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.

High blood flow rates with adjustment of needle diameter do not increase hemolysis during hemodialysis treatment.

BACKGROUND: Higher blood flow in dialysis therapy is often avoided due to concerns about shear-induced blood damage despite the lack of reliable data. OBJECTIVE: This study investigated the influence of higher blood flow rates on plasma free hemoglobin (Hb) concentration after hemodialysis (HD) treatment. METHODS: Thirty-two chronic HD patients were treated once with a blood flow rate of 250 mL/min using a 17G needle, and once with a blood flow rate of 500 mL/min using a 14G needle. Arterial and venous pressure and blood pressure (BP) were recorded before and after treatment. Blood samples were taken before and after treatment for analysis of plasma free Hb, pH, HCO3, base excess, hematocrit value, urea, sodium, potassium and calcium. RESULTS: HD treatment at blood flow rates of 500 mL/min did not increase plasma free Hb compared to treatments at blood flow rates of 250 mL/min. Frequency of intradialytic BP drops was not different either. By adaptation of the needle size, negative arterial pressure could be kept at a similar level. Urea reduction rates were significantly higher during treatments with higher blood flow rates. CONCLUSION: Higher blood flow rates can be applied without an increased hemolysis risk provided that needle sizes are adapted accordingly.

Longer treatment time and slower ultrafiltration in hemodialysis: associations with reduced mortality in the DOPPS.

Longer treatment time (TT) and slower ultrafiltration rate (UFR) are considered advantageous for hemodialysis (HD) patients. The study included 22,000 HD patients from seven countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Logistic regression was used to study predictors of TT > 240 min and UFR > 10 ml/h/kg bodyweight. Cox regression was used for survival analyses. Statistical adjustments were made for patient demographics, comorbidities, dose of dialysis (Kt/V), and body size. Europe and Japan had significantly longer (P < 0.0001) average TT than the US (232 and 244 min vs 211 in DOPPS I; 235 and 240 min vs 221 in DOPPS II). Kt/V increased concomitantly with TT in all three regions with the largest absolute difference observed in Japan. TT > 240 min was independently associated with significantly lower relative risk (RR) of mortality (RR = 0.81; P = 0.0005). Every 30 min longer on HD was associated with a 7% lower RR of mortality (RR = 0.93; P < 0.0001). The RR reduction with longer TT was greatest in Japan. A synergistic interaction occurred between Kt/V and TT (P = 0.007) toward mortality reduction. UFR > 10 ml/h/kg was associated with higher odds of intradialytic hypotension (odds ratio = 1.30; P = 0.045) and a higher risk of mortality (RR = 1.09; P = 0.02). Longer TT and higher Kt/V were independently as well as synergistically associated with lower mortality. Rapid UFR during HD was also associated with higher mortality risk. These results warrant a randomized clinical trial of longer dialysis sessions in thrice-weekly HD.

Detection limit of methods to assess fluid status changes in dialysis patients.

Technical systems for an accurate and practicable fluid management of dialysis patients are urgently needed, since current clinical methods are partially subjective, imprecise, and time consuming. Such new systems should not only allow the determination of the target normohydration weight, but also must be able to detect clinically relevant changes in fluid volume ( approximately 1 l). This study focuses on the systematic analysis of the detection limit of several candidate methods for fluid management. In a cohort of 16 new dialysis patients, several candidate methods were applied in parallel during each treatment of the initial weight reduction phase: the measurement of vena cava diameter (VCD), vena cava collapsibility index (CI), the blood volume drop during an ultrafiltration (UF) bolus (Deltarelative blood volume (RBV)-), the rebound after the UF bolus (DeltaRBV+), and the extracellular fluid volume determined with whole body bioimpedance spectroscopy (BIS). A clinical reference method was used to manage the fluid status of patients. All methods showed significant correlations with predialysis weight. The detection limits W(lim) of candidate methods for changes in fluid status were assessed as W(lim)=0.87 kg+/-0.64 kg (BIS), 1.74 kg+/-1.56 kg (VCD), 2.3 kg+/-1.0 kg (DeltaRBV-), 7.4 kg+/-8.5 kg (CI), 40 kg+/-108 kg (DeltaRBV+). Only BIS shows a satisfactorily low detection limit W(lim), whereas W(lim) was rated as critical for the VCD and DeltaRBV- methods, and as unacceptable for the CI and DeltaRBV+ methods. Bioimpedance spectroscopy appears to be the most promising method for a practical fluid management system in dialysis.

Extracorporeal pressure monitoring and the detection of vascular access stenosis.

Prospective monitoring of static venous pressure is an established tool to detect outflow stenoses in a vascular access. However, with this method it is not possible to identify vascular stenoses which are localized between the arterial and venous dialysis needle. We describe a new approach based on both static arterial and venous extracorporeal pressures. Pressure data of 9 dialysis patients with normal vascular access function and 9 patients with stenotic access were analyzed. Extracorporeal pressure was found to depend on the position of the heart relative to the extracorporeal blood circuit. All patients with venous outflow stenoses had an elevated ratio of arterial and venous intra-access pressure to mean arterial pressure. In case of access stenosis between arterial and venous needle the ratio of venous pressure to mean arterial pressure was normal, and only the arterial pressure ratio was elevated. We conclude that combined arterial and venous intraaccess pressure measurement normalized by mean blood pressure detects venous stenosis as well as stenosis between the arterial and venous dialysis needle. To minimize the rate of access thrombosis both arterial and venous intra-access pressure should be monitored.

Cellular interleukin-1 receptor antagonist production in patients receiving on-line haemodiafiltration therapy.

BACKGROUND: Repetitive exposure to cytokine-inducing substances (pyrogens) results in chronic inflammation, which may significantly contribute to some of the long-term complications in dialysis patients. On-line dialysis modalities, such as on-line haemodiafiltration (HDF), raise particular concerns because of the administration of infusate prepared from potentially contaminated dialysis fluid. Hence, great retention capability for pyrogens is of critical importance for the safe performance of on-line systems. METHODS: The microbiological safety of a novel on-line system, ONLINEplus(TM), was assessed in clinical practice in five centres for 3 months. Infusate and dialysis fluid were regularly monitored for microbial counts, endotoxins, and cytokine-inducing activity. Levels of interleukin-1 receptor antagonist (IL-1Ra) were determined in supernatants of whole blood incubated either under pyrogen-free conditions (spontaneous cytokine production) or following low-dose endotoxin exposure (LPS-stimulated cytokine production). RESULTS: We failed to detect microorganisms or endotoxin contamination of infusate during the entire study period. Moreover, neither infusate nor dialysis fluid demonstrated cytokine-inducing activity. Intradialytic IL-1Ra induction was not detected, as there was no difference between pre- and post-session values for both spontaneous and LPS-stimulated IL-1Ra production (115+/-26 vs 119+/-27 and 2445+/-353 vs 2724+/-362 pg/10(6) white blood cells (WBC), respectively). Neither the number of immunocompetent cells nor their capacity to produce IL-1Ra declined during this period, indicating that cells were not significantly stimulated during treatment. Spontaneous and LPS-induced exvivo IL-1Ra generation remained unchanged after 3 months of on-line HDF therapy as compared with the start of the study (71+/-30 pre- vs 48+/-14 post-study, and 2559+/-811 vs 2384+/-744 pg/10(6) WBC, respectively). CONCLUSIONS: The present on-line system performed safely from a microbiological view-point as both the dialysis fluid and infusate were consistently free of microorganisms, endotoxins, and cytokine-inducing substances. As a result, on-line HDF therapy had no effect upon the chronic inflammatory responses in end-stage renal disease patients.

Regular dialysis treatment in Germany: the role of non-profit organisations.

Germany's healthcare system is almost entirely premium-funded through compulsory insurance. Doctors practicing in an outpatient setting are obliged to be members of the "Kassenarztliche Vereinigung" (KV), a kind of union for physicians that has to guarantee adequate medical care for all insured patients. Health money is transferred from health insurances to KV and then distributed to individual doctors. In 1998, 47,000 patients were treated in Germany by dialysis, 40% in privately-owned units, 22% in hospital units and 40% by non-profit facilities. Of these, 35% have diabetes mellitus, 50% of the patients new to dialysis. A total of 92% are treated in HD units, 1.5% at home, and 6.7% by PD. Not-for-profit organisations were founded in 1969 to overcome the shortage of dialysis facilities. These organisations provide all the non-medical components of dialysis therapy such as machines, disposables, buildings, employment, and management of staff. Nephrologists who are employed by or work with not-for-profit organisations are free to choose the best medical therapy, with no economic bias. Assessment of dialysis quality is not yet official in Germany and it is not clear whether there are different provider associated outcomes.

On-line haemodiafiltration versus low-flux haemodialysis. A prospective randomized study.

BACKGROUND: Current methods of renal replacement therapy lead only to an insignificant removal of larger, potentially toxic, substances, which are excreted by healthy kidneys. On-line preparation of substituate from dialysate and the use of high-flux membranes allow substantial convective removal of such substances. A modified on-line haemodiafiltration method with the use of a large membrane surface and a high convective part was chosen to test whether the elimination of larger substances, such as low-molecular-mass proteins, has a clinical impact. METHODS: In a prospective, controlled study over 24 months, 44 unselected chronic dialysis patients were randomized to undergo either low-flux haemodialysis (HD; n = 21) or haemodiafiltration (HDF; n = 23). To eliminate confounding factors, low-molecular efficacy was matched (Kt/V 1.8), and the same membrane material (polysulfone), ultrapure dialysate and the same treatment duration (4.5 h) were applied to each group. RESULTS: Morbidity, mortality, blood pressure, dialysis-associated hypotensive episodes, haematocrit and erythropoietin dose did not differ between the groups. The same was true for body weight and, accordingly, bioimpedance values, clinical hydration score, skinfold thickness, plasma albumin, prealbumin and transferrin. beta2-Microglobulin in the plasma did not change in the HD group and varied between 32 and 43 mg/l throughout the 2 years. In HDF, beta2 microglobulin decreased from similar values to 18 mg/l predialysis (P<0.01) in the first 6 months of HDF treatment and then remained constant during the remaining 18 months. CONCLUSION: In the absence of any clinical marker of uraemic toxicity the removal of larger molecules over the time-span of 2 years during HDF had no clinical implication compared with extremely (and for routine practice unrealistically) well-dialysed patients with low-flux HD. In the absence of any side-effects of on-line HDF and supposing that plasma beta2-microglobulin is a marker of morbidity, on-line HDF ensures an excellent dialysis quality which apparently takes time to translate into measurable clinical sequelae.

A prospective randomised European multicentre study of medium-long run mortality and morbidity comparing acetate-free biofiltration and bicarbonate dialysis.

In recent years, the progressive increase in the mean age of the population entering chronic dialysis treatment has been responsible, on the one hand, for the growing number of patients undergoing regular dialysis, and on the other, for the high number of "critical" patients, both as a result of their age and the presence of concomitant morbidity. Thus, dialysis treatment today is not only aimed at waste removal and water-electrolyte homeostasis, but also at a reduction in morbidity and mortality, and at improving the patients' quality of life, thanks to the use of biocompatible materials and the achievement of good cardiovascular tolerance to treatment. Consequently, diffusive-convective dialysis procedures have been on the increase, since they combine better depuration with the use of biocompatible high-flux membranes. Acetate-free biofiltration (AFB) is a diffusive-convective dialysis procedure which utilises a high-flux membrane, AN69, post-dilution infusion of a sodium bicarbonate solution (NaHCO3), and a dialysate which is completely free of any buffer, and thus also free of acetate, which may have various negative effects on the patient. A number of studies have already shown the better hemodynamic stability and the reduction of intradialytic side-effects during AFB. All these, however, were short-term studies. To verify the beneficial effects of AFB in the long run, a three year multicentre randomised European trial has been proposed to compare bicarbonate hemodialysis (BD), a technique used in nearly 80% of the world's dialysis population, and AFB. The specific aim of the investigation is to verify, in a large number of patients, the results of hemodialysis treatment in terms of morbidity, mortality and quality of life. The study involves 80 hemodialysis units across Italy, France, Germany, Spain, Slovenia and Croatia, with enrollment of about 400 patients considered "critical" for at least one of the following reasons: age, diabetes, dialysis cardiovascular instability. Fifty percent of the patients are to undergo AFB with the AN69 membrane and bicarbonate solution infusion (NaHCO3 145 or 167 mEq/lt), and the other fifty percent are to be treated by BD, with any membrane except the nonmodified cellulosic one. Biochemical, cardiological, and nutritional parameters will be considered throughout the study. Mortality, morbidity both in terms of intra- and interdialysis symptoms - and hospitalisation rate, as well as the patients' quality of life, evaluated by the SF36 questionnaire, will be analysed.

Dynamic pressure measurement for detection of blood access stenosis.

A novel method for detection of access failure has been developed. It is based on the continuous evaluation of pre-pump arterial and venous pressure in the extracorporeal circuit. Knowing the flow resistance properties of the arterial and venous branches of the extracorporeal circuit from in-vitro measurements and the height differences, calculating the fistula pressure dynamically is possible. The fistula pressure allows identification of access failure as has been shown by other authors. The dynamic measurement however allows identification of bad needle placement. Dynamic measurement at different flow rates and comparison with static measurements allow for the identification of intra-access stenosis. The mathematical algorithm is described and pressure-flow curves for two sets of extracorporeal circuits are shown. In-vivo examples show a "normal" fistula and a fistula with intra-access stenosis.

[Coronary risk factors in chronic hemodialysis patients]. / Koronare Risikofaktoren bei chronisch hämodialysierten Patienten.

BACKGROUND: In contrast to persons with normal renal function, coronary risk factors or indicators until yet could not clearly be defined in renal insufficiency. PATIENTS AND METHODS: 30 patients under chronic hemodialysis therapy were investigated; 15 patients with severe coronary artery disease and 15 patients with normal coronary angiogram were compared. Numerous factors of the manner of living (diet, smoking behaviour etc.) were registered and glucose and lipid metabolism, hemostatic and fibrinolytic system as well as blood pressure level were investigated. RESULTS: Besides higher HDL-cholesterol and tissue plasminogen activator (TPA) levels in patients without coronary heart disease, no significant difference could be found between both groups. The higher HDL levels were mainly due to the higher percentage of women in the coronary healthy group. There was no evidence of insulin resistance as a major pathogenic factor in the group with coronary heart disease. The blood pressure levels were not significantly different in both groups. CONCLUSION: Our quantitative examination of accepted or suspected coronary risk factors revealed no entity which turned out to be a reliable risk indicator for practical purposes.

Coronary artery disease in dialysis patients.

Coronary artery disease is a frequent condition in dialysis patients and-probably due to the atypical symptomatology-is frequently underdiagnosed. Noninvasive tests are of limited value in establishing diagnosis, whereby arteriography is frequently necessary. Secondary prophylaxis is the same as in nondialysis patients. Due to a high reocclusion rate following PTCA bypass grafting is the preferred therapeutical option. When medical therapy is indicated, hemodialysis therapy should be adapted to coexistent coronary artery disease by avoiding dialysis hypotension and overhydration. In coronary patients renal anemia worsens coronary perfusions and should be treated targeting at least a hematocrit of 35%.

Protein adsorption by artificial membrane materials under filtration conditions.

Elevated plasma levels of numerous low molecular weight proteins (LMWP) in renal insufficiency are likely to contribute to the uremic syndrome. Dialysis-related amyloidosis, caused by the accumulation of beta 2-microglobulin (beta 2M), has highlighted the need for a renal replacement therapy that allows the elimination of LMWP in addition to small solutes. Synthetic membrane materials employed under hemofiltration conditions proved to be most effective in lowering elevated beta 2M plasma levels. In addition to convection, protein adsorption to artificial membrane materials is an important mechanism for beta 2M removal. Using an in vitro setup, 12 commercially available hemofilters representing 11 different membrane materials were perfused with human blood containing 125I-labeled plasma proteins. Under filtration conditions, total protein adsorption ranged from 338-2,098 mg/m2 of membrane surface, and the fraction of adsorbed LMWP varied between 14-70% of total protein adsorption and was negatively correlated to total protein adsorption. beta 2M adsorption showed up to an 8-fold difference between membranes, and was negatively correlated with total protein adsorption and positively correlated with the adsorption of LMWPs.

Influence of hydration state on plasma volume changes during ultrafiltration.

To assess the influence of hydration state on plasma volume (PV) changes during ultrafiltration, 11 clinically normhydrated patients on maintenance hemodialysis were studied intraindividually during 2 hydration states differing by 2-15% of lean body mass (LBM). Plasma volume was measured continually during a 15-min ultrafiltration test including an ultrafiltration of 1% of target weight and during a 45-min follow-up period of blood recirculation through the dialyzer without ultrafiltration. In all patients a maximal decrease in relative PV was more pronounced when there was less hydration and when the grade of hydration correlated inversely with the maximal response of PV decrease (r = -0.68, p < 0.001). The same was observed between the hydration state and the slope of the PV decrease (r = -0.69, p < 0.001). Plasma refilling was estimated in the period following ultrafiltration. The slope of the plasma volume increase correlated with the grade of hydration (r = 0.31, p < 0.05) as did the asymtote of PV (r = 0.4, p < 0.01). It is concluded that the less hydrated a dialysis patient is, the more pronounced will be the fall of the ultrafiltration-induced plasma volume and the less distinct will be the recovery of the plasma volume after the discontinuation of ultrafiltration.