Deborah Zimmerman

Intensive Hemodialysis Associates with Improved Survival Compared with Conventional Hemodialysis

Patients undergoing conventional maintenance hemodialysis typically receive three sessions per week, each lasting 2.5-5.5 hours. Recently, the use of more intensive hemodialysis (>5.5 hours, three to seven times per week) has increased, but the effects of these regimens on survival are uncertain. We conducted a retrospective cohort study to examine whether intensive hemodialysis associates with better survival than conventional hemodialysis. We identified 420 patients in the International Quotidian Dialysis Registry who received intensive home hemodialysis in France, the United States, and Canada between January 2000 and August 2010. We matched 338 of these patients to 1388 patients in the Dialysis Outcomes and Practice Patterns Study who received in-center conventional hemodialysis during the same time period by country, ESRD duration, and propensity score. The intensive hemodialysis group received a mean (SD) 4.8 (1.1) sessions per week with a mean treatment time of 7.4 (0.87) hours per session; the conventional group received three sessions per week with a mean treatment time of 3.9 (0.32) hours per session. During 3008 patient-years of follow-up, 45 (13%) of 338 patients receiving intensive hemodialysis died compared with 293 (21%) of 1388 patients receiving conventional hemodialysis (6.1 versus 10.5 deaths per 100 person-years; hazard ratio, 0.55 [95% confidence interval, 0.34-0.87]). The strength and direction of the observed association between intensive hemodialysis and improved survival were consistent across all prespecified subgroups and sensitivity analyses. In conclusion, there is a strong association between intensive home hemodialysis and improved survival, but whether this relationship is causal remains unknown.

Vascular Smooth Muscle Cell Differentiation to an Osteogenic Phenotype Involves TRPM7 Modulation by Magnesium

Arterial calcification, common in vascular diseases, involves vascular smooth muscle cell (VSMC) transformation to an osteoblast phenotype. Clinical studies suggest that magnesium may prevent this, but mechanisms are unclear. We assessed whether increasing magnesium levels reduce VSMC calcification and differentiation and questioned the role of the Mg2+ transporter, transient receptor potential melastatin (TRPM)7 cation channels in this process. Rat VSMCs were exposed to calcification medium in the absence and presence of magnesium (2.0 to 3.0 mmol/L) or 2-aminoethoxy-diphenylborate (2-APB) (TRPM7 inhibitor). VSMCs from mice with genetically low (MgL) or high-normal (MgH) [Mg2+]i were also studied. Calcification was assessed by von Kossa staining. Expression of osteocalcin, osteopontin, bone morphogenetic protein (BMP)-2, BMP-4, BMP-7, and matrix Gla protein and activity of TRPM7 (cytosol:membrane translocation) were determined by immunoblotting. Calcification medium induced osteogenic differentiation, reduced matrix Gla protein content, and increased expression of the sodium-dependent cotransporter Pit-1. Magnesium prevented calcification and decreased osteocalcin expression and BMP-2 activity and increased expression of calcification inhibitors, osteopontin and matrix Gla protein. TRPM 7 activation was decreased by calcification medium, an effect reversed by magnesium. 2-APB recapitulated the VSMC osteoblastic phenotype in VSMCs. Osteocalcin was increased by calcification medium in VSMCs and intact vessels from MgL but not MgH, whereas osteopontin was increased in MgH, but not in MgL mice. Magnesium negatively regulates vascular calcification and osteogenic differentiation through increased/restored TRPM7 activity and increased expression of anticalcification proteins, including osteopontin, BMP-7, and matrix Gla protein. New molecular insights are provided whereby magnesium could protect against VSMC calcification.

Systematic review and meta-analysis of incidence, prevalence and outcomes of atrial fibrillation in patients on dialysis

BACKGROUND The reported incidence, prevalence and outcomes of atrial fibrillation (AF) in patients with end-stage renal disease (ESRD) are variable. The risks and benefits of warfarin anticoagulation need to be defined as the risk of bleeding in ESRD patients may overwhelm the benefits of embolic stroke prevention. We undertook a systematic literature review to clarify these issues. METHODS A literature search was undertaken using Medline and EMBASE from 1990 to September 2011. Studies that reported incidence, prevalence or selected outcomes in ESRD patients with AF were included. Cross-sectional, cohort and randomized controlled trials with >25 participants were included. The lists of authors and abstracts from the search were reviewed by two investigators to determine the manuscripts for full text review. Data were abstracted to a form designed specifically for this study. The quality of the studies was assessed using the Newcastle-Ottawa scale. Event rates were calculated using a random-effects model. RESULTS Twenty-five studies met our inclusion criteria. The prevalence of AF was 11.6% and the overall incidence was 2.7/100 patient-years. The risk of mortality and stroke was increased in ESRD patients with AF at 26.9 and 5.2/100 patient-years versus 13.4 and 1.9/100 patient-years compared with ESRD patients without AF. The majority of studies do not support a protective effect for warfarin in ESRD patients with AF. CONCLUSIONS The incidence and prevalence of AF in ESRD patients are higher than in the general population and are associated with an increased risk of stroke and mortality. An appropriately designed randomized controlled trial is required to determine whether anticoagulation is an appropriate therapeutic strategy in patients with end-stage renal disease and atrial fibrillation.

Predicting treatment dose for novel therapies using urea standard Kt/V.

Calculation of urea standard Kt/V (stdKt/V) as a dose measure for guiding novel hemodialysis or hemofiltration therapy prescription is complex since this parameter depends on the magnitude of posttreatment urea rebound. We propose here a two‐step procedure for calculating urea stdKt/V from single‐pool urea Kt/V values (spKt/V) determined from serum urea concentrations in pretreatment and posttreatment blood samples. First, the dependence of urea stdKt/V on equilibrated Kt/V (eKt/V) was derived from a fixed‐volume single‐pool model. Second, an empirical equation for predicting urea eKt/V from urea spKt/V values was determined using multiple linear regression and available data during 4‐hour hemodialysis, 2‐hour hemodialysis, and 2‐hour hemofiltration treatments. This empirical (rate/dose) equation is likely more robust for novel therapies than other equations derived from only data during conventional (4‐hour) hemodialysis treatments. The combination of these formulas allowed construction of nomograms for calculating urea stdKt/V from spKt/V during novel therapies. These principles were further illustrated by calculating the predicted treatment dose for daily (six times per week) hemofiltration therapy required to achieve a given urea stdKt/V.

Antiplatelet Medications in Hemodialysis Patients: A Systematic Review of Bleeding Rates

BACKGROUND AND OBJECTIVES Patients with end stage renal disease (ESRD) are often prescribed antiplatelet medications. However, these patients are also at increased risk of bleeding compared with the general population, and an aim was made to quantify this risk with antiplatelet agents. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A systematic review of the literature (Medline, EMBASE, Cochrane CENTRAL and Google Scholar databases) was done to determine the bleeding risk in ESRD patients prescribed antiplatelet therapy. The secondary outcome was the effect on access thrombosis. All case series, cohort studies and clinical trials were considered if they included ten or more ESRD patients, assessed bleeding risk with antiplatelet agents, and lasted for more than 3 mo. RESULTS Sixteen studies, including 40,676 patients, were identified that met predefined inclusion criteria. Due to study heterogeneity and weaknesses in methodology, bleeding rates were not pooled across studies. However, the bleeding risk appears to be increased for hemodialysis patients treated with combination antiplatelet therapy. The results are mixed for studies using a single antiplatelet agent. Antiplatelet agents appear to be effective in preventing shunt and central venous catheter thrombosis, but not for preventing thrombosis of arteriovenous grafts. CONCLUSION The risks and benefits of antiplatelet agents in ESRD patients remain poorly defined. Until a clinical trial addresses this in the dialysis population, individual risk stratification taking into account the increased risk of bleeding should be considered before initiating antiplatelet agents, especially in combination therapy.

DAILY HEMODIALYSIS—SELECTED TOPICS: Predicting Treatment Dose for Novel Therapies Using Urea Standard Kt/V

Calculation of urea standard Kt/V (stdKt/V) as a dose measure for guiding novel hemodialysis or hemofiltration therapy prescription is complex since this parameter depends on the magnitude of posttreatment urea rebound. We propose here a two‐step procedure for calculating urea stdKt/V from single‐pool urea Kt/V values (spKt/V) determined from serum urea concentrations in pretreatment and posttreatment blood samples. First, the dependence of urea stdKt/V on equilibrated Kt/V (eKt/V) was derived from a fixed‐volume single‐pool model. Second, an empirical equation for predicting urea eKt/V from urea spKt/V values was determined using multiple linear regression and available data during 4‐hour hemodialysis, 2‐hour hemodialysis, and 2‐hour hemofiltration treatments. This empirical (rate/dose) equation is likely more robust for novel therapies than other equations derived from only data during conventional (4‐hour) hemodialysis treatments. The combination of these formulas allowed construction of nomograms for calculating urea stdKt/V from spKt/V during novel therapies. These principles were further illustrated by calculating the predicted treatment dose for daily (six times per week) hemofiltration therapy required to achieve a given urea stdKt/V.

A multinational cohort study of in-center daily hemodialysis and patient survival

Increasing hemodialysis frequency from three to six times per week improves left-ventricular mass and health-related quality of life; however, effects on survival remain uncertain. To study this, we identified 556 patients in the International Quotidian Dialysis Registry who received daily hemodialysis (more than five times per week) between 2001 and 2010. Using propensity score-based matching, we matched 318 of these patients to 575 contemporaneous patients receiving conventional (three times weekly) hemodialysis in the Dialysis Outcomes and Practice Patterns Study. All patients had session times of <5 h, and received dialysis in the clinic or hospital setting. Mortality rates between groups were compared using Cox proportional hazards regression. Mean dialysis frequency in the daily group was 5.8 sessions per week. Mean weekly treatment time was 15.7 h for daily and 11.9 h for conventional patients. During 1382 patient-years of follow-up, 170 patients died. Those receiving daily hemodialysis had a significantly higher mortality rate than those receiving conventional hemodialysis (15.6 and 10.9 deaths per 100 patient-years, respectively: hazard ratio 1.6). Similar results were found in prespecified subgroup and sensitivity analyses. Unlike previous studies, we found that in-center daily hemodialysis was not associated with any mortality benefit. Thus, decisions to undertake daily hemodialysis should be based on quality-of-life improvements, rather than on claims of improved survival.

Canadian Society of Nephrology Commentary on the 2009 KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of CKD–Mineral and Bone Disorder (CKD-MBD)

Professional societies throughout the world, ncluding the Canadian Society of Nephrology CSN), agree there is a need for developing linical practice guidelines for patients with hronic kidney disease (CKD). However, as illusrated by the case of the plethora of anemia uidelines for CKD that have been completed and updated) by many national professional ocieties since 2000, creation of guidelines by ndividual professional societies results in signifiant duplication of effort. In this context, KDIGO Kidney Disease: Improving Global Outcomes) as established in 2003 with its stated mission to improve the care and outcomes of kidney disase patients worldwide through promoting coorination, collaboration, and integration of initiaives to develop and implement clinical practice uidelines.” The KDIGO Clinical Practice Guideline for he Diagnosis, Evaluation, Prevention, and Treatent of Chronic Kidney Disease–Mineral and

Canadian Society of Nephrology guidelines for the management of patients with ESRD treated with intensive hemodialysis.

Intensive (longer and more frequent) hemodialysis has emerged as an alternative to conventional hemodialysis for the treatment of patients with end-stage renal disease. However, given the differences in dialysis delivery and models of care associated with intensive dialysis, alternative approaches to patient management may be required. The purpose of this work was to develop a clinical practice guideline for the Canadian Society of Nephrology. We applied the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach for guideline development and performed targeted systematic reviews and meta-analysis (when appropriate) to address prioritized clinical management questions. We included studies addressing the treatment of patients with end-stage renal disease with short daily (≥5 days per week, <3 hours per session), long (3-4 days per week, ≥5.5 hours per session), or long-frequent (≥5 days per week, ≥5.5 hours per session) hemodialysis. We included clinical trials and observational studies with or without a control arm (1990 and later). Based on a prioritization exercise, 6 interventions of interest included optimal vascular access type, buttonhole cannulation, antimicrobial prophylaxis for buttonhole cannulation, closed connector devices, and dialysate calcium and dialysate phosphate additives for patients receiving intensive hemodialysis. We developed 6 recommendations addressing the interventions of interest. Overall quality of the evidence was very low and all recommendations were conditional. We provide detailed commentaries to guide in shared decision making. The main limitation was the very low overall quality of evidence that precluded strong recommendations. Most included studies were small single-arm observational studies. Three randomized controlled trials were applicable, but provided only indirect evidence. Published information for patient values and preference was lacking. In conclusion, we provide 6 recommendations for the practice of intensive hemodialysis. However, due to very low-quality evidence, all recommendations were conditional. We therefore also highlight priorities for future research.

Should patients with advanced chronic kidney disease and atrial fibrillation receive chronic anticoagulation

Atrial fibrillation is prevalent in dialysis patients. Both ischaemic and haemorrhagic stroke are common in patients on dialysis with atrial fibrillation. In the general population, warfarin is highly effective for prophylaxis of ischaemic stroke, and though warfarin use likely increases the risk of intracranial haemorrhage, the absolute increase in risk is small. In the general population, absolute and relative increases in major extracranial bleeding from warfarin use are also both modest. In patients on dialysis, the effectiveness of warfarin as a prophylaxis for ischaemic stroke and its effects on intracranial or extracranial bleeding have not been assessed in randomized trials. Cohort studies vary greatly in their estimates of the magnitude of the increased risk of bleeding from warfarin use. A single cohort study found rates of intracranial haemorrhage in patients on dialysis with atrial fibrillation to be in an order of magnitude that is greater than those in the general population with atrial fibrillation, and that intracranial haemorrhage more than doubled in association with warfarin use. Basic, translational and limited clinical observations also implicate warfarin in the pathogenesis of vascular calcification, which is likely on the causal pathway to patient-important vascular outcomes. Finally, the effect of warfarin on ischaemic stroke in three recent large observational studies has been in the direction of harm, no benefit, and modest, non-statistically significant benefit, respectively. We believe that no clear recommendation can be made between three alternative approaches. It is acceptable to withhold or discontinue warfarin in patients on dialysis, to offer anticoagulants to all dialysis patients without a contraindication whose congestive heart failure, hypertension, age, diabetes and previous stroke or transient ischaemic attack (CHADS(2)) score >1 or 2 and to discuss and individualize prophylaxis on a patient-by-patient basis. Randomized trials of new agents are needed in this area.