Bruce A. Cooper

A randomized, controlled trial of early versus late initiation of dialysis

BACKGROUND In clinical practice, there is considerable variation in the timing of the initiation of maintenance dialysis for patients with stage V chronic kidney disease, with a worldwide trend toward early initiation. In this study, conducted at 32 centers in Australia and New Zealand, we examined whether the timing of the initiation of maintenance dialysis influenced survival among patients with chronic kidney disease. METHODS We randomly assigned patients 18 years of age or older with progressive chronic kidney disease and an estimated glomerular filtration rate (GFR) between 10.0 and 15.0 ml per minute per 1.73 m2 of body-surface area (calculated with the use of the Cockcroft-Gault equation) to planned initiation of dialysis when the estimated GFR was 10.0 to 14.0 ml per minute (early start) or when the estimated GFR was 5.0 to 7.0 ml per minute (late start). The primary outcome was death from any cause. RESULTS Between July 2000 and November 2008, a total of 828 adults (mean age, 60.4 years; 542 men and 286 women; 355 with diabetes) underwent randomization, with a median time to the initiation of dialysis of 1.80 months (95% confidence interval [CI], 1.60 to 2.23) in the early-start group and 7.40 months (95% CI, 6.23 to 8.27) in the late-start group. A total of 75.9% of the patients in the late-start group initiated dialysis when the estimated GFR was above the target of 7.0 ml per minute, owing to the development of symptoms. During a median follow-up period of 3.59 years, 152 of 404 patients in the early-start group (37.6%) and 155 of 424 in the late-start group (36.6%) died (hazard ratio with early initiation, 1.04; 95% CI, 0.83 to 1.30; P=0.75). There was no significant difference between the groups in the frequency of adverse events (cardiovascular events, infections, or complications of dialysis). CONCLUSIONS In this study, planned early initiation of dialysis in patients with stage V chronic kidney disease was not associated with an improvement in survival or clinical outcomes. (Funded by the National Health and Medical Research Council of Australia and others; Australian New Zealand Clinical Trials Registry number, 12609000266268.)

An Update and Practical Guide to Renal Stone Management

Renal stone disease covers kidney and lower urinary tract stones caused by a variety of conditions, including metabolic and inherited disorders, and anatomical defects with or without chronic urinary infection. Most cases are idiopathic, in which there is undoubtedly a genetic predisposition, but where environmental and lifestyle factors play an important role. Indeed, it is becoming apparent that renal stone disease is often part of a larger ‘metabolic picture’ commonly associated with type 2 diabetes, obesity, dyslipidaemia, and hypertension. Renal stone disease is a growing problem in the UK (and other developed and developing populations) with a cross-sectional prevalence of ∼1.2%. This means that there are currently ∼720,000 individuals with a history of kidney stones in the UK. Almost 40% of first-time stone formers will form a second stone within 3 years of the first episode if no prophylactic measures are instituted to prevent stone recurrence, since removal or disintegration of the first stone does not treat the underlying cause of stones in the majority of patients. The age of onset is getting younger and the sex ratio (until recently more men than women) is becoming almost even. Metabolic screening remains an important part of investigating renal stone disease, but to the disappointment and frustration of many doctors, medical treatment is still essentially pragmatic, except perhaps in cystinuria, and to a limited extent in primary hyperoxaluria (if pyridoxine-sensitive); although newer treatments may be emerging. This review summarizes current thinking and provides a practical basis for the management of renal stone disease.

Cost-Effectiveness of Initiating Dialysis Early: A Randomized Controlled Trial

BACKGROUND Planned early initiation of dialysis therapy based on estimated kidney function does not influence mortality and major comorbid conditions, but amelioration of symptoms may improve quality of life and decrease costs. STUDY DESIGN Patients with progressive chronic kidney disease and a Cockcroft-Gault estimated glomerular filtration rate of 10-15 mL/min/1.73 m(2) were randomly assigned to start dialysis therapy at a glomerular filtration rate of either 10-14 (early start) or 5-7 mL/min/1.73 m(2) (late start). SETTING & POPULATION Of the original 828 patients in the IDEAL (Initiation of Dialysis Early or Late) Trial in renal units in Australia and New Zealand, 642 agreed to participate in this cost-effectiveness study. STUDY PERSPECTIVE & TIMEFRAME: A societal perspective was taken for costs. Patients were enrolled between July 1, 2000, and November 14, 2008, and followed up until November 14, 2009. INTERVENTION Planned earlier start of maintenance dialysis therapy. OUTCOMES Difference in quality of life and costs. RESULTS Median follow-up of patients (307 early start, 335 late start) was 4.15 years, with a 6-month difference in median duration of dialysis therapy. Mean direct dialysis costs were significantly higher in the early-start group (

A Novel Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor (GSK1278863) for Anemia in CKD: A 28-Day, Phase 2A Randomized Trial.

10,777; 95% CI,

Effect of early initiation of dialysis on cardiac structure and function: results from the echo substudy of the IDEAL trial

313 to

Effect of timing of dialysis commencement on clinical outcomes of patients with planned initiation of peritoneal dialysis in the ideal trial

22,801). Total costs, including costs for resources used to manage adverse events, were higher in the early-start group (

Outcomes of patients with planned initiation of hemodialysis in the IDEAL trial

18,715; 95% CI, -

Maintenance of elevated versus physiological iron indices in non-anaemic patients with chronic kidney disease: a randomized controlled trial

3,162 to

When should we commence dialysis? The story of a lingering problem and today's scene after the IDEAL study

43,021), although not statistically different. Adjusted for differences in baseline quality of life, the difference in quality-adjusted survival between groups over the time horizon of the trial was not statistically different (0.02 full health equivalent years; 95% CI, -0.09 to 0.14). LIMITATIONS Missing quality-of-life questionnaires and skewed cost data, although similar in each group, decrease the precision of results. CONCLUSION Planned early initiation of dialysis therapy in patients with progressive chronic kidney disease has higher dialysis costs and is not associated with improved quality of life.

Challenges in conducting clinical trials in nephrology: conclusions from a Kidney Disease—Improving Global Outcomes (KDIGO) Controversies Conference

BACKGROUND Anemia associated with chronic kidney disease (CKD) often requires treatment with recombinant human erythropoietin (EPO). Hypoxia-inducible factor-prolyl hydroxylase inhibitors (PHIs) stimulate endogenous EPO synthesis and induce effective erythropoiesis by non-EPO effects. GSK1278863 is an orally administered small-molecule PHI. STUDY DESIGN Multicenter, single-blind, randomized, placebo-controlled, parallel-group study. SETTING & PARTICIPANTS Anemic non-dialysis-dependent patients with CKD stages 3-5 (CKD-3/4/5 group; n=70) and anemic hemodialysis patients with CKD stage 5D (CKD-5D group; n=37). INTERVENTIONS Patients with CKD-3/4/5 received placebo or GSK1278863 (10, 25, 50, or 100mg), and patients with CKD-5D received placebo or GSK1278863 (10 or 25mg) once daily for 28 days. OUTCOMES & MEASUREMENTS Primary pharmacokinetic and pharmacodynamic (increase and response rates in achieving the target hemoglobin [Hb] concentration, plasma EPO concentrations, reticulocyte count, and others]) and safety and tolerability end points were obtained. RESULTS Both CKD-3/4/5 and CKD-5D populations showed a dose-dependent increase in EPO concentrations and consequent increases in reticulocytes and Hb levels. Percentages of GSK1278863 participants with an Hb level increase > 1.0g/dL (CKD-3/4/5) and >0.5g/dL (CKD-5D) were 63% to 91% and 71% to 89%, respectively. Per-protocol-defined criteria, high rate of increase in Hb level, or high absolute Hb value was the main cause for withdrawal (CKD-3/4/5, 30%; CKD-5D, 22%). A dose-dependent decrease in hepcidin levels and increase in total and unsaturated iron binding were observed in all GSK1278863-treated patients. LIMITATIONS Sparse pharmacokinetic sampling may have limited covariate characterization. EPO concentrations at the last pharmacodynamic sample (5-6 hours) postdose may not represent peak concentrations, which occurred 8 to 10 hours postdose in previous studies. Patients were not stratified by diabetes status, potentially confounding vascular endothelial growth factor and glucose analyses. CONCLUSIONS GSK1278863 induced an effective EPO response and stimulated non-EPO mechanisms for erythropoiesis in anemic non-dialysis-dependent and dialysis-dependent patients with CKD.