[Interdisciplinary interaction in vascular diseases of the eye, diabetes and diabetic retinopathy]. / Interdisziplinäre Interaktion bei vaskulärer Erkrankung des Auges, Diabetes und diabetischer Retinopathie.

The incidence of diabetes mellitus type 2 is greatly increasing worldwide. An early therapy with intensified control of diabetes and blood pressure is especially important to avoid delayed complications. In addition to diabetic foot syndrome, diabetic retinopathy and diabetic nephropathy still represent commonly occurring problems. Despite improvements in the quality of care, the targets of the St. Vincent Declaration have still not yet been achieved. Diabetic retinopathy and diabetic nephropathy show parallels in the course of the disease and in the pathological anatomical alterations which have led to the inauguration of a diabetic renal-retinal syndrome. The ophthalmological assessment of the retina was previously considered to be a diagnostic aid for assessment of diabetic nephropathy; however, nowadays a simple estimation of the glomerular filtration rate using the modification of diet in renal disease (MDRD) formula and determination of microalbuminuria can in contrast give ophthalmologists an early indication of the possible presence of microangiopathic alterations.

[When is the right time point to start dialysis?]. / Wann ist der richtige Zeitpunkt des Dialysebeginns?

The transition from CKD 5 to dialysis treatment (CKD 5 D) is characterized by a high mortality risk for patients with chronic kidney disease (CKD). Therefore, the right time to start dialysis is of special interest. While there was a trend towards an earlier initiation of dialysis many years ago, new studies could not demonstrate a benefit on survivals for patients who start dialysis in a higher glomerular filtration rate (GFR). Delaying the start of dialysis to a lower GFR is possible in CKD patients with stable conditions when close nephrological supervision is provided. In patients with cardiorenal syndrom and acute on chronic renal failure, an earlier start of dialysis might be necessary as well as the re-evaluation after re-compensation. In elderly patients the possibilities and risks of a conservative treatment without dialysis should be discussed. Consequently, current guidelines define the optimal time to start dialysis on the basis of the individual risk of the patients, clinical symptoms and underlying disease and not only on the GFR alone.

Evaluation of maintenance of stable haemoglobin levels in haemodialysis patients converting from epoetin or darbepoetin to monthly intravenous C.E.R.A.: the MIRACEL study.

BACKGROUND AND OBJECTIVES: C.E.R.A., a continuous erythropoietin receptor activator, offers once-monthly dosing without compromising haemoglobin control. This study was undertaken to examine whether monthly C.E.R.A. using pre-filled syringes maintains stable haemoglobin levels when administered according to local clinical judgement. RESEARCH, DESIGN AND METHODS: MIRACEL was a prospective, open-label, single-arm, multicentre study performed at 90 nephrology centres in Germany. After a 2-month screening phase, haemodialysis patients receiving epoetin or darbepoetin were converted to monthly intravenous C.E.R.A., with a 5-month titration phase followed by a 2-month evaluation phase. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov: NCT00413894 RESULTS: Of 661 patients screened, 424 (64.1%) started C.E.R.A. therapy (previous treatment: 72.2% epoetin, 27.8% darbepoetin); 416 were eligible for inclusion in the intent-to-treat population. A mean of two C.E.R.A. dose changes were required during the 7-month treatment period. The primary efficacy variable, haemoglobin within 11-12.5 g/dL or 10-13 g/dL during the evaluation phase, was achieved in 109 (30.8%) and 265 (74.9%) of the 354 evaluable patients, respectively, with no differences observed between patients formerly receiving epoetin or darbepoetin or different dosing frequencies. During the screening, titration and evaluation phases, mean haemoglobin was 11.7 +/- 0.7 g/dL, 11.6 +/- 0.9 g/dL and 11.4 +/- 1.0 g/dL, respectively, and 90.6% (377/416), 70.4% (293/416) and 82.9% (345/416) of patients exhibited < or = 1 g/dL change from phase-specific individual means. C.E.R.A. was well-tolerated with a safety profile similar to that reported in phase III studies. CONCLUSIONS: In this single-arm, open-label, multicentre study, conversion of a large population of haemodialysis patients from epoetin or darbepoetin to monthly C.E.R.A. administration using pre-filled syringes was shown to be practical, convenient and offer good control of haemoglobin levels, regardless of the previous type of therapy or dosing frequency.

Efficacy and safety of DALI LDL-apheresis at high blood flow rates: a prospective multicenter study.

Direct adsorption of lipids (DALI) is the first LDL-apheresis method compatible with whole blood. Usually, the blood flow rate is adjusted at 60-80 ml/min, which results in session times of about 2 hr. The present study was performed to test the safety and efficacy of low-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) [Lp(a)] removal by DALI at high blood flow rates in order to reduce treatment time. Thirteen chronic DALI patients in seven centers suffering from hypercholesterolemia (LDL-C 162 +/- 42 mg/dl at baseline) and coronary artery disease were treated on a weekly or biweekly basis by DALI apheresis. The blood flow rate QB was held constant for at least two sessions, respectively, and was increased from 60 to 80, 120, 160, 200, and 240 ml/min. All patients had pre-existing av-fistulas. The anticoagulation was performed by a heparin bolus plus ACD-A at a ratio of citrate:blood ranging from 1:20 to 1:90. Clinically, the sessions were well tolerated and only 26/201 sessions (12%) of the treatments were fraught with minor adverse events. Acute LDL-C reductions (derived from LDL-C levels determined by lipoprotein electrophoresis) averaged 72/66/60/53/50/48% for QB=60/80/120/160/200/240 ml/min. Lp(a) reductions were 68/67/62/60/58/56%, whereas HDL-C losses were < or =10%. Routine blood chemistries and blood cell counts remained in the normal range. Treatment times averaged 142/83/45 min at Qb=60/120/240 ml/min. On average, DALI LDL-apheresis could be performed safely and effectively at high blood flow rates up to at least 120 ml/min in patients with good blood access, which significantly reduced treatment time from 142 to 83 min (-42%).

Tolerability and efficacy of multidose epoetin beta (Reco-Pen) for subcutaneous administration in patients with anemia due to renal failure.

AIMS: To assess the tolerability, safety and efficacy of the epoetin beta multidose cartridge formulation, self-administered subcutaneously via a pen device (Reco-Pen), in adult patients with renal anemia. METHODS: Patients receiving maintenance epoetin therapy were switched to the subcutaneous (SC) multidose formulation of epoetin beta (NeoRecormon). The frequency of adverse events, local tolerability, and changes in blood pressure and laboratory variables were recorded. Hematologic parameters, transfusion requirements and epoetin beta dosage were also assessed. RESULTS: A total of 406 patients were entered in the intention-to-treat analysis. Mean treatment duration was 82.3 days. Fifty patients (12.3%) withdrew from the study; 14 (3.4%) discontinued because of adverse events. Treatment was well tolerated, with adverse events considered probably related to treatment in only 5 cases, and 1 case of local intolerability. There were no clinically significant changes in blood pressure or laboratory variables, and no changes in hematologic parameters or transfusion requirements. Unexpectedly, the epoetin beta dose was reduced by almost one-third in patients previously maintained on SC epoetin. CONCLUSION: SC administration of this multidose epoetin beta formulation with the Reco-Pen device was well tolerated and effective. It is possible that the improved capacity to individualize dose may have contributed to the considerable reduction in SC epoetin beta dosage requirement.

Comparison of body fluid distribution between chronic haemodialysis and peritoneal dialysis patients as assessed by biophysical and biochemical methods.

BACKGROUND: The control of extracellular volume is a key parameter for reducing hypertension and the incidence of cardiovascular mortality in dialysis patients. In recent years bioimpedance measurement (BIA) has been proven as a non-invasive and accurate method for measuring intracellular and extracellular fluid spaces in man. In addition, plasma atrial natriuretic peptide (ANP) and cyclic guanosine monophosphatase (cGMP) concentrations have been shown to reflect central venous filling. Using these methods, we compared body fluid status between stable patients on haemodialysis and peritoneal dialysis. METHODS: Thirty-nine chronic haemodialysis patients, 43 chronic peritoneal dialysis patients and 22 healthy controls were included in the study. Multifrequency BIA was performed using the Xitron BIS4000B device (frequencies from 5 to 500 kHz were scanned and fitted) in patients before and after haemodialysis. Peritoneal dialysis patients were measured after drainage of the dialysate. Plasma ANP and cGMP levels were measured in plasma using a (125)I solid phase RIA. Serum albumin concentrations and serum osmolality were measured in all patients. The body fluid data were analysed in relation with the clinical findings. RESULTS: Total body water (TBW) was 0.471+/-0.066 l/kg before haemodialysis and 0.466+/-0.054 l/kg after haemodialysis. Peritoneal dialysis patients had a TBW (0.498+/-0.063 l/kg) that was greater than the before and after dialysis values of haemodialysis patients. The extracellular body fluid (V(ecf)) was increased pre-haemodialysis. It was even greater in peritoneal dialysis patients compared with patients both pre- and post-haemodialysis (pre 0.276+/-0.037 l/kg; post 0.254+/-0.034 l/kg; peritoneal dialysis 0.293+/-0.042 l/kg, P<0.05). However, plasma ANP concentrations (representing intravascular filling) in peritoneal dialysis patients were comparable with post-haemodialysis values (284+/-191 pg/ml vs 286+/-144 pg/ml). The correlation coefficient between sysRR and V(ecf) was r=0.257 in haemodialysis (P=0.057) and r=0.258 in peritoneal dialysis (P<0.05). A significant negative correlation was found between serum albumin and V(ecf)/TBW in peritoneal dialysis patients (r= -0.624). CONCLUSION: Body fluid analysis by BIA demonstrated that TBW and V(ecf) were increased in peritoneal dialysis patients, and were comparable or even greater than values found before haemodialysis. However, plasma ANP levels indicated that intravascular filling was not increased in peritoneal dialysis. The ratio of V(ecf) to TBW was correlated to systolic pressure and negatively to serum albumin in peritoneal dialysis patients.

The influence of different glucose concentrations in haemodialysis solutions on metabolism and blood pressure stability in diabetic patients.

In recent years the percentage of diabetic patients on haemodialysis has increased. Considering the high frequency of intradialytic hypotensive and hypoglycaemic episodes experienced by these patients, it was the aim of the present study to evaluate the influence of different dialysate glucose concentrations (5.5 mmol/L or 11 mmol/L) on blood pressure and glycaemic regulation, using special dialysis equipment - the GENIUS System. This cross-over, prospective and randomised study, total duration 14 weeks, included 20 diabetic patients on maintenance haemodialysis. Group 1: 9 patients dialysed using dialysate with a glucose concentration of 5.5 mmol/L and after 7 weeks switched to dialysate with a glucose concentration of 11 mmol/L. Group 2: vice versa. Results show a statistically higher number of patients with hypoglycaemic and hypotensive episodes using dialysate with a 5.5 mmol/L glucose concentration. Also, mean serum glucose values were higher during haemodialysis sessions with a glucose dialysate concentration of 11 mmol/L. There were no statistical differences between the groups in laboratory values, HbA1C, insulin doses or in anthropometric parameters. Our results suggest that fewer diabetic patients undergoing haemodialysis using a higher dialysate glucose concentration of 11 mmol/L have hypoglycaemic and hypotensive episodes. Since this dialysate glucose concentration had no influence on lipid or hepatic metabolism, anthropometric parameters and especially HbA/1C values in this short-term study, the long term examination of its effects is warranted.

Long-term experience with an ultrapure individual dialysis fluid with a batch type machine.

BACKGROUND: This paper discusses long-term experience with a specific type of dialysis equipment which has been used more than 15 years without variation. The system was designed to allow easy individualization of dialysis fluid composition and to deliver dialysate of the highest hygienic quality. METHODS: Data from 399 patients covering the period from 1971 onwards were analysed retrospectively. Survival probabilities were estimated by the Kaplan-Meier method and the median number of days in hospital was calculated. Additional data collected from patient subgroups included serum albumin level, erythropoietin requirement and antihypertensive treatments. Kt/V and PCR from one subgroup were computed using the formulae of Daugirdas and Depner. RESULTS: The estimated survival probability after 5 years for all patients was 59.1% (95% CI: 52.6-65.6%). The main risk factors from the available covariables were age and IDDM. The cumulative incidence of carpal tunnel syndrome after 10 years of dialysis was estimated as 7% (95% CI: 0-14%). Data from the subgroups revealed that 82% of the patients had serum albumin levels >4.0 g/dl, 65% of the patients received no antihypertensive drugs and 39% received erythropoietin (37 +/- 28 units/kg bw/week) to correct dialysis anaemia (haemoglobin level = 98 +/- 8 g/l). Average Kt/V was 1.21 +/- 0.17, PCR was 1.10 +/- 0.22 g/kg/day. CONCLUSIONS: The setup described permits individualized therapy of high quality. The high serum albumin values and our very low incidence of carpal tunnel syndrome underline the importance of water and dialysate quality.

LDL hemoperfusion--a new procedure for LDL apheresis: biocompatibility results from a first pilot study in hypercholesterolemic atherosclerosis patients.

Current lipid apheresis techniques can remove atherogenic lipoproteins only from plasma. The initial mandatory separation of plasma and blood cells renders the extracorporeal circuit complex. We recently described the first clinical application of a new lipid adsorber that adsorbs low-density lipoprotein (LDL) and lipoprotein (a) (Lp[a]) directly from whole blood. In continuation of our work, this paper describes the clinical biocompatibility of this new LDL hemoperfusion system. In a 2 center phase II clinical trial, 12 hypercholesterolemic patients suffering from overt coronary or peripheral artery disease were treated once with LDL hemoperfusion. The new LDL adsorber (DALI, Fresenius, St. Wendel, Germany) contained 480 ml of polyacrylate coated polyacrylamide gel. The anticoagulation protocol consisted of an initial heparin bolus followed by an acid citrate dextrose-A (ACD-A) infusion during the treatment. One patient blood volume was treated per session. All sessions were clinically uneventful. No signs of hemolysis or extracorporeal clot formation could be detected, and cell counts remained virtually constant. In a subgroup of patients (n = 4-6), further biocompatibility parameters were studied. Activation of leukocytes (elastase release), thrombocytes (beta-thromboglobulin [beta-TG] extrusion), and monocytes (interleukin (IL)-1beta and IL-6) were minimal. Complement activation (C3a and C5a generation) was negligible. The chosen anticoagulation protocol was both safe (constant ionized calcium levels) and effective (low thrombin-antithrombin formation). In summary, within the scope of a first pilot study, this new LDL hemoperfusion procedure combined the features of excellent clinical tolerance, good biocompatibility, and ease of handling. Phase III clinical trials will have to show whether these encouraging preliminary results can be corroborated in a larger patient population.

LDL hemoperfusion--a new procedure for LDL apheresis: first clinical application of an LDL adsorber compatible with human whole blood.

To date, lipid apheresis procedures can remove low-density lipoprotein (LDL) cholesterol (LDL-C) only from plasma. Thus, initially plasma has to be separated from the blood cells, which increases the costs and complexity of the extracorporeal circuit. This paper describes the first clinical application of a new LDL adsorber that eliminates LDL directly from whole blood. The goal of this pilot study was to test the efficacy, safety, and feasibility of direct lipoprotein adsorption in patients. In a 2 center Phase II clinical trial, 12 hypercholesterolemic patients suffering from overt coronary or peripheral artery disease were treated once with LDL hemoperfusion. The new LDL adsorber (DALI, Fresenius, St. Wendel, Germany) contained 480 ml of polyacrylate coated polyacrylamide gel. The anticoagulation consisted of an initial heparin bolus followed by an acid citrate dextrose (ACD)-A infusion during the treatment. The processing of nearly 1 patient blood volume resulted in a reduction of LDL-C by 45 +/- 8% and triglycerides by 23 +/- 20%. HDL-C, fibrinogen, and cell counts were not significantly influenced. In a subgroup of 5 patients who exhibited elevated lipoprotein (a) (Lp[a]) levels, Lp(a) reduction was 43 +/- 15% (all results corrected for plasma volume shifts). The sessions were clinically uneventful; the system was technically safe and easily handled. In conclusion, short-term LDL hemoperfusion by the DALI proved to be a safe, effective, and simple procedure for the treatment of patients suffering from symptomatic recalcitrant hypercholesterolemia. The present study represents a solid basis for the clinical long-term evaluation of this new technique in the future.

Regression of carotid plaques during low density lipoprotein cholesterol elimination.

We performed serial prospective ultrasound examinations of four flat and 17 soft carotid plaques during an average of 17 months in seven patients with heterozygous hypercholesterolemia during heparin-induced extracorporeal low density lipoprotein elimination on precipitation from plasma. By means of a specially designed quantitative three-dimensional ultrasound analysis, significant plaque volume reduction could be evaluated in all subjects, along with a marked reduction of total and low density lipoprotein cholesterol and fibrinogen serum levels.

Sodium lithium countertransport is acutely influenced by heparin-induced extracorporal LDL precipitation.

Sodium lithium countertransport may be a genetic marker for arterial hypertension and for the risk of diabetic nephropathy in type 1 diabetic patients. Since various factors seem to influence the transport velocity including serum lipid alterations, erythrocytes of seven patients with severe hyperlipoproteinaemia who were chronically and intermittently treated with LDL apheresis were examined before and immediately after therapy. The LDL apheresis reduced sodium lithium countertransport significantly (0.383 vs 0.269, P less than 0.02). Therefore, we conclude that serum lipid composition must be considered when interpreting sodium lithium countertransport velocity.

[Diabetic nephropathy. Pathogenetic, diagnostic and therapeutic concepts]. / Diabetische Nephropathie. Pathogenetische, diagnostische und therapeutische Konzepte.

Today the clinical picture of diabetes mellitus is often determined by its late complications. Diabetic nephropathy appears in about 40% of all diabetic patients with type 1 (insulin-dependent) diabetes mellitus within a period of 10-15 years. Early diagnosis is crucial for the prognosis as appropriate therapy may delay or even arrest the reduction of filtration fraction and terminal renal failure. Most important for the early diagnosis is the measurement of albumin and protein excretion.

[Acute effects of extracorporeal LDL cholesterol and fibrinogen elimination on blood rheology and microcirculation]. / Akute Wirkungen der extrakorporalen LDL-Cholesterin-und Fibrinogen-Elimination auf Blutrheologie und Mikrozirkulation.

Long-term intermittent heparin-induced extracorporeal low-density lipoprotein (LDL)-cholesterol precipitation was performed in three men - aged 32, 52 and 56 years - with severe familial hypercholesterolaemia and angiographically demonstrated coronary heart disease. This significantly lowered by 65-70% their LDL-cholesterol concentration and by 48-54% their fibrinogen concentration. Fibrinogen elimination reduced plasma viscosity by 13-14% and clearly raised the transcutaneously measured partial pressure of oxygen by 33-50%. Clinically the improved microcirculation achieved a decrease in angina symptoms: the walking distance of the 52-year-old man increased from about 100 m to 4000 m, the daily need of glyceryl trinitrate falling from an average of 12 to 4 aerosol doses.

[Rheologic changes in the postprandial phase]. / Rheologische Veränderungen in der Postprandialphase.

In this study, the postprandial changes of blood rheology and lipid parameters after a lipid-enriched test meal (75% lipids) versus a normal lipid composition control meal (30% lipids) were monitored. Six healthy volunteers were given a high lipid test meal (85 g lipids, 3800 kJ) as well as a control test meal (30% lipids, 3730 kJ) after 7 days. 3-6 hours after ingestion of the test meal, triglyceride levels peaked with an increase of about 120% after the lipid-enriched test meal and of about 55% after the control meal. The mean levels of plasma viscosity increased from 1.25 mPas to 1.29 mPas 3 hours after ingestion of the lipid-enriched test meal, whereas the blood rheology parameters, such as plasma viscosity and red blood cell aggregation, were nearly unchanged after the control meal with normal lipid composition. The changes of plasma viscosity after the lipid-enriched test meal were caused by an increase of triglyceride levels and an increase of fibrinogen levels in the postprandial phase by nearly 60% (mean value). Two different rheological reaction patterns have been demonstrated. Whereas 5 individuals showed the increase of blood rheology parameters mentioned above, one person had a very pronounced increase of plasma viscosity from 1.34 to 1.42 mPas and fibrinogen levels from 155 mg/dl to 280 mg/dl after the lipid-enriched test meal. This marked postprandial increase of blood viscosity may contribute to a flow limitation of myocardial microcirculation in patients with coronary artery disease.