the reduction of LDL-C. In conclusion, in this rare patient group regular assessment of both the AV, as well as all arteries accessible by ultrasound should be performed to adjust the intensity of multimodal lipid lowering therapy with the goal to prevent ASCVD events and aortic surgery.

Multiple sclerosis (MS) is an inflammatory disease mainly affecting the central nervous system. In MS, abnormal immune mechanisms induce acute inflammation, demyelination, axonal loss, and the formation of central nervous system plaques. The long-term treatment involves options to modify the disease progression, whereas the treatment for the acute relapse has its focus in the administration of high-dose intravenous methylprednisolone (up to 1000 mg daily) over a period of three to five days as a first step. If symptoms of the acute relapse persist, it is defined as glucocorticosteroid-unresponsive, and immunomodulation by apheresis is recommended. However, several national and international guidelines have no uniform recommendations on using plasma exchange (PE) nor immunoadsorption (IA) in this case. A systematic review and meta-analysis was conducted, including observational studies or randomized controlled trials that investigated the effect of PE or IA on different courses of MS and neuromyelitis optica (NMO). One thousand, three hundred and eighty-three patients were included in the evaluation. Therapy response in relapsing-remitting MS and clinically isolated syndrome was 76.6% (95%CI 63.7&ndash, 89.8%) in PE- and 80.6% (95%CI 69.3&ndash, 91.8%) in IA-treated patients. Based on the recent literature, PE and IA may be considered as equal treatment possibilities in patients suffering from acute, glucocorticosteroid-unresponsive MS relapses.

Zusammenfassung Einleitung Zur Prävention kardiovaskulärer Risikofaktoren (RF) existieren zahlreiche Empfehlungen von Fachgesellschaften, die sich auf die persönliche Lebensweise von Menschen beziehen (z. B. Ernährung/Diät, körperliche Aktivität, Stressabbau etc.). Die Umsetzung dieser Empfehlungen ist bislang mangelhaft. In der ELITE-Studie sollen in der Region Oldenburger Münsterland prospektiv Daten zu RF, Ernährungsverhalten, körperlicher Aktivität und Lebensqualität erhoben und durch individuelle Information verbessert werden. Gründe für fehlende Umsetzung von Präventionsmaßnahmen sollen erkannt werden. Methoden Die Studie wird als interventionelle Kohorten-Untersuchung durchgeführt (DRKS-Nr.: 00 006 813; Ethikvotum Universität Göttingen). Bis zu 5000 Personen (mit oder ohne Vorerkrankungen) sollten eingeschlossen werden. Alle Teilnehmer erhalten einen computergenerierten Report ihres persönlichen Risikoprofils mit hieraus resultierenden ausführlichen Empfehlungen, die sich an den aktuellen Leitlinien orientieren. Ergänzend wird empfohlen, den Hausarzt aufzusuchen, um die Befunde zu besprechen und ggf. diagnostische oder therapeutische Maßnahmen einzuleiten. Im Jahresabstand erfolgen über bis zu 5 Jahre Follow-Up-Untersuchungen. Ergebnisse Bis zum 31.12.2017 wurden 4602 Teilnehmer (mittleres Alter 51,5 (± 15,7) Jahre; 53,7 % weiblich) aufgenommen. Übergewichtig sind 39 % der Teilnehmer, adipös 20,4 %. Häufigster anamnestischer RF ist Bluthochdruck (31,4 %), mittlerer Blutdruck 138,4 ± 16,6/83,0 ± 9,9 mmHg. 2165 (47,0 %) Teilnehmer weisen hypertone Blutdruckwerte auf. Zweithäufigster anamnestischer RF sind Fettstoffwechselstörungen (16,6 %). Schlussfolgerung Die Häufigkeit von Teilnehmern mit mindestens einem anamnestisch angegebenen kardiovaskulären RF ist sehr hoch (49,5 %; 16,6 % mehrere RF). Die Häufigkeit von RF entspricht anderen epidemiologischen Daten in Deutschland, sodass das ELITE-Kollektiv einen guten Vergleich mit anderen Erhebungen zulässt.

Though drug adherence is supposed to be low in hypertensive crisis (HTN‐C), there are no data available from direct adherence assessments. The aim of the present study was to evaluate adherence to prescribed antihypertensives and potential interactions of concomitant drugs and foods with prescribed antihypertensives in patients with HTN‐C by a direct evaluation via biochemical urine analysis. In the present cross‐sectional study, 100 patients with HTN‐C, admitted to the emergency department (ED), were included. A biochemical urine analysis using gas chromatography‐tandem mass spectrometry was performed. Out of 100 patients, 86 received antihypertensives. Urine analyses could be evaluated unambiguously in 62 patients. In 15 of these 62 patients (24%), a nonadherence could be demonstrated, and in 21 patients (34%), a partial nonadherence could be demonstrated. Patients with nonadherence or partial nonadherence showed a longer hypertension history (15[5‐22] vs 10[3‐15] years, P = 0.04) were prescribed more general medication (number 7.1 ± 3.4 vs 3.4 ± 1.8; P

Baroreflex activation therapy (BAT) is approved for the treatment of resistant hypertension. In addition to blood pressure (BP) reduction, pilot studies suggested several organoprotective effects of BAT. Thirty‐two patients with resistant hypertension were prospectively treated with BAT. Besides office BP and 24‐hour ambulatory BP (ABP) measurements, detection of a urinary proteome‐based classifier (CKD273), which has been shown to predict chronic kidney disease (CKD) progression, was carried out at baseline and after 6 months of BAT. Office BP significantly decreased from 170 ± 25/90 ± 18 to 149 ± 29/82 ± 18 mm Hg. Analysis of CKD273 score and eGFR with CKD‐EPI equation at baseline revealed strong correlation (r = 0.568, P

Baroreflex activation therapy (BAT) is a sympathoinhibitory procedure for treatment of therapy-resistant hypertension (rsHTN) and severe heart failure with reduced ejection fraction (HFrEF) that been available for several years. The double-blind, randomized Rheos Pivotal Trial demonstrated a blood pressure lowering effect in patients with rsHTN for the first-generation BAT device. A smaller randomized study in heart failure showed that the Barostim Neo system is safe and can improve heart failure symptoms and decrease neuroendocrine activation. However, for this unilateral system, which is currently in clinical use, no data from large randomized trials exist. Despite existing data for BAT in rsHTN and HFrEF, large randomized trials, showing reduction of blood pressure and cardiovascular events are still lacking. Therefore, BAT's efficacy and safety cannot be conclusively assessed.

Acute decompensated heart failure (ADHF) is one of the biggest challenges in the management of chronic heart failure. Despite several advances in medical and device therapy, high readmission and mortality rates continue to be a burden on healthcare systems worldwide. The aim of the current review is to provide an overview on current as well as future approaches in cardiorenal interactions in patients with ADHF. One of the strongest predictors of adverse outcomes in ADHF is renal dysfunction, referred to as cardiorenal syndromes (CRS) or cardiorenal interactions. Patients with ADHF frequently develop worsening of renal function (WRF) and/or acute kidney injury (AKI). Recent studies brought new information about biomarkers in diagnosing and predicting prognosis of CRS. Among others, dry weight at hospital discharge is considered a surrogate marker of successful treatment in ADHF patients with/without renal dysfunction. The etiology of WRF appears to be an important factor for determining risk related to WRF as well as clinical management. The hypertonic saline used as adjunctive therapy for intravenous loop diuretics and/or induction of aquaresis (e.g., using tolvaptan) may be promising and efficient approaches in the future.

Following the publication of the new US guidelines, especially the new classifications of hypertension and the general reduction in treatment targets were discussed worldwide. Applying the US guidelines to a recent German cohort study would in practice lead to a significant increase in the diagnosis of “hypertension” in untreated patients. The number of under-adjusted patients would also increase sharply, increasing more than those predicted in the US Guidelines. Affected by an intensified antihypertensive therapy would be particularly elderly patients, in which adverse drug reactions but also occur more frequently. It seems doubtful whether the massive increase in the diagnosis “hypertension” can improve the supply situation: the opposite effect of avoiding therapists and patients could occur. Determining the individual risk with suitable, evaluated instruments certainly makes sense to treat more targeted patients. More important than new blood pressure limits is a more accurate classification of blood pressure. Repeated self-measurements and ambulatory blood pressure measurement lead to a better selection of patients benefiting from a therapy.

Die therapieresistente und -refraktare arterielle Hypertonie unterscheiden sich in der Haufigkeit, Pathogenese, Prognose und dem therapeutischen Vorgehen. In beiden Fallen bedarf es eines strukturierten Vorgehens mit Ausschluss einer Pseudoresistenz und daran anschliesend einer sekundaren Hypertonie. Die resistente Hypertonie spricht erfahrungsgemas besser auf eine intensivierte diuretische Therapie an, wohingegen die refraktare Hypertonie mutmaslich einer sympathoinhibitorischen Therapie bedarf. Sind Allgemeinmasnahmen und die medikamentose Step-up-Therapie ausgeschopft, stehen interventionelle Verfahren zur Verfugung.

Heart failure and kidney dysfunction are common comorbidities with overlapping and synergizing mechanisms. Coincidence of both pathologies aggravates disease progression rates, symptoms, and outcomes. The treatment of patients with advanced renal insufficiency is faced with limited evidence for therapies that are standard of care in patients with normal and moderate kidney failure, frequent deterioration of kidney function during therapy, and onset of hyperkalemia, which pose challenges for clinical care, requiring intensified physician-patient contacts. A special challenge is the so-called diuretic resistance, which may require extracorporeal drainage.

Baroreceptor activation therapy (BAT) has been available for several years for treatment of therapy-refractory hypertension (trHTN). This procedure is currently being carried out in a limited number of centers in Germany, also with the aim of offering a high level of expertise through sufficient experience; however, a growing number of patients who are treated with BAT experience problems that treating physicians are confronted with in routine medical practice. In order to address these problems, a consensus conference was held with experts in the field of trHTN in November 2016, which summarizes the current evidence and experience as well as the problem areas in handling BAT patients.

Background Baroreceptor-activating therapy (BAT) has been shown to control resistant hypertension in one sham-controlled and further observational studies. Incremental but significant reincrease of blood pressure (BP) have been described after open-label temporary withdrawal of such therapy. Method Our study in 16 randomized patients investigated the course of automated office, ambulatory, and home BP in a randomized, controlled cross-over design. Results After 4 weeks of blinded and randomized withdrawal in hypertension-controlled long-term carriers of BAT (2.67 ± 1.3 years, 145/104 mmHg), the primary end point of 35 mmHg difference, similar to initial BP drop after BAT initiation, was not reached in any patient. Ambulatory BP rose significantly during BAT off by 10/8 ± 4/3 mmHg (3.13/2.10, P = 0.007/0.002) and automated office BP by 10/4 ± 2/1 (4.17/0.58, P = 0.005/0.03) at 4 weeks after BAT on while mean home BP did not change significantly by 2/2 ± 3/2 mmHg (-5.9/-3.5, P = 0.6/0.5). Conclusion Our data in a limited study population show, that BP rise after temporary BAT withdrawal is significant but does not reach a magnitude comparable with the initial drop after de novo implantation. Such results points to preserved hypertension control after electrical BAT withdrawal and deserves further pathophysiological and clinical clarification.

Arterial baroreflex activation through electrical carotid sinus stimulation has been developed for the treatment of resistant hypertension. Previous studies suggested that the peripheral chemoreflex is tonically active in hypertensive patients and may inhibit baroreflex responses. We hypothesized that peripheral chemoreflex activation attenuates baroreflex efficacy evoked by electrical carotid sinus stimulation. We screened 35 patients with an implanted electrical carotid sinus stimulator. Of those, 11 patients with consistent acute depressor response were selected (7 men/4 women, age: 67±8 years, body mass index: 31.6±5.2 kg/m 2 , 6±2 antihypertensive drug classes). We assessed responses to electrical baroreflex stimulation during normoxia, isocapnic hypoxia (SpO 2 : 79.0±1.5%), and hyperoxia (40% end-tidal O 2 fraction) by measuring heart rate, blood pressure, ventilation, oxygen saturation, end-tidal CO 2 and O 2 fractions, and muscle sympathetic nerve activity. During normoxia, baroreflex activation reduced systolic blood pressure from 164±27 to 151±25 mm Hg (mean±SD, P P =0.002), and muscle sympathetic nerve activity from 42±12 to 36±12 bursts/min ( P =0.004). Hypoxia increased systolic blood pressure 8±12 mm Hg ( P =0.057), heart rate 10±6 bpm ( P P =0.031), and ventilation 10±7 L/min ( P =0.002). However, responses to electrical carotid sinus stimulation did not differ between hypoxic and hyperoxic conditions: systolic blood pressure: −15±7 versus −14±8 mm Hg ( P =0.938), heart rate: −2±3 versus −2±2 bpm ( P =0.701), and muscle sympathetic nerve activity: −6±4 versus −4±3 bursts/min ( P =0.531). We conclude that moderate peripheral chemoreflex activation does not attenuate acute responses to electrical baroreflex activation therapy in patients with resistant hypertension. These patients provided insight into human baroreflex-chemoreflex interactions that could not be gained otherwise.

Corrected Proof Children with Alport syndrome develop renal failure early in life. Since the safety and efficacy of preemptive nephroprotective therapy are uncertain we conducted a randomized, placebo-controlled, double-blind trial in 14 German sites of pediatric patients with ramipril for three to six years plus six months follow-up to determine these parameters. Pretreated children and those whose parents refused randomization became an open-arm control, which were compared to prospective real-world data from untreated children. The co-primary endpoints were safety (adverse drug reactions) and efficacy (time to progression). Out of 66 oligosymptomatic children, 22 were randomized and 44 joined the open-arm comparison. Ramipril therapy showed no safety issues (total of 216.4 patient-years on ramipril; adverse event rate-ratio 1.00; 95% confidence interval 0.66-1.53). Although not significant, our results cautiously showed that ramipril therapy was effective: in the randomized arm, Ramipril decreased the risk of disease progression by almost half (hazard ratio 0.51 (0.12–2.20)), diminished the slope of albuminuria progression and the decline in glomerular filtration. In adjusted analysis, indications of efficacy were supported by prospective data from participants treated open label compared with untreated children, in whom ramipril again seemed to reduce progression by almost half (0.53 (0.22-1.29)). Incorporating these results into the randomized data by Bayesian evidence synthesis resulted in a more precise estimate of the hazard-ratio of 0.52 (0.19-1.39). Thus, our study shows the safety of early initiation of therapy and supports the hope to slow renal failure by many years, emphasizing the value of preemptive therapy. Hence, screening programs for glomerular hematuria in children and young adults could benefit from inclusion of genetic testing for Alport-related gene-variants.

Baroreflex activation therapy (BAT) reduces office blood pressure (BP) in patients with resistant hypertension (HTN). Whereas sustained effects from the BAT Rheos device have already been reported, no long-term data on 24-h ambulatory BP (ABP) are currently available for the unilateral BAT Neo device. Patients treated with the BAT neo device for resistant hypertension were prospectively included into this observational study. Office and ABP measurements were performed before BAT implantation as well as 6, 12 and 24 months after initiation of BAT. A total of 60 patients with resistant HTN (office BP 172 ± 25/90 ± 17 mmHg, 24-h ABP 150 ± 16/80 ± 12 mmHg, median of antihypertensive drugs 7 (IQR 6–8)) were included. After 24 months, there was a significant reduction of − 25 ± 33/− 9 ± 18 mmHg (n = 50, both p

Activation of the sympathetic nervous system increases sodium retention in resistant hypertension. Baroreflex activation therapy (BAT) is an interventional method to reduce sympathetic overactivity in patients with resistant hypertension. This study aimed to assess the effect of BAT on urinary sodium excretion. From 2012 to 2015, consecutive patients with resistant hypertension and blood pressure (BP) above target despite polypharmacy strategies were consecutively included in this observational study. BAT was provided with the individual adaption of programmed parameters over the first months. 24-h urinary sodium excretion (UNa) was estimated at baseline and after 6 months using the Kawasaki formula in patients undergoing BAT. Additionally, the fractional sodium excretion, plasma renin activity, and aldosterone levels were assessed. Forty-two patients completed the 6-month follow-up period. Office systolic and ambulatory 24-h systolic BP at baseline were 169 ± 27 mmHg and 148 ± 16 mmHg despite a median intake of 7(3–9) antihypertensive drugs. After 6 months of BAT, systolic office BP decreased to 150 ± 29 mmHg (p

Context Clinical reasoning is an essential skill, the foundations of which should be acquired during undergraduate medical education. Student performance in clinical reasoning can be assessed using key feature examinations. However, within a paradigm of test-enhanced learning, such examinations may also be used to enhance long-term retention of procedural knowledge relevant to clinical reasoning. Objectives This study tested the hypothesis that repeated testing with key feature questions is more effective than repeated case-based learning in fostering clinical reasoning. Methods In this randomised crossover trial, Year 4 medical students attended 10 weekly computer-based seminars during which patient case histories covering general medical conditions were displayed. The presentation format was switched between groups every week. In the control condition, students studied long case narratives. The intervention condition used the same content but augmented case presentation with a sequence of key feature questions. Using a within-subjects design, student performance on intervention and control items was assessed at 13 weeks (exit examination) and 9 months (retention test) after the first day of term. Results A total of 87 of 124 eligible students provided complete data for the longitudinal analysis (response rate: 70.2%). In the retention test, mean ± standard deviation student scores on intervention items were significantly higher than those on control items (56.0 ± 25.8% versus 48.8 ± 24.7%; p

Background Plasma exchange (PE) and immunoadsorption (IA) are alternative treatments of steroid-refractory relapses of multiple sclerosis (MS) or neuromyelitis optica (NMO). Methods Adverse events and neurological follow-ups in 127 MS- (62 PE, 65 IA) and 13 NMO- (11 PE, 2 IA) patients were retrospectively analyzed. Response was defined by improvements in either expanded disability status scale (EDSS) by at least 1.0 or visual acuity (VA) to 0.5, confirmed after 3 and/or 6 months. Results Hundred and forty patients were included in safety analysis, 102 patients provided sufficient neurological follow-up-data. There were no significant differences between IA and PE in side effects (3.9% vs 3.6%, P = .96) or response-rate (P = .65). Responders showed significant lower age (P = .02) and earlier apheresis-initiation (P = .01). Subgroup-analysis confirmed significant lower age in patients with relapsing-remitting MS (RRMS) /clinical isolated syndrome (CIS). Conclusion IA and PE seem equally safe and effective in steroid-resistant MS- or NMO-relapses. Early apheresis and low patient age are additional prognostic factors.

Unlike safety data of baroreflex activation therapy device (Rheos), only few data of the currently used second device (Barostim neo) are available and little is reported about common side effects.We prospectively analyzed patients with resistant hypertension treated with Barostim neo. A standardized interview regarding side effects of the therapy was performed in routine follow-up visits after device implantation in 42 patients to determine adverse events staged into three degrees.Within 6 months of baroreflex activation therapy, the office mean arterial blood pressure decreased from 169 ± 27 to 148 ± 29 mmHg systolic (P 0.001), respectively, to 145 ± 24 mmHg after 1 year (P 0.001), whereas the number of prescribed antihypertensive classes decreased from 6.6 ± 1.5 to 5.6 ± 1.8 (P 0.001). Adverse events were combination of the following field depending on the severity (I° mild: local discomfort, clinical observation only, no intervention indicated; II° moderate: medically significant such as occurrence of hypertensive crisis, syncope, arrhythmias; III° severe: life-threatening events or urgent medical intervention indicated). Adverse events I° were present in almost all patients (97.6%), and occurred mainly within first 6 months after device activation. Device-related events were most frequently and could be resolved by optimization of device parameters. Most procedure-related adverse events were directly related to the incision or anesthetic procedure. Adverse events II° occurred in 28.6% patients treated with Barostim neo, whereas patients' elevated individual risks might be potential triggers. Because of individual diversity of blood pressure response and the occurrence of adverse events, no standardization of parameters of implantable pulse generator could be found. By adapting the pulse generator settings individually, most of adverse events I° resolved without sequel.Though there are common side effects, Barostim neo significantly lowers blood pressure in resistant hypertension and provides an adequate safety profile. Regular patient visits are necessary to register side effects.

Baroreflex activation through electrical carotid sinus stimulation has been developed for the treatment of patients with arterial hypertension not sufficiently responding to pharmacological therapy. Previous studies suggested that peripheral chemoreflex afferents located in proximity to carotid baroreceptors are tonically active in hypertensive patients and may inhibit baroreflex responses. Therefore, we hypothesized that peripheral chemoreflex activation attenuates the efficacy of electrical carotid sinus stimulation.

Detection of renal artery stenosis (RAS) using Doppler is difficult to evaluate, particularly under conditions such as bilateral RAS or difficultly accessible renal arteries (RA). The objective of the present study was to assess the utility of splenic arterial compared to renal flow as an additional parameter in the Doppler evaluation of RAS. The difference between the resistive indices (RI) determined in renal and splenic parenchymal arteries (ΔRI(K−S)) was evaluated in 181 hypertensive subjects without any evidence of RAS. Subsequently 47 RA in 24 patients with suspected RAS were angiographically assessed. A ΔRI(K−S) of 0.055 (median) was determined in the population without any evidence of RAS similar to RA with angiographically excluded stenosis (ΔRI(K−S) 0.068). In contrast, in angiographic proven RAS, ΔRI(K−S) was significantly lower (−0.050; P

Progression of chronic kidney disease remains a principal problem in clinical nephrology and there is a pressing need for novel therapeutics and biomarkers. Aberrant promoter CpG island methylation and subsequent transcriptional silencing of specific genes have emerged as contributors to progression of chronic kidney disease. Here, we report that transcriptional silencing of the Ras-GTP suppressor RASAL1 contributes causally to progression of kidney fibrosis and we identified that circulating methylated RASAL1 promoter DNA fragments in peripheral blood correspond with levels of intrarenal levels of RASAL1 promoter methylation and degree of fibrosis in kidney biopsies, enabling non-invasive longitudinal analysis of intrarenal CpG island methylation. Retrospective analysis of patients with hypertensive nephrosclerosis revealed that circulating methylated RASAL1 promoter DNA fragments in peripheral blood decrease with Dihydralazine treatment in patients with hypertensive nephrosclerosis, and provided evidence that low-dose Dihydralazine delays decline of excretory kidney function, whereas Dihydralazine at standard doses had no protective effect. We demonstrate that the protective effect of Dihydralazine is due to induction of endogenous Tet3/Tdg-mediated DNA-de-methylation activity reversing aberrant promoter CpG island methylation, while HIF1α induction at standard doses counterbalances its protective activity. We conclude that RASAL1 promoter methylation is a therapeutic target and a biomarker of renal fibrosis. Our study suggests that therapeutic use of low-dose Dihydralazine in patients with chronic kidney disease and fibrosis deserves further consideration., Highlights • Aberrant RASAL1 promoter methylation contributes causally to progression of kidney fibrosis. • Degree of intrarenal RASAL1 methylation is reflected by levels of circulating methylated RASAL1 promoter fragments. • Low-dose Hydralazine induces endogenous Tet3-dependent de-methylation and inhibits progression of kidney fibrosis.

Activation of baroreceptors in the carotid modulates the autonomic nervous system. Baroreflex activation therapy (BAT), which activates baroreceptors in the carotid, has become available in the treatment of resistant hypertension. Besides this, a carotid implant modulating baroreceptors as well as pharmacological modulation of carotid bodies were quite recently presented. This review will underscore currently available and promising approaches that activate baroreceptors in the carotid, and thereby contribute to beneficial effects in patients with arterial hypertension, and discusses potential organoprotective BAT effects beyond blood pressure (BP) reduction. A systematic review and meta-analysis was conducted including observational studies or randomized controlled trials that investigated the effect of BAT on BP in resistant hypertension. Nine studies, seven observational and two randomized, with a total of 444 patients, were included in the evaluation. Analysing the longest follow-up visit from the different studies, there was a significant reduction of systolic BP after BAT of -36 mmHg [95% confidence interval (CI) -42 to -30 mmHg]. Separate meta-analysis of the short-term (1-6 months) and long-term effects (≥12 months) revealed a reduction of -21 mmHg (95% CI -26 to -17 mmHg) and -38 mmHg (95% CI -46 to -30 mmHg), respectively. There are promising data both in the experimental and the clinical application for BAT. Though the present meta-analysis suggests beneficial effects of BAT on BP, the results must be interpreted extremely carefully. Considering that evidence from controlled trials is very limited, it is evident that there is a strong need for further investigation.

Background: Microhematuria (MH) is a symptom frequently leading to uncertainty as to when a nephrology referral is appropriate. Because MH may be indicative of severe kidney disorders, prompt diagnosis and potential treatment initiation can be important. We aimed to identify further variables that point at a nephrological cause, in particular of glomerulonephritis (GN), when MH is diagnosed. Methods: A retrospective analysis of data acquired from patients attending a nephrology office due to MH was performed. Demographic information and diagnostic tests were evaluated in order to identify factors that were associated with a nephrological cause. Results: Patients with MH (n = 805) as indicated by a urine stick analysis were included. Of these, MH was confirmed by urine sediment analysis in 543 patients (67.5%). Of those, 48.3% had a nephrological cause, including 12.4% with GN and 2.9% with rapid progressive GN (RPGN). A urine dipstick finding of ≥ 250 erythrocytes per microliter, microalbuminuria and elevated leukocytes increased the probability of having a GN to 62.4%. Furthermore, the presence of microalbuminuria, GFR < 60 mL/min, history of hypertension and diabetes mellitus increased the probability for all nephrological causes to 95.4%. Conclusion: There are a number of factors available that help to assess the need for a nephrology referral in patients with microhematuria. J Clin Med Res. 2017;9(7):560-566 doi: https://doi.org/10.14740/jocmr2993w

Background/Aims: Resistant hypertension and chronic kidney disease (CKD) are interlinked via sympathetic overdrive. Baroreflex activation therapy (BAT) has been shown to chronically reduce blood pressure (BP) in patients with resistant hypertension. The effect of BAT on renal function in CKD patients with resistant hypertension has not been reported. The aim of this study was to investigate the effect of sympathetic inhibition on renal function in CKD patients. Methods: 23 CKD patients with resistant hypertension were prospectively treated with BAT. Analyses were performed before and 6 months after the start of BAT. The renal function was analyzed by creatinine, cystatin C, glomerular filtration rate (GFR), renin, aldosterone, fractioned and 24-hour sodium excretion and analyses of urine marker proteins. The purpose of the control group was to investigate the influence of treating patients in a center for hypertension and regression to the mean on investigated variables. Results: The office mean BP decreased from 116.9 ± 20.9 mm Hg to 104.2 ± 22.2 mm Hg (p < 0.01), while the number of prescribed antihypertensive classes decreased from 6.6 ± 1.6 to 6.1 ± 1.7 (p = 0.02). Proteinuria and albuminuria decreased from a median of 283.9 and 47.7 to 136.5 (p = 0.01) and 45.0 mg/g creatinine (p = 0.01) with pronounced effects in higher CKD stage III + IV compared to I + II (p < 0.01). CKD-EPI cystatin C equation improved from 53.6 ± 22.7 to 60.4 ± 26.1 ml/min (p = 0.02). While creatinine and GFR were impaired after a period of 6 months, no changes of proteinuria, albuminuria, or BP were obtained in control patients. Conclusion: The data of this prospective trial demonstrate potential nephroprotective effects of BAT in therapy-resistant hypertension in CKD patients by a reduction of BP, proteinuria and moreover, a stabilization of estimated GFR.

ObjectiveThrombophilic risk factors (TRFs) occur rather frequently in hemodialysis (HD) patients. However, little is known about their significance in HD patients, besides their potential impact on arteriovenous (AV) access failure, with varying results. We examined the effects of a wide variety of TRFs on both early AV fistula occlusion and survival among HD patients in long-term follow-up.MethodsIn this single-center, observational study, 70 consecutive HD patients from our dialysis center were examined with respect to shunt occlusion within the first 2 years after fistula creation and patient survival in a long-term follow-up (at least 16 years). We examined the presence of factor V, prothrombin, and MTHFR mutations using real-time fluorescence polymerase chain reaction. Furthermore, antithrombin (AT), protein C, protein S, and antiphospholipid antibodies (APL-Abs) were assessed.ResultsAmong the 70 patients, 32 had MTHFR mutations, 10 had heterozygous factor V Leiden mutations, 4 had prothrombin mutations, 4 had protein S deficiency, 2 had protein C deficiency, 9 had AT deficiency, and 14 had APL-Abs. 40 patients had shunt occlusion. TRFs were associated with a significantly increased risk for shunt thrombosis (PConclusionsTRFs in hemodialysis patients have a strong impact on patient survival and early AV fistula failure; however, patient survival is not significantly affected by early shunt occlusion.

Recombinant interferon α (IFN-α) and interferon β (IFN-β) are efficient drugs for clinical use in multiple sclerosis, hepatitis C virus infection, and malignant diseases. We report a case of a 40-year-old woman with relapsing-remitting multiple sclerosis who was treated with interferon beta-1b for several years before being admitted to our department with nephrotic-range proteinuria (protein excretion, 8.3 g/d) and serum albumin level of 2.9 g/dL without any clinical and laboratory change typical for a systemic autoimmune disease. The kidney biopsy led to the diagnosis of immune complex-mediated membranoproliferative glomerulonephritis with immunoglobulin and complement deposits visible by immunohistology, as well as subendothelial deposits and tubuloreticular inclusions evident by electron microscopy. Subsequently replacing interferon beta-1b with glatiramer acetate resulted in partial remission, with proteinuria decreasing to protein excretion of 1.0 g/d 2 months thereafter. The association of a focal mesangiocapillary glomerular change and immunoglobulin-complement deposits with tubuloreticular inclusions suggests lupus nephritis. To our knowledge, this is the first report of an interferon beta-1b-induced immune complex glomerulonephritis characterized by histologic, immunohistologic, and ultrastructural features that resembled lupus nephritis, but that occurred in a patient without evidence of systemic lupus erythematosus. Our review of experimental data and earlier case reports suggests a pathogenic role of recombinant IFN in some autoimmune diseases, especially those with the potency to induce systemic lupus erythematosus-like syndromes.

The vast majority of patients with end-stage renal disease are treated with intermittent hemodialysis as a form of renal replacement therapy. To investigate the impact of hemodialysis membrane material on vital protein removal, dialysates from 26 well-characterized hemodialysis patients were collected 5 min after beginning, during 5h of treatment, as well as 5 min before ending of the dialysis sessions. Dialysis sessions were performed using either modified cellulose (n=12) (low-flux and high flux) or synthetic Polyflux (n=14) (low-flux and high-flux) dialyzer. Protein removal during hemodialysis was quantified and the dialysate proteome patterns were analyzed by 2-DE, MS and Western blot. There was a clear correlation between the type of membrane material and the amount of protein removed. Synthetic Polyflux membranes exhibit strong interaction with plasma proteins resulting in a significantly higher protein loss compared to modified cellulosic membrane. Moreover, the proteomics analysis showed that the removed proteins represented different molecular weight range and different functional groups: transport proteins, protease inhibitors, proteins with role in immune response and regulations, constructive proteins and as a part of HLA immune complex. The effect of this protein removal on hemodialysis treatment outcome should be investigated in further studies.

The most common immunosuppressive regimens after renal transplantation include calcineurin inhibitors (CNI). However, due to renal toxicity long-term graft survival does not seem to be positively affected by CNIs.In the present study, we investigated 17 patients, in which the CNI immunosuppression was converted to a CNI-free, mycophenolate sodium (MPS) regimen. Conversion was performed due to progressive impairment of the graft function from suspected CNI toxicity. We retrospectively analyzed graft function as well as toxicity and surrogate markers for 4 years before and 4 years after conversion using a repeated-measures mixed model data analysis and/or a paired sample t-test.The mean time point of therapy conversion was 11.2 ± 4.6 years after transplantation. Within 1 month of CNI discontinuation, allograft function improved significantly, remaining at a significant level for 2 years. The estimated glomerular filtration rate increased from 43.4 ± 14.8 to a maximum of 55.7 ± 21.7 mL/min at 1 year after conversion (P = .0027). After 4 years, the end of the observation period, renal function was similar to the baseline. There were no significant side effects.These data suggested that, when chronic CNI-toxicity is suspected, renal allograft recipients may benefit from CNI withdrawal in favor of a MPS-including immunosuppressive regimen.

The risk of infection in patients with rheumatic diseases is elevated, but a clear marker to differentiate the cause of the systemic inflammation is missing. We assessed the ability urinary immunoglobulin free light chains (FLCs) to indicate the presence of infection in patients with rheumatic disease. We performed a retrospective analysis of patients with rheumatic disease attending the Georg-August University Hospital in Goettingen, Germany, from January 2011 to December 2013. Subjects were included if they had urine levels of κ and λ FLCs available. A reference group of patients without autoimmune disease, but with documented infection, was constructed. A total of 1500 patients had their urinary FLCs quantified during the study period. Of the 382 patients with rheumatic disease, 172 (45%) displayed no systemic inflammation, 162 (42%) had inflammation due to the underlying disease activity, and 48 (13%) had inflammation due to a confirmed infection. Urinary FLC concentrations were much higher in patients with rheumatic diseases and infection (κ 68.8 ± 81.8 mg/L, λ 31.4 ± 53.5 mg/L) compared to those with inflammation due to rheumatic disease activity (κ 22.7 ± 26.3 mg/L, λ 8.1 ± 9.1 mg/L, κ p

Objectives Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is accompanied by increased cardiovascular (CV) risk. Treatment of AAV patients includes the management of conventional CV risk factors, primarily hypertension and hypercholesterolemia, while lipoprotein(a) (LP(a)) is an emerging potential target. Methods We performed a multicenter, retrospective study in Germany. Patients were considered if they were between 18 and 90 years old and presented with AAV. Patients with arterial hypertension but no autoimmune disease were used as a control group (HTN reference group). Results Compared to the reference group (n = 52), CV disease burden was significantly greater in patients with AAV (n = 53). Hypercholesterolemia was also more common in the AAV patients (71.7% vs 46.2% for the HTN; P = .008). Lipoprotein(a) levels were elevated in both groups, with 11.3% and 17.3% of the AAV and HTN groups, respectively, displaying a level above 0.6 g/l (P = .083). Guideline-recommended targets for low-density lipoprotein cholesterol and blood pressure levels were rarely met. According to Kidney Disease: Improving Global Outcomes guidelines, 72.5% of the patients with AAV should have been taking statins and/or ezetimibe for treatment of hyperlipidemia; however, only 24.3% of them were receiving such treatment. Blood pressure below ≤140/90 mmHg was reached in 78.6% of the patients with chronic kidney disease. However, for patients with chronic kidney disease and an albumin excretion rate of >30 mg/day, the recommended blood pressure is ≤130/80 mmHg, a value that was not reached in 65% of the AAV patients. Conclusion Patients with AAV are at high CV risk, but management of the associated risk factors is poor. In addition to improving the treatment of hypercholesterolemia and hypertension, lipoprotein(a) is a further potential target for reducing CV risk in individuals with AAV.

In patients with rheumatic diseases, reliable markers for determining disease activity are scarce. One potential parameter is the level of immunoglobulin free light chains (FLCs), which is known to be elevated in the blood of patients with certain rheumatic diseases. Few studies have quantified FLCs in urine, a convenient source of test sample, in patients with different rheumatic diseases. We carried out a retrospective analysis of patients with rheumatic disease attending the University hospital of Goettingen, Germany. Subjects were included if they had urine levels of both κ and λ FLCs available and did not have myeloma. Data regarding systemic inflammation and kidney function were recorded, and FLC levels were correlated with inflammatory markers. Of the 382 patients with rheumatic disease, 40.1 % had chronic polyarthritis, 21.2 % connective tissue disease, 18.6 % spondyloarthritis and 15.7 % vasculitis. Elevated levels of κ FLCs were found for 84 % of patients and elevated λ for 52.7 %. For the patients with rheumatoid arthritis, FLCs correlated with C-reactive protein (κ, r = 0.368, p

BACKGROUND Both baroreflex activation therapy (BAT) and renal denervation modulate sympathetic activity. The aim of this study was to systematically investigate whether additive modulation of autonomic nervous system by BAT lowers blood pressure (BP) in patients who still suffer from uncontrolled resistant hypertension despite prior renal denervation. METHODS From 2012 to January 2015, patients treated with BAT for uncontrolled resistant hypertension, who prior received renal denervation were consecutively analyzed in four German centers for hypertension. Analyses of office BP, 24-h ambulatory BP, central hemodynamics, parameters of renal function were performed. RESULTS A total of 28 patients, who underwent renal denervation at least 5 months before and still suffer from uncontrolled BP, were subsequently treated with BAT. The office SBP decreased from 182 ± 28 to 163 ± 27 mmHg (P

Objective— Lipoprotein(a)-hyperlipoproteinemia (Lp(a)-HLP) along with progressive cardiovascular disease has been approved as indication for regular lipoprotein apheresis (LA) in Germany since 2008. We aimed to study the long-term preventive effect of LA and to assess hypothetical clinical correlations of apolipoprotein(a) (apo(a)) by analyzing genotypes and phenotypes. Approach and Results— This prospective observational multicenter study included 170 patients with Lp(a)-HLP and progressive cardiovascular disease (48.9 years median age at diagnosis) despite other cardiovascular risk factors, including low-density lipoprotein cholesterol had maximally been treated (mean baseline low-density lipoprotein cholesterol: measured, 2.56 mmol/L [98.9 mg/dL] and corrected, 1.72 mmol/L [66.3 mg/dL]). Patients were prospectively investigated during a 5-year period about annual incidence rates of cardiovascular events. In addition, apo(a) isoforms and polymorphisms at the apo(a) gene ( LPA ) were characterized. One hundred fifty-four patients (90.6%) completed 5 years of follow-up. Mean Lp(a) concentration before commencing regular LA was 108.1 mg/dL. This was reduced by a single LA treatment by 68.1% on average. Significant decline of the mean annual cardiovascular event rate was observed from 0.58±0.53 2 years before regular LA to 0.11±0.15 thereafter ( P Conclusions— Results of 5 years of prospective follow-up confirm that LA has a lasting effect on prevention of cardiovascular events in patients with Lp(a)-HLP. Patients clinically selected by progressive cardiovascular disease were characterized by a highly frequent expression of small apo(a) isoforms. Only Lp(a) concentration seemed to comprehensively reflect Lp(a)-associated cardiovascular risk, however.

Acute kidney injury (AKI) is a common condition with significant associated morbidity and mortality. The insensitivity and non-specificity of traditional markers of renal dysfunction prevent timely diagnosis, estimation of the severity of renal injury, and the administration of possible therapeutic agents. Here, we determine the prognostic ability of urinary liver-type fatty acid-binding protein (L-FABP), and further characterize its sensitivity and specificity as a biomarker of AKI. Initial western blot studies found increased urinary L-FABP in patients with confirmed AKI. A more extensive cross-sectional study found significant increases in urinary L-FABP, normalized to urinary creatinine, in 92 patients with established AKI compared with 62 patients without clinical evidence of AKI. In hospitalized patients, the diagnostic performance of urinary L-FABP for AKI, assessed by the area under the receiver operating characteristic curve, was 0.93. This compares favorably with other established biomarkers of AKI such as kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, N-acetyl-β-glucosaminidase, and interleukin-18. Our study shows that age-adjusted urinary L-FABP levels were significantly higher in patients with poor outcome, defined as the requirement for renal replacement therapy or the composite end point of death or renal replacement therapy.

Backgrounds: Criteria that may guide early renal replacement therapy (RRT) initiation in patients with acute kidney injury (AKI) currently do not exist. Methods: In 120 consecutive patients with AKI, clinical and laboratory data were analyzed on admittance. The prognostic power of those parameters which were significantly different between the two groups was analyzed by receiver operator characteristic curves and by leave-1-out cross validation. Results: Six parameters (urine albumin, plasma creatinine, blood urea nitrogen, daily urine output, fluid balance and plasma sodium) were combined in a logistic regression model that estimates the probability that a particular patient will need RRT. Additionally, a second model without daily urine output was established. Both models yielded a higher accuracy (89 and 88% correct classification rate, respectively) than the best single parameter, cystatin C (correct classification rate 74%). Conclusions: The combined models may help to better predict the necessity of RRT using clinical and routine laboratory data in patients with AKI.

Background. The effect of clearance of so-called middleand high-molecular weight proteins on clinical outcome of patients treated by peritoneal dialysis is still a matter of debate. In our present study, we investigated the impact of short-time alteration of the glucose concentration and the osmolarity of the peritoneal dialysis solution (PDS) on protein removal. Methods. Peritoneal dialysis liquids (PDL) were collected from 19 well-characterized continuous ambulatory peritoneal dialysis (CAPD) patients treated with two types of PDS: Baxter (n ¼ 10) and Fresenius (n ¼ 9). The patients were treated with two different glucose concentration of each PDS in 4-h cycles. The depletion of the six interfering highabundant proteins from the PDL samples was performed with the Multiple Affinity Removal LC Column—Human 6. The resulting protein fractions were analysed by 2D gel electrophoresis, differential in gel electrophoresis, mass spectrometry and 2D western blot. Results. Proteomics investigation of the PDL fractions after depletion allowed the identification of 198 polypeptides of 424 excised spots. These polypeptides equates to 48 non-redundant proteins. Comparative analyses of 2D gel electrophoresis protein pattern revealed a clear correlation between protein removal and PDS glucose concentration and osmolarity. An increase for 4 h in the PDS osmolarity (with 43–51 mosmol/L) resulted qualitatively in 18–23% more protein removal in PDL. Moreover, 2D western blot analyses of the protein glycation pattern showed that the short-time increase in PDS glucose concentration (45–50 mM) resulted in significant alteration of the advanced glycosylation end products (AGEs) pattern. Conclusions. The data presented in this study demonstrate a clear correlation between the short-time changes in glucose concentration and osmolarity of the PDS, and the augmentation of the protein removal and the appearance of AGEs during CAPD.

Lipid-apheresis (LA) is thought to improve microcirculation. However, limited data are available on the effects on peripheral microcirculation. We investigated upper limb microcirculation of 22 patients undergoing regular LA on a weekly basis before and after LA. Using standardized semiquantitative scales, we analyzed blood flow, vasomotor function, and erythrocyte aggregation by capillary microscopy. In addition, capillary blood flow in quiescence and under heat and cryo-stress was evaluated by photoplethysmographic and laser Doppler anemometry. Moreover, levels of vasoactive mediators adrenalin, noradrenalin, endothelin-1 (ET-1), atrial natriuretic peptide (ANP), asymmetrical dimethyl-arginine (ADMA), as well as total protein and fibrinogen were measured. We found a significant increase in blood flow, the number of perfused capillaries and an improvement of erythrocyte aggregation by capillary microscopy. Using laser Doppler anemometry, we were able to show that this increase was predominantly located in the superficial layer capillaries (Δ44.53 ± 135.81%, n.s.) and less so in deeper layer arterioles (Δ2.75 ± 24.84%, n.s.). Vascular response to heat and cryo stress was also improved after LA but failed to reach significance. LA significantly reduced levels of epinephrin (-33 ± 39.2%), ANP (-28.8 ± 20.2%), ADMA (-74.1 ± 23%), and fibrinogen (-45.4 ± 19.7%) when comparing before LA and after LA values. In summary, we found an improvement in the microcirculation of the upper limbs under LA, which may result from a decrease of vasoconstrictors, improvement of vasomotor function, and a decrease in blood viscosity or erythrocyte aggregation.

Background: Bone morphogenetic protein-5 (BMP-5) has been shown to be essential for nephrogenesis. Its role in adult kidney and in patients with hypertensive nephrosclerosis is still unknown. Methods: BMP-5 expression was evaluated by immunostaining and real-time PCR in tissue samples from normal and nephrosclerotic human kidneys. The impact of transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α) and angiotensin-II (AT-II) on expression of BMP-5 and its receptors was quantified in proximal tubular cells (HK-2). Functional characteristics of BMP-5 were evaluated by testing its influence on TGF-β–induced epithelial-to-mesenchymal transition (EMT), TNF-α–induced apoptosis of HK-2 cells and inflammatory cell infiltration. Results: BMP-5 expression was localized in tubular epithelial cells and significantly decreased in nephrosclerotic kidneys. Stimulation of HK-2 cells with TGF-β, TNF-α and AT-II resulted in a significant decreased expression of BMP-5 and its receptors. BMP-5 attenuated TGF-β–induced EMT, TNF-α–induced apoptosis and migration of mononuclear cells. Conclusions: BMP-5 is expressed in the tubuli of adult kidneys. Its decreased expression in nephrosclerosis along with its regenerative capabilities in HK-2 cells may point to a protective role in hypertensive nephrosclerosis.

We retrospectively analyzed 10 906 lipid apheresis sessions (heparin-induced lipoprotein precipitation, direct adsorption of lipoproteins, double filtration plasmapheresis, dextran sulfate adsorption, and immunoadsorption) in 38 patients who were consecutively treated in our department during the last 20 years. The incidences of major cardiovascular events (MACE) (death, cerebrovascular accident, myocardial infarction, limb amputation, and renal vascular involvement) were taken separately as primary end-points or as a combined end-point. The time-course of secondary end-points (coronary and extracranial status of arteries, left ventricular function, occlusive artery disease, and calculated glomerular filtration rate [cGFR]) were also evaluated, as well as the extent of the reduction in plasma lipids and lipoproteins and the incidence of therapy associated side-effects. MACE decreased from 7.02% events per patient per year at the start of lipid apheresis to 1.17% during lipid apheresis and the rate of myocardial revascularization decreased from 22.8% to 3.8% per patient per year. Classical (diabetes mellitus, arterial hypertension, and smoking history), as well as novel risk factors (cGFR < 60 mL/min, statin withdrawal, mixed hyperlipoproteinemia, and elevated lipoprotein (a)) were associated with an elevated risk for MACE. All applied methods had comparable effects. All lipid apheresis methods proved to be safe and suitable for long-term treatment. The present data demonstrate that treatment with lipid apheresis is very effective and leads to long-term reduction in cardiovascular mortality and morbidity.

We report a case of a 27-year-old female with thrombotic microangiopathy as an initial presentation of an unexpected disseminated gastric carcinoma. Based on clinical features and laboratory findings, thrombotic thrombocytopenic purpura (TTP) was diagnosed and plasma exchange started. However, she had responded poorly to plasmapheresis, developed multiorgan failure and died 72 h after admission. Autopsy revealed a disseminated gastric adenocarcinoma with metastatic infiltration of dura mater and disseminated tumor cell emboli in the microcirculation of the liver and lungs. Genetic analysis revealed amplification of KRAS oncogene and aberrations in DCC tumor suppressor gene, which can explain the young age and advanced disease at presentation. The role of plasmapheresis in cancer-associated TTP is uncertain. Plasmapheresis delivers fresh coagulation factors and may theoretically promote microthrombi formation and lead to worsening of the disease. Thrombotic thrombocytopenic purpura seems to be a late and prognostically poor manifestation of an underlying malignancy, with majority of patients dying soon after diagnosis. It is important to be aware of this possibility in thrombotic microangiopathy, especially with atypical features and poor response to standard treatment.

The occurrence of microalbuminuria or albuminuria indicates a disturbance of the barrier function of endothelial cells, basement membrane or of a structural-renal disease (including diseased podocytes). The prevalence of microalbuminuria in the general population is about 8 %, however, in high risk groups, prevalence rates of 50 % and more have been observed. Its incidence is strongly associated with increased cardiovascular morbidity and mortality. Blood pressure control and the blockade of the renin-angiotensin-aldosteron-system (RAAS), respectively, is the central mechanism to reduce cardio-vascular-renal end points as well as mortality.

Endothelin is the most potent endogenous vasoconstrictor and is involved in several vascular disorders such as arterial hypertension. Its intense interaction with other vasoactive hormone systems revealed the consideration about the endothelin gene as an interesting candidate for influencing the development of essential hypertension and hypertensive endorgan damage. The purpose of this study was to investigate the role of endothelin-1 Lys198Asn polymorphism in patients with severe arterial hypertension as well as associated endorgan damages.In 400 hypertensive patients and 150 normotensive controls we examined the endothelin-1 Lys198Asn polymorphism by DNA sequencing and patients were divided according to their genotype (GG, GT, and TT). Moreover, the frequency of endothelin-1 Lys198Asn polymorphism was investigated with respect to the prevalence of several actual or historical endorgan damages (renal disorder, coronary artery disease, vascular events, vascular damage, and congestive heart failure) in hypertensive patients.Genotype distribution for endothelin-1 Lys198Asn polymorphism was 57.3% (GG), 41.3% (GT), and 1.43% (TT) in normotensive individuals; and in hypertensive individuals was 54.75% (GG), 43% (GT) and 2.25% (TT). Genotype distribution was unaffected in patients with severe hypertension, renal disorder, vascular events, vascular damage, and congestive heart failure. We, however, found a significant difference in hypertensive individuals with coronary artery disease and TT genotype (P=0.004).Homozygous TT carrier contributes to a higher prevalence of coronary artery disease, especially for three-vessel disease in hypertensive individuals. Thus, the polymorphism at position 198 could serve as a possibility to differentiate high-risk subgroups in the heterogeneous population of hypertensive patients.

The inhibition of several chemokine/chemokine receptors has been shown to reduce progressive renal interstitial fibrosis. In this study, we examined the expression of the CX 3 C receptor in human renal biopsies with interstitial fibrosis and from normal kidneys by real-time polymerase chain reaction (PCR) and immunohistochemistry. The CX 3 C receptor was not only detected in mononuclear, tubular epithelial, and dendritic cells but also in α -smooth muscle actin and vimentin-positive interstitial myofibroblasts in fibrotic kidneys. Real-time PCR indicated a significant upregulation of CX 3 C receptor mRNA in fibrotic kidneys compared with non-fibrotic nephropathies or donor biopsies. In renal fibroblasts in vitro , hydrogen peroxide increased the expression of the CX 3 C receptor, an increase that was inhibited by N -acetylcysteine and catalase. However, neither proinflammatory nor profibrotic cytokines resulted in this upregulation. Stimulation of fibroblasts by CX 3 C ligand led to a significant enhancement of migration, which was abrogated by pre-incubation with a blocking anti-CX 3 C receptor antibody. Our studies indicate that renal fibrosis is associated with the expression of CX 3 C receptors on human renal fibroblasts. The expression is induced by reactive oxygen species suggesting a role of oxidative stress.