Rationale and design of the oral HEMe iron polypeptide Against Treatment with Oral Controlled Release Iron Tablets trial for the correction of anaemia in peritoneal dialysis patients (HEMATOCRIT trial).

BACKGROUND: The main hypothesis of this study is that oral heme iron polypeptide (HIP; Proferrin ES) administration will more effectively augment iron stores in erythropoietic stimulatory agent (ESA)-treated peritoneal dialysis (PD) patients than conventional oral iron supplementation (Ferrogradumet). METHODS: Inclusion criteria are peritoneal dialysis patients treated with darbepoietin alpha (DPO; Aranesp(R), Amgen) for >or= 1 month. Patients will be randomized 1:1 to receive either slow-release ferrous sulphate (1 tablet twice daily; control) or HIP (1 tablet twice daily) for a period of 6 months. The study will follow an open-label design but outcome assessors will be blinded to study treatment. During the 6-month study period, haemoglobin levels will be measured monthly and iron studies (including transferring saturation [TSAT] measurements) will be performed bi-monthly. The primary outcome measure will be the difference in TSAT levels between the 2 groups at the end of the 6 month study period, adjusted for baseline values using analysis of covariance (ANCOVA). Secondary outcome measures will include serum ferritin concentration, haemoglobin level, DPO dosage, Key's index (DPO dosage divided by haemoglobin concentration), and occurrence of adverse events (especially gastrointestinal adverse events). DISCUSSION: This investigator-initiated multicentre study has been designed to provide evidence to help nephrologists and their peritoneal dialysis patients determine whether HIP administration more effectively augments iron stores in ESP-treated PD patients than conventional oral iron supplementation. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry number ACTRN12609000432213.

N-of-1 randomized trials to assess the efficacy of gabapentin for chronic neuropathic pain.

OBJECTIVE: The objective of this study was to compare the efficacy of gabapentin with placebo for neuropathic pain at the individual and population levels. DESIGN: This study used an n-of-1 trial methodology with three double-blind, randomized, crossover comparisons of gabapentin with placebo. SETTING: This study was carried out at specialist outpatient clinics at two Australian hospitals. Patients. The patients are adults with chronic neuropathic pain. INTERVENTIONS: Following a dose-finding period, participants underwent three comparisons of 2-week periods on gabapentin (600-1,800 mg per day) and placebo. The dose-finding period was commenced by 112 patients, of whom 39 had no response so they did not enroll, leaving 73 trial participants. Of these, 48 completed and 7 partially completed their trials, and 18 withdrew. OUTCOME MEASURES: The five outcome measures were the visual analog scale (0-10) of pain, sleep interference and functional limitation; frequency of adverse events and medication preference. The aggregate response was determined by weighting the response to each measure equally. RESULTS: Of the 55 participants who completed at least one cycle, the aggregate response to gabapentin was better than placebo in 16 (29%), of whom 15 continued gabapentin posttrial. No difference was shown in 38 (69%), and 1 (2%) showed a better response to placebo. Fifteen of these 39 continued gabapentin posttrial. Meta-analysis of the mean scores showed lower mean (standard deviation) scores for gabapentin by 0.8 (0.2) for pain, 0.6 (0.2) for sleep interference, and 0.6 (0.2) for functional limitation. CONCLUSIONS: The response rate and mean reduction in symptoms with gabapentin were small. Gabapentin prescribing posttrial was significantly influenced by the trial results.

The effect of oral iron admiinistration on mycophenolate mofetil absorption in renal transplant recipients: a randomized, controlled trial.

BACKGROUND: Oral iron supplements are frequently prescribed to renal transplant recipients in the early posttransplant period. A recent trial in seven healthy volunteers demonstrated a significant 91% reduction in mycophenolate mofetil (MMF) absorption when coadministered with oral iron. However, the effect of iron on MMF absorption in renal transplant patients has not been studied. METHODS: An open-label, randomized, controlled trial was undertaken in which new renal transplant recipients were randomly allocated to receive iron supplements with a morning dose of MMF, iron supplements given 4 hr after MMF at midday, or no iron supplements. Blood samples were taken for estimation of mycophenolic acid (MPA) area under the curve (AUC) at day 5 posttransplant. The primary endpoint was the day 5 MPA AUC, with secondary endpoints including acute rejection and MMF toxicity in the first 4 weeks posttransplant. Prospective power calculations indicated that a minimum of 13 patients in each group would be required to have a 90% probability of detecting a clinically significant reduction (10 mg/hr/L) in MPA AUC for iron-treated patients. RESULTS: Forty patients completed the study. There were no differences in baseline demographic data between the groups. The mean+/-standard deviation MPA AUC measurements for the groups receiving no iron (n=13), iron and MMF together (n=14), and iron and MMF spaced apart (n=13) were 34.5+/-8.7, 33.7+/-11.4, and 32.1+/-8.1 microg/hr/mL, respectively (P=0.82). Rates of acute rejection, cytopenia, infection, and gastrointestinal intolerance were comparable between the groups. CONCLUSIONS: There is no significant effect of oral iron supplements on MMF absorption as determined by measured blood concentrations. The practice of routinely giving oral iron in such patients seems safe from an immunosuppression drug-interaction standpoint.

Metformin and serious adverse effects.

Attention to known contraindications and intercurrent illness can avoid life-threatening acidosis.

Efficacy and side-effect profile of sevelamer hydrochloride used in combination with conventional phosphate binders.

BACKGROUND: Poor phosphate control is common among patients with end-stage renal disease. Sevelamer hydrochloride has been demonstrated to be a safe and effective phosphate binder when used as a monotherapy. However, cost limits its usefulness in many countries. Data assessing its effectiveness and safety in combination with conventional phosphate binders are lacking. METHODS: Dialysis patients meeting the following inclusion criteria participated in this study: (i) hyperphosphataemia >1.8 mmol/L (5.6 mg/dL); and (ii) an inability to tolerate currently available binders. The trial was conducted in three phases each lasting 3 months: (i) an observation phase (patients continued on their regular phosphate binders); (ii) a titration phase (sevelamer was added at a dose of 403 mg three times daily with meals, titrated to a maximum of 1209 mg three times daily); and (iii) a maintenance phase. RESULTS: Twenty-five patients were recruited into the study. Eighteen patients completed all three trial phases. Mean serum phosphate dropped from 2.11 +/- 0.06 mmol/L (6.6 +/- 0.2 mg/dL) during the observation period to 1.91 +/- 0.01 mmol/L (5.9 +/- 0.003 mg/dL) during the maintenance phase (P=0.02). Calcium x phosphate product fell from 5.49 +/- 0.17 mmol2/L2 (68.64 +/- 2.11 mg2 dL2) to 4.89 +/- 0.27 mmol2/L2 (61.36 +/- 3.35 mg2 dL2) (P=0.02). There was no significant change in serum calcium or parathyroid hormone. Total serum cholesterol fell from 3.8 mmol/L (3.4-4.37) 147 mg/dL (131-169) to 3.55 mmol/L (2.97-4.2) 137 mg/dL (115-162) (P=0.02). Serum low-density lipoprotein cholesterol also fell significantly from 1.67 +/- 0.10 mmol/L (65 +/- 4 mg/dL) to 1.52 +/- 0.11 mmol/L (59 +/- 4 mg/dL) (P=0.04). The average prescribed dose of sevelamer was 2.4 g/day. Elemental calcium dropped from 3.4 g/day (1.4 to 4.6) to 1.2 g/day (0.6-2.4) (P=0.04). Seventy-two per cent of patients reported mild flatulence, nausea and indigestion. Three patients discontinued treatment because of adverse effects. CONCLUSIONS: Sevelamer in combination with conventional phosphate binders is effective in lowering serum phosphate and calcium-phosphate product in patients with refractory hyperphosphataemia. Beneficial effects on lipid profile were also observed. Mild gastrointestinal upset is common.

Predictors of decline of residual renal function in new peritoneal dialysis patients.

OBJECTIVE: The aim of this study was to prospectively evaluate the risk factors for decline of residual renal function (RRF) in an incident peritoneal dialysis (PD) population. DESIGN: Prospective observational study of an incident PD cohort at a single center. SETTING: Tertiary-care institutional dialysis center. PARTICIPANTS: The study included 146 consecutive patients commencing PD at the Princess Alexandra Hospital between 1 August 1995 and 1 July 2001 (mean age 54.8 +/- 1.4 years, 42% male, 34% diabetic). Patients with failed renal transplants (n = 26) were excluded. MAIN MEASUREMENTS: Timed urine collections (n = 642) were performed initially and at 6-month intervals thereafter to measure RRF. The development of anuria was also prospectively recorded. RESULTS: The mean (+/- SD) follow-up period was 20.5 +/- 14.8 months. The median slope of RRF decline was -0.05 mL/minute/month/1.73 m2. Using binary logistic regression, it was shown that the 50% of patients with more rapid RRF loss (< -0.05 mL/min/month/1.73 m2) were more likely to have had a higher initial RRF at commencement of PD [adjusted odds ratio (AOR) 1.83, 95% confidence interval (CI) 1.39-2.40] and a higher baseline dialysate/ plasma creatinine ratio at 4 hours (D/P creat; AOR 44.6, 95% CI 1.05-1900). On multivariate Cox proportional hazards model analysis, time from commencement of PD to development of anuria was independently predicted by baseline RRF [adjusted hazard ratio (HR) 0.81, 95% CI 0.60-0.81], D/P creat (HR 2.87, 95% CI 2.06-82.3), body surface area (HR 6.23, 95% CI 1.53-25.5), dietary protein intake (HR 2.87, 95% CI 1.06-7.78), and diabetes mellitus (HR 1.65, 95% CI 1.00-2.72). Decline of RRF was independent of age, gender, dialysis modality, urgency of initiation of dialysis, smoking, vascular disease, blood pressure, medications (including angiotensin-converting enzyme inhibitors), duration of follow-up, and peritonitis rate. CONCLUSIONS: The results of this study suggest that high baseline RRF and high D/P creat ratio are risk factors for rapid loss of RRF. Moreover, a shorter time to the onset of anuria is independently predicted by low baseline RRF, increased body surface area, high dietary protein intake, and diabetes mellitus. Such at-risk patients should be closely monitored for early signs of inadequate dialysis.