Björn Wikström

Kappa-opioid system in uremic pruritus: multicenter, randomized, double-blind, placebo-controlled clinical studies.

Uremic pruritus is a very common and frustrating condition for both patients and clinicians because no treatment has been demonstrated to be effective in relieving the itch. In this report, nalfurafine, a new kappa-opioid receptor agonist, was used to treat uremic pruritus in patients who were undergoing routine hemodialysis. Two multicenter, randomized, double-blind, placebo-controlled studies enrolled 144 patients with uremic pruritus to postdialysis intravenous treatment with either nalfurafine or placebo for 2 to 4 wk. A meta-analysis approach was used to assess the efficacy of nalfurafine. Statistically significant reductions in worst itching (P = 0.0212), itching intensity (P = 0.0410), and sleep disturbances (P = 0.0003) were noted in the nalfurafine group as compared with placebo. Improvements in itching (P = 0.0025) and excoriations (P = 0.0060) were noted for the nalfurafine-treated patients. Nalfurafine showed similar types and incidences of drug-related adverse events as did placebo. Nalfurafine was shown to be an effective and safe compound for use in this severely ill patient population.

Prognostic value of aortic stiffness and calcification for cardiovascular events and mortality in dialysis patients: outcome of the calcification outcome in renal disease (CORD) study

BACKGROUND AND OBJECTIVES Radiographic calcification and arterial stiffness each individually are predictive of outcome in dialysis patients. However, it is unknown whether combined assessment of these intermediate endpoints also provides additional predictive value. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Scoring of abdominal aortic calcification (AAC) using plain lateral abdominal x-ray and measurement of carotid-femoral pulse wave velocity (PWV) were performed in a cohort of 1084 prevalent dialysis patients recruited from 47 European dialysis centers. RESULTS During a follow-up of 2 years, 234 deaths and 91 nonfatal cardiovascular (CV) events occurred. Compared with the lowest tertile of AAC, the risk of an event was increased by a factor 3.7 in patients with a score of 5 to 15 (middle tertile), and by a factor 8.6 in patients with scores of 16 to 24. Additionally, each 1-m/s increase in PWV was associated with a 15% higher risk. At higher AAC (scores ≥ 5), the effect of PWV was attenuated because of a negative PWV × AAC interaction (hazard ratio [HR]: 0.895 and 0.865 for middle and upper AAC tertiles). After accounting for age, diabetes, and serum albumin, AAC and PWV remained independent predictors of outcome. CONCLUSIONS AAC and central arterial stiffness are independent predictors of mortality and nonfatal CV events in dialysis patients. The risk associated with an increased PWV is less pronounced at higher levels of calcification. Assessment of AAC and PWV is feasible in a clinical setting and both may be used for an accurate CV risk estimation in this heterogeneous population.

Comorbidity and Acute Clinical Events as Determinants of C-Reactive Protein Variation in Hemodialysis Patients: Implications for Patient Survival

BACKGROUND Patients with chronic kidney disease stage 5 have high comorbidity and are prone to inflammation that may contribute to the high cardiovascular mortality risk. STUDY DESIGN Three-month observational cohort study of prevalent hemodialysis patients. SETTINGS & PARTICIPANTS 228 hemodialysis patients (44% women) were included, median age of 66 years, median time on dialysis therapy of 29 months. PREDICTORS & OUTCOMES In part 1, comorbidity and intercurrent illness were predictors and C-reactive protein (CRP) level was the outcome. In part 2, serial CRP values were predictors and survival was the outcome. MEASUREMENTS High-sensitivity CRP was measured weekly and interleukin 6 (IL-6), tumor necrosis factor alpha, and IL-10 were measured monthly. Data for comorbidity were collected from patient records to calculate Davies comorbidity score, and self-reported clinical events were recorded weekly. RESULTS Median baseline CRP level was 6.7 mg/L (25th to 75th percentiles, 2.5 to 21 mg/L). Baseline CRP level correlated with time-averaged CRP (Spearman rho = 0.76) and individual median of serial CRP values (rho = 0.78; both P < 0.001). Part 1: comorbidity score was significantly associated with greater CRP and IL-6 levels. Age, sex, comorbidity, and 7 of 12 clinical events had significant effects on CRP level variation. Part 2: during a mean follow-up of 29 months, 38% of patients died. Median and mean serial CRP levels were associated with a greater hazard ratio for death (1.013; 95% confidence interval, 1.004 to 1.022) and 1.012 (95% confidence interval, 1.004 to 1.020) than baseline, maximum, and minimum CRP values during the study. Other significant covariates were age, Davies risk group, dialysis vintage, and albumin level. LIMITATIONS The study is based on observational data for prevalent dialysis patients. CONCLUSIONS Comorbidity and clinical events are strongly associated with inflammation in hemodialysis patients. Despite variability over time, inflammation assessed by using CRP level is a strong predictor of mortality. Serial measurements provide additional information compared with a single measurement.

Abdominal aortic calcification in dialysis patients: results of the CORD study

Background. Patients with chronic kidney disease stage 5 have a high prevalence of vascular calcification, but the specific anatomical distribution and severity of abdominal aortic calcification (AAC), in contrast to coronary calcification, is less well documented. AAC may be recorded using plain radiographs. The present report is an analysis of baseline data on AAC in patients enrolled in the CORD (Calcification Outcome in Renal Disease) study. Methods. A total of 47 centres in six European countries participated in this cross-sectional study. Inclusion criteria were age ≥18 years and duration of dialysis ≥3 months. Lateral lumbar radiography of the abdominal aorta was used to determine the overall AAC score, which is related to the severity of calcific deposits at lumbar vertebral segments L1–L4. The reliability of the method was tested by double reading of 64 radiographs (coefficient of correlation 0.9). Results. A lateral lumbar radiograph was obtained in 933 patients. Calcification (AAC score ≥ 1) was present in 81% of the patients; its severity increased significantly from L1 to L4 (P < 0.0001) and affected all of these segments in 51% of patients. Independent predictors for the presence and severity of calcification were age (odds ratio [OR] 1.103/year; P < 0.0001), duration of dialysis (OR 1.110/year; P = 0.002) and history of cardiovascular disease (OR 3.247; P < 0.0001). Conclusions. AAC detected by lateral lumbar radiograph is associated with several risk factors of uraemic calcification. This semi-quantitative method is more widely available and less expensive than the current procedures for studying calcification and could form part of a pre-transplant workup and cardiovascular risk stratification.

Biochemical and Clinical Effects of the Prophylactic Treatment of Renal Calcium Stones with Magnesium Hydroxide

Prophylactic treatment with magnesium hydroxide ws instituted in 56 consecutive cases with renal calcium stones. The patients had been investigated previously with regard to the magnesium metabolism. The urinary magnesium excretion increased promptly and remained on a higher level during treatment. No changes were observed in the serum or urinary calcium concentrations. Most patients have undergone treatment for at least 2 years and 45 have been free of recurrences of formations of new stones. The mean stone episode rate during treatment was 0.03 stones per year compared to 0.8 stones per year before treatment was instituted. The natural history of stone disease also was followed in 34 patients with stones who had received no prophylactic therapy and 15 have experienced recurrences after 2 years. Therefore, in comparison, treatment with magnesium hydroxide appeared to reduce the recurrence rate. Apart from minor gastrointestinal discomfort no adverse effects were observed during treatment.

Incidence and clinical importance of renal tubular defects in recurrent renal stone formers.

Renal tubular function was studied in 318 consecutive recurrent renal stone formers. Impaired acidification capacity was found in 19% of the patients, and tubular proteinuria in 13% of the patients. Most of the patients with defective acidification of the urine had the incomplete form of renal tubular acidosis (RTA), rpoximal and distal defects being equally common. The incidence of impaired acidification was much higher in the female (38%) than in the male (13%) stone formers. A further analysis of the clinical picture in patients with acidification defects revealed a more severe stone disease than among other stone formers. Characteristic findings were an early onset, multiple recurrences were an increased need for surgery. Stone analyses showed a high frequency of calcium phosphate stones. Investigations of renal tubular functions appear to be a valuable adjunct in the evaluation of recurrent renal stone disease.

Plasma exchange or immunoadsorption in patients with rapidly progressive crescentic glomerulonephritis : A Swedish multi-center study

A therapeutic removal of antibodies may be achieved by immunoadsorption (IA) or by plasma exchange (PE). The aim of this prospective randomised study was to compare the efficacy of these different techniques with regard to treatment of patients with rapidly progressive glomerulonephritis (RPG) having at least 50% crescents. Forty-four patients with a RPG were included for treatment either by IA or PE (with albumin as substitution for removed plasma). All patients were additionally treated with immunosuppression. A median of 6 sessions of PEs were performed in 23 patients compared with 6 IAs in 21 patients. Goodpastures syndrome (GP) was present in 6 patients (PE 3, IA 3). All of them started and ended in dialysis, two died. Among the remaining 38 patients (26 men, 12 women) 87% had antibodies to ANCA. Creatinine clearance for PE versus IA were at a median at start 17.1 and 19.8 ml/min, and at 6 months 49 and 49 ml/min, respectively. At 6 months 7 of 10 patients did not need dialysis (remaining: IA 0/5 and PE 2/5, n.s.). The extent of improvement did not differ between the groups. Three patients died during the observation period of 6 months (IA 2; PE 1, on HD). Although no difference was found between the IA or the PE group this study shows that the protocol used was associated with an improved renal function in most patients (except for Goodpastures syndrome) whereas 70% of them could leave the dialysis program.

World apheresis registry 2003-2007 data

OBJECTIVES Seventy-five centers from many countries have applied for a login code to the WAA apheresis registry. Fifteen centers from 7 countries have been actively entering data at the internet site from 2003 until 2007. We report on data from the registry so far. METHODS This is a web-based registry. A link is available from the WAA homepage (www.worldapheresis.org). So far data from 2013 patients (12,448 procedures) have been included. A median of 6 treatments have been performed (range 1-140). Mean age 51 years (range 1-94 years; 45% women). Seven percent of the patients were < or = 21 years and 4% were < or = 16 years. RESULTS The purpose of the apheresis procedure was therapeutic in 67% and retrieval of blood components in 33%. Main indications: neurological and hematological diseases, lipid apheresis and stemcell collection (autologous, and some allogeneic). Blood access: peripheral vessels (71%), central dialysis catheter through jugular (6.5%) or subclavian veins (6.7%), femoral vein (8%) and AV fistula (4%). ACD was used for anticoagulation in 73% of the procedures. Albumin was mainly used as replacement fluid. Adverse events (AE) were registered in 5.7% of the procedures. AE was graded as mild (2.5%), moderate (2.7%) or severe (0.5%). No death occurred due to treatment. The procedures were interrupted in 2.6%. Most frequent AEs were blood access problems (29%), tingling around the mouth (20%), hypotension (18%), and urticaria (9%). There were significant differences between the centers regarding mild and moderate AEs. Data indicate that centers using continuous infusion of calcium had fewer AEs. CONCLUSION There was a limited number of severe AEs. Centers use various standard procedures for apheresis. By learning from the experience of others the treatment quality will improve further. In the near future, an update of the registry will enable more extensive evaluation of the data.

Treatment of recurrent calcium stone formation with cellulose phosphate.

Sodium cellulose phosphate was given to 35 patients for recurrent formation of calcium-containing stones. During therapy urinary calcium decreased by 40% in the first month and remained at this lower level. In addition, urinary magnesium excretion was reduced and the urinary magnesium/calcium ratio remained unaffected. In these patients, who mostly had had calcium oxalate stones, the prophylactic effects of sodium cellulose phosphate was poor, with a 47% recurrence rate after 2 years. This lack of prevention, despite the significant reduction of the urinary calcium, is assumed to be owing to the effects of treatment on magnesium and oxalate metabolism. Side effects were common, mainly consisting of moderate gastrointestinal discomfort, and caused withdrawal of treatment in 8 patients. This fact contributes further to our opinion that sodium cellulose phosphate is not the drug of choice in cases of calcium oxalate stone formation.

Crystal inhibition: the effects of polyanions on calcium oxalate crystal growth

The inhibition of calcium oxalate crystal growth by the glycosaminoglycans, chondroitin sulphates and heparin, by the low-molecular-weight heparin analogue pentosan polysulphate and by Tamm-Horsfall glycoprotein extracted from human urine, was measured by using a seeded crystal procedure and compared with the inhibition by pyrophosphate. It was found that the most pronounced inhibition was obtained with the polyanions with the highest charge density, i.e., heparin and pentosan polysulphate. Tamm-Horsfall glycoprotein caused an inhibition of a similar magnitude as urinary chondroitin sulphates. Urinary polyanions with a high affinity to Sepharose 4B were more efficient inhibitors than those with a low or no affinity to the gel. It is concluded that urinary polyanions are important inhibitors of calcium oxalate crystal growth and that the potency of inhibition increases with the charge density.