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

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

The German Lipoprotein Apheresis Registry-Summary of the ninth annual report.

During 2012-2020, 89 German apheresis centers collected retrospective and prospective observational data of 2028 patients undergoing regular lipoprotein apheresis (LA) for the German Lipoprotein Apheresis Registry (GLAR). More than 47 500 LA sessions are documented in GLAR. In 2020, all patients treated with LA showed a high immediate median reduction rate of LDL-C (68.2%, n = 1055) and Lp(a) (72.4%, n = 994). Patient data were analyzed for the incidence rate of major coronary events (MACE) 1 and 2 years before the beginning of LA treatment (y-2 and y-1) and prospectively up to 7 years on LA (y + 1 to y + 7). During the first 2 years of LA (y + 1 and y + 2), a MACE reduction of 78% was observed. Current analysis of GLAR data shows very low incidence rates of cardiovascular events in patients with high LDL-C and/or high Lp(a) levels, progressive ASCVD, and maximally tolerated lipid lowering medication regular by LA results.

Novel Insights into the Management of Patients with Very High Cardiovascular Risk Eligible for PCSK9 Inhibitor Treatment: Baseline Findings from the PERI-DYS Study.

AIM: The PERI-DYS study aims to characterize two groups of patients with dyslipidaemia at very high CV risk: PCSK9i receivers and patients qualifying for but not receiving PCSK9i. METHODS: This is an observational study by office-based and clinic-based physicians, mainly cardiologists and other internists in Germany, with data extracted from patient charts. CLINICALTRIALS: gov identifier NCT03110432. RESULTS: A total of 1659 patients were enrolled across 70 sites. The majority of patients (91.0%) were reported as having mixed dyslipidaemia or non-familial or heterozygous familial hypercholesterolemia. At enrolment, 794 (47.9%) of patients were PCSK9i receivers (of these 65.9% ongoing, and 34.1% newly treated within 30 days before their baseline visit). Among PCSK9i receivers, the majority had evolocumab 140 mg (n = 632, 38.1% of total). PCSK9i receivers compared to non-receivers were about 2 years younger and had a lower proportion of males. In terms of comorbidities, they had (statistically significantly) more often CAD, and less often PAD, diabetes mellitus, arterial hypertension and chronic renal disease. The calculated untreated median LDL-C was 187 mg/dl (IQR 127; 270) in ongoing PCSK9i receivers, 212 mg/dl (IQR 132; 277) in newly treated PCSK9i receivers, and 179 mg/dl (IQR 129; 257) in non-receivers. Physician-reported statin intolerance was much more common in the two PCSK9i receiver groups as compared to non-receivers (67.3% versus 15.3%). Consequently, patients in the PCSK9i groups received fewer concomitant statins. Mean total cholesterol (143 vs. 172 mg/dl) and LDL-C (69 vs. 99 mg/dl) were considerably lower in ongoing PCSK9i receivers compared to non-receivers. CONCLUSIONS: PCSK9i receivers are characterized by higher baseline LDL-C and a higher portion of statin intolerance compared to those qualified for but not-receiving PCSK9i treatment. On-treatment, LDL-C was lower in PCSK9i receivers. Ongoing follow-up will determine the prognostic importance of these findings.

Post COVID and Apheresis - Where are we Standing?

A continual increase in cases of Long/Post COVID constitutes a medical and socioeconomic challenge to health systems around the globe. While the true extent of this problem cannot yet be fully evaluated, recent data suggest that up to 20% of people with confirmed SARS-CoV-2 suffer from clinically relevant symptoms of Long/Post COVID several weeks to months after the acute phase. The clinical presentation is highly variable with the main symptoms being chronic fatigue, dyspnea, and cognitive symptoms. Extracorporeal apheresis has been suggested to alleviate symptoms of Post/COVID. Thus, numerous patients are currently treated with apheresis. However, at present there is no data from randomized controlled trials available to confirm the efficacy. Therefore, physicians rely on the experience of practitioners and centers performing this treatment. Here, we summarize clinical experience on extracorporeal apheresis in patients with Post/COVID from centers across Germany.

Overexpression of alanine-glyoxylate aminotransferase 2 protects from asymmetric dimethylarginine-induced endothelial dysfunction and aortic remodeling.

Elevated plasma concentrations of asymmetric dimethylarginine (ADMA) are associated with an increased risk of mortality and adverse cardiovascular outcomes. ADMA can be metabolized by dimethylarginine dimethylaminohydrolases (DDAHs) and by alanine-glyoxylate aminotransferase 2 (AGXT2). Deletion of DDAH1 in mice leads to elevation of ADMA in plasma and increase in blood pressure, while overexpression of human DDAH1 is associated with a lower plasma ADMA concentration and protective cardiovascular effects. The possible role of alternative metabolism of ADMA by AGXT2 remains to be elucidated. The goal of the current study was to test the hypothesis that transgenic overexpression of AGXT2 leads to lowering of plasma levels of ADMA and protection from vascular damage in the setting of DDAH1 deficiency. We generated transgenic mice (TG) with ubiquitous overexpression of AGXT2. qPCR and Western Blot confirmed the expression of the transgene. Systemic ADMA levels were decreased by 15% in TG mice. In comparison with wild type animals plasma levels of asymmetric dimethylguanidino valeric acid (ADGV), the AGXT2 associated metabolite of ADMA, were six times higher. We crossed AGXT2 TG mice with DDAH1 knockout mice and observed that upregulation of AGXT2 lowers plasma ADMA and pulse pressure and protects the mice from endothelial dysfunction and adverse aortic remodeling. Upregulation of AGXT2 led to lowering of ADMA levels and protection from ADMA-induced vascular damage in the setting of DDAH1 deficiency. This is especially important, because all the efforts to develop pharmacological ADMA-lowering interventions by means of upregulation of DDAHs have been unsuccessful.

Relapsing and Progressive Complications of Severe Hypertriglyceridemia: Effective Long-Term Treatment with Double Filtration Plasmapheresis.

BACKGROUND: Severe hypertriglyceridemia (HTG) is associated with major complications such as acute or relapsing pancreatitis (AP) and atherosclerotic cardiovascular disease (ASCVD). Rapid elimination of triglyceride (TG)-rich lipoproteins (LP) with double filtration plasmapheresis (DFPP) without need for substitution has been found to be effective for the acute, short-term treatment of HTG-induced AP. Data on the long-term use of DFPP to prevent HTG-associated complications are scarce. OBJECTIVES: To evaluate the use and efficacy of regular DFPP treatment in clinical practice for preventing recurrence of HTG-associated complications in thera-py refractory patients. METHODS: Retrospective multicenter study in patients with severe symptomatic drug and diet refractory HTG with regular DFPP treatment. Patients' incidence of HTG-associated pancreatic or cardiovascular complications was compared before treatment and with regular DFPP treatment. RESULTS: Ten patients (3 female) were identified with baseline maximal TG concentrations of 2,587-28,090 mg/dL (median 5,487 mg/dL; interquartile range [IQR] 4,340-12,636). The mean observation period was 3.9 ± 3.4 years before and 3.8 ± 3.0 years after commencement of DFPP. In 5 patients, severe HTG was related to chylomicronemia, 2 patients had familial partial lipodystrophy Dunnigan, and 1 patient had additional LP(a)-hyperlipoproteinemia. The main HTG-associated complication was recurrent AP in 8 patients, including 1 patient treated during pregnancy. Two patients presented severe progressive ASCVD. With long-term DFPP treatment, the annual rate of HTG-associa-ted pancreatic or cardiovascular complications declined from median 1.4 (IQR 0.7-2.6) to 0 (IQR 0.0-0.4; p < 0.005). The absolute number of events was reduced by 77%. In 6 patients (60%) episodes of AP did not occur, nor was progression of ASCVD detected clinically or by routine imaging techniques. DFPP was effective in the elimination of TG-rich LP from plasma, and was safe and well-tolerated. CONCLUSION: Long-term, regular DFPP treatment resulted in stabilization of patients with severe HTG and related recurrent AP or progression of ASCVD, who were refractory to conventional dietary and drug therapy.

[C3 glomerulopathy and MPGN - current classification]. / C3-Glomerulopathie und MPGN ­ aktuelle Klassifikationen.

Membranoproliferative glomerulonephritis (MPGN) and glomerulopathy with dominant C3 deposits are very rare autoimmune disorders of the kidney that had been classified in its current form in 2010 due to a better understanding of the underlying pathophysiology.Today, the immune complex-associated membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G) represent a disease spectrum which is heterogeneous in terms of pathophysiology and the clinical time course. Interestingly, recent research demonstrated more common pathophysiological aspects with respect to secondary causes, autoantibodies, and genetics of IC-MPGN and C3G than it had been suggested with the creation of the 2010 classification.This knowledge of the underlying pathophysiology is of specific importance for the identification of potential secondary causes. Therefore, following histologic diagnosis a comprehensive complement analysis, accompanied by antibody screening and human genetics should be carried out consistently. The published evidence provides a robust basis for the use of available therapeutic approaches for these often rapidly progressive and relapsing diseases.

ADMA elevation does not exacerbate development of diabetic nephropathy in mice with streptozotocin-induced diabetes mellitus.

BACKGROUND AND AIMS: Cardiovascular disease is nowadays the major cause of mortality and morbidity worldwide. The risk of developing cardiovascular disease is significantly increased in patients with diabetic nephropathy. It has been suggested that asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthases (NOS), may play an important role in the pathogenesis of diabetic nephropathy. ADMA is mainly metabolized by dimethylarginine dimethylaminohydrolase 1 (DDAH1). The goal of this study was to test the hypothesis that elevation of systemic ADMA levels by knocking out DDAH1 would exacerbate functional and structural glomerular abnormalities in a murine model of diabetic nephropathy. METHODS: Streptozotocin (STZ) was used to induce diabetes in adult DDAH1 knock-out and wild type mice. Healthy mice served as controls. Mice were sacrificed after 20 weeks of diabetes. Plasma ADMA levels were assessed by isotope-dilution tandem mass spectrometry and albumin by ELISA. Kidneys were used for FACS analysis and were also stained for markers of inflammation, cell proliferation, glomerular cells and cell matrix. RESULTS: STZ led to development of diabetes mellitus in all injected animals. Deficiency of DDAH1 led to a significant increase in plasma ADMA levels in healthy and diabetic mice. The diabetic state itself did not influence systemic ADMA levels. Diabetic mice of both genotypes developed albuminuria and had increased glomerulosclerosis index. There were no changes in desmin expression, glomerular cell proliferation rate, matrix expansion and expression of Mac-2 antigen in the diabetic mice of both genotypes as compared to the healthy ones. CONCLUSIONS: In summary, STZ-induced diabetes led to the development of early features of diabetic nephropathy. Deficiency of DDAH1 and subsequent increase in systemic ADMA levels did not exacerbate these changes, indicating that ADMA is not the major mediator of diabetic nephropathy in this experiment model.

Kidney and liver are the main organs of expression of a key metabolic enzyme alanine:glyoxylate aminotransferase 2 in humans.

BACKGROUND: The metabolic syndrome is a cluster of cardiovascular risk factors and is highly predictive for development of cardiovascular diseases. An association between elevated plasma levels of the endogenous inhibitor of nitric oxide synthases asymmetric dimethylarginine (ADMA) and risk of cardiovascular diseases has been demonstrated in numerous epidemiological studies. ADMA can be catabolized by dimethylarginine dimethylaminohydrolase (DDAH) or metabolized through a much less understood alternative pathway by alanine:glyoxylate aminotransferase 2 (AGXT2) with the formation of α-keto-δ-(N,N-dimethylguanidino)valeric acid (ADGV). Previous RT-PCR and Western Blot studies suggested that Agxt2 is expressed in the mouse kidney and liver at comparable levels, while Northern Blot and in-situ RNA-hybridisation experiments demonstrated that the kidney is the main organ of Agxt2 expression in rats. Given this discrepancy, the goal of the current study was to analyse the expression of AGXT2 in human tissues. MATERIAL AND METHODS: We analyzed AGXT2 expression in human tissues from a normal tissue bank by RT-PCR and further validated the results by Western Blot. We also performed immunohistochemical staining for AGXT2 and double fluorescent staining with an anti-AGXT2 antibody and a monoclonal anti-mitochondrial antibody. RESULTS: We saw the strongest expression of AGXT2 in the kidney and liver and confirmed this results on protein level. By IHC staining we were able to show that AGXT2 is present in the convoluted tubule in the kidney and in the liver hepatocytes. The double fluorescent staining revealed mitochondrial localization of AGXT2. CONCLUSIONS: Our current data suggest that both hepatocytes and kidney tubular epithelial cells are the major sources of AGXT2 in humans. We also demonstrated the mitochondrial localization of human AGXT2 enzyme.

Lipoprotein(a) - Marker for cardiovascular risk and target for lipoprotein apheresis.

Lipoprotein(a) (Lp(a)) consists of an LDL particle whose apolipoprotein B (apoB) is covalently bound to apolipoprotein(a) (apo[a]). An increased Lp(a) concentration is a causal, independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and a predictor of incident or recurrent cardiovascular events. Although Lp(a) was first described as early as 1963, only the more recent results of epidemiological, molecular, and genetic studies have led to this unequivocal conclusion. More than 20% of Western populations have elevated Lp(a) values. Lp(a) concentrations should be always part of the lipid profile when ASCVD risk is assessed. However, presence of other risk factors, laboratory findings, medical history and family history must be considered to conclude on its clinical relevance in an individual patient. Early or progressive ASCVD or a familial predisposition are key findings which can be associated with elevated Lp(a). The cholesterol portion contained in Lp(a) is also included in the various methods of LDL-C measurement. To assess proximity to the cardiovascular risk related target value for LDL-C, appropriate correction should be applied when high Lp(a) values are obtained to estimate the LDL-C that can actually be treated by lipid lowering drugs. Initial study data show that antisense oligonucleotides, which selectively decrease apolipoprotein(a), are promising as future treatment options. Currently, lipoprotein apheresis, which has a reimbursement guideline in Germany, is the therapy of choice for patients with Lp(a)-associated progressive ASCVD, with the aim of sustained prevention of further cardiovascular events.

Lipoprotein apheresis in Germany - Still more commonly indicated than implemented. How can patients in need access therapy?

BACKGROUND: Although lipid-lowering drugs, especially statins, and recently also PCSK9 inhibitors can reduce LDL cholesterol (LDL-C) and decrease the risk for cardiovascular disease (CVD) including coronary artery disease (CAD) events most efficiently, only 5-10% of high-risk cardiovascular patients reach the target values recommended by international guidelines. In patients who cannot be treated adequately by drugs it is possible to reduce increased LDL-C and/or lipoprotein(a) (Lp(a)) values by the use of lipoprotein apheresis (LA) with the potential to decrease severe CVD events in the range of 70%->80%. Even in Germany, a country with well-established reimbursement guidelines for LA, knowledge about this life-saving therapy is unsatisfactory in medical disciplines treating patients with CVD. Starting in 1996 our aim was to offer LA treatment following current guidelines for all patients in the entire region of our clinic as standard of care. METHODS: Based on the experience of our large apheresis competence center overlooking now nearly 80,000 LA treatments in the last two decades, we depict the necessary structure for identification of patients, defining indication, referral, implementation and standardisation of therapy as well as for reimbursement. LA is unfamiliar for most patients and even for many practitioners and consultants. Therefore nephrologists performing more than 90% of LA in Germany have to form a network for referral and ongoing medical education, comprising all regional care-givers, general practitioners as well as the respective specialists and insurances or other cost bearing parties for offering a scientifically approved therapeutic regimen and comprehensive care. The German Lipid Association (Lipid-Liga) has implemented the certification of a lipidological competence center as an appropriate way to realize such a network structure. RESULTS: Working as a lipidological and apheresis competence center in a region of 400,000 to 500,000 inhabitants, today we treat 160 patients in the chronic LA program. In spite of the availability of PCSK9 inhibitors since 2015, LA has remained as an indispensable therapeutic option for targeted lipid lowering treatment. An analysis of nearly 37,000 LA treatments in our own center documented a >80% reduction of cardiovascular events in patients treated by regular LA when comparing with the situation before the start of the LA therapy. We have implemented the concept of an apheresis competence center characterised by ongoing medical education with a focus on lipidological and cardiovascular aspects, interdisciplinary networking and referral. CONCLUSIONS: Incidence and prevalence of LA patients in our region demonstrate that based on our ongoing patient-centered approach the access of patients in need to LA is substantially above the German average, thus contributing to an extraordinary reduction of cardiovascular events in the population we in particular feel responsible for.

Effect of evolocumab on lipoprotein apheresis requirement and lipid levels: Results of the randomized, controlled, open-label DE LAVAL study.

BACKGROUND: Lipoprotein apheresis (LA) can effectively lower lipoproteins but is an invasive procedure. OBJECTIVE: The objective of this study was to evaluate whether evolocumab can reduce LA requirement in patients undergoing chronic LA. METHODS: Patients on regular weekly or every-2-week LA and moderate- to high-intensity statin (if tolerated) with pre-LA low-density lipoprotein cholesterol (LDL-C) levels ≥2.6 mmol/L (100 mg/dL) to ≤4.9 mmol/L (190 mg/dL) were randomized to continue the same LA frequency, or discontinue LA and receive evolocumab 140 mg every-2-weeks subcutaneously for 6 weeks. At week 6, all patients received only open-label evolocumab for 18 weeks. The primary endpoint was LA avoidance at the end of 6 weeks based on achieving pre-LA LDL-C <2.6 mmol/L at week 4. RESULTS: Thirty-nine patients (mean [SD] age 62 [10] years, 59% male, 82% with familial hypercholesterolemia) were randomized (evolocumab, n = 19; LA, n = 20). At the end of 6 weeks, more patients receiving evolocumab avoided LA than those receiving LA (84% vs 10%; treatment difference, 74% [95% CI: 45, 87]; P < .0001). Thirty patients (77%) did not require LA at 24 weeks. Evolocumab reduced pre-LA LDL-C by 50% from the baseline to week 4 compared with a 3% increase in the LA arm. Pre-LA LDL-C <1.8 mmol/L (70 mg/dL) was achieved by 10 patients (53%) receiving evolocumab and none receiving LA (week 4). Safety was comparable between arms. CONCLUSION: Evolocumab treatment significantly reduced LA requirement in patients undergoing chronic LA. In addition, >50% of patients achieved LDL-C <1.8 mmol/L on evolocumab alone, demonstrating that in patients with pre-LA LDL-C ≤4.9 mmol/L, evolocumab may replace LA.

Systematic review and meta-analysis of randomised controlled clinical trial evidence refutes relationship between pharmacotherapy with angiotensin-receptor blockers and an increased risk of cancer.

AIMS: The potential influence of angiotensin-receptor blockers (ARBs) on carcinogenesis is a much-debated topic. Both observational, as well as preclinical studies in rodent carcinogenic assays, suggest a major role of the Renin-Angiotensin-Aldosterone-System (RAAS) in cancer development. Therefore, a systematic review and meta-analysis with available study data on ARBs and carcinogenicity in general as primary outcome were conducted. Secondary outcomes were defined as tumour-specific mortality rates and the frequency of new cases of specific tumour types with particular emphasis on lung, breast, and prostate cancer. METHODS: A systematic literature research was performed in MEDLINE, EMBASE, Cochrane Library, and TOXLINE. We used a combination of MeSH terms, keywords and substance names of ARBs and searched between 1950 and 2016. At least 100 participants in each study arm and a minimum follow-up for one year were necessary for study inclusion. Odds ratios (OR) were calculated by a random-effects model. RESULTS: A total of 8818 potentially eligible publications were identified of whom seven randomised controlled trials, four case-control studies and one cohort study met our inclusion criteria. As a key result, we found no effect on carcinogenesis in randomised controlled trials for ARB usage. (OR 1.02, 95% CI 0.87-1.19; p = .803). Conflicting results with observational studies could be explained by poor reporting- and study qualities. CONCLUSIONS: The results of our meta-analysis focusing only on high evidence levels and study designs (RCTs) did not reveal any relationship between pharmacotherapy with an ARB and an increased risk for cancer in general.

Progenitor Renin Lineage Cells are not involved in the regeneration of glomerular endothelial cells during experimental renal thrombotic microangiopathy.

Endothelial cells (EC) frequently undergo primary or secondary injury during kidney disease such as thrombotic microangiopathy or glomerulonephritis. Renin Lineage Cells (RLCs) serve as a progenitor cell niche after glomerular damage in the adult kidney. However, it is not clear whether RLCs also contribute to endothelial replenishment in the glomerulus following endothelial injury. Therefore, we investigated the role of RLCs as a potential progenitor niche for glomerular endothelial regeneration. We used an inducible tet-on triple-transgenic reporter strain mRen-rtTAm2/LC1/LacZ to pulse-label the renin-producing RLCs in adult mice. Unilateral kidney EC damage (EC model) was induced by renal artery perfusion with concanavalin/anti-concanavalin. In this model glomerular EC injury and depletion developed within 1 day while regeneration occurred after 7 days. LacZ-labelled RLCs were restricted to the juxtaglomerular compartment of the afferent arterioles at baseline conditions. In contrast, during the regenerative phase of the EC model (day 7) a subset of LacZ-tagged RLCs migrated to the glomerular tuft. Intraglomerular RLCs did not express renin anymore and did not stain for glomerular endothelial or podocyte cell markers, but for the mesangial cell markers α8-integrin and PDGFRß. Accordingly, we found pronounced mesangial cell damage parallel to the endothelial injury induced by the EC model. These results demonstrated that in our EC model RLCs are not involved in endothelial regeneration. Rather, recruitment of RLCs seems to be specific for the repair of the concomitantly damaged mesangium.

Long-term follow-up of circulating oxidative stress markers in patients undergoing lipoprotein apheresis by Direct Adsorption of Lipids (DALI).

OBJECTIVE: Beyond its well-established efficacy in lowering atherogenic lipids and lipoproteins, DALI (Direct Adsorption of Lipids) apheresis has been shown to have acute anti-inflammatory and endothelium-protective effects. In the present study, we investigated long-term effects of DALI procedures on circulating oxidative stress markers. METHODS: Thirteen patients involved in the study underwent regular DALI apheresis for nearly two years. At sessions 1, 40 and 80 conventional lipid status and changes of systemic oxidative stress markers (oxidized LDL, anti-oxidized LDL antibodies, advanced oxidation protein products (AOPP), and myeloperoxidase (MPO)) were examined. RESULTS: DALI procedure efficiently reduced atherogenic lipids/lipoproteins. On day three after apheresis lipid parameters returned to pre-apheresis values. They showed no tendency to increase or to decrease over time. No significant differences were found between 1st, 40th and 80th sessions. In a similar way, levels of oxidative stress biomarkers acutely decreased after apheresis sessions and rebounded on day three after apheresis. No significant differences were observed between sessions 1, 40, and 80. CONCLUSION: DALI apheresis repeatedly decreases atherogenic lipid/lipoprotein profile and oxidative stress biomarker levels during each session. Among all investigated parameters no longitudinal effects over two years could be observed.

Rationale and design of MultiSELECt: A European Multicenter Study on the Effect of Lipoprotein(a) Elimination by lipoprotein apheresis on Cardiovascular outcomes.

BACKGROUND: Dyslipidemia is a well-known risk factor for atherosclerosis and subsequent cardiovascular disease (CVD). While low density lipoprotein cholesterol (LDL-C) is well-established and taken into consideration for risk management and therapy, lipoprotein(a) is another established CVD risk factor frequently not undergoing screening due to a lack of medical treatment options. For patients suffering from CVD due to massive elevation of Lp(a) in presence of normal LDL-C levels, lipoprotein apheresis is the only available treatment option. While this constellation is an accepted indication for lipoprotein apheresis (LA) in Germany, prospective studies including a control group are still lacking. OBJECTIVE: Primary objective of this trial is to evaluate the clinical benefit of lipoprotein apheresis on myocardial infarction, PCI, CABG and death from cardiovascular disease in subjects with elevated Lp(a). This study evaluates the clinical benefit of weekly LA in subjects with progressive cardiovascular disease, as accepted by the German Federal Joint Committee (treatment group). Comparator will be well-matched subjects under maximum tolerated lipid lowering therapy without access to LA treatment (control group). METHODS: MultiSELECt, is a prospective, multicenter, multinational, two-arm matched-pair cohort study designed to directly compare subjects with significantly elevated Lp(a) approved for LA subsequently undergoing weekly apheresis treatment versus a continuation of maximal medical therapy. The follow-up period will be 2 years after the baseline visit and until at least 60 events of the primary end-point occurred in the control group. A central trial expert committee will review all subjects with respect to their potential indication for LA according to established German guidelines in a blinded fashion. All control subjects will be contacted monthly via telephone visits to compensate for the more frequent visits during apheresis. Approximately 150 matched pairs will be necessary to detect an event reduction of at least 10% in subjects under LA treatment. CONCLUSION: The MultiSELECt trial provides the unique opportunity to demonstrate the efficiency of LA on CVD in patients with elevated Lp(a) under strongly controlled conditions.

H.E.L.P apheresis exerts long term effects on the capacity of circulating proangiogenic cells.

BACKGROUND: Severe forms of mono- and polygenetic hypercholesterolemia as well as elevated Lipoprotein (a) (LP(a)) with progressing cardiovascular (CV) disease are indication for lipoprotein apheresis (LA) in Germany. Many studies investigated pleiotropic effects of LA that might contribute to beneficial effects in advanced atherosclerosis. The present study aimed at investigating the potential role of Proangiogenic Cells (PAC) in patients with new onset or chronic LA using the heparin induced extracorporeal LDL-precipitation (H.E.L.P.) apheresis system. METHODS: Patients (n = 10) new to LA and HELP treatment were investigated immediately before, shortly after, 24 h later and 4 weeks following LA. Peripheral blood was used to count PAC in circulation via flow cytometry. In a second step, blood cells from patients were cultured in endothelial selective medium and further evaluated for adhesion in fibronectin coated chamber slides and migratory capacity (stromal cell-derived factor-1 (SDF-1) induced migration). RESULTS: Cells expressing typical EPC markers were rarely detected in blood samples. No differences occurred over time in CD34+; CD34+ CD133+ CD45-; CD34+/KDR+ and CXCR4+/CD14+ positive PAC. We found no differences in cell adhesion at the different time points, while significantly more cells migrated into the SDF-1 medium following four weeks of continuing apheresis therapy. CONCLUSION: Using well established systems, this study was not able to demonstrate relevant acute effects of LA on PAC in patients new to LA. The increased migratory capacity of PAC might be an indicator of chronic beneficial pleiotropic effects in patients undergoing H.E.L.P. apheresis.

Successful and well-tolerated bi-weekly immunoadsorption regimen in pemphigus vulgaris.

BACKGROUND: Pemphigus vulgaris is a chronic autoimmune disease characterized by blisters and erosions forming in the mucous membranes and the skin. Many patients are severely impaired by pain, weight loss and increased risk of infections. The disease is mediated by specific autoantibodies directed against desmogleins that contribute to connect keratinocytes in the epidermis. Autoantibody deposition in the skin causes inflammation and intraepidermal akantholysis. The concentration of autoantibodies in serum correlates with disease activity. Therefore, the removal of autoantibodies by immunoadsorption is a targeted therapeutic intervention for patients with pemphigus vulgaris. PATIENTS AND METHODS: A total of 9 patients with pemphigus vulgaris resistant to the standard treatment regimen were treated by immunoadsorption using the TheraSorb™-Ig adsorber system and analyzed retrospectively. Patients received immunoadsorption on two or four consecutive days. Cycles were repeated every two or four weeks, respectively. Treatment was performed for a mean period of 17.5 months (range 6-26). Outcome was measured as improvement in clinical disease analyzed by the investigators global assessment and the reduction of autoantibodies in serum measured by indirect immunofluorescence and ELISA. Tolerability of treatment by patients was evaluated using a visual analog scale. RESULTS: Retrospective analysis of 9 patients consecutively treated by immunoadsorption revealed an 80% reduction of the autoantibody concentration in serum after 6 months of treatment, led to a clinical improvement of disease in combination with classical immunosuppression. Steroid consumption could be reduced by 50% after 30 and 75% after 90 days. Therapy resulted in a total response rate of 89%, with 56% of patients reaching partial and 33% complete remission. The bi-weekly treatment regimen resulted in effective improvement of disease and was in favor to the 4-weekly regimen by the subjective judgment of tolerability by the patients. CONCLUSION: Immunoadsorption for the treatment of pemphigus vulgaris is safe and effective. The good tolerability of a bi-weekly treatment regimen shown here might be a valuable therapeutic option in further studies defining the optimal frequency of immunoadsorption required in treatment of pemphigus.