Lipoprotein apheresis is an optimal therapeutic option to reduce increased Lp(a) levels.

BACKGROUND: Lipoprotein(a) (Lp(a)) is a genetic risk factor for cardiovascular disease (CVD) and is associated with the induction and sustaining of atherosclerotic cardiovascular diseases (ASCVD). Since 2008 Lp(a) along with progressive CVD has been approved as an indication for regular lipoprotein apheresis (LA) in Germany. The German Lipoprotein Apheresis Registry (GLAR) has been initiated to provide statistical evidence for the assessment of extracorporeal procedures to treat dyslipidemia for both LDL-cholesterol (LDL-C) and Lp(a). The GLAR now allows prospective investigations over a 5-year period about annual incidence rates of cardiovascular events. Here Lp(a) patients (LDL-C < 100 mg/dl; Lp(a) > 60 mg/dl or >120 nmol/l) showed the same reduction of major coronary (83%) and non-coronary events (63%) as had been formerly shown in the Pro(a)LiFe study. However, Lp(a) is not only an apolipoprotein(a) (apo(a)) and LDL-C containing particle, which is covalently bound to a LDL-C core by a disulphide bridge. The composition of this particle, inter alia containing oxidized phospholipids, gives pro-atherosclerotic, pro-inflammatory, and pro-thrombotic properties, inducing atherosclerotic processes mainly in the arterial wall. However, recent investigations have shown that a reduction of inflammatory settings without LDL-C or Lp(a) reduction may reduce ASCVD events. Lipoprotein apheresis (LA) could not only reduce LDL-C and Lp(a) in parallel, but also different inflammatory and coagulation parameters. In summary lipoprotein apheresis is not only anti-atherosclerotic, but also anti-inflammatory and anti-thrombotic and therefore an ideal treatment option with respect to the shown reduction of major adverse coronary events (MACE) and major adverse non-coronary events (MANCE) by reducing Lp(a) levels.

Primary and secondary prevention of cardiovascular disease in patients with hyperlipoproteinemia (a).

General lipoprotein (Lp) (a) screening can help to identify patients at high risk for cardiovascular disease. Non-invasive methods allow early detection of clinically asymptomatic incipient atherosclerotic disease. Medical treatment options are still unsatisfactory. Lp(a) apheresis is an established treatment in Germany for secondary prevention of progressive cardiovascular disease. Statin-based lowering of LDL cholesterol and thrombocyte aggregation inhibitors still represent the basis of medical treatment. Target levels for LDL-cholesterol should be modified in patients with hyperlipoproteinemia (a).

Long-lasting solid lubrication by CNT-coated patterned surfaces.

The use of lubricants (solid or liquid) is a well-known and suitable approach to reduce friction and wear of moving machine components. Another possibility to influence the tribological behaviour is the formation of well-defined surface topographies such as dimples, bumps or lattice-like pattern geometries by laser surface texturing. However, both methods are limited in their effect: surface textures may be gradually destroyed by plastic deformation and lubricants may be removed from the contact area, therefore no longer properly protecting the contacting surfaces. The present study focuses on the combination of both methods as an integral solution, overcoming individual limitations of each method. Multiwall carbon nanotubes (MWCNT), a known solid lubricant, are deposited onto laser surface textured samples by electrophoretic deposition. The frictional behaviour is recorded by a tribometer and resulting wear tracks are analysed by scanning electron microscopy and Raman spectroscopy in order to reveal the acting tribological mechanisms. The combined approach shows an extended, minimum fivefold longevity of the lubrication and a significantly reduced degradation of the laser textures. Raman spectroscopy proves decelerated MWCNT degradation and oxide formation in the contact. Finally, a lubricant entrapping model based on surface texturing is proposed and demonstrated.

Current insights into the German lipoprotein apheresis standard: PCSK9-inhibitors, lipoprotein apheresis or both?

According to current European guidelines, lipid lowering therapy for progressive cardiovascular disease including cardiovascular events has to be focused on a target level for LDL-C. In contrast for Lp(a) a threshold has to be defined with respect to the method of measurement. However, due to new lipid lowering drug developments like PCSK9-inhibitors (PCSK-9-I) a therapeutic algorithm for patients with severe hypercholesterolemia or isolated Lipoprotein(a)-hyperlipoproteinemia with progressive cardiovascular disease may be necessary to manage the use of PCSK9-I, lipoprotein apheresis (LA) or both. The therapeutic approach for patients with homozygous familial hypercholesterolemia is unambiguous: In addition to LA, in order to improve LDL-C reduction, PCSK9-I could be applied. In patients with heterozygous familial hypercholesterolemia, PCSK9-I is to be applied first. If in addition to a pronounced LDL-C elevation, cardiovascular complications exist or if imaging techniques documented atherosclerotic changes pre-disposing for a cardiovascular event while LDL-C reduction is insufficiently reduced (LDL-C > 100 mg/dl (2.6 mmol/l)), LA treatment should then be applied as last resort. In patients with elevated Lp(a) concentrations (Lp(a) > 60 mg/dl (>120 nmol/l)) and established cardiovascular disease, therapy should rely primarily on LA methods. If in addition to high Lp(a) levels insufficiently treated LDL-C concentrations (LDL-C > 100 mg/dl (2.6 mmol/l)) exist, in rare cases PCSK9-I can supplement the lipid lowering concept.

The German Lipoprotein Apheresis Registry (GLAR) - almost 5 years on.

BACKGROUND: Since 2005 an interdisciplinary German apheresis working group has been established by members of both German Societies of Nephrology and of Lipidologists and completed the data set for the registry according to the current guidelines and the German indication guideline for apheresis in 2009. In 2011 the German Lipoprotein Apheresis Registry (GLAR) was launched and data are available over nearly 5 years now. METHODS AND RESULTS: During the time period 2012-2016, 71 German apheresis centers collected retrospective and prospective observational data of 1435 patients undergoing lipoprotein apheresis (LA) treatment of high LDL-C levels and/or high Lp (a) levels suffering from cardiovascular disease (CVD) or progressive CVD. A total of 15,527 completely documented LA treatments were entered into the database. All patients treated by LA showed a median LDL-C reduction rate of 67.5%, and a median Lp (a) reduction rate of 71.1%. Analog to the Pro(a)LiFe pattern, patient data were analyzed to the incidence rate of coronary events (MACE) 1 and 2 years before the beginning of LA treatment (y-2 and y­1) and prospectively two years on LA treatment (y + 1 and y + 2). During two years of LA treatment a MACE reduction of 78% was observed. In the years considered, side effects of LA treatment were low (5.9%) and mainly comprised puncture problems. CONCLUSIONS: The data generated by the GLAR shows that LA lowers the incidence rate of cardiovascular events in patients with high LDL-C and/or high Lp (a) levels, progressive CVD, and maximally tolerated lipid lowering medication. In addition, LA treatments were found to be safe with a low rate of side effects.

Current insights into the German Lipoprotein Apheresis Registry (GLAR) - Almost 5 years on.

BACKGROUND: In recent years the Federal Joint Committee (G-BA), a paramount decision-making body of the German health care system required a reassessment of the approval of chronic lipoprotein apheresis therapy for regular reimbursement. Since 2005 an interdisciplinary German apheresis working group has been established by members of both German Societies of Nephrology. In 2009 the working group completed the indication for lipoprotein apheresis with respect to current cardiovascular guidelines and current scientific knowledge for the registry. In 2011 the German Lipoprotein Apheresis Registry (GLAR) was launched and data acquired over nearly 5 years can now be reported. METHODS AND RESULTS: All data were collected and analyzed during the time period 2012-2015. Over this time interval, 68 German apheresis centers collected retrospective and prospective observational data of 1.283 patients undergoing lipoprotein apheresis (LA) treatment of high LDL-cholesterol (LDL-C) levels and/or high lipoprotein(a) (Lp(a)) levels suffering from progressive cardiovascular disease (CVD). A total of 15,167 documented LA treatments were investigated. All patients treated by LA exhibited a median LDL-C reduction rate of 68.6%, and a median Lp(a) reduction rate of 70.4%. Analogue to the Pro(a)LiFe pattern, patient data were analyzed and compared with respect to the incidence rate of coronary events (MACE) 1 and 2 years before the start of LA treatment (y-2 and y-1) and prospectively one year on LA treatment (y+1). During the first year of LA treatment a MACE reduction of 97% was be observed. In the years considered, LA treatment side effects occurred at a low rate (ca. 5%) and mainly comprised puncture problems. CONCLUSIONS: For the first time data generated by the GLAR shows that LA lowers the incidence rate of cardiovascular events in patients with high LDL-C and/or high Lp(a) levels, progressive CVD and maximally tolerated lipid lowering medication. In addition LA treatments were found to be safe, exhibiting a low rate of side effects.

[The history of kidney transplantation]. / Die Geschichte der Nierentransplantation.

The history of kidney transplantation is a history of many unsuccessful efforts and setbacks, but also the history of perseverance, pioneering spirit, and steadfast courage. The first successful transplantation of a dog kidney was done by the Austrian Emerich Ullmann (1861-1937) in 1902. The kidney was connected to the carotid artery of the dog and the ureter ended freely. The organ produced urine for a couple of days before it died. In 1909, there were efforts to transplant human kidneys from deceased patients to monkeys and in the following year the first xenotransplantation in humans was completed. Different kinds of donors were tried: dogs, monkeys, goats and lambs, all without success. In 1939, the first transplantation from a deceased human donor was done by the Russion Yurii Voronoy, the patient survived for only a couple of days, and the organ never worked. In 1953, the first temporarily successful transplantation of a human kidney was performed by Jean Hamburger in Paris. A 16-year-old boy received the kidney of his mother as living donor transplantation. Then in 1954, a milestone was made with the first long-term successful kidney transplantation by Joseph Murray: the transplantation was done between monozygotic twins; the organ survived for 8 years. For his efforts in kidney transplantation, Murray was honored with the Nobel Prize in medicine in 1990. In 1962, the first kidney transplantation between genetically nonrelated patients was done using immunosuppression and in 1963 the first kidney transplantation in Germany was done by Reinhard Nagel and Wilhelm Brosig in Berlin. The aim of this article is to present the history of kidney transplantation from the beginning until today.

In vivo effects of recombinant human erythropoietin on circulating human hemopoietic progenitor cells.

Recombinant human erythropoietin (rhEpo), now available, has become increasingly more important for clinical use, e.g., in the treatment of anemia of chronic renal failure, and has been shown to reverse anemia in these patients. When patients with anemia of chronic renal failure were treated with rhEpo at dosages between 40 and 120 U/kg three times per week, the numbers of circulating erythroid burst-forming units (BFU-E) and granulocyte-erythrocyte-macrophage-megakaryocyte colony-forming units (CFU-GEMM) significantly increased during the first week of therapy. In contrast, the incidence of circulating granulocyte-monocyte CFU (CFU-GM) was not significantly altered.

Indications for apheresis as an ultima ratio treatment of refractory hyperlipidemias.

Lipid apheresis is at present well established in routine treatment of diverse hyperlipoproteinemias refractory to conventional dietary and medical regimens, especially in countries with high medical and socioeconomic standards. Severe familial hypercholesterolemia with atherosclerotic vessel disease involving the coronary arteries is the most frequent indication for lipid apheresis as well as homozygous familial hypercholesterolemia before the development of cardiovascular complications.In hyperlipoproteinemia (a) with progressive vessel disease, lipid apheresis is regularly accepted in Germany. The indication of apheresis in Refsum's disease and the chylomicronemia syndrome is described.

Echocardiographic findings in patients on maintenance hemodialysis substituted with recombinant human erythropoietin.

Cardiomegaly and impaired myocardial function are frequent in patients on maintenance hemodialysis. One important reason is probably severe renal anemia. Substitution with recombinant human erythropoietin (rhEPO) results in long-term correction of renal anemia. We investigated the changes in cardiac function under rhEPO therapy using echocardiography. 13 patients with severe renal anemia (hct less than 26%) but independent of regular blood transfusions during the last six months were treated with 40-120 IU/kg rhEPO intravenously three times/week. Echocardiographic studies were performed in the anemic state and when hematocrit values were stable at levels above 30%. Left ventricular end-diastolic diameter (LVEDD) and end-systolic diameter (LVESD) were reduced (LVEDD: 53.9 +/- 4.2 mm vs. 51.4 +/- 5.8 mm; LVESD: 35.7 +/- 5 mm vs. 32.8 +/- 5 mm). Mean end-diastolic volume (LVEDV) and end-systolic volume (LVESV) were also diminished (LVEDV: 141.9 +/- 25.4 ml vs. 128.1 +/- 32.5 ml; LVESV: 54.8 +/- 18.6 ml vs. 45.1 +/- 17 ml). Stroke volume (SV) fell slightly from 87.1 ml to 83 ml resulting in a decrease of cardiac output (CO) from 6.9 +/- 1.6 l/min to 6.2 +/- 1.7 l/min. The thickness of the left ventricular posterior wall (LVPW) and of the septum interventriculare (IVS) remained constant. Myocardial contractility indicated by ejection fraction (EF), fractional shortening (FS) and the velocity of circumferential fiber shortening (VCF) frequently improved. Our data indicate that correction of renal anemia by rhEPO can improve myocardial function in patients on maintenance hemodialysis.

Differences in calcium kinetic pattern between CAPD and HD patients.

To assess the effect of different dialysis modalities on calcium turnover, we studied 57 patients on maintenance hemodialysis treatment (HD) and 38 patients on continuous ambulatory peritoneal dialysis (CAPD) with tracer kinetic studies using two calcium isotopes (45Ca by mouth and 47Ca intravenously). The two groups were comparable in age, sex and prevalence of diabetes. The groups did not differ in their serum concentrations of intact parathyroid hormone (iPTH), calcium, inorganic phosphate and 1,25-dihydroxyvitamin D. 25-hydroxy-vitamin D and alkaline phosphatase were found to be significantly higher in HD patients. Despite these similarities, CAPD patients showed a significantly lower calcium kinetic response as measured by calcium retention and plasma calcium efflux than HD patients. Mean calcium retention was 39.5% in HD patients compared to 31.2% in the CAPD group (p < 0.05). Plasma calcium efflux was significantly lower in the CAPD group (2.7 vs 3.2 respectively; p < 0.01). iPTH correlated with calcium retention and plasma calcium efflux in HD patients (r = 0.69 and r = 0.67 respectively). In CAPD patients, the correlation coefficient between iPTH and calcium retention was markedly lower (r = 0.54), whereas no correlation was found between iPTH and plasma calcium efflux (r = 0.08). In addition, the slope of the correlation curve were higher in HD patients (p < 0.01 and p < 0.001, respectively), indicating a better response of this patient group to the action of parathyroid hormone. Our data are in accordance with recently published results showing that the dialysis modality has a major impact on bone turnover and on the progression of uremic bone disease. It has been shown that CAPD is an independent risk factor for the development of the adynamic form of renal bone disease. This finding may be explained by the lower response of calcium turnover to the action of PTH as shown here with tracer kinetic studies.

Daily subcutaneous administration of recombinant human erythropoietin (rhEPO) in peritoneal dialysis patients: a European dose-response study.

In a prospective randomized open multicenter study, 107 anemic (Hct < = 28%) peritoneal dialysis (PD) patients were treated with s.c. rhEPO daily. The mean observation period was 299 days (range 14-479 days). Patients were randomly assigned to 3 groups with different initial doses: 5 U/kg (G5), 10 U/kg (G10), 20 U/kg (G20). Initial doses were maintained for at least 8 weeks unless the target Hct (30-35%) was achieved earlier. The weekly increase of Hct was significantly (p < 0.05) dose-dependent: 0.19% in G5, 0.5% in G10 and 0.94% in G20. In case of insufficient response (< 0.5% per week), the dose was doubled every 4 weeks. Final doses on achieving the target Hct ranged from 5 to 40 U/kg (median 20 U/kg). The dose was then reduced to 50% and adjusted individually. The median maintenance dose was 9.9 U/kg/day. No tendency towards higher blood pressure or intensification of antihypertensive treatment was observed. When rhEPO is administered daily, 10 U/kg/day (70 U/kg weekly) is the recommended starting dose. The need for higher doses used in unsatisfactory response, should lead to further examination to rule out iron deficiency and other reasons for non-response. The median maintenance dose reported here is the lowest published in the literature for PD patients and seems to be linked to the daily injections.

Effect of recombinant human erythropoietin on iron balance in maintenance hemodialysis: theoretical considerations, clinical experience and consequences.

Iron deficiency is the main reason for insufficient response to rEPO therapy. Serum ferritin and transferrin saturation give valuable information on storage iron and iron transport. Iron demand for correction of anemia can easily be estimated after HCT (vol%) x average blood volume (dl) = mg iron. Inadequate iron supply of the bone marrow in the presence of sufficient storage iron in the RES develops frequently under rEPO, possibly explaining the improvement of bone marrow response to rEPO by concomitant intravenous iron supply. The reasons of functional iron deficiency are still speculative.

Management of iron deficiency in renal anemia: guidelines for the optimal therapeutic approach in erythropoietin-treated patients.

Much progress has been made in recent years in the management of anemia associated with chronic and renal failure with recombinant human erythropoietin (r-Hu EPO). However, there remains much debate surrounding the diagnosis and treatment of iron deficiency. To ensure that full benefit from erythropoietin therapy is received, most patients require iron supplement during treatment. There are, however, few guidelines for the use of iron therapy. Iron deficiency results in an inadequate response to r-Hu EPO and is the main cause of resistance to this treatment. Oral iron therapy is of limited value in patients receiving r-Hu EPO. Thus, intravenous iron supplementation should be administered only in patients who do not tolerate available intravenous iron preparations or who are on continuous ambulatory peritoneal dialysis with no evidence of functional iron deficiency. This article provides guidelines for the diagnosis of absolute or functional iron deficiency in patients with renal anemia and suggests treatment schedules for intravenous iron supplementation. We hope that all dialysis patients will be able on this basis to achieve a satisfactory iron status and benefit fully from r-Hu EPO therapy.

Effects of lovastatin (20-80 mg daily) on lipoprotein fractions in patients with severe primary hypercholesterolemia.

The effect of lovastatin on lipids, lipoproteins and apolipoproteins was studied in 10 patients with primary hypercholesterolemia. After four weeks diet/placebo alone, patients received diet plus lovastatin at daily doses of 20 mg (weeks 1-4), 40 mg (weeks 5-8) and 80 mg (weeks 9-12). Twelve weeks of treatment with lovastatin resulted in a lowering of total cholesterol and LDL-cholesterol by 34% and 41%, respectively. Triglycerides and VLDL-cholesterol decreased by 19% and by 42%, respectively. HDL-cholesterol and HDL2-cholesterol increased, whereas HDL3-cholesterol was not affected. IDL-cholesterol decreased by 50%, suggesting that the clearance of remnant lipoproteins was enhanced by lovastatin. In the VLDL and the IDL fraction, the triglyceride to cholesterol mass ratio increased significantly after twelve weeks of therapy. Lipoprotein(a) was not affected. Lovastatin was well tolerated and the data shows that lovastatin exerts favorable effects on plasma lipoprotein fractions. It may, therefore, prove a useful drug in the primary and secondary prevention of atherosclerotic vessel diseases.

Decrease in peritonitis rate by integrated disconnect system in patients on continuous ambulatory peritoneal dialysis.

The prevention of peritonitis is of major concern for successful long-term continuous ambulatory peritoneal dialysis (CAPD) treatment. The effect of a Y-system on peritonitis incidence and patient morbidity was observed in a comparative, retrospective single-center analysis over a period of 5 years. The integrated disconnect system prolonged the peritonitis-free period from 1:11 patient-months, observed with the conventional system, to greater than 1:50 patient-months. The rate of hospitalization was reduced by 45%.

Factors influencing transperitoneal calcium balance during CAPD.

A dialysate containing a calcium concentration of 1.75 mmol/L has been the standard in CAPD for a long time. This concentration was chosen to achieve a positive calcium balance to suppress hyperparathyroidism. In the measurement of peritoneal calcium mass transfer, conflicting results have been published, with positive and negative calcium balances reported. These differences have been explained by differences in the filtration rate, and a negative correlation between the filtration rate and the peritoneal calcium mass transfer can be found. Whereas nearly all patients in this study had a negative calcium balance using a glucose solution of 3.86%, a wide variation was found for the 1.36% glucose solution. There were several patients who had a positive calcium balance despite a positive filtration rate. The explanation for this finding lay in differences in serum concentrations of calcium, and especially differences in the size of the total exchangeable calcium pool that contains the plasma calcium compartment. A negative correlation between peritoneal calcium balance and the size of the total exchangeable calcium pool could be demonstrated. This finding may explain the differences in the peritoneal calcium flux reported in the literature. As an enlargement of the exchangeable calcium pool correlates with the progression of vascular calcification, therapeutic efforts should be directed toward prevention of an enlargement of this pool.

Iron metabolism under rEPO therapy in patients on maintenance hemodialysis.

Therapy with recombinant human erythropoietin (rEPO) can correct anemia in RDT patients. However, iron deficiency can develop making treatment unsuccessful. Eighteen non-transfused RDT patients with hematocrit less than 26% were treated with rEPO to raise the HCT to 30-35%; then the dose was individually adjusted to maintain the HCT. The mean HCT rose from 22.3% to 31.5%. Ten patients received iron substitution before rEPO. During rEPO therapy five further patients had to be supplemented with iron; all patients needed an increase in the oral iron doses and three required i.v. iron. During the correction phase mean serum ferritin dropped from 203 micrograms/l to a minimum of 71 micrograms/l and was 102 micrograms/l after six months. Serum iron and TIBC changed only moderately. It thus appears that iron demand rises markedly during rEPO therapy, requiring iron substitution in most patients. Serum ferritin is the most sensitive parameter for development of iron deficiency.

[Renal artery dilatation in renovascular hypertension. Acute and long-term outcome in a large patient sample]. / Nierenarteriendilatation bei renovaskulärer Hypertonie. Akut- und Langzeitergebnisse eines grossen Patientenkollektivs.

BACKGROUND: Renal angioplasty is an established therapy for treatment of renovascular hypertension. This study was performed to evaluate short- and long-term outcome of this procedure up until 3 years afterwards. PATIENTS AND METHODS: Altogether, 111 renal artery stenosis in 92 patients were dilated. Among these were 31 fibromuscular and 70 arteriosclerotic lesions, 4 transplant artery stenosis and 6 occlusions. RESULTS: The primary success rate for dilatation was approximately 90%. Serious complications occurred in 5 of the patients including 2 fatal myocardial infarctions about 2 weeks after the procedure. Restenosis (altogether 25%) almost exclusively occurred during the first few months after angioplasty (more often in arteriosclerotic lesions than in fibromuscular disease). Successful dilatation resulted in better blood pressure control. In several patients with preexisting chronic renal failure improvement of renal function was observed; in this group, however, restenosis occurred in about 1 third of the patients. CONCLUSIONS: Renal angioplasty is a suitable method for therapy of renovascular hypertension; in patients with preexisting renal failure improvement of renal function may ensue. The decision to treat with angioplasty must be weighted carefully against other established and also newer methods (surgery vs. antihypertensive medication vs. stent implantation) and should be reserved for specialized centers.