Technology in Diabetes Treatment: Update and Future.

Worldwide the number of people with diabetes mellitus is increasing. There are estimations that diabetes is one of the leading causes of death. The most important goals for the treatment of diabetes are self-management of the disease and an optimal quality of diabetes control. In the therapy new technologies, like real-time continuous interstitial glucose monitoring, continuous subcutaneous insulin infusion (CSII), electronic tools for the monitoring of therapeutic approaches, automated bolus calculators for insulin and electronic tools for education and information of patients, have become widespread and play important roles. All these efforts are related to the interaction between patients, caregivers, scientists or researchers and industry. The presentation of different aspects of new technological approaches in the present article should give more information about different technologies. However, because of the rather quickly appearance of new technologies, the presentation can only be a spotlight. Further studies are mandatory to analyze the effects and long-term benefits of each technology and electronic device.

LDL-apheresis: technical and clinical aspects.

The prognosis of patients suffering from severe hyperlipidemia, sometimes combined with elevated lipoprotein (a) levels, and coronary heart disease refractory to diet and lipid-lowering drugs is poor. For such patients, regular treatment with low-density lipoprotein (LDL) apheresis is the therapeutic option. Today, there are five different LDL-apheresis systems available: cascade filtration or lipid filtration, immunoadsorption, heparin-induced LDL precipitation, dextran sulfate LDL adsorption, and the LDL hemoperfusion. There is a strong correlation between hyperlipidemia and atherosclerosis. Besides the elimination of other risk factors, in severe hyperlipidemia therapeutic strategies should focus on a drastic reduction of serum lipoproteins. Despite maximum conventional therapy with a combination of different kinds of lipid-lowering drugs, sometimes the goal of therapy cannot be reached. Hence, in such patients, treatment with LDL-apheresis is indicated. Technical and clinical aspects of these five different LDL-apheresis methods are shown here. There were no significant differences with respect to or concerning all cholesterols, or triglycerides observed. With respect to elevated lipoprotein (a) levels, however, the immunoadsorption method seems to be most effective. The different published data clearly demonstrate that treatment with LDL-apheresis in patients suffering from severe hyperlipidemia refractory to maximum conservative therapy is effective and safe in long-term application.

Rehabilitation in Germany 2004-2016 A Multicenter Analysis Over a Period of 13 Years in Children and Adolescents with Diabetes Mellitus.

In the treatment of children/adolescents with diabetes medical rehabilitation plays an important role. It was the aim of the survey to analyze trends in the number of patients admitted to rehabilitation, the quality of diabetes care, the incidence of acute complications, risk factors for cardiovascular co-morbidities like lipids and blood pressure and the familial status nationwide and over a period of 13 years. METHODS: Currently seven hospitals offer in-patient rehabilitation for children/adolescents with diabetes in Germany. Six hospitals participated in the survey. All children/adolescents (n=7.163) who participated in an in-patient rehabilitation 01/01/2004-31/12/2016 were included. Clinical/familial data were assessed: age, sex, family situation, type/duration of diabetes, insulin dosage, self-monitoring, acute complications, height, body weight, blood pressure and laboratory parameters. For collecting and storage of data the computer software DPV® (Diabetes-Patienten-Verlaufsdokumentation, University of Ulm, Germany) was used. Statistical analyses were performed using the programme SAS (Statistical Analysis Software 9.4, SAS Institute Inc, Cary, North Carolina, USA). RESULTS: During the study period 7.163 patients took part in 10.987 in-patient rehabilitation procedures. The yearly number of patients participating in rehabilitation remained stable. There was no change in the quality of diabetes control (HbA1c: p=0.30, fasting blood glucose: p=0.80). The incidence of severe hypoglycaemia decreased (p<0.001). The incidence of ketacidosis remained stable (p=0.18). The frequency of blood glucose self-monitoring increased (p<0.001). The same was true for patients treated with CSII (p<0.001), whereas the numbers of patients treated with CT or ICT decreased (both p<0.001). There was no change in patients' total insulin dose (p=0.01). There was a decrease of the number of patients living with both parents (p<0.001), the percentage of children/adolescents living with mother or father alone increased (p<0.001). The percentage of children/adolescents living in mixed cultural families or having a background of immigration increased (p<0.001). CONCLUSIONS: There is a change in medical rehabilitation: The number is stable, the proportion of patients using CSII increased, the number of patients living with single parents and the percentage of patients from culturally mixed families increased also.

Therapeutic Apheresis in Immunologic Renal and Neurological Diseases.

Since the mid 1970s, when membrane modules became available, plasma separation techniques have gained in importance especially in the past few years. The advantages of this method are a complete separation of the corpuscular components from the plasma and due to increased blood flow rate and higher efficacy. Systemic autoimmune diseases based on an immune pathogenesis produce autoantibodies and circulating immune complexes, which cause inflammation in the tissues of various organs. In most cases, these diseases have a poor prognosis without treatment. Therapeutic apheresis (TA) in combination with immunosuppressive therapies has led to a steady increase in survival rates over the last 40 years. The updated information on immunology and molecular biology of different immunologic diseases are discussed in relation to the rationale for apheresis therapy and its place in combination with other modern treatments. The different diseases can be treated by various apheresis methods such as therapeutic plasma exchange (TPE) with substitution solution, or with online plasma or blood purification using adsorption columns, which contain biological or non-biological agents. Here, the authors provide an overview of the most important pathogenic aspects indicating that TA can be a supportive therapy in systemic autoimmune diseases such as renal and neurological disorders. For the immunological diseases that can be treated with TA, the guidelines of the German Working Group of Clinical Nephrology and of the Apheresis Committee of the American Society for Apheresis are cited.

Therapeutic Apheresis in Hematologic, Autoimmune and Dermatologic Diseases With Immunologic Origin.

The process of curing a patient by removing his illness by extracting blood is a very old one. Many years ago, phlebotomy was practiced to cure illness. Now, this old process, placed on a rational basis with therapeutic apheresis (TA), is being followed in clinical practice. Therapeutic plasma exchange (TPE) with hollow fiber modules has been used in different severe diseases for more than 40 years. Based on many years of experience with the extracorporeal circulation in end-stage renal disease, the authors herein give an overview of TA in immunological diseases, especially in hematologic, autoimmune and dermatologic diseases. Updated information on immunology and molecular biology of different immunological diseases is discussed in relation to the rationale for apheresis therapy and its place in combination with other modern therapies. With the introduction of novel and effective biologic agents, TA is indicated only in severe cases, such as in rapid progression despite immunosuppressive therapy and/or biologic agents. In mild forms of autoimmune disease, treatment with immunosuppressive therapies and/or biologic agents seems to be sufficient. The prognosis of autoimmune diseases with varying organ manifestations has improved in recent years, due in part to very aggressive therapy schemes. For the immunological diseases that can be treated with TA, the guidelines of the German Working Group of Clinical Nephrology and of the Apheresis Applications Committee of the American Society for Apheresis are cited. TA has been shown to effectively remove the autoantibodies from blood and lead to rapid clinical improvement.

Is lipoprotein (a)-apheresis useful?

Numerous epidemiological investigations have shown the importance of cholesterol, and in particular low density lipoprotein (LDL), and of the lipoproteins in the development of coronary sclerosis. A continuing relationship between cholesterol levels and coronary morbidity has been established. The LDL concentration in the blood is, in particular, to be made responsible for the development of arteriosclerosis and especially of coronary heart disease (CHD). Lipoprotein (a) [Lp(a)], as a risk factor for premature cardiovascular and cerebrovascular diseases, can be lowered by LDL-apheresis. Especially in isolated high levels of Lp(a) with CHD or polygenic hypercholesterolemia with elevated Lp(a) levels, LDL-apheresis can be indicated and can be useful to improve endothelium regulation and induce changes in coronary tone by an increase in endothelial derived relaxing factor. Lipoprotein (a) can be dramatically lowered by LDL-apheresis, but clinical improvement especially by low LDL is not still not clarified. Studies with weekly apheresis with statins versus drug therapy alone are necessary. To clarify the controversial discussions of whether lowering Lp(a) may be unnecessary or necessary to arrest progression of CHD, more clinical and randomized studies are needed. Lipoprotein (a) can be also lowered by current LDL-apheresis methods.

Silver coating of dialysis catheters to reduce bacterial colonization and infection.

Complications resulting from infection remain a major problem for hemodialysis catheters, with significant numbers of catheters being removed due to catheter-related sepsis. Numerous strategies have been employed to reduce the occurrence of infection and improve long-term outcomes, with varying degrees of success. One promising approach is coating the external surface of catheters with silver using physical vapor deposition processes. This article reviews results of animal and clinical experiments conducted to assess efficacy and biocompatibility of silver-coated dialysis catheters. It is concluded that silver coatings can reduce bacterial colonization and occurrence of infection associated with these devices.

Low-density lipoprotein apheresis: an overview.

Atherosclerosis with myocardial infarction, stroke, and peripheral cellular disease still maintains its position at the top of morbidity and mortality statistics in industrialized nations. Established risk factors widely accepted are smoking, arterial hypertension, diabetes mellitus, and central obesity. Furthermore, there is a strong correlation between hyperlipidemia and atherosclerosis. The prognosis of patients suffering from severe hyperlipidemia, sometimes combined with elevated lipoprotein (a) (Lpa) levels, and coronary heart disease (CHD) refractory to diet and lipid-lowering drugs is poor. For such patients, regular treatment with low-density lipoprotein (LDL) apheresis is the therapeutic option. Today, there are four different LDL apheresis systems available: immunoadsorption, heparin-induced extracorporeal LDL/fibrinogen precipitation, dextran sulfate LDL adsorption and LDL hemoperfusion. Regarding the different LDL apheresis systems used, there is no significant difference with respect to the clinical outcome or concerning total cholesterol, LDL, high-density lipoprotein (HDL), or triglyceride concentrations. With respect to elevated Lpa levels, however, the immunoadsorption method seems to be the most effective. In 45 patients (25 women, 20 men) suffering from familial hypercholesterolemia resistant to diet and lipid lowering drugs, low-density lipoprotein (LDL) apheresis was performed over 95.6 +/- 44.7 months. Four different systems (Liposorber, 32 of 45, Kaneka, Osaka, Japan; Therasorb, 6 of 45, Baxter, Munich, Germany; Lipopak, 2 of 45, Pocard, Moscow, Russia; and Dali, 5 of 45, Fresenius, St. Wendel, Germany) were used. With all methods, average reductions of 57% for total cholesterol, 55.9% for LDL, 75.8% for lipoprotein a (Lpa), and 45.9% for triglycerides, and an average increase of 14.3% for HDL were reached. Severe side-effects such as shock or allergic reactions were very rare (0.3%) in all methods. In the course of treatment, an improvement in general well-being and increased performance were experienced by 44 of 45 patients. The present data demonstrate that treatment with LDL apheresis of patients suffering from familial hypercholesterolemia resistant to maximum conservative therapy is very effective and safe even in long-term application.

Side-effects and complications in large-bore catheters for apheresis.

Vascular catheters have become essential tools for management of hospitalized or chronically ill patients requiring intensive medical treatments such as extracorporeal detoxification procedures. The increased use of such devices has been accompanied by a corresponding increase in complications, such as bloodstream infection and thrombosis. In a retrospective study 332 large bore catheters which were inserted in 182 patients in the inferior or superior vena cava were investigated. The complication rate was in internal jugular vein puncture (N = 231) with 20% low and in the subclavian vein puncture (N = 94) with 60.5% and in the femoral vein puncture (N = 7) with 57.1% very high. The majority of complications were puncture not possible, puncture of the artery, abscess, septicemia, bleeding and thrombosis. To minimize the complication rate the surface of some catheters were treated and the microdomain structured surface inserted. The first results are very encouraging and should help to make large bore catheters safer.

Long-term catheters for apheresis and dialysis with surface treatment with infection resistance and low thrombogenicity.

Infection, thrombosis, and stenosis are among the most frequent complications associated with blood-contacting catheters. These problems are usually related to surface properties of the base catheter material. Surface treatment processes, such as ion implantation and ion beam assisted deposition (IBAD) and microdomain structured surfaces, can be used to mitigate such complications. This study evaluated silver coated and implanted large bore catheters used for extracorporeal detoxification. In a 186 patient prospective study, 225 large bore catheters were inserted into the internal jugular or subclavian veins. Eighty-five surface-treated catheters (Spi-Argent, Spire Corporation, Bedford, MA, USA) and 28 catheters with surface treatment (Spi-Silicone, Spire Corporation) were inserted in 90 patients. One hundred and twelve untreated catheters placed in 96 patients served as controls, After removal, the catheters were cultured for bacterial colonization using standard microbiologic assays. They also were examined using a scanning electron microscope (SEM). Bacterial colonization was observed in 8% of the treated catheter compared with 46.4% of untreated catheters. The SEM investigations showed all treated catheters to possess low thrombogenicity. Catheters with microdomain structured surfaces showed same results in preliminary observation. The surface treatments of the large bore catheters can be used to improve thrombus and infection resistance of blood contacting catheters.

Therapeutic apheresis in autoimmune diseases.

Systemic autoimmune diseases based on an immune pathogenesis produce autoantibodies and circulating immune complexes, which cause inflammation in the tissues of various organs. In most cases, these diseases have a bad prognosis without treatment. Therapeutic apheresis in combination with immunosuppressive therapies has led to a steady increase in survival rates over the last 35 years. Here we provide an overview of the most important pathogenic aspects indicating that therapeutic apheresis can be a supportive therapy in some systemic autoimmune diseases, such as systemic lupus erythematosus, antiphospholipid syndrome, rheumatoid arthritis, and inflammatory eye disease. With the introduction of novel and effective biologic agents, therapeutic apheresis is indicated only in severe cases, such as in rapid progression despite immunosuppressive therapy and/or biologic agents, and in patients with renal involvement, acute generalized vasculitis, thrombocytopenia, leucopenia, pulmonary, cardiac, or cerebral involvement. In mild forms of autoimmune disease, treatment with immunosuppressive therapies and/or biologic agents seems to be sufficient. The prognosis of autoimmune diseases with varying organ manifestations has improved considerably in recent years, due in part to very aggressive therapy schemes.

Surface-Treated versus Untreated Large-Bore Catheters as Vascular Access in Hemodialysis and Apheresis Treatments.

Background. Catheter-related infections, thrombosis, and stenosis are among the most frequent complications associated with catheters, which are inserted in vessels. Surface treatment processes of the outer surface, such as ion-beam-assisted deposition, can be used to mitigate such complications. Methods. This retrospective study (1992-2007) evaluated silver-coated (54 patients) and noncoated (105 patients) implanted large-bore catheters used for extracorporeal detoxification. The catheters were inserted into the internal jugular or subclavian veins. After removal, the catheters were cultured for bacterial colonization using standard microbiologic assays. They also were examined using scanning electron microscope. Results. The silver coated catheters showed a tendency towards longer in situ time. The microbiologic examinations of the catheter tips were in both catheter types high positive, but not significant. Conclusion. The silver-coated catheters showed no significantly reduction in infection rate by evaluation of all collected data in this retrospective study. There was no association between both catheters in significantly reducing savings in treatment costs and in reducing patient discomfort. Other new developed catheter materials such as the microdomain-structured inner and outer surface are considered more biocompatible because they mimic the structure of natural biological surface.

Therapeutic apheresis in the treatment of hemolytic uremic syndrome in view of pathophysiological aspects.

Hemolytic-uremic syndrome (HUS) is a disease that can lead to acute kidney injury and often to other serious sequelae, including death. The disease is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. In view of the different courses of HUS, a minimum of three different pathogenetic types leading to HUS can be subdivided as follows: HUS caused by infection, idiopathic HUS (non-Shiga toxin HUS), and HUS in systemic diseases and after toxin exposure. The etiology and pathogenesis of HUS are not completely understood and its therapy is complicated. After the introduction of therapeutic apheresis as a supportive therapy in HUS, several authors reported successful treatment in more than 87% of treated patients. The supportive therapy is indicated basically in severe courses of HUS and is superior to available therapy interventions.

Low-density lipoprotein apheresis: clinical results with different methods.

In 40 patients (22 women, 18 men) suffering from familial hypercholesterolemia resistant to diet and lipid lowering drugs, low-density lipoprotein (LDL) apheresis was performed over 84.9 +/- 43.2 months. Four different systems (Liposorber, 28 of 40, Kaneka, Osaka, Japan; Therasorb, 6 of 40, Baxter, Munich, Germany; Lipopak, 2 of 40, Pocard, Moscow, Russia; and Dali, 4 of 40, Fresenius, St. Wendel, Germany) were used. With all methods, average reductions of 50.6% for total cholesterol, 52.2% for LDL, 64.3% for lipoprotein (a) (Lp[a]), and 43.1% for triglycerides, and an average increase of 10.3% for high-density lipoprotein (HDL) were reached. Severe side effects such as shock or allergic reactions were very rare (0.5%) in all methods. In the course of treatment, an improvement in general well being and increased performance were experienced by 39 of 40 patients. Assessing the different apheresis systems used, at the end of the trial, there were no significant differences with respect to the clinical outcome experienced with the patients' total cholesterol, LDL, HDL, and triglyceride concentrations. However, to reduce high Lp(a) levels, the immunoadsorption method with special Lp(a) columns (Lipopak) seems to be most effective: -59% versus -25% (Kaneka) - (Baxter), and -29% (Dali). The present data demonstrate that treatment with LDL apheresis of patients suffering from familial hypercholesterolemia resistant to maximum conservative therapy is very effective and safe even in long-term application.

Complications in large-bore catheters for extracorporeal detoxification methods.

Catheters for large vessels have become essential tools for the management of hospitalized or chronically ill patients requiring intensive medical treatments such as extracorporeal detoxification procedures. The increased use of such devices has been accompanied by a corresponding increase in complications, such as infection, sepsis, and thrombosis. In two retrospective studies, the first (1979-1990) with 1672 patients and 2626 large-bore catheters and the second (1996-2001) with 182 patients and 332 acute catheters, the frequency of infections, thrombosis, bleeding, and other side-effects were investigated. All complications and side-effects are presented. In total, the complication rate was in the first study 27.7% (internal jugular vein 23.8% in 2105 catheters, subclavian vein 43.5% in 521 catheters) and in the second study 32.2% (internal jugular vein 20% in 231 catheters, subclavian vein 60.6% in 94 catheters, femoral vein 57.1% in 7 catheters). The majority of complications were puncture not possible, puncture of the artery abscess, septicemia, bleeding, thrombosis, and faults in catheter material. To minimize these complication rates the handling of the inserted catheters before, during, and after the hemodialysis or apheresis treatment is minimized.

Large bore catheters with surface treatments versus untreated catheters for vascular access in hemodialysis.

Infection, thrombosis, and stenosis are among the most frequent complications associated with blood-contacting catheters. Complications resulting from infection remain a major problem for hemodialysis catheters, with significant numbers of catheters being removed due to catheter-related sepsis. Numerous strategies have been employed to reduce the occurrence of infection and im-prove long-term outcomes, with varying degrees of success. The most important is the careful and sterile handling by the attending staff of the catheters during hemodialysis treatments to minimize or stop a microbial colonization of the skin and the catheter. Another approach is coating the external surface of the catheters with substances which are antibacterial like silver and/or substances with low thrombogenicity like silicone. This investigation reviews results of animal and clinical experiments conducted to assess the efficacy and biocompatibility of silver and silicone coated dialysis catheters. It is concluded that silver coatings can reduce bacterial colonization and occurrence of infection associated with these devices. The catheters employing ion implantation of silicone rubber showed low thrombogenicity. Results of the studies indicate that ion beam based processes can be used to improve thrombus and infection resistance of blood contacting catheters. A new development is the microdomain structured surface (PUR-SMA coated catheters). Preliminary results with these catheters are very encouraging.

Efficacy and safety of a new whole-blood low-density lipoprotein apheresis system (Liposorber D) in severe hypercholesterolemia.

Low-density lipoprotein (LDL) apheresis is an extracorporeal modality to lower LDL cholesterol. While most of the devices eliminate LDL particles from plasma, a recently introduced whole-blood perfusion column (DALI) adsorbs lipoproteins directly from whole blood. We investigated the efficacy and safety of a new whole-blood LDL apheresis system (Liposorber D) in 10 patients with severe hypercholesterolemia in a multicenter trial. In 93 LDL aphereses, the mean reduction in LDL cholesterol and lipoprotein(a) was 62.2 +/- 11.5% and 55.6 +/- 16.9%, respectively (P < 0.01). If hemodilution during apheresis was considered, the reductions were 58.0 +/- 10.9 and 55.3 +/- 10.9%, respectively (P < 0.01), while high-density lipoprotein (HDL) cholesterol did not change significantly. Three mild episodes of hypocalcemia and two mild episodes of arterial hypotension were observed; however, LDL apheresis could be continued in each case. In conclusion, the new whole-blood LDL apheresis with Liposorber D is a safe, simple, and useful modality to reduce LDL cholesterol and lipoprotein(a) in cardiovascular high-risk patients.