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. 2007 Oct 17;2007:2002.

End stage renal disease

Yoshio N Hall 1,#, Glenn M Chertow 2,#
PMCID: PMC2943808  PMID: 19450356

Abstract

Introduction

End stage renal disease (ESRD) affects over 1500 people per million population in countries with a high prevalence, such as the USA and Japan. Approximately two thirds of people with ESRD receive haemodialysis, a quarter have kidney transplants, and a tenth receive peritoneal dialysis.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of different doses and osmotic agents for peritoneal dialysis? What are the effects of different doses and membrane fluxes for haemodialysis? What are the effects of interventions aimed at preventing secondary complications? We searched: Medline, Embase, The Cochrane Library and other important databases up to April 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 20 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: cinacalcet, darbepoetin, dextrose solutions, erythropoietin, haemodialysis (standard-dose, increased-dose), high-membrane-flux haemodialysis, icodextrin, increased-dose peritoneal dialysis, low-membrane-flux haemodialysis, mupirocin, sevelamer, and standard-dose dialysis.

Key Points

End stage renal disease (ESRD) affects over 1500 people per million population in countries with a high prevalence, such as the USA and Japan. Approximately two thirds of people with ESRD receive haemodialysis, a quarter have kidney transplants, and a tenth receive peritoneal dialysis.

  • Risk factors for ESRD include advanced age, hypertension, diabetes mellitus, obesity, a history of renal disease, and tobacco, heroin, or analgesic use.

  • ESRD leads to fluid retention, anaemia, disturbances of bone and mineral metabolism, and increased risk of cardiovascular disease.

In people receiving peritoneal dialysis, 7.5% icodextrin solution may increase fluid loss compared with lower concentration dextrose solutions. Icodextrin may affect the accuracy of blood glucose measurement.

In people receiving haemodialysis, there seems to be no difference in mortality for high membrane flux compared with low membrane flux, or increased-dose haemodialysis compared with standard dose.

Erythropoietin and darbepoetin may help maintain haemoglobin levels in people with ESRD, but are associated with mortality, and with serious cardiovascular, arterial, and venous thromboembolic events in people with kidney disease.

Disorders of calcium and phosphate metabolism may contribute to the increased risk of cardiovascular disease in people with ESRD.

  • Phosphate binders (sevelamer) may slow down arterial calcification, and may reduce serum low density lipoprotein cholesterol levels, but we don't yet know whether this reduces cardiovascular events or mortality.

About this condition

Definition

End stage renal (ESRD) is defined as irreversible decline in a person's own kidney function, which is severe enough to be fatal in the absence of dialysis or transplantation. ESRD is included under stage 5 of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative classification of chronic kidney disease (CKD), where it refers to individuals with an estimated glomerular filtration rate below 15 mL per minute per 1.73 m2 body surface area, or those requiring dialysis irrespective of glomerular filtration rate. Reduction in or absence of kidney function leads to a host of maladaptive changes including fluid retention (extracellular volume overload), anaemia, disturbances of bone and mineral metabolism, dyslipidaemia, and protein energy malnutrition. This review deals with ESRD in adults only. Fluid retention in people with ESRD contributes significantly to the hypertension, ventricular dysfunction, and excess cardiovascular events observed in this population. Anaemia associated with CKD is normocytic and normochromic, and is most commonly attributed to reduced erythropoietin synthesis by the affected kidneys. Additional factors contribute to the anaemia, including: iron deficiency from frequent phlebotomy, blood retention in the dialyser and tubing, and gastrointestinal bleeding; severe secondary hyperparathyroidism; acute and chronic inflammatory conditions (e.g. infection); and shortened red blood cell survival. Disturbances of bone and mineral metabolism such as hyperparathyroidism, hyperphosphataemia, and hypo- or hypercalcaemia, are common in people with CKD. If untreated, these disturbances can cause pain, pruritus, anaemia, bone loss, and increased fracture risk, and can contribute to hypertension and cardiovascular disease.

Incidence/ Prevalence

The incidence and prevalence of ESRD continue to grow worldwide. According to data collected from 120 countries with dialysis programmes, at the end of 2005 about 1,900,000 people were receiving renal replacement therapy (RRT).Among these individuals, 1,297,000 (68%) received haemodialysis and 158,000 (8%) received peritoneal dialysis, although an additional 445,000 (23%) were living with a kidney transplant.Precise estimates of ESRD incidence and prevalence remain elusive, because international databases of renal registries exclude individuals with ESRD who do not receive RRT.International comparisons of RRT pose similar challenges because of differences in healthcare systems, government funding, acceptance of treatment, demographics, and access to care. Worldwide, the highest incidence and prevalence rates are reported from the USA, Taiwan, and Japan. Prevalence data from several countries are listed below, although this list is not exhaustive. According to the US Renal Data System 2006 annual report, there were 104,364 new cases of ESRD in 2004 — equivalent to an annual incidence of 342 cases per million population.The prevalence of ESRD in the USA in 2003 was 494,471 (1555 cases per million population). According to reports published by the Japanese Society for Dialysis Therapy, 267 people per million population started dialysis in 2004. In 2005, there were 2018 people per million population in Japan receiving dialysis — the highest reported prevalence for industrialised nations.According to Taiwanese government reports, the prevalence of ESRD in 2004 was 1706 cases per million population, and the incidence was 376 cases per million population. In comparison, based on data pooled from the European Renal Association-European Dialysis and Transplant Association Registry and UK Renal Registry, the incidence of treated ESRD (based on the incidence of RRT) in 2004 ranged from 75 cases per million population in Iceland to 195 cases per million population in Greece. The prevalence of treated ESRD in 2004 ranged from about 479 cases per million population in Iceland to 1022 cases per million population in Italy. In 2004, the Australia and New Zealand Dialysis and Transplant Registry reported an annual incidence of treated ESRD of 95 people per million population in Australia and 110 people per million population in New Zealand. The prevalence of treated ESRD in 2004 was 707 people per million population for Australia and 737 people per million population for New Zealand.

Aetiology/ Risk factors

The amount of daily proteinuria remains one of the strongest predictors of progression to ESRD. Hypertension is a strong independent risk factor for progression to ESRD, particularly in people with proteinuria. Age is also a predictor for ESRD; people over 65 years of age have a four- to fivefold increase in risk of ESRD compared with people under 65 years of age. Additional risk factors for developing ESRD include a history of chronic renal insufficiency, diabetes mellitus, heroin abuse, tobacco or analgesic use, non-white race or ethnicity, lower socioeconomic status, obesity, hyperuricaemia, and a family history of kidney disease.

Prognosis

The overall prognosis of untreated ESRD remains poor. Most people with ESRD eventually die from complications of cardiovascular disease, infection, or, if dialysis is not provided, progressive uraemia (hyperkalaemia, acidosis, malnutrition, altered mental functioning). Precise mortality estimates, however, are unavailable because international renal registries omit individuals with ESRD who do not receive renal replacement therapy. Among people receiving renal replacement therapy, cardiovascular disease is the leading cause of mortality, and accounts for more than 40% of deaths in this population. Extracellular volume overload and hypertension — which are common among people with chronic kidney disease — are known predictors of left ventricular hypertrophy and cardiovascular mortality in this population. Even after adjustment for age, sex, race, or ethnicity, and the presence of diabetes, annual cardiovascular mortality remains roughly an order of magnitude higher in people with ESRD than in the general population, particularly among younger individuals.

Aims of intervention

To prolong life; prevent uraemic complications such as hyperphosphataemia, dyslipidaemia, and anaemia; to reduce complications of cardiovascular disease (myocardial infarction, congestive heart failure, and stroke); to manage blood pressure and volume overload; and improve quality of life, with minimal adverse effects.

Outcomes

Primary outcomes of interest include: death; incidence of cardiovascular complications (myocardial infarction, congestive heart failure, and stroke); frequency and severity of uraemic complications; incidence and severity of hypertension and anaemia; blood pressure; quality of life; and adverse effects of treatment.

Methods

BMJ Clinical Evidence search and appraisal April 2007. The following databases were used to identify studies for this systematic review: Medline 1966 to April 2007, Embase 1980 to April 2007, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2007, Issue 1. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and National Institute for Health and Clinical Excellence (NICE). We also searched for retractions of studies included in this review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the authors for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, including open studies, and containing more than 20 individuals of whom more than 60% were followed up. There was no minimum length of follow up required to include studies. We also did a search for cohort studies on specific harms of interventions. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).

Table.

GRADE evaluation of interventions for end stage renal disease

Important outcomes Effectiveness of dialysis, complications, mortality, adverse effects
Number of studies (participants) Outcome Comparison Type of evidence Quality Consistency Directness Effect size GRADE Comment
What are the effects of different doses and osmotic agents for peritoneal dialysis?
4 (391) Effectiveness of dialysis (fluid loss) Icodextrin v dextrose 4 –3 0 –1 0 Very low Quality points deducted for open-label RCT, incomplete reporting of results, poor follow-up, and no intention-to-treat analysis in one RCT. Consistency point deducted for conflicting results. Directness point deducted for differences in membrane characteristics
2 (90) Effectiveness of dialysis (body weight) Icodextrin v dextrose 4 –3 0 –1 0 Very low Quality points deducted for sparse data, open-label RCT, and incomplete reporting of results. Directness point deducted for differences in membrane characteristics
1 (965) Mortality Increased-dose v standard-dose dialysis 4 –1 0 –2 0 Very low Quality point deducted for incomplete reporting of results. Directness points deducted for population recruited decreasing generalisability of results and differences in number of dialysis sessions between the groups
What are the effects of different doses and membrane fluxes for haemodialysis?
1 (1846) Mortality High v low membrane flux 4 –1 0 –2 0 Very low Quality point deducted for methodological weaknesses (not directly comparing high and low doses). Directness points deducted for population recruited decreasing generalisability of results, and for differences in dialysis times at baseline
1 (1846) Mortality Increased-dose v standard-dose haemodialysis 4 –1 0 –2 0 Very low Quality point deducted for methodological weaknesses (not directly comparing high and low doses). Directness points deducted for population recruited decreasing generalisability of results, and for differences in dialysis times at baseline
What are the effects of interventions aimed at preventing secondary complications
1 (522) Secondary complications Erythropoetin v darbepoetin 4 0 0 0 0 High
1 (283) Secondary complications Sevelamer v calcium salts 4 –1 0 0 0 Moderate Quality point deducted for open label RCTs
1 (200) Mortality Sevelamer v calcium salts 4 –2 0 0 0 Low Quality points deducted for open label RCTs and for incomplete reporting of results
2 (1136) Secondary complications Cinacalcet v placebo 4 0 0 0 0 High
1 (267) Secondary complications Mupirocin v placebo (CAPD) 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
2 (186) Secondary complications Mupirocin v no treatment (haemodialysis) 4 –2 0 0 0 Low Quality points deducted for sparse data and for open label RCTs
Open in a new tab

Type of evidence: 4 = RCT; 2 = Observational; 1 = Non-analytical/expert opinion. Consistency: similarity of results across studies Directness: generalisability of population or outcomes Effect size: based on relative risk or odds ratio

Glossary

Continuous ambulatory peritoneal dialysis

Most common form of peritoneal dialysis worldwide that typically involves four daily 2.0–2.5 L exchanges of 4–8 hour duration (dwell) each.

Dialysis

Process by which the solute composition of a solution is altered by exposure to a second solution through a semipermeable membrane.

Electron beam tomography

is a method of computed tomography designed for cardiac imaging, which can be used to quantify ventricular anatomy, global and regional function, coronary artery calcified plaque, and non-invasive coronary angiography.

Extracellular water

Surrogate for estimating extracellular fluid volume.

High-quality evidence

Further research is very unlikely to change our confidence in the estimate of effect

Kidney Disease Outcomes Quality Initiative

Initiative supported by the US National Kidney Foundation and designed by health care providers to offer evidence based practice guidelines for all stages of chronic kidney disease.

Low transporters

Terminology referring to individuals who have slower and less complete equilibration for creatinine and urea because of a relatively small effective peritoneal surface area or low intrinsic membrane permeability.

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Membrane flux

Refers to the membrane pore characteristics of haemodialyzers. “High flux” dialysis membranes typically have pores of sufficient size to allow the passage of large molecules such as beta2 microglobulin (molecular weight 11 800).

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Peritoneal creatinine clearance

Creatinine clearance attributed to the peritoneal dialysis prescription (as opposed to creatinine clearance from residual renal function) — typically measured in litres a week.

Peritoneal equilibration test

Method for measuring peritoneal transport characteristics, which are important determinants of clearances (principally urea, creatinine, etc.) in peritoneal dialysis.

Ultrafiltration

Mechanism of solute transport across a semipermeable membrane (i.e. dialyser in haemodialysis, peritoneal membrane in peritoneal dialysis) — also known as convective transport. In clinical practice, the terminology “ultrafiltration” often refers to the amount of fluid (volume) removed during dialysis.

Very low-quality evidence

Any estimate of effect is very uncertain.

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

Yoshio N Hall, Division of Nephrology, Department of Medicine, Univeristy of Washington, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.

Glenn M Chertow, Stanford University School of Medicine, Stanford, California, USA.

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BMJ Clin Evid. 2007 Oct 17;2007:2002.

Icodextrin versus dextrose

Summary

EFFECTIVENESS OF DIALYSIS Compared with dextrose: Icodextrin solution for the long dwell may be more effective than various strengths of dextrose solutions at increasing ultrafiltration (fluid loss) at 24 hours or long overnight dwells in people receiving continuous ambulatory peritoneal dialysis or automated peritoneal dialysis ( very low-quality evidence ). Icodextrin may be more effective at 3–6 months than dextrose at reducing left ventricular mass or body-weight in people receiving continuous ambulatory peritoneal dialysis or automated peritoneal dialysis (very low-quality evidence). NOTE The FDA has issued public health advice to inform people that icodextrin has been associated with falsely high blood glucose readings, and has advised people who monitor their blood glucose using a glucose dehydrogenase pyrroloquinolinequinone to contact the manufacturer to make sure that icodextrin will not interfere with the test results.

Benefits

Icodextrin versus dextrose:

We found no systematic review. We found four RCTs that compared the effects of icodextrin (a glucose polymer) versus conventional dextrose solutions for the long dwell in people receiving continuous ambulatory peritoneal dialysis or automated peritoneal dialysis. The first RCT (open label; 40 non-diabetic adults) found that, after 4 months, 7.5% icodextrin reduced extracellular water volume and left ventricular mass significantly more than dextrose solution 1.36% (mean change in extracellular water volume: –1.7 L with icodextrin v +0.9 L with dextrose; P = 0.013; mean change in left ventricular mass: –12.9 g with icodextrin v +1 g with dextrose; P = 0.05). The 24-hour ultrafiltration increased significantly in the icodextrin group at 4 months, but not in the dextrose group (24 hour ultrafiltration: 744 mL at baseline to 1670 mL at 4 months with icodextrin; P = 0.012; 907 mL at baseline to 1063 mL at 4 months with dextrose; P reported as not significant; between-group comparison not reported). The second RCT (double blind; 50 people with high solute transport characteristics on peritoneal equilibration testing) found that 7.5% icodextrin significantly increased 24-hour ultrafiltration at 3 months compared with 2.27% dextrose (mean change in ultrafiltration from baseline: +87.9 mL with icodextrin v –311.1 mL with dextrose; P less than 0.05). However, the increase in 24-hour ultrafiltration with icodextrin was not statistically significant at 6 months (mean change in ultrafiltration from baseline: +193.4 mL with icodextrin v –201.7 mL with dextrose; P greater than 0.1). Icodextrin significantly reduced body weight and total body water compared with dextrose at 3 and 6 months (mean body weight change from baseline displayed graphically; mean between group difference: 1.67 kg at 3 months; P = 0.026; 2.3 kg at 6 months; P = 0.036; mean total body water change from baseline displayed graphically; mean between-group difference: 1.53 kg at 3 months; P = 0.003; 1.39 kg at 6 months; P = 0.036). The third RCT (209 adults) randomised participants to either 7.5% icodextrin or dextrose for 6 months; the dextrose group was analysed according to the concentration of solution used for the overnight dwell (1.36% or 3.86%; see comment below). It found that icodextrin significantly increased mean ultrafiltration during 8- and 12-hour overnight dwells compared with 1.36% dextrose (8-hour dwell: 527 mL with icodextrin v 150 mL with 1.36% dextrose; P less than 0.0001; 12-hour dwell: 561 mL with icodextrin v 101 mL with 1.36% dextrose; P less than 0.0001). However, it found no significant difference in mean ultrafiltration during 8- or 12-hour dwells between icodextrin and 3.86% dextrose (8-hour dwell: 510 mL with icodextrin v 448 mL with 3.86% dextrose; P = 0.44; 12-hour dwell: 552 mL with icodextrin v 414 mL with 3.86% dextrose; P = 0.06). The fourth RCT compared 7.5% icodextrin versus 4.25% dextrose for 2 weeks in people with high-average to high transport characteristics on peritoneal equilibration testing. It found that icodextrin significantly increased mean ultrafiltration during the long overnight dwell at 2 weeks (14–16 hours) compared with 4.25% dextrose (92 adults; mean ultrafiltration: 540 mL with icodextrin v 195 mL with dextrose; P less than 0.001).

Harms

Icodextrin versus dextrose:

In the first RCT, one person in the icodextrin group withdrew because of a hypersensitivity reaction (exfoliative dermatitis), which resolved after stopping icodextrin. Two people in the dextrose group withdrew because of peritonitis; there were no peritonitis-related withdrawals from the icodextrin group (significance not reported). Technique failure was similar in the icodextrin and 1.36% dextrose solution groups (1 person in each group switched to haemodialysis). The second RCT reported that no icodextrin-related adverse events were observed, and did not report on adverse events in the dextrose group. The third RCT found that the number of major adverse events (primarily cardiovascular events) was similar in the icodextrin and dextrose groups (8 events with icodextrin v 6 events with dextrose; P value not reported). The peritonitis rate was slightly higher in the icodextrin than the dextrose group, but this difference was not significant, and may have been confounded by baseline differences between groups (7.7 episodes per 100 participant months with icodextrin v 6.3 episodes per 100 participant months with dextrose; P reported as not significant). The number of people withdrawing because of adverse events during treatment was higher in the icodextrin group, but the significance of this difference was not reported (8/106 [8%] with icodextrin v 6/103 [6%] with dextrose; P value not reported). In the fourth RCT, seven people stopped treatment because of adverse events (4/47 [9%] with icodextrin v 3/45 [7%] with dextrose; significance assessment not performed). Rash occurred significantly more often in the icodextrin than the dextrose group (8/47 [2%] with icodextrin v 0/45 [0%] with dextrose; P = 0.006).

Drug safety alert:

The United States Food and Drug Administration (FDA) issued public health advice to inform people that that icodextrin was associated with falsely high blood glucose readings. It advised people who monitor their blood glucose using a glucose dehydrogenase pyrroloquinolinequinone (GDH PQQ) method to contact the manufacturer of the monitor and test strips to make sure that icodextrin will not interfere with the test results.

Comment

The third RCT had a high rate of withdrawal (34%; 39/106 [37%] from the icodextrin group v 32/103 [31%] from the dextrose group). A large proportion of these withdrawals was attributed to either transplantation (16 people) or adverse effects (15 people). Analysis was not by intention to treat, and the dextrose group was split into two subgroups for analysis, which may have reduced power and introduced confounding.

Substantive changes

Icodextrin versus dextrose United States Food and Drug Administration (FDA) harms alert added,informing people that that icodextrin has been associated with falsely high blood glucose readings; categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2007 Oct 17;2007:2002.

Increased-dose versus standard-dose dialysis

Summary

MORTALITY Compared with standard-dose dialysis: We don't know whether increased-dose peritoneal dialysis is more effective than standard-dose dialysis at reducing overall mortality ( very low-quality evidence ).

Benefits

Increased-dose versus standard-dose dialysis:

We found no systematic review. We found one RCT (multicentre design; 965 adults having continuous ambulatory peritoneal dialysis), which compared standard-dose dialysis (4 daily exchanges using 2 L of standard peritoneal dialysis solution) versus increased-dose dialysis (4–5 daily exchanges of 2.5–3.0 L to reach a target creatinine clearance of 60 L/week/1.73 m2 ; see comment below). It found no significant difference in overall mortality between increased-dose dialysis and standard-dose dialysis (results presented graphically; RR 1.00, 95% CI 0.80 to 1.24). Increased-dose dialysis significantly reduced death from congestive heart failure or uraemia compared with standard-dose dialysis (deaths from congestive heart failure: 6% with increased dose v 13% with standard dose; P less than 0.05; deaths from uraemia 5% with increased dose v 12% with standard dose; P less than 0.05). However, there was no significant difference between treatments in death from acute myocardial infarction (28% with increased dose v 22% with standard dose; P reported as not significant).

Harms

Increased dose versus standard dose dialysis:

There was no significant difference between treatments in hospital admissions or peritonitis rates (hospital admissions per person per year: 1.17 with increased dose v 1.03 with standard dose; P = 0.17; peritonitis rates: 23.3 participant months per episode with increased dose v 24.4 participant months per episode with standard dose; P = 0.62). However, significantly more people receiving increased-dose dialysis withdrew from the study owing to discomfort from increased peritoneal volume compared with standard-dose dialysis (study withdrawal: 17/481 [3.5%] with increased dose v 1/484 [0.2%] with standard dose; P less than 0.001), although significantly more people receiving standard-dose dialysis withdrew because of uraemia compared with people receiving increased-dose dialysis (withdrawal because of uraemia: 0/481 [0%] with increased dose v 24/484 [5%] with standard dose; P less than 0.0001). There was no significant difference in generalised infections or stroke between groups (data not reported).

Comment

In the increased-dose group, the initial dose of peritoneal dialysis was calculated based on body surface area, and a maximum of two modifications in dialysis dose were allowed to achieve the clearance target. Therefore, over the duration of the study, some people received more dialysis and others less. The mean peritoneal creatinine clearances achieved over the entire duration of the study were 56.9 ± 0.48 L a week per 1.73 m2 in the increased-dose group and 46.1 ± 0.45 L a week per 1.73 m2 in the standard-dose group (P less than 0.001). The RCT may have limited generalisability because participants were generally younger (mean age 47 years) and healthier than the general peritoneal dialysis population. For instance, only people with a peritoneal creatinine clearance of less than 60 L a week per 1.73 m2, with or without residual renal function, were eligible for inclusion in the trial — effectively excluding smaller individuals and people with high peritoneal transport characteristics (i.e. those at the highest risk of death). Similarly, people with heart disease were also excluded (1 observational study found that the prevalence of a history of cardiovascular disease in people receiving continuous ambulatory peritoneal dialysis was about 34% in a Canadian cohort and 42% in a US cohort), and it is possible that the relative increase in mortality owing to heart failure in the control group compared with the intervention group might have been more striking if such people had been included in the study. Thus, the study may have selected for a population less dependent on peritoneal clearance of small solutes.

Substantive changes

No new evidence

BMJ Clin Evid. 2007 Oct 17;2007:2002.

High-membrane-flux versus low-membrane-flux haemodialysis

Summary

MORTALITY Compared with low-membrane flux: We don't know whether high-membrane-flux haemodialysis is more effective at 4.5 years than low-membrane-flux haemodialysis (with standard- or increased-dose haemodialysis) at reducing all-cause mortality ( very low-quality evidence ).

Benefits

High versus low membrane flux:

We found no systematic review. We found one multicentre RCT (1846 adults receiving maintenance haemodialysis; see comment below), which compared four treatments in a factorial design: low membrane flux, high membrane flux, standard-dose dialysis, and increased-dose dialysis (see benefits of increased-dose versus standard-dose haemodialysis). It found no significant difference in the primary outcome of all-cause mortality between high- and low-flux dialysis after a mean follow-up of 4.5 years (AR 442/925 [48%] with low flux v 429/921 [47%] with high flux; adjusted RR 0.92, 95% CI 0.81 to 1.05). Secondary outcomes of the RCT included mortality from cardiac causes, and first admission to hospital owing to cardiac causes or mortality. It found that high-flux dialysis significantly reduced the risk of mortality from cardiac causes compared with low-flux dialysis (AR 187/925 [20%] with low flux v 156/921 [17%] with high flux; RR and CI presented graphically; P less than 0.05). It found that high-flux dialysis reduced the risk of the combined outcome of first admission to hospital owing to cardiac causes or mortality compared with low-flux dialysis, but the difference did not reach significance (AR 550/925 [59%] with low flux v 529/921 [57%] with high flux; adjusted RR 1.10, 95% CI 0.99 to 1.20).

Harms

High versus low membrane flux:

The RCT found no significant difference between low- and high-flux dialysis in the combined outcome of first admission to hospital owing to infection or death (AR 562/925 [61%] with low flux v 542/921 [59%] with high flux; RR and CI displayed graphically). It found no significant difference between groups in risk of death from infection (AR 104/925 [11.2%] with low flux v 97/921 [10.5%] with high flux; RR and CI displayed graphically).

Comment

The results of this RCT should be interpreted with caution because of limitations in the 2 x 2 factorial design. Specifically, the study did not purely compare high versus low flux, but instead compared high flux (pooling standard and increased dose) versus low flux (pooling standard and increased dose). See comment on increased-dose versus standard-dose haemodialysis.

Substantive changes

No new evidence

BMJ Clin Evid. 2007 Oct 17;2007:2002.

Increased-dose versus standard-dose haemodialysis

Summary

MORTALITY C ompared with standard-dose haemodialysis: We don't know whether increased-dose haemodialysis is more effective than standard-dose haemodialysis (at high or low membrane flux) at reducing all-cause mortality ( very low-quality evidence ).

Benefits

Increased-dose versus standard-dose haemodialysis:

We found no systematic review. We found one multicentre RCT (1846 adults receiving maintenance haemodialysis). It compared four treatments in a factorial design: standard-dose dialysis (equilibrated Kt/V of 1.05), increased-dose dialysis (equilibrated Kt/V of 1.45), low-membrane-flux dialysis, and high-membrane-flux dialysis. It found no significant difference in the primary outcome of all-cause mortality after a mean follow up of 4.5 years between increased-dose and standard-dose dialysis (AR 440/926 [47.5%] with standard-dose v 431/920 [46.8%] with increased-dose dialysis; adjusted RR 0.96, 95% CI 0.84 to 1.10; see comment below). Secondary outcomes of the RCT included mortality from cardiac causes and first admission to hospital owing to cardiac causes or mortality. It found no significant difference between groups in the risk of mortality from cardiac causes (AR 169/926 [18.3%] with standard-dose v 174/920 [18.9%] with increased-dose dialysis; RR and CI displayed graphically). It found no significant difference between groups in the composite outcome of first admission to hospital owing to cardiac causes or mortality (AR 545/926 [58.9%] with standard-dose v 534/920 [58.0%] with increased-dose dialysis; adjusted RR 1.01, 95% CI 0.88 to 1.12; P = 0.91).

Harms

Increased-dose versus standard-dose haemodialysis:

The RCT found no significant difference in first admission to hospital owing to infection or death between increased-dose and standard-dose dialysis (557/926 [60%] with standard dose v 547/920 [59%] with increased dose dialysis; adjusted RR 1.03, 95% CI 0.91 to 1.14; P = 0.60). It found no significant difference between groups in deaths from infection (AR 99/926 [10.7%] with standard-dose v 102/920 [11.1%] with increased-dose dialysis; RR and CI displayed graphically).

Comment

The results of this RCT should be interpreted with caution because of limitations in the 2 x 2 factorial design. Specifically, the study did not purely compare increased-dose versus standard-dose dialysis, but instead compared increased dose (pooling low and high flux) versus standard dose (pooling low and high flux). The RCT was powered to detect a 25% reduction in mortality between groups, and so smaller differences in clinical effect cannot be excluded. This RCT may have limited generalisability, because of the younger age of participants (mean age 57.6 years), and an over-representation of African-Americans compared with the general US dialysis population (62% African Americans v 37% general US dialysis population). African-Americans are known to have improved survival on haemodialysis compared with age-matched white people. The study also included people with a relatively long baseline time on dialysis (mean 3.7 years), effectively selecting for a fitter population that may not have benefited as much from an increase in dialysis dose or membrane flux. This selection bias also raises the question of potential carryover effects in people previously treated with either a higher dialysis dose (baseline mean equilibrated Kt/V 1.43 ± 0.21) or high flux membrane (baseline use 60.2%).

Substantive changes

No new evidence

BMJ Clin Evid. 2007 Oct 17;2007:2002.

Erythropoietin versus darbepoetin

Summary

SECONDARY COMPLICATIONS Erythropoietin compared with darbepoetin: Recombinant human erythropoietin seems as effective at 25–32 weeks as darbepoetin alfa at maintaining haemoglobin levels in people receiving haemodialysis or peritoneal dialysis ( high-quality evidence ). ADVERSE EFFECTS Erythropoiesis Stimulating Agents, darbepoetin alfa, and recombinant human erythropoietin may be associated with mortality and serious cardiovascular, arterial, and venous thromboembolic events.

Benefits

Erythropoietin versus darbepoetin:

We found one RCT (522 people receiving haemodialysis or peritoneal dialysis, and on stable recombinant human erythropoietin [rHuEPO] treatment given 1–3 times weekly). It randomised people (2:1) to either continue rHuEPO treatment (1–3 times weekly) or switch to reduced-frequency treatment with darbepoetin alfa (once every 2 weeks or once a week). It found no significant difference in effectiveness in maintaining haemoglobin levels at 25–32 weeks between darbepoetin and rHuEPO (adjusted mean change from baseline [mean baseline]: –0.03 g/dL with darbepoetin v –0.06 [11.0] g/dL with rHuEPO; adjusted mean difference: +0.03 [11.0] g/dL, 95% CI –0.16 g/dL to +0.21 g/dL). See comment below.

Harms

Erythropoietin versus darbepoetin:

The RCT found that adverse events were common, and occurred at a similar frequency with darbepoetin alfa and with rHuEPO (AR for experiencing at least 1 adverse event: 96% with darbepoetin v 95% with rHuEPO; P value not reported). There was no significant difference between treatments in six prespecified adverse events related to increasing haemoglobin in people with end stage renal disease (AR for events for darbepoetin v rHuEPO; hypertension: 30% v 28%; vascular access thrombosis: 10% v 9%; cerebrovascular disorder: 2% v 1%; myocardial infarction: 1% v 2%; seizures: 2% v 2%; transient ischaemic attack: 0% v 1%; P at least 0.682 for all 6 outcomes). Pruritus was significantly more common with darbepoetin than with rHuEPO (14% with darbepoetin v 5% with rHuEPO; OR and CI presented graphically).

Drug safety alert:

The United States Food and Drug Administration (FDA) issued a public health advisory to inform people about mortality and serious cardiovascular, arterial, and venous thromboembolic events associated with Erythropoiesis Stimulating Agents, darbepoetin alfa, and recombinant human erythropoietin. FDA and Amgen, the manufacturer of Aranesp, Epogen and Procrit, have changed the full prescribing information for these drugs. The new product labeling includes a new boxed warning, updated warnings, and a change to the dosage and administration sections for all Erythropoiesis Stimulating Agents.

Comment

Clinical guide:

Since the introduction of rHuEPO in 1989, numerous studies have shown improvements in various physiological and quality-of-life parameters (e.g. sexual, muscle, and cognitive function; regression of left ventricular hypertrophy; physical activity; among others) with the correction of anaemia in people with chronic kidney disease. Several observational studies have also shown that the survival of people receiving dialysis declines as the haematocrit falls below a range of 30–33%. One RCT comparing the effects of maintaining a normal haematocrit target (42%) versus low haematocrit target (30%) in people with end stage renal disease and clinically evident congestive heart failure or ischaemic heart disease found an overall higher mortality in the normal haematocrit group.Subsequent studies found no difference in the risk of cardiovascular events or in the rate of progression of chronic kidney disease with the correction of anaemia to normal levels in people who do not yet require dialysis (estimated GFR 15 to 35 ml/min/1.73 m2). However, the optimal haemoglobin/haematocrit level in people with end stage renal disease remains a source of ongoing debate. Based on collective data from observational trials and RCTs, the Kidney Disease Outcomes Quality Initiative Anemia Work Group now recommends maintaining a haemoglobin level of no greater than 13.0 g/dL in people with ESRD who receive Erythropoiesis Stimulating Agent (ESA) therapy.The US Food and Drug Administration (FDA) has placed an upper limit for target haemoglobin at 12.0 g/dL in approved labeling for darbepoetin alfa and recombinant human erythropoietin. Additional prospective studies are needed to further elucidate the relationship between anaemia and clinical outcomes in people with end stage renal disease.

Substantive changes

Erythropoietin versus darbepoetin United States Food and Drug Administration harms alert added about mortality, and serious cardiovascular, arterial, and venous thromboembolic events associated with Erythropoiesis Stimulating Agents, darbepoetin alfa and recombinant human erythropoietin. Categorisation changed from Likely to be beneficial to Trade-off between benefits and harms.

BMJ Clin Evid. 2007 Oct 17;2007:2002.

Phosphate binders

Summary

SECONDARY COMPLICATIONS Compared with calcium salts: Sevelamer is more effective at 52 weeks than calcium salts at reducing the progression of coronary artery and aortic calcification in people with end stage renal disease ( moderate-quality evidence ). Sevelamer is more effective than calcium salts at reducing serum low-density lipoprotein cholesterol levels and the incidence of hypercalcaemia in people with end stage renal disease, but is no more effective at reducing serum phosphorous levels (moderate-quality evidence). MORTALITY Compared with calcium salts: We don't know whether sevelamer is more effective than calcium salts at reducing mortality in people with end stage renal disease ( low-quality evidence ). NOTE We found no clinically important results about sevelamer compared with aluminium or lanthanum carbonate in people with end stage renal disease.

Benefits

Sevelamer versus calcium:

We found two RCTs. The first multicentre RCT (open label; 200 adults with end stage renal disease) compared sevelamer (a non-absorbed, non-calcium-containing phosphate binder) versus calcium salts (calcium carbonate and calcium acetate) for 52 weeks. It found that sevelamer significantly reduced the progression of coronary artery and aortic calcification (as measured by electron beam tomography) at 52 weeks compared with calcium salts (quantified using the Agatston score, a higher score indicating more severe calcification; mean score change from baseline in coronary artery calcification score: –46 with sevelamer v +151 with calcium salts; P = 0.04; mean score change from baseline in aortic calcification score: –532 with sevelamer v +185 with calcium salts; in participants with calcification scores 30 or more at baseline: median change in coronary artery calcification score: +6% with sevelamer v +25% with calcium salts; P = 0.02; in participants with calcification scores 30 or more at baseline: median change in aortic calcification score: +5% with sevelamer v +28% with calcium salts; P = 0.02). It also found that serum low-density lipoprotein (LDL) cholesterol levels significantly decreased with sevelamer after 52 weeks compared with calcium salts (mean change in LDL cholesterol: –37 mg/dL with sevelamer v +1 mg/dL with calcium salts; P less than 0.0001). It found similar mortality in both groups (AR 6/99 [6%] with sevelamer v 5/101 [5%] with calcium salts; significance not reported). The second RCT (open label, crossover trial with 2-week washout period; 83 adults on maintenance haemodialysis) compared sevelamer versus calcium acetate for 8 weeks. The study did not present the results before crossover. It found no significant difference between groups in the reduction of serum phosphate from baseline at the end of treatment (mean reduction: 2.0 mg/dL with sevelamer v 2.1 mg/dL with calcium acetate; P = 0.71). In addition, serum LDL cholesterol levels decreased significantly more with sevelamer than with calcium acetate (mean change: –25.3 mg/dL with sevelamer v +4.1 mg/dL with calcium acetate; P less than 0.0001).

Sevelamer versus aluminium:

We found no RCTs.

Sevelamer versus lanthanum carbonate:

We found no RCTs.

Harms

Sevelamer versus calcium:

The first RCT found that both sevelamer and calcium salts were well tolerated. Significantly more people experienced at least one hypercalcaemic episode over 52 weeks with calcium salts compared with sevelamer (AR for hypercalcaemia: 17% with sevelamer v 43% with calcium salts; P = 0.0005). Serum bicarbonate concentrations were significantly higher in the calcium-treated group (19.2 mEq/L with sevelamer v 22.1 mEq/L with calcium salts; P = 0.0003). There was no significant difference between groups in the risk of hospital admission and the number of days spent in hospital (AR for hospital admission: 37/99 [37%] with sevelamer v 48/101 [47%] with calcium salts; P = 0.15; total hospital days: 567 days with sevelamer v 980 days with calcium; P = 0.23). The causes of hospital admission were not reported. Post hoc analysis of this RCT found that calcium salts significantly reduced vertebral bone mineral density compared with sevelamer (proportion of people with decline in attenuation at least 10% on electron beam tomography: 32% with calcium salts v 10% with sevelamer; P = 0.006). The second RCT reported no serious adverse effects with either treatment. There was no significant difference between groups in gastrointestinal complaints (34% with sevelamer v 28% with calcium acetate; P = 0.26). It found that serum alkaline phosphatase was significantly increased from baseline with sevelamer (from 87 U/L to 106 U/L; P less than 0.0001) but not with calcium acetate (from 106 U/L to 96 U/L; P = 0.85). It was unclear whether this reflected effects on bile acid metabolism or bone turnover. No significant changes in the bone or liver subfractions of alkaline phosphatase were noted, and no adverse hepatic events were observed. The RCT found that significantly fewer people developed hypercalcaemia with sevelamer compared with calcium acetate (hypercalcaemia defined as serum calcium at least 11.0 mg/dL; AR 5% with sevelamer v 22% with calcium acetate; P = 0.0001). During treatment with sevelamer, 18/80 (23%) people required an evening dose of calcium carbonate to maintain serum calcium concentrations, and 15/80 (18%) people developed hypocalcaemia (serum calcium less than 8 mg/dL).

Sevelamer versus aluminium:

We found no RCTs.

Sevelamer versus lanthanum carbonate:

We found no RCTs.

Comment

Clinical guide:

Traditional risk factors for coronary artery disease account for only a portion of the remarkable increase in cardiovascular mortality observed in people receiving dialysis. Disorders of mineral metabolism (i.e. abnormalities of calcium, phosphorus, parathyroid hormone, and vitamin D) may play an important role in the accelerated atherosclerosis unique to the dialysis population. Since the late 1980s, calcium salts have served as the conventional treatment for controlling hyperphosphataemia. Several observational studies have shown a direct correlation between elevated levels of serum phosphorus and calcium, and higher coronary artery calcification scores and mortality in people receiving chronic haemodialysis. In clinical practice, elevations in serum calcium and phosphorus often limit the use of conventional calcium salts and vitamin D analogues in controlling abnormalities of mineral metabolism seen in patients with end stage renal disease. Thus, recent attention has focused on the effects of non-calcium-containing phosphate binders. Sevelamer is also known to act as a bile acid sequestrant. Hence, it is unclear whether the effects of sevelamer on serum LDL cholesterol contributed significantly to the beneficial effects on vascular calcification. Further studies investigating the effects of sevelamer on all-cause mortality and cardiovascular events are currently in progress.

Lanthanum carbonate:

Studies investigating the effects of lanthanum carbonate on bone and mineral metabolism are currently in progress.

Substantive changes

No new evidence

BMJ Clin Evid. 2007 Oct 17;2007:2002.

Cinacalcet

Summary

SECONDARY COMPLICATIONS Compared with placebo: Cinacalcet is more effective at 26 weeks than placebo at improving control of secondary hyperparathyroidism, and at improving calcium–phosphorus homeostasis in people with end stage renal disease receiving maintenance haemodialysis, or peritoneal haemodialysis ( high-quality evidence ).

Benefits

Cinacalcet versus placebo:

We found two RCTs. The first RCT compared cinacalcet versus placebo for 26 weeks (efficacy was measured from week 13 to week 26). It found that cinacalcet significantly improved control of secondary hyperparathyroidism compared with placebo (multicentre, double-blind RCT; 741 adults with end stage renal disease receiving maintenance haemodialysis; AR of reaching a mean intact parathyroid hormone level of 250 pg/mL or less: 160/371 [43%] with cinacalcet v 19/370 [5%] with placebo; P less than 0.001). It also found that cinacalcet improved calcium–phosphorus homeostasis compared with placebo (% change in mean serum calcium: –6.8% with cinacalcet v +0.4% with placebo; P less than 0.001; % change in mean serum phosphorus: –8.4% with cinacalcet v +0.2% with placebo; P less than 0.001). Mean doses of phosphate binders and vitamin D sterols did not significantly differ between the two groups at 26 weeks (figures not reported). The second RCT also compared cinacalcet versus placebo for 26 weeks (efficacy was measured from week 18 to week 26). It found that cinacalcet significantly improved control of secondary hyperparathyroidism compared with placebo (multicentre, double-blind RCT; 395 adults with end stage renal disease receiving maintenance haemodialysis and peritoneal dialysis; AR of reaching a mean intact parathyroid hormone level of 250 pg/mL or less: 111/288 [39%] with cinacalcet v 7/100 [7%] with placebo; P less than 0.001). It also found that cinacalcet improved calcium–phosphorus homeostasis compared with placebo (% change in mean serum calcium: –6.5% with cinacalcet v +0.9% with placebo; P less than 0.001; % change in mean serum phosphorus: –7.2% with cinacalcet v –2.2% with placebo; P = 0.039).

Harms

Cinacalcet versus placebo:

The first RCT found that adverse events were common, and occurred at a similar frequency with cinacalcet and with placebo (AR for experiencing at least 1 adverse event: 333/365 [91%] with cinacalcet v 346/369 [94%] with placebo; P = 0.21). Nausea, vomiting, and hypocalcaemia (serum calcium less than 7.5 mg/dL) occurred more often with cinacalcet than with placebo (AR for cinacalcet v placebo; nausea: 32% v 19%; P less than 0.001; vomiting: 30% v 16%; P less than 0.001; hypocalcaemia: 5% v less than 1%; P less than 0.001). On the other hand, hypotension and upper respiratory tract infection occurred less commonly in people receiving cinacalcet compared with placebo (AR for cinacalcet v placebo; hypotension: 6% v 12%; P = 0.014; upper respiratory tract infection: 7% v 13%; P = 0.007). The second RCT reported a higher incidence of gastrointestinal adverse effects in people receiving cinacalcet compared with placebo (AR for cinacalcet v placebo; nausea: 30% v 22%; vomiting: 23% v 12%; diarrhoea: 24% v 19%; significance assessments not performed). Hypocalcaemia (serum calcium less than 7.5 mg/dL) was more common with cinacalcet over 26 weeks than with placebo (AR for hypocalcaemia: 5% with cinacalcet v less than 1% with placebo; significance assessment not performed).

Comment

Clinical guide:

The second RCT found that the efficacy of cinacalcet was similar for peritoneal dialysis and haemodialysis (AR of reaching mean intact parathyroid hormone level of 250 pg/mL or less with cinacalcet: 13/34 [38%] in people receiving peritoneal dialysis v 98/254 [39%] in people receiving haemodialysis; significance assessment not performed). In clinical practice, elevations in serum calcium and phosphorus often limit the use of conventional calcium salts and vitamin D analogues for controlling abnormalities of mineral metabolism seen in people with end stage renal disease. Cinacalcet acts by binding to the calcium-sensing receptor of the parathyroid gland. It is designed, therefore, to enhance the sensitivity of the calcium-sensing receptor to extracellular calcium — thereby reducing parathyroid hormone secretion while simultaneously reducing serum calcium and phosphorus concentrations. We identified one pooled analysis of safety data from four RCTs, two of which were phase II trials and had participant overlap with the two RCTs described in the benefits section above, and therefore are not reported separately. The pooled analysis (1184 adults with end stage renal disease receiving dialysis) found that cinacalcet reduced the risk of cardiovascular hospitalisation (cinacalcet v placebo: 15 v 20 events per 100 person years; HR 0.61, 95% CI 0.43 to 0.86), fracture (3 v 7 events per 100 person years; HR 0.46, 95% CI 0.22 to 0.95), and parathyroidectomy (0.3 v 4.1 events per 100 person years; HR 0.07, 95% CI 0.01 to 0.55) compared with placebo. It found no significant difference in overall mortality between cinacalcet and placebo (5.2 v 7.4 deaths per 100 person years in people receiving cinacalcet v placebo; HR 0.81, 95% CI 0.45 to 1.45). Such results should be interpreted with caution because the safety outcomes were not primary outcomes of interest in the studies. Further prospective studies are needed to evaluate whether reductions in parathyroid hormone, calcium, and phosphorus concentrations favourably influence cardiovascular health and overall survival.

Substantive changes

No new evidence

BMJ Clin Evid. 2007 Oct 17;2007:2002.

Mupirocin (nasal or catheter exit site application)

Summary

SECONDARY COMPLICATIONS Compared with placebo: Nasal mupirocin is more effective than placebo at reducing the rate of Staphylococcus aureus exit-site infections in S aureus carriers receiving continuous ambulatory peritoneal dialysis, but not the rate of catheter-tunnel infection or peritonitis ( moderate-quality evidence ). Compared with no treatment: Mupirocin applied to the catheter exit site may be more effective than placebo at reducing the rate of Staphylococcus aureus infections in people receiving haemodialysis ( low-quality evidence ).

Benefits

Mupirocin versus placebo or no treatment:

We found three RCTs. The first RCT compared nasal mupirocin versus placebo for 18 months. It found that, compared with placebo, nasal mupirocin (applied twice daily, 5 days per week) significantly reduced the rate of exit-site infection caused by Staphylococcus aureus (multicentre, double-blind RCT; 267 adult nasal carriers of S aureus receiving continuous ambulatory peritoneal dialysis; exit-site S aureus infection: 10.1 events per 1000 person months with mupirocin v 35.6 events per 1000 person months with placebo; P = 0.006). It found no significant differences in the rate of catheter-tunnel infection (6.5 events per 1000 person months with mupirocin v 8.1 events per 1000 person months with placebo; difference reported as not significant; P value not reported) or peritonitis caused by S aureus (12.3 events per 1000 person months with mupirocin v 18.6 events per 1000 person months with placebo; difference reported as not significant; P value not reported). The second RCT compared mupirocin applied to the haemodialysis uncuffed catheter exit site versus no additional treatment. All participants had their catheter sites disinfected with povidone iodine solution. Median duration of follow-up was 22.5 days (range 3–143 days). It found that mupirocin reduced the risk of S aureus exit-site infection compared with no mupirocin treatment (single centre, open label RCT; 136 adults requiring maintenance haemodialysis; AR for S aureus exit site infection: 3/69 [4%] with mupirocin v 16/67 [24%] with no treatment; P = 0.001) and the rate of S aureus bacteraemia (0.35 events per 1000 person days with mupirocin v 5.95 events per 1000 person days with no treatment; P less than 0.001). The third RCT compared mupirocin applied to the haemodialysis cuffed catheter exit site versus no additional treatment. All participants had their catheter sites disinfected with povidone iodine solution. The RCT found that, compared with no treatment, mupirocin reduced the rate of exit-site infection (single-centre, open label RCT; 50 adults receiving maintenance haemodialysis; 0 events per 1000 catheter days with mupirocin v 6.6 events per 1000 catheter days with no treatment; P less than 0.05) and bacteraemia (1.6 events per 1000 catheter days with mupirocin v 10.5 events per 1000 catheter days with no treatment; P less than 0.05).

Harms

Mupirocin versus placebo or no treatment:

The first RCT found that mupirocin and placebo were well tolerated. Six people (6/134 [4%]) in the mupirocin group experienced rhinitis, nasal irritation and/or discharge compared with seven people (7/133 [5%]) in the placebo group (difference reported as not significant; P value not reported). The RCT found no difference in colonisation by high level resistant (minimum inhibitory concentration of mupirocin greater than 256 mg/L) isolates of S aureus (figures not reported). The second and third RCTs reported that there were no adverse local or systemic reactions to mupirocin during the study period. The second RCT reported that the overall proportion of Gram-negative organisms recovered from the nares, pericatheter skin, and blood did not differ between groups (figures not reported). This result suggests that regular mupirocin use did not result in selection for colonisation by Gram-negative organisms. The third RCT noted that mupirocin-resistant S aureus isolates were not detected in either group.

Comment

Clinical guide:

Dialysis access infections remain a substantial source of morbidity and mortality among people with end stage renal disease. Among people undergoing continuous ambulatory peritoneal dialysis, peritonitis, and catheter-tunnel infections are the most common causes of catheter removal and technique failure. In the first RCT, it is important to note that, when exit-site infections as a whole were analysed, there was no significant difference between mupirocin and placebo. This implies that nasal mupirocin was mainly of benefit for the prevention of S aureus exit-site infection only. Nasal carriers of S aureus undergoing peritoneal dialysis appear to be at risk for catheter-tunnel infections. Among people receiving haemodialysis, the native arteriovenous fistula continues to be the preferred choice of vascular access because of lower associated rates of infection and thrombosis compared with synthetic (polytetrafluoroethylene) arteriovenous grafts and haemodialysis cuffed catheters. However, many patients, particularly in North America, continue to rely on haemodialysis cuffed catheters for long-term vascular access, despite their being associated with higher rates of infection, thrombosis, bacteraemia, hospitalisation, and death. Haemodialysis uncuffed catheters are associated with an even higher risk of infection compared with haemodialysis cuffed catheters, and therefore the US National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines recommend that uncuffed catheters only be used in the short term (no longer than 3 weeks). Further prospective studies are needed to determine whether the use of mupirocin results in significant long-term increase in the incidence of moderate- or high-level resistant isolates of S aureus, or in the incidence of Gram-negative organisms. We await more convincing studies on whether mupirocin significantly impacts outcomes such as peritonitis, infection-related hospitalisations, premature catheter removal, and dialysis technique failure.

Substantive changes

No new evidence

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