Władysław Sułowicz

Once-Monthly Subcutaneous C.E.R.A. Maintains Stable Hemoglobin Control in Patients with Chronic Kidney Disease on Dialysis and Converted Directly from Epoetin One to Three Times Weekly

BACKGROUND C.E.R.A., a continuous erythropoietin receptor activator, is in development to provide anemia correction and stable maintenance of hemoglobin (Hb) levels at extended administration intervals in patients with chronic kidney disease (CKD). This study examined its efficacy and safety when administered up to once monthly in patients who have CKD and are on dialysis and randomly convert directly from epoetin alpha or beta one to three times weekly. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS In this three-arm, comparator-controlled, open-label, randomized, parallel-group, Phase III study, 572 dialysis patients (> or =18 yr) who were receiving stable subcutaneous epoetin one to three times weekly were randomly assigned (1:1:1) to continue epoetin or to receive subcutaneous C.E.R.A. once monthly or twice monthly for 52 wk. Dosage was adjusted to maintain Hb +/-1.0 g/dl of baseline level. Primary end point was mean change in Hb level between baseline and the evaluation period (weeks 29 to 36). RESULTS Mean Hb levels during the evaluation period were similar between groups (once-monthly C.E.R.A. 11.5 g/dl; twice-monthly C.E.R.A. 11.7 g/dl; epoetin 11.5 g/dl). The difference between C.E.R.A. and epoetin in mean change (97.5% confidence interval) in Hb concentration between baseline and evaluation was -0.022 g/dl (-0.262 to 0.217) for once monthly and 0.141 g/dl (-0.098 to 0.380) for twice monthly. Analysis demonstrated that C.E.R.A. was as effective as epoetin in maintaining Hb and was well tolerated. CONCLUSIONS Subcutaneous C.E.R.A. once or twice monthly successfully maintained tight and stable Hb levels in patients who were on dialysis and randomly converted directly from epoetin one to three times weekly.

Output of Peritoneal Cells into Peritoneal Dialysate

The quantitative and qualitative characteristics of cells in the peritoneal dialysate from 12 patients were examined. The number of cells in each subsequent fraction of dialysate decreased, while the

Single dose pharmacokinetics of the transdermal rotigotine patch in patients with impaired renal function

AIM To evaluate the influence of different stages of chronic renal insufficiency on the pharmacokinetics and safety/tolerability of the transdermally applied dopamine agonist rotigotine in an open label group comparison including 32 subjects (healthy, mild, moderate or severe impairment of renal function and patients with end-stage renal insufficiency requiring haemodialysis). METHODS All subjects received a single transdermal 10 cm² patch (24 h patch-on period) containing 4.5 mg rotigotine (nominal drug release 2 mg 24 h⁻¹). Main evaluations included relative bioavailability and renal elimination of rotigotine and its metabolites. RESULTS Point estimates for the ratios between the groups with moderate to severe renal impairment and healthy subjects for the pharmacokinetic parameters AUC(0,t(last) ) and C(max) for the active substance unconjugated rotigotine were near 1:0.88 for AUC and 0.93 for C(max) for moderate renal impairment, 1.14 and 1.18 for severe renal impairment and 1.05 and 1.25 for end-stage renal insufficiency requiring haemodialysis. There was no correlation of these parameters with creatinine clearance. The amount of unconjugated rotigotine excreted into urine and renal clearance decreased with increasing severity of renal insufficiency but had no observable effect on total clearance as the amounts excreted were below 1% of the administered dose. Occurrence of adverse events did not increase with the degree of renal insufficiency. CONCLUSIONS The pharmacokinetic profiles of unconjugated rotigotine were similar in healthy subjects and subjects with impaired renal function indicating that no dose adjustments are required for transdermal rotigotine in patients with different stages of chronic renal insufficiency including patients on haemodialysis.

Dose-finding Study of Peginesatide for Anemia Correction in Chronic Kidney Disease Patients

BACKGROUND AND OBJECTIVES Peginesatide is a synthetic, PEGylated, investigational, peptide-based erythropoiesis-stimulating agent. We report the first assessment of its efficacy and safety in correcting renal anemia in a population of 139 nondialysis chronic kidney disease patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Chronic kidney disease patients who were not on dialysis and not receiving treatment with erythropoiesis-stimulating agents in the 12 weeks before study drug administration were sequentially assigned to one of 10 cohorts; cohorts differed in starting peginesatide dose (different body weight-based or absolute doses), route of administration (intravenous or subcutaneous), and frequency of administration (every 4 or 2 weeks). RESULTS Across all cohorts, 96% of patients achieved a hemoglobin response. A dose-response relationship was evident for hemoglobin increase. Comparable subcutaneous and intravenous peginesatide doses produced similar hemoglobin responses. Rapid rates of hemoglobin rise and hemoglobin excursions >13 g/dl tended to occur more frequently with every-2-weeks dosing than they did with every-4-weeks dosing. The range of final median doses in the every-4-weeks dosing groups was 0.019 to 0.043 mg/kg. Across all cohorts, 20% of patients reported serious adverse events (one patient had a possibly drug-related serious event) and 81% reported adverse events (11.5% reported possibly drug-related events); these events were consistent with those routinely observed in this patient population. CONCLUSIONS This study suggests that peginesatide administered every 4 weeks can increase and maintain hemoglobin in nondialysis chronic kidney disease patients. Additional long-term data in larger groups of patients are required to further elucidate the efficacy and safety of this peptide-based erythropoiesis-stimulating agent.

Selenium status indices, laboratory data, and selected biochemical parameters in end-stage renal disease patients

We investigated the relations between selenium status (SeS) parameters, indexes of nutrition, erythropoiesis, and uremic toxemia, serum electrolytes, and other biochemical markers in end-stage renal disease (ESRD) patients, as no multivariate statistical analysis concerning all of these parameters was performed so far. SeS was evaluated by plasma Se concentration (plSe) and glutathione peroxidase (plGSHPx) activity in 69 uremic patients treated with hemodialysis (HD) and 40 healthy controls. The hierarchical multivariate partial least squares model (PLS2) was employed to establish data structure and correlations between parameters investigated. plSe and plGSHPx activity were significantly lower in patients when compared with controls (p=0.000). plSe was positively associated with indexes of erythropoiesis and nutritional status, as well as serum electrolytes and parameters of uremic toxemia. plGSHPx was inversely dependent on the pair of parameters: intact parathyroid hormone (iPTH) and aluminum plasma concentration (Al). We conclude that (1) ESRD strongly decreases selenium status and (2) the PLS2 approach revealed the existence of significant interactions among plSe, plGSHPx, and selected biochemical parameters or groups of such parameters; some of these associations need further studies to be clarified.

Carpal tunnel syndrome in hemodialysis patients as a dialysis-related amyloidosis manifestation--incidence, risk factors and results of surgical treatment.

Summary Background Carpal tunnel syndrome (CTS) is the most common complication of dialysis-related amyloidosis (DRA) developing in patients on long-term dialysis therapy. The aim of this study was to evaluate the incidence of CTS and identify factors influencing the development of CTS in patients on maintenance hemodialysis, as well as results of its surgical treatment. Material/Methods The study included 386 patients, among whom CTS was diagnosed in 40 patients (10.4%) on the basis of signs and physical symptoms, as well as by nerve conduction. The group of patients with CTS and the group of patients without CTS were compared according to age (mean 54.50 vs. 56.48 years) and duration of dialysis treatment. Initial analysis of CTS incidence by sex, presence of anti-HCV antibodies, and location of arterio-venous fistula (AV fistula) was undertaken. Results Duration of dialysis treatment was the statistically significant risk factor for the development of CTS (16.05 vs. 4.51 years; p<0.0001). Among patients treated for a long period on hemodialysis (20–30 years), 100% required surgical release procedures, while 66.66% of those treated for 15–19 years, 42.1% of those treated for 10–14 years, and 1.6% of those treated for less than 10 years. CTS was diagnosed more often in anti-HCV-positive patients as compared with anti-HCV-negative patients (47.5 vs. 6.9%; p<0.0001). No significant differences were found when comparing CTS incidence by sex or between the development of CTS requiring surgical release intervention and location of the AV fistula. Conclusions Surgical release procedure of the carpal tunnel gave good treatment results in patients with CTS.

Timely referral to the nephrologist: Essential to optimizing patient outcomes

Annual mortality on renal replacement therapy is about 10% in Western Europe and reaches 20% in the United States. The reasons responsible for this excess mortality include among others advanced age, high prevalence of diabetes and comorbid conditions, susceptibility to infections, and cancer. An additional cause that should be considered is late referral to overall renal care and for renal replacement therapy. It has been demonstrated recently that early referral may provide many advantages for the patient, such as prevention of organ damage secondary to uremia and even delay the onset of end‐stage renal disease. These benefits prompted numerous recommendations for timely referral, both for dialysis and for long‐term renal follow‐up. Despite available guidelines for nephrology referral the current practice is still suboptimal, resulting in delayed initiation of dialysis and clinical outcomes that are not ideal. There is an urgent need in the renal community to change the current practice of referral. Beyond the benefits for patients, society may also expect potential cost effectiveness from early renal care.

Discontinuation of mycophenolate mofetil from a tacrolimus-based triple regimen 2 months after renal transplantation: a comparative randomized, multicentre study.

Previous clinical data suggested that with a tacrolimus‐based regimen adjunctive immunosuppressives may be withdrawn after an initial treatment period. This study investigated the early discontinuation of mycophenolate mofetil (MMF) from a standard triple regimen. Patients were randomized either to receive a continued tacrolimus/MMF/steroids triple regimen (control group) or to reduce and then stop the MMF dose (MMF stop group). Both groups received identical daily tacrolimus and corticosteroid doses. The initial MMF dose was 1 g/day in both arms, but in the MMF stop group the dose was reduced to 0.5 g/day from week 7 to week 12 and then stopped. The intent‐to‐treat population consisted of 74 (control) and 78 (MMF stop) patients. MMF was tapered off as planned in 82.9% of the patients in the MMF stop arm. The 6‐month incidence of biopsy‐proven acute rejection was similar in both arms (21.6% control, 16.7% MMF stop). Graft loss occurred in 5.4% (control) and 3.8% (MMF stop) of the patients. MMF could be safely discontinued from a tacrolimus‐based triple therapy early after transplantation without any rebound in efficacy during the 6‐month follow‐up period.

Trends and dynamics of changes in aortic pulse wave velocity over one-year observation period in patients treated with peritoneal dialysis.

important co-morbid condition affecting patients with chronic renal failure (1). There is an increasing body of evidence suggesting that mortality on dialysis largely depends upon initial and follow-up serum levels of proinflammatory cytokines and acute phase proteins (2, 3). Chronic inflammation is closely associated with atherosclerosis, which to a cer tain extent may be considered an inflammatory disease (4). Aortic pulse wave velocity (AoPWV) assessment proved its cl inical usefulness in patients with chronic renal disease, including those on maintenance hemodialysis (5-9). For uncertain reasons this problem was seldom studied in peritoneal dialysis (PD) patients. The aim of the present study was to assess the trends and dynamics of changes in AoPWV in the group of stable PD patients over one year and to search for possible correlations between these changes and one-year profile of selected cytokines, acute phase proteins and other variables that may be considered as risk factors for atherosclerosis progression. Forty seven patients (25M, 22F, aged mean 52.7 ± 12.8 years and on dialysis for 19.1 ± 21.6 months) were analyzed. AoPWV was measured using an automatic device with two pressure transducers (TY-306; Fukuda Denshi) placed on the carotid and femoral arteries and connected to an automatic processor (Complior® Colson). AoPWV was assessed at baseline and after 12 months. In each patient an absolute difference in PWV between two mentioned time-points was calculated (∆AoPWV). Serum Interleukin 6 (IL-6) and Tumor Necrosis Factor alpha (TNFα) were analyzed as proinflammatory cytokines (ELISA; Quantikine, R&D Systems), and C-reactive protein (high sensitive assay), lipoprotein (a) and fibrinogen – as acute phase reactants (immuno-nephelometry; Dade Boehring). In all patients total, LDL-, HDL-cholesterol and triglyceride serum levels, as well as serum calcium and phosphate were measured (Hitachi 917). All biochemical and inflammatory parameters were assessed at baseline, and after 6 and 12 months. At the end of the study mean concentrations of all analyzed biochemical parameters from three assessments was calculated. Blood pressure was measured at baseline, after 6 and 12 months, and mean arterial pressure (MAP) as well as pulse pressure (PP) were calculated. Mean AoPWV did not change significantly for the whole study group after one year (from 11.2 ± 2.26 to 11.7 ± 2.4 m/s, p= 0.07; ∆AoPWV +0.48 ± 1.77 m/s). However, in the population studied two categories of patients might be distinguished: subjects who progressed in AoPWV (29 patients, 61.7%, from 10.6 ± 2.3 to 12.3 ± 2.65 m/s; p< 0.05; ∆AoPWV +1.6 ± 1.14) and those with regression after 12 months (18 patients, 38%, from 12.2 ± 1.89 to 10.8 ± 1.67 m/s; p< 0.05; ∆AoPWV -1.31 ± 0.89). The entire group ‘averaged’ in terms of AoPWV value after 12 months, as the differences between “Pregressors” and “Regressors” were significant at the study commencement (p< 0.01) and only borderline significant (p= 0.08) at its completion. Patients who progressed were character ized by significantly higher values of mean serum phosphates, TNFα and Lp (a) levels as well as mean PP calculated from three assessments in comparison to “Regressors” (p< 0.05 for all differences). No significant difference was found between groups in terms of age, PD duration, and Short Communication The International Journal of Artificial Organs / Vol. 27 / no. 10, 2004/ pp. 904-906