Interventions for preventing infection in nephrotic syndrome
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
This review aims to assess the benefits and harms of any prophylactic intervention for reducing the risk of any infection in adults and children with nephrotic syndrome, regardless of any cause or pathologic change.
Background
Infection is one of the most common complications in patients with nephrotic syndrome, especially in nephrotic children. Prior to the introduction and widespread use of corticosteroids and antibiotics, sepsis was the commonest cause of death and it remains a major problem in the developing world. The mortality rate for children with nephrotic syndrome was about 20 ‐ 40%, and the majority of these deaths were due to bacterial infection (Lawson 1959; Arneil 1961; Cornfeld 1966). Hospital‐based, retrospective case series from the 1960s to 1980s had consistently shown the annual incidence of invasive bacterial infection to be about 1 ‐ 2%, and a cumulative risk of 10 ‐ 20% for the 10 year susceptibility period (McIntyre 1998). In China, many studies have also reported a high incidence rate of nosocomial infection of about 34 ‐ 64% in nephrotic children (Du 1996; Ma 1996; Wu 1998; Wu 2000), and 22% in adults (Li 1996). Death from infective complications has now become rare due to the considerable therapeutic improvements in the management of nephrotic syndrome. Despite this, the international study group of kidney disease in children indicated that, of the 10 deaths amongst the nearly 400 children with minimal change disease followed for 5‐10 years, six occurred after infection, resulting in a cumulative infection‐related mortality incidence of 1.5% (RISKDC 1984). Therefore infections still remain a significant cause of morbidity and occasionally mortality in nephrotic patients all over the world (Tain 1999).
There are several explanations for this increased risk, including oedema (which may predispose to entry and spread of infection), urinary losses of factor B and D of the alternative complement pathway, impaired polymorph phagocytic function and secondary effects of corticosteroids and cytotoxic therapy (Johnson 2000; Shroff 2002).
Many efforts have being made to investigate the effectiveness of various interventions for dealing with this problem worldwide. At present, multiple different prophylactic interventions are used and/or recommended for reducing the risk of infection in patients with nephrotic syndrome in clinical practice. These include avoidance of nephrosis, chemoprophylaxis with antibiotics, pneumococcal vaccines and immunoglobulin replacement therapies (McIntyre 1998; Shroff 2002). In China, several studies have also demonstrated that immunoglobulin replacement therapies are beneficial for preventing nosocomial infection in children with nephrotic syndrome (Dang 1999; Zhang 2000). But whether the existing evidence is scientifically rigorous and which prophylactic intervention can be recommended for routine use based on the current evidence is still unknown. Two previous narrative reviews about the prevention of bacterial infection in nephrotic syndrome indicated that there were insufficient data (controlled trials) for recommending prophylactic use of antibiotics and pneumococcal vaccination (McIntyre 1998; Shroff 2002). However where penicillin‐resistant pneumococci are common, they recommended the administration of pneumococcal vaccination in pediatric practices and claimed that it would favourably alter the outcome of children with nephrotic syndrome, making treatment with prophylactic antibiotics obsolete. Some antibiotics, pneumococcal vaccine and other prophylactic therapies are expensive and have some adverse effects. Before these prophylactic interventions can be recommended for routine use in patients with nephrotic syndrome, rigorous randomised evidence should be provided to show its effectiveness.
The aim of this review is to analyse systematically all the randomised controlled trials (RCTs) of prophylactic interventions for reducing risk of infection in nephrotic syndrome.
Objectives
This review aims to assess the benefits and harms of any prophylactic intervention for reducing the risk of any infection in adults and children with nephrotic syndrome, regardless of any cause or pathologic change.
Methods
Criteria for considering studies for this review
Types of studies
All RCTs and quasi‐RCTs (e.g. allocation using alternative, case record numbers, date of birth or day of the week) looking at the benefits and harms of any prophylactic intervention (pharmacological or non‐pharmacological) compared with placebo, no treatment or other pharmacological or non‐pharmacological treatment will be eligible for inclusion. The first period of randomised cross‐over studies shall also be included.
Types of participants
INCLUSION CRITERIA
Trials which include patients of any age or sex, with any type of nephrotic syndrome (primary or secondary) regardless of pathologic changes will be eligible. Nephrotic syndrome can be diagnosed by the excretion of large amount of protein in the urine per day (> 3.5 g/24h urine/day) and low serum protein (< 30 g/L).
EXCLUSION CRITERIA
There will be no exclusions.
Types of interventions
Trials evaluating any prophylactic therapies, pharmacological or not, administered for patients with nephrotic syndrome to prevent appearance of any types of infection will be included (e.g. oral antibiotics, long‐term, low dose antibiotics, pneumococcal vaccination).
Comparisons that will be investigated in this review are:
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any prophylactic intervention compared to placebo
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any prophylactic intervention compared to no treatment
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prophylactic intervention in addition to baseline medication or treatment compared to baseline medication or treatment alone
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any prophylactic intervention compared to another treatment.
Types of outcome measures
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Number of patients who develop any type of infection. We will use the authors definition for the diagnosis of infections.
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Mortality
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Quality of life
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Adverse events
Search methods for identification of studies
Relevant trials will be obtained from the following sources:‐
Cochrane Renal Group Specialised Register of Randomised Controlled Trials.
Cochrane Central Register of Controlled Trials (CENTRAL) ‐ latest issue for any "New" records not yet incorporated in the Specialised Register. Search strategy for CENTRAL:
#1 nephrotic syndrome/
#2 nephrosis, lipoid/
#3 nephrotic syndrome.tw. #4 lipoid nephrosis.tw.
#5 minimal change nephr$.tw.
#6 minimal change glomerl$.tw.
#7 minimal lesion glomerl$.tw.
#8 or/1‐7
#9 exp "bacterial infections and mycoses"/
#10 exp virus diseases/
#11 infection$.tw.
#12 or/9‐11
#13 8 and 12
MEDLINE and Pre‐MEDLINE 1966 ‐ present ‐ to ensure all trials have been identified.
The following MEDLINE subject‐specific search strategy will be used (modified as appropriate for other databases):
1. nephrotic syndrome/
2. nephrosis, lipoid/
3. nephrotic syndrome.tw.
4. lipoid nephrosis.tw.
5. minimal change nephr$.tw.
6. minimal change glomerul$.tw.
7. minimal lesion glomerul$.tw.
8 or/1‐7
9. exp "bacterial infections and mycoses"/
10. exp virus diseases/
11. infection$.tw.
12. or/9‐11
13. 8 and 12
This will be combined with the Cochrane highly sensitive search strategy for identifying RCTs in MEDLINE (Dickersin 1994), and a similar strategy for EMBASE (Lefebvre 1996). Please see Cochrane Renal Group Module for details of these strategies.
EMBASE 1980 ‐ present ‐ to ensure all trials have been identified
China Biological Medicine Database (CBMdisc, 1979 to most recent) which is a Chinese biological research literature disk.
Reference lists of nephrology textbooks, review articles and relevant trials.
Reference lists of abstracts from nephrology scientific meetings.
Letters seeking information about unpublished or incomplete trials to investigators known to be involved in previous trials.
Data collection and analysis
INCLUDED AND EXCLUDED STUDIES
The review will be undertaken by two reviewers, Wu HM and Sha ZH. The search strategy described will be used to obtain titles and abstracts of studies that may be relevant to the review. The titles and abstracts will be screened independently by Wu and Sha, who will discard studies that are not applicable, however studies and reviews that might include relevant data or information on trials will be retained initially. Wu and Sha will independently assess retrieved abstracts and, if necessary the full text, of these studies to determine which studies satisfy the inclusion criteria. Data extraction will be carried out independently by the same reviewers using standard data extraction forms. Studies reported in non‐English language journals will be translated before assessment. Where more than one publication of one trial exists, only the publication with the most complete data will be included. Any further information required from the original author will be requested by written correspondence and any relevant information obtained in this manner will be included in the review. Disagreements will be resolved in consultation with a third member of this workgroup(Tang JL).
STUDY QUALITY
The quality of studies to be included will be assessed independently by Wu and Sha without blinding to authorship or journal using the checklist developed for the Cochrane Renal Group. Discrepancies will be resolved by discussion with a third member (Tang). The quality items to be assessed are allocation concealment, intention‐to‐treat analysis, completeness to follow‐up and blinding of investigators, participants and outcome assessors.
QUALITY CHECKLIST
1. Allocation Concealment
A. Adequate ‐ Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study
B. Unclear ‐ Randomisation stated but no information on method used is available
C. Inadequate ‐ Method of randomisation used such as alternate medical record numbers or unsealed envelopes; any information in the study that indicated that investigators or participants could influence intervention group
2. Blinding
Blinding of investigators: Yes/No/not stated
Blinding of participants: Yes/No/not stated
Blinding of outcome assessor: Yes/No/not stated
Blinding of data analysis: Yes/No/not stated
The above are considered not blinded if the treatment group can be identified in >20% of participants because of the side effects of treatment.
3. Intention‐to‐treat analysis
Yes ‐ Specifically reported by authors that intention‐to‐treat analysis was undertaken and this was confirmed on study assessment.
No ‐ Not reported and lack of intention‐to‐treat analysis confirmed on study assessment. (Patients who were randomised were not included in the analysis because they did not receive the study intervention, they withdrew from the study or were not included because of protocol violation)
Not stated
4. Completeness to follow‐up
proportion(%) of participants excluded
STATISTICAL ASSESSMENT
For dichotomous outcomes (mortality, appearance of infection and severe adverse effects), the results will be expressed as relative risk (RR) with 95% confidence intervals (CI). Data will be pooled using the random effects model however the fixed effects model will also be analysed to ensure robustness of the model chosen and susceptibility to outliers. Where continuous scales of measurement are used (effects of treatment in immunologic function changes and quality of life), the weighted mean difference (WMD) will be used, or the standardised mean difference (SMD) if different scales have been used. Heterogeneity will be analysed using a Chi squared test on N‐1 degrees of freedom, with an alpha of 0.05 used for statistical significance.
Subgroup analysis will be used to explore possible sources of heterogeneity (e.g. participants, type of nephrotic syndrome, treatments and study quality). Heterogeneity among participants could be related to age, causes and renal pathology. Heterogeneity in treatments could be related to the type of nephrotic syndrome (primary or secondary) prior agent(s) used and the agent, dose and duration of therapy. Adverse effects will be tabulated and assessed with descriptive techniques, as they are likely to be different for the various agents used. Where possible, the risk difference (RD) with 95% CI will be calculated for each adverse effect, either compared to no treatment or to another agent.
If sufficient RCTs are identified, an attempt will be made to examine for publication bias using a funnel plot (Egger 1997).
