Volker Schettler

Highly effective reduction of C-reactive protein in patients with coronary heart disease by extracorporeal low density lipoprotein apheresis.

An association between C-reactive protein (CRP) and coronary heart disease (CHD) has been shown. CRP is present in atherosclerotic lesions, and there is increasing evidence that it may contribute to inflammation. Reduction of CRP concentrations otherwise considered normal may thus be of therapeutic value. Heparin-induced extracorporeal low density lipoprotein precipitation (HELP) is an established apheresis procedure to treat CHD patients with hypercholesterolemia. CRP concentrations were determined pre- and post-apheresis in 13 hypercholesterolemic CHD patients, during a total of 31 treatment procedures as well as in the interval between two treatments in six-patients using a high-sensitivity CRP assay. In addition, the effect of the HELP precipitation buffer on serum CRP concentrations was investigated in vitro. HELP treatment reduced CRP concentrations on average by 65%. The presence of CRP in the LDL precipitate of a patient was also confirmed by Western-blot analysis. In vitro experiments with serum samples revealed that CRP was partly co-precipitated with LDL. Greater fluctuation was observed in the post-apheresis concentrations of CRP compared with LDL. These results show that CRP can be very effectively lowered in CHD patients through the HELP system. This may further explain the stabilization and reduction of atherosclerotic plaques in hypercholesterolemic patients previously demonstrated with this treatment procedure.

First data from the German Lipoprotein Apheresis Registry (GLAR)

OBJECTIVE In recent years the Federal Joint Committee (G-BA), a paramount decision-making body of the German health care system challenged the approval of diagnostic and therapeutic procedures for regular reimbursement, including lipoprotein apheresis therapy. Years before an interdisciplinary German apheresis working group, established by members of both German Societies of Nephrology (Verband Deutsche Nierenzentren (VDN), Deutsche Gesellschaft für Nephrologie (DGfN)), initiated a revision of the indication of lipoprotein apheresis therapy according to current guidelines and recommendations for the treatment of lipid disorders. This working group was convinced, that data derived from a registry would support lipoprotein apheresis as a therapy for severe hyperlipidemic patients suffering from progressive cardiovascular diseases. METHODS AND RESULTS In 2009 the working group established the indication for lipoprotein apheresis with respect to current cardiovascular guidelines and scientific knowledge for the registry, which are in line with the reimbursement guidelines. In 2011 financing by sponsors was secured and an internet-based registry was created. A pilot project with 5 apheresis centers finished in 2012 - since then the registry is available to all German apheresis centers. CONCLUSIONS There has been consensus between the medical societies and health care carriers regarding the need for a German Lipoprotein Apheresis Registry (GLAR). The launch of this registry complies with requirements of the Federal Joint Committee (G-BA). Complementing the Pro(a)LiFe-Study, first data from GLAR support the safety of the different apheresis treatment procedures. In addition these first data suggest, with respect to the results of Pro(a)LiFe-Study, effectiveness in preventing cardiovascular progression as well. Here, further data are needed to statistically substantiate these early findings.

Impact of regular LDL apheresis on the development of restless legs syndrome

We examined 25 hyperlipidaemic patients with coronary heart disease undergoing regular low‐density lipoprotein apheresis (LA) treatment in weekly intervals. In this patient population, half were found to have concomitant restless legs syndrome (RLS). Laboratory investigations suggest that iron metabolism is modified by regular LA treatment and this change may be involved in the pathogenesis of this previously unrecognised form of secondary RLS. Substitution of iron therefore may be a promising line of treatment for LA‐induced RLS.

Lack of plasma lipid peroxidation during LDL-apheresis by heparin-induced extracorporeal LDL-precipitation

Abstract. The heparin‐induced extracorporeal precipitation of low density lipoproteins (HELP) is a well established clinical apheresis procedure to markedly reduce cholesterol levels. The biocompatibility of this filter system was investigated by the determination of lipid peroxidation products. Both lipid hydro‐peroxides and thiobarbituric acid reactive substances (TBARS) were determined before, during and after 38 aphereses in 21 patients undergoing regular HELP treatment. Although HELP patients had significantly elevated TBARS compared to 93 healthy controls (3.13 ±0.64 vs. l.66±0.50 μmol L‐1; P<0.01), no significant differences were observed compared to either 104 patients suffering from angiographically confirmed coronary heart disease (3.42 ±0.81 μmol L‐1; P> 0.05 vs. HELP patients) or 38 aged‐matched hyperlipidaemic patients (3.30 ±0.75 μmol L‐1; P>0.05 vs. HELP patients), neither of which were included in the HELP programme. No lipid hydroperoxides were detected in the plasma of HELP patients either before or after the extracorporeal treatment. After the LDL‐apheresis TBARS were significantly decreased (2.60 ± 0.52 μmol L‐1) compared to the values before the treatment (P<0.01). There was no evidence for the formation of lipid hydroperoxides within the HELP circuit. It is suggested, therefore, that plasma lipids are not oxidized by the HELP procedure.

Lipoprotein apheresis – More than just cholesterol reduction?

Lipoprotein apheresis is a well-established extracorporeal treatment in modality of severe hyperlipoproteinemia. Besides the reduction of LDL cholesterol and modifications to physiology of lipoprotein and lipid metabolism, Lipoprotein apheresis may have crucial effects on many other atherogenic factors as vascular inflammation, rheology and gene expressions in blood cells. These different effects of lipoprotein apheresis treatments are reviewed with respect to oxidative stress in plasma, red and white blood cells and in consequence to progression of atherosclerosis. However, in consideration of these reviewed aspects as a factor of biocompatibility lipoprotein apheresis remains safe.

Impact of Lipid Apheresis on Egr-1, c-Jun, c-Fos, and Hsp70 Gene Expression in White Blood Cells

Lipid apheresis treatment has been suggested to cause oxidative stress. Cells respond to oxidative stress in many ways, including, among others, altered gene expressions. In the present investigation we investigated whether the gene expression of known stress genes was affected in the WBCs of patients undergoing lipid apheresis. For this purpose cellular early‐growth‐response gene‐1 (Egr‐1), c‐Jun, c‐Fos, and heat shock protein 70 (Hsp70) mRNA expression was followed before and immediately after lipid apheresis treatments (N = 24). Gene expression was determined by quantitative reverse transcription‐polymerase chain reaction. With the exception of c‐Fos, the expression of Egr‐1, c‐Jun, and Hsp70 mRNA was not affected in WBCs by a single lipid apheresis treatment (median [16th percentile; 84th percentile]): Egr‐1, before 0.30 (0.13; 0.53), after 0.31 (0.14; 1.33); c‐Jun, before 0.03 (0.03; 0.16), after 0.05 (0.03; 0.18); Hsp70, before 0.49 (0.23; 1.07), after 0.53 (0.20; 1.61)). Expression of c‐Fos was significantly decreased (P < 0.01) after lipid apheresis treatment (before 2.18 [1.06; 5.27], after 1.65 [0.74; 4.12]). Hsp70 and c‐Fos expression in lipid apheresis patients was not different from that in 35 healthy blood donors, whereas Egr‐1 and c‐Jun were significantly decreased (P < 0.05) in lipid apheresis patients when compared to controls (Egr‐1 0.96 [0.42; 1.83], c‐Jun 0.64 [0.40; 0.98], c‐Fos 2.77 [1.32; 4,02], Hsp70 0.43 [0.28; 0.61]). These results show that lipid apheresis procedures do not induce stress gene expression in WBCs. Therefore, all the lipid apheresis systems used seem to be safe with respect to oxidative stress and other injuries induced in WBCs due to contact with extracorporeal tubing and membranes.

Body weight telemetry is useful to reduce interdialytic weight gain in patients with end-stage renal failure on hemodialysis.

Lacking compliance with liquid intake restrictions is one of the major problems in patients on hemodialysis and causes an increased mortality. In 120 patients on hemodialysis with an average interdialytic weight gain (IWG) exceeding 1.5 kg on at least 2 days during the 4 weeks preceding the intervention, the effect of telemetric body weight measurement (TBWM) on IWG, ultrafiltration rate, and blood pressure was evaluated over a period of 3 months. Patients of the telemetric group (TG) were supplied with automatic scales, which transferred the weight via telemetry on a daily basis. In the case of IWG of more than 0.75 kg/24 h, a telephonic contact was made as required, and in the case of an IWG of more than 1.5 kg, telephonic contacting was obligatory along with the advice of a liquid intake restriction to 0.5 L/day until the next dialysis. The patients of the control group (CG) received standard treatment without telemetric monitoring. We examined specific data of the second interdialytic interval (IDI2) and the average within 1 week. The average difference of IWG between TG and CG was not significant before the start of the study but 0.2 kg (p=0.027) (IDI2)/0.27kg (p=0.001) (WP) at the end of the study, respectively. The average difference in the ultrafiltration rate within 1 week was 19.0 mL/h (p=0.282) (IDI2)/8.2 mL/h (p=0.409) before the start of the study but 28.4 mL/h (p=0.122) (IDI2)/30.9 mL/h (p=0.004) at the end of the study, respectively. Thus, TBWM is a feasible method for optimizing the IWG and reducing the ultrafiltration rate.

Plaquestabilisierung durch LDL-Apherese?

ZusammenfassungVuinerable lipidreiche Plaques sind häufig der Ausgangspunkt akuter atherothrombotischer Ereignisse, die zur instabilen Angina und/oder zum akuten Myokardinfarkt führen. Eine langfristige medikamentöse LDL-Senkung führt hingegen zu einer Stabilisierung der Plaques. In den großen Interventionsstudien wird dieses von einer signifikanten Reduktion der Reinfarktinzidenz begleitet.Wie erste Analysen behandelter Patienten zeigen, kann eine regelmäßig durchgeführte extrakorporale LDL-Elimination die Inzidenz der klinischen Ereignisse möglicherweise viel früher reduzieren: Die in acht- bis 14tägigem Intervall mit einer einzelnen Behandlung erreichte „aggressive” LDL-Senkung von über 60% ist offensichtlich mit einer frühen Regression lipidreicher Gefäßläsionen assoziiert. Zusätzlich führt die LDL-Apherese zu einer Verringerung der auf die vulnerablen Plaques wirkenden Scherkräfte. Dies ist einmal bedingt durch eine Verminderung der Plasmaviskosität und zum anderen durch eine verbesserte vasomotorische Reserve, die mit einem geringeren arteriellen Widerstand einhergeht. Außerdem eliminiert man durch LDL-Apherese die inflammatorisch wirksamen oxidierten LDL-Partikel, die einer Plaquestabilisierung entgegenwirken. Die Affinität der verschiedenen Verfahren zu einzelnen Gerinnungsfaktoren führt zur Normalisierung einer vorhandenen Hyperkoagulabilität.AbstractVulnerable lipid-rich plaques are often the cause of atherothrombotic events leading to unstable angina and/or to acute myocardial infarction. Consequent long-term LDL-lowering by drugs as shown by the most important intervention studies lead to plaque stabilization as shown by the significant reduction of myocardial reinfarction.First studies in patients undergoing regular extracorporeal LDL-elimination indicate, that clinical events might be reduced much earlier as by drug therapy alone: A more than 60% reduction of LDL at weekly intervals is obviously associated with an early regression of lipid-rich vascular lesions. LDL-apheresis, mainly by HELP and by double filtration reduces the shear-stress of the flowing blood on vulnerable plaques either by its effect on plasmaviscosity and/or on the vasomotoric reserve thus leading to a lower peripheral arterial resistance. Furthermore oxidized LDL, which might counteract plaque stabilisation by its inflammatory effects are effectively eliminated by LDL-apheresis. The affinity of different LDL-apheresis procedures to coagulation factors normalizes hypercoagulatory states thus avoiding atherothrombotic events at the site of vulnerabie or erosive plaques.Vulnerable lipid-rich plaques are often the cause of atherothrombotic events leading to unstable angina and/or to acute myocardial infarction. Consequent long-term LDL-lowering by drugs as shown by the most important intervention studies lead to plaque stabilization as shown by the significant reduction of myocardial reinfarction. First studies in patients undergoing regular extracorporeal LDL-elimination indicate, that clinical events might be reduced much earlier as by drug therapy alone: A more than 60% reduction of LDL at weekly intervals is obviously associated with an early regression of lipid-rich vascular lesions. LDL-apheresis, mainly by HELP and by double filtration reduces the shear-stress of the flowing blood on vulnerable plaques either by its effect on plasmaviscosity and/or on the vasomotoric reserve thus leading to a lower peripheral arterial resistance. Furthermore oxidized LDL, which might counteract plaque stabilisation by its inflammatory effects are effectively eliminated by LDL-apheresis. The affinity of different LDL-apheresis procedures to coagulation factors normalizes hypercoagulatory states thus avoiding atherothrombotic events at the site of vulnerable or erosive plaques.

A case report of darbepoetin treatment in a patient with sickle cell disease and chronic renal failure undergoing regular hemodialysis procedures that induce a dose-dependent extension of blood transfusion intervals.

Abstract:  In this case, a female Nigerian patient suffered from sickle cell disease (SCD, hemoglobin SS)‐induced chronic renal failure and was undergoing hemodialysis treatment. Due to SCD crisis and renal anemia the patient received regular blood transfusions when the hemoglobin concentration fell below 5.0 g/L. Blood transfusion associated iron‐overload was noticed. To reduce the iron‐overload side effects, we started an erythropoietin therapy (darbepoetin) to extend the blood transfusion interval, using 30–150 µg/week. As a result of our investigation we observed that darbepoetin can significantly extend blood transfusion intervals without increasing SCD crisis. To substantiate our observation, further investigations are needed with more SCD patients undergoing regular hemodialysis treatment.

No acute impact of lipid apheresis treatment on free radical scavenging enzyme gene expression in white blood cells

Background Lipid apheresis (LA) treatment has been suggested to cause oxidative stress. Defense against oxygen‐radical‐mediated damage is provided by nonenzymatic and enzymatic antioxidants. In the present investigation we have investigated whether gene expression of free radical scavenging enzymes (FRSE) is affected in leukocytes of patients undergoing LDL‐apheresis.