Interventions for Kidney Disease in HSP

8/11/2019 Interventions for Kidney Disease in HSP

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T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .6BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

14 ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . .21DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23 AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23 ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .24REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .44DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Prednisone compared with placebo/supportive treatment for prevention of persistent kidney disease, Outcome 1 Persistent kidney disease at any time after treatment. . . . . . . . . . . . . . 46

Analysis 1.2. Comparison 1 Prednisone compared with placebo/supportive treatment for prevention of persistent kidney disease, Outcome 2 Number of children with continuing kidney disease at different time points. . . . . . 47

Analysis 1.3. Comparison 1 Prednisone compared with placebo/supportive treatment for prevention of persistent kidney disease, Outcome 3 Continuing kidney disease at different time points (study with high risk of bias excluded). 48

Analysis 1.4. Comparison 1 Prednisone compared with placebo/supportive treatment for prevention of persistent kidney disease, Outcome 4 Number of children with kidney disease in rst month/with kidney disease at follow-up. . 50

Analysis 1.5. Comparison 1 Prednisone compared with placebo/supportive treatment for prevention of persistent kidney disease, Outcome 5 Number developing severe kidney disease. . . . . . . . . . . . . . . . . . 50

Analysis 1.6. Comparison 1 Prednisone compared with placebo/supportive treatment for prevention of persistent kidney disease, Outcome 6 Duration of kidney disease. . . . . . . . . . . . . . . . . . . . . . . 51

Analysis 1.7. Comparison 1 Prednisone compared with placebo/supportive treatment for prevention of persistent kidney disease, Outcome 7 Gastrointestinal complications requiring hospital admission. . . . . . . . . . . . 51

Analysis 2.1. Comparison 2 Antiplatelet agents (dipyridamole, cyproheptadine, salicylates) compared with supportivetherapy for prevention of persistent kidney disease, Outcome 1 Kidney disease at any time. . . . . . . . 52

Analysis 2.2. Comparison 2 Antiplatelet agents (dipyridamole, cyproheptadine, salicylates) compared with supportivetherapy for prevention of persistent kidney disease, Outcome 2 Kidney disease at any time. . . . . . . . 52

Analysis 3.1. Comparison 3 Heparin compared with placebo for prevention of persistent kidney disease, Outcome 1 Any kidney disease at 3 months after onset or relapse. . . . . . . . . . . . . . . . . . . . . . . 53

Analysis 3.2. Comparison 3 Heparin compared with placebo for prevention of persistent kidney disease, Outcome 2 Typeof kidney disease at 3 months or more after onset or relapse. . . . . . . . . . . . . . . . . . . 53

Analysis 3.3. Comparison 3 Heparin compared with placebo for prevention of persistent kidney disease, Outcome 3 Timeto development of kidney disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

Analysis 4.1. Comparison 4 Cyclophosphamide compared with supportive treatment for treatment of severe kidney disease,Outcome 1 Persistent kidney disease. . . . . . . . . . . . . . . . . . . . . . . . . . . 54

Analysis 4.2. Comparison 4 Cyclophosphamide compared with supportive treatment for treatment of severe kidney disease,Outcome 2 Persistent severe kidney disease. . . . . . . . . . . . . . . . . . . . . . . . 55

Analysis 4.3. Comparison 4 Cyclophosphamide compared with supportive treatment for treatment of severe kidney disease,Outcome 3 ESKD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

Analysis 5.1. Comparison 5 Cyclosporin compared with methylprednisolone for treatment of severe kidney disease,Outcome 1 Number without remission at 3 months. . . . . . . . . . . . . . . . . . . . . 56

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Analysis 5.2. Comparison 5 Cyclosporin compared with methylprednisolone for treatment of severe kidney disease,

Outcome 2 Number without remission at last follow-up. . . . . . . . . . . . . . . . . . . . 5656 APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .60 WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .60HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .60CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .61DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .61DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .61INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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[Intervention Review]

Interventions for preventing and treating kidney disease inHenoch-Schnlein Purpura (HSP)

Wattana Chartapisak 2 , Sauwalak Opastirakul2, Elisabeth M Hodson1 , Narelle S Willis3, Jonathan C Craig 4

1a) Centre for Kidney Research,The Childrens Hospital at Westmead, b) School of Public Health, The University of Sydney, Westmead, Australia. 2Department of Pediatrics, Chiang Mai University, Chiang Mai, Thailand. 3Cochrane Renal Group, Centre for Kidney Research, The Childrens Hospital at Westmead, Westmead, Australia. 4(a) Cochrane Renal Group, Centre for Kidney Research, TheChildrens Hospital at Westmead, (b) School of Public Health, The University of Sydney, Westmead, Australia

Contact address: Elisabeth M Hodson, a) Centre for Kidney Research, The Childrens Hospital at Westmead, b) School of PublicHealth, The University of Sydney, Locked Bag 4001, Westmead, NSW, 2145, Australia. [email protected].

Editorial group: Cochrane Renal Group.Publication status and date: Edited (no change to conclusions), published in Issue 4, 2010.Review content assessed as up-to-date: 26 November 2008.

Citation: Chartapisak W, Opastirakul S, Hodson EM, Willis NS, Craig JC. Interventions for preventing and treating kidney dis-ease in Henoch-Schnlein Purpura (HSP). Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD005128. DOI:10.1002/14651858.CD005128.pub2.

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

A B S T R A C T

Background

To determine the benets and harms of therapies used to prevent or treat kidney disease in Henoch-Schnlein Purpura (HSP).

Objectives

To evaluate the benets and harms of different agents (used singularly or in combination) compared with placebo or no treatment oranother agent for the prevention or treatment of kidney disease in patients with HSP.

Search strategy

Randomised controlledtrials (RCTs) andquasi-RCTs were identiedfrom the CochraneRenal Groups specialised register, the CochraneCentral Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE using optimally sensitive search strategies combined with search terms for HSP.

Selection criteria

RCTs comparing any intervention used to prevent or treat kidney disease in HSP compared with placebo, no treatment or other agents were included.

Data collection and analysis

Three authors independently assessed trial quality and extracted data from each study. Statistical analyses were performed using therandom effects model and the results were expressed as risk ratio (RR) for dichotomous outcomes and mean difference (MD) forcontinuous outcomes with 95% condence intervals (CI).

1Interventions for preventing and treating kidney disease in Henoch-Schnlein Purpura (HSP) (Review)Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
mailto:[email protected]:[email protected]


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Main results

Ten studies (1230 children) were identied. There was no signicant difference in the risk of persistent kidney disease at six months(3 studies, 379 children: RR 0.51, 95% CI 0.24 to 1.11) and 12 months (3 studies, 498 children: RR 1.02, 95% CI 0.40 to 2.62) inchildren given prednisone for 14 to 28 days at presentation of HSP compared with placebo or supportive treatment. In children withsevere kidney disease, there was no signicant difference in the risk of persistent kidney disease with cyclophosphamide compared withsupportive treatment (1 study, 56 children: RR 1.07, 95% CI 0.65 to 1.78) and with cyclosporin compared with methylprednisolone(1 study, 19 children: RR 0.39, 95% CI 0.14 to 1.06).

Authors conclusions

Data from RCTs for any intervention used in improve kidney outcomes in children with HSP are very sparse except for short-termprednisone. There was no evidence of benet of prednisone in preventing serious long-term kidney disease in HSP.

P L A I N L A N G U A G E S U M M A R Y

Interventions to prevent or treat serious kidney disease in patients with Henoch-Schnlein Purpura

Henoch-Schnlein Purpura (HSP) causes inammation of small blood vessels in children and affects approximately 20/100,000children annually. Symptoms and signs include a purpuric skin rash (which comprises small spots and larger bruises), abdominal pain,gastrointestinal bleeding, joint pain and swelling, facial swelling and evidence of kidney disease with blood and protein in the urine.Kidney disease occurs in about one third of children with HSP. In the majority this is mild (small amounts of blood in the urineonly) and resolves completely but a few children have persistent kidney disease that can progress to kidney failure. Treatments withmedications that suppress the immune system (prednisone) and treatments to prevent blood clotting (aspirin, heparin) have beenadministered to children at diagnosis to prevent serious kidney disease. Also treatmentswhich suppress the immune system(prednisone,methylprednisolone, cyclophosphamide and cyclosporin) have been used in an attempt to treat serious kidney disease in HSP andprevent progression to kidney failure.

This review identied ve studies (789 children) which compared prednisone tablets given for 14-28 days with placebo tablets orno specic treatment for the prevention of serious kidney disease at 6-12 months after onset of HSP. No signicant reduction in thefrequency of serious kidney disease was demonstrated. Two studies (138 children) showed no benet of aspirin and dipyridamole(antiplatelet agents) to prevent serious kidney disease. One study (228 children) suggested that heparin given by injection could reducethe risk for serious kidney disease but this treatment has the potential side effect of severe bleeding so its administration is not justied when only one third of children develop kidney disease and in most this is not serious and resolves completely.

In children with serious kidney disease, one study (56 children) showed that cyclophosphamide was no more effective than supportivetreatment in preventing kidney failure. A second study (19 children) found no difference in benet between cyclosporin and methyl-prednisolone/prednisone but numbers were too small to exclude a benet completely.

Most studies did not provide data on side effects of the treatments given.

There are few data from randomised studies examining interventions used to prevent or treat serious kidney disease in HSP except forshort-term prednisone to prevent kidney disease. There was no evidence of benet of prednisone compared with placebo or no specictherapy in preventing serious kidney disease in HSP.



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S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [ Explanation ]

Prednisone versus placebo/supportive treatment for preventing persistent kidney disease in Henoch-Schonlein Purpura (HSP)

Patient or population: patients with HSPSettings: secondary and tertiary paediatric and paediatric nephrology servicesIntervention: prednisone versus placebo/supportive treatment

Outcomes Illustrative comparative risks* (95% CI) Relative effect(95% CI)

No of Participants(studies)

Quality(GRAD

Assumed risk Corresponding risk

Control prednisoneversus placebo/support-ive treatment

Persistent kidney dis-ease at any time aftertreatment(follow-up: 6-12 months1)

Medium risk population RR 0.73(0.43 to 1.24)

789(5) modera

105 per 1000 77 per 1000(45 to 130)

Number of children withcontinuing kidney dis-ease at different timepoints - Three months(follow-up: 6-12 months)


636(4) modera

156 per 1000 128 per 1000(70 to 234)

Number of children withcontinuing kidney dis-ease at different timepoints - Six months(follow-up: 6-12 months)


379(3) modera

53 per 1000 27 per 1000(13 to 59)

3

I n t er v en t i on s f or pr e v en t i n g an d t r e a t i n gk i d n e y d i s e a s ei nH en o ch - S ch nl ei nP ur p ur a ( H S P ) ( R e vi e w )

C o p yr i gh t 2 0 1 0 Th e C o ch r an e C ol l a b or a t i on .P u b l i s h e d b y J oh n Wi l e y & S on s ,L t d .
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Number of children withcontinuing kidney dis-ease at different time

points - Twelve months(follow-up: 6-12 months)


498(3) modera

103 per 1000 105 per 1000(41 to 270)

Continuing kidney dis-ease at different timepoints, study with highrisk of bias excluded -Three months(follow-up: 6-12 months)


468(3) modera

207 per 1000 197 per 1000(137 to 282)

Continuing kidney dis-ease at different timepoints, study with high

risk of bias excluded -Twelve months(follow-up: 6-12 months)


330(2) modera

104 per 1000 133 per 1000(73 to 241)

Number developing se-vere kidney disease(follow-up: 6-12 months)


461(2) low4, 5

21 per 1000 40 per 1000(12 to 136)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio;

GRADE Working Group grades of evidanceHigh quality: Further research is very unlikely to change our confidence in the estimate of effect.Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change thLow quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to chaVery low quality: We are very uncertain about the estimate.

1 Islek 1999 did not specify duration of follow-up2 Mollica 1992 (with inadequate allocation concealment and no blinding) showed benefit of prednisone4




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3 Wide confidence intervals related to small numbers in studies4 Ronkainen 2006 did not provide definition of serious disease5 Small numbers of events

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B A C K G R O U N D

Henoch-Schnlein Purpura (HSP) is a primary small vessel vas-culitis. It is the most common systemic vasculitis in childrenthough adults may also be affected. The annual incidence of HSP in children varies between 13.5 and 20/100,000 (Gardner-Medwin2002;Steward1988). Theincidenceis highestin childrenaged four to six years (70.3/100,000 children) (Gardner-Medwin2002). This immunologically-mediated vasculitis involves vari-ous organ systems including skin, kidney, muscle, joints, gut andbrain. Clinical manifestations include purpuric skin lesions, ab-dominal pain, gastrointestinal bleeding, arthropathy and kidney disease (Saulsbury 1999). The international Consensus Confer-ence on Nomenclature of Systemic Vasculitides has characterisedthis syndrome as a vasculitis with IgA dominant immune de-

posits affecting small vessels and typically involving skin, gut, andglomeruli and associated with arthralgias and arthritis ( Jennette1994).

Glomerulonephritis (GN) is one of the major complications of HSP. Clinically, kidney involvement is manifested by microscopicor macroscopic haematuria, proteinuria, nephrotic syndrome andreduced kidney function. In a systematic reviewof studies (Narchi2005) of unselectedpatients,kidney involvement occurredin 34%of children;80% had isolatedhaematuriaand/orproteinuriawhile20% had acute nephritic syndrome or nephrotic syndrome. Kid-ney disease, if it did occur, developed early - by four weeks in85% and by six months in nearly all children. Persistent kidney

disease (hypertension, reduced function, nephrotic or nephriticsyndrome) occurred in 1.8% of children overall but the incidencevaried with the severity of the kidney disease at presentation. Itoccurred in 5% of children with isolated haematuria and/or pro-teinuria but in 20% who had acute nephritic syndrome and/ornephrotic syndrome in the acute phase. In one series of 100 con-secutive patients, kidney disease occurred in 40 children. Of these33 (83%) had microscopic haematuria alone and seven (17%)had macroscopic haematuria. Twenty ve (63%) patients also hadproteinuria and three (7.5%) had nephrotic syndrome (Saulsbury 1999).

In general, the prognosis for long-term kidney function in HSP isexcellent in children with microscopic or macroscopic haematuria alone. However patients with nephrotic syndrome and reducedkidney function frequently show a progressive course to end-stagekidney disease (ESKD). In a study of 78 children with HSP andkidney involvement presenting to two paediatric nephrology ser-vices, 44% of children presenting with acute nephritic syndromeand/or nephrotic syndrome compared with 13% presenting withhaematuria and/or proteinuria had hypertension or impaired kid-ney function at a mean follow-up of 23.4 years (Goldstein 1992).

Corticosteroid therapy is commonly used in the acute phase of HSP, particularly for abdominal pain. Controversy remains as to whether corticosteroids can prevent the development of kidney involvement and/or reduce its severity in HSP. One systematic re-

view concluded that early corticosteroid therapy may reduce the

risk of developing persistent kidney disease ( Weiss 2007). How-ever two other systematic reviews concluded that the benet of corticosteroids in preventing persistent kidney disease remainedunproven ( Wyatt 2001; Zaffanello 2007). Similarly there remainsconsiderable uncertainty about the efcacy of therapies to preventprogression to chronic or ESKD in children with HSP-associatedacute nephritis or nephrotic syndrome. Corticosteroid therapy,azathioprine, cyclophosphamide, cyclosporine, antiplatelet ther-apy, anticoagulants and plasmapheresis have been used in suchpatients (Bergstein 1998; Flynn 2001; Foster 2000; Iijima 1998;Niaudet 1998; Ronkainen 2003; Shenoy 2007). Although multi-ple treatment modalities has been used for treat GN in HSP, thereis no consensus on the efcacy of various therapies. The aims of this systematic review were to determine the benets and harmsof different interventions used to prevent or treat persistent kid-ney disease in HSP. The scope was deliberately broad because ran-domised controlled trials (RCTs) in HSP are few, and variability in the spectrum of kidney disease included in the relevant studies was very likely.

O B J E C T I V E S

To evaluate the benets and harms of different agents (used sin-gularly or in combination) compared with placebo, no treatmentor a single agent for:

The prevention of severe kidney disease in patients withHSP without kidney disease at presentation.

The prevention of severe kidney disease in patients withHSP and mild kidney disease (microscopic haematuria, mildproteinuria) at presentation.

The treatment of established severe kidney disease(macroscopic haematuria, proteinuria, nephritic syndrome,nephrotic syndrome with or without acute kidney failure) inHSP.

The prevention of recurrent episodes of HSP associatedkidney disease.

M E T H O D S

Criteria for considering studies for this review

Types of studies

All RCTs and quasi-RCTS (RCTs in which allocation to treat-ment wasobtained by alternation,useof alternatemedical records,date of birth or other predictable methods) looking at the benets



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Data extraction and management

Data extraction was carried out by three authors independently using standard data extraction forms. No studies reported in non-English language journals were identied. No duplicate publica-tions were identied. Further information from the original au-thor wasrequested bywritten correspondence to four authors from whom additional trial information wasobtained from two authors(Dudley 2007; Ronkainen 2006a ). Disagreements were resolvedby discussion.

Assessment of risk of bias in included studies

The following items will be assessed using the risk of bias assess-ment tool (Higgins 2008) (see Appendix 2).

Was there adequate sequence generation? Was allocation adequately concealed? Was knowledge of the allocated interventions adequately

prevented during the study? Were incomplete outcome data adequately addressed? Are reports of the study free of suggestion of selective

outcome reporting? Was the study apparently free of other problems that could

put it at a risk of bias?

Measures of treatment effect

For dichotomous outcomes (any kidney disease) results were ex-pressed as risk ratio (RR) with 95% CIs. For continuous out-comes (duration of haematuria or proteinuria), the mean differ-ence (MD) with 95% CIs was calculated. Data were pooled us-ing the random effects model but the xed effect model was alsoanalysed to ensure robustness of the model chosen. Adverse effects were inadequately reported so could not be tabulated.

Assessment of heterogeneity

Heterogeneity wasanalysed usinga chisquaredtest onN-1degreesof freedom, with an alpha of 0.05 used for statistical signicanceand with the I test (Higgins 2003). I values of 25%, 50% and75% correspond to low, medium and high levels of heterogeneity.

Assessment of reporting biasesInsufcient studies on any intervention were available to assessreporting bias using funnel plots.

Subgroup analysis and investigation of heterogeneity

We hypothesised that certain between-study differences in partic-ipants (severity of kidney disease, kidney pathology, age), inter-ventions (agent, dose and duration of treatment) and study qual-ity might explain any observed heterogeneity of treatment effects.Examination of these possible between-study differences by sub-group analysis was attempted but was limited by insufcient study data.

R E S U L T S

Description of studies

See:Characteristics of includedstudies;Characteristics of excludedstudies.Twelvestudies wereidentiedfrom the literaturesearch. Two stud-ies were excluded because neither could be conrmed to be RCTs( Jin 2003; Yu 2001). One study ( Yoshimoto 1987a ; Yoshimoto1987b) compared two different interventions with the control in-tervention and was treated as two studies, thus effectively data on 1230 children from 11 studies were included. Seven studies

were identied by full text review to be RCTs from 907 stud-ies obtained from the electronic search (Huber 2004; Islek 1999;Ronkainen 2006a ; Ronkainen 2006b; Tarshish 2004; Yanyan2001; Yoshimoto 1987a ; Yoshimoto 1987b). Two studies wereidentied from reference lists of review articles (Mollica 1992;Peratoner 1990). Thetenthstudy wasidentied from theNationalResearch Register, National Health Service, United Kingdom andfurther information on study methodology and results was ob-tained directly from the trialists and from a published abstract(Dudley 2007). Four studies were available in abstract form only (Islek 1999; Ronkainen 2006b; Yanyan 2001; Yoshimoto 1987a ; Yoshimoto 1987b). Allincludedstudies were publishedin English.Five studies (789 children) examined the effects of short-duration

corticosteroids (14 to 28 days) on preventing persistent HSP as-sociated kidney disease at 6 to 12 months after presentation incomparison with placebo (Dudley 2007; Huber 2004; Ronkainen2006a ) or supportive treatment (Islek1999; Mollica 1992). Threestudies included children with kidney disease at randomisation(Dudley 2007; Huber 2004; Ronkainen 2006a ). Childrenconsid-ered to have established HSP associated kidney disease (protein-uria exceeding 300 mg/L or haematuria exceeding 10 red cells/high power eld) were excluded from Ronkainen 2006a whileDudley 2007 and Huber 2004 included children with any degreeof kidney disease at randomisation. Islek 1999 and Mollica 1992only included children with no haematuria or proteinuria at pre-sentation.

Peratoner 1990, Yoshimoto 1987a and Yoshimoto 1987b (138children) evaluated antiplatelet agents (dipyridamole, cyprohep-tadine and salicylates) in comparison with supportive treatmentand Yanyan 2001 (228 children) compared heparin with placebo.Peratoner 1990providedoutcomedataseparately forchildrenwithand without kidney disease at presentation while the other studiesonly included children without kidney disease at randomisation.Two studies examined the treatment of severe HSP associatedkidney disease (nephrotic range proteinuria, International Study of Kidney Disease in Children grade III-IV changes on biopsy);Tarshish 2004(56 children) comparedcyclophosphamide with nospecic treatment and Ronkainen 2006b (19 children) comparedcyclosporin with methylprednisolone.



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Table 1. Denition of kidney disease used in outcome assessment (Continued)

Yoshimoto 1987b Unclear ND ND ND ND

Cr - creatinine; ESKD - end-stage kidney disease; GFR - glomerular ltration rate; HPF - high power eld; ND - not dened; P:Cr -protein/creatinine ratio; RBC - red blood cell

Among the eight studies evaluating interventions to prevent per-sistent HSP associated kidney disease, Dudley 2007 used urinary protein/creatinine ratio as the primary end point while in the re-maining studies the primary end point of kidney disease was de-ned by a composite of haematuria and proteinuria. In the twostudies evaluating interventions for severe HSP associated kidney disease, the primary end point was dened by composite of pro-teinuriaandreducedkidney function(Ronkainen 2006b; Tarshish2004).

Risk of bias in included studies

Figure 1 describes the graphical representation of the risk of biasassessment for all studies.

Figure 1. Methodological quality graph: review authors judgements about each methodological qualityitem presented as percentages across all included studies.

Allocation

Three studies (Dudley 2007; Huber 2004; Ronkainen 2006a ) re-porteda satisfactory sequence generation while themethodof ran-domisation was not reported in the remaining studies. Four stud-

ies(Dudley 2007; Huber 2004; Ronkainen2006a ; Tarshish 2004)reported adequate allocation concealment and one reported inad-equate allocation concealment (Mollica 1992). In the remaining studies allocation concealment was unclear.



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Blinding

Blinding of participants and investigators occurred in three stud-ies (Dudley 2007; Huber 2004; Ronkainen 2006a ). In one study participants in both treatment groups received intravenous medi-cations but it was not clear whether the investigators were blinded( Yanyan 2001). Blinding of outcome assessors was reported inthree studies (Dudley 2007; Huber 2004; Ronkainen 2006a ).Blinding was not reported in the remaining studies and the out-come measure of urinalysis reported by participants or investiga-tors is a subjective outcome measure and could be inuenced by lack of blinding.

Incomplete outcome data

Reported outcome data was consideredsatisfactory with a low risk of bias in three studies (Dudley 2007; Huber 2004; Ronkainen2006a ). In Mollica 1992, reporting of outcome data was consid-ered incomplete and likely to increase risk of bias. In the remain-ing studies insufcient information was provided to determine whether all patients entering the study were included in the anal-ysis so the risk of bias was unclear.

Selective reporting

Reporting appeared to include all important kidney outcomes insix studies (Dudley 2007; Huber 2004; Mollica 1992; Peratoner1990; Tarshish 2004; Yanyan 2001). In the remaining studies it was unclear whether important kidney outcomes (nephrotic syn-drome, reduced kidney function) had not occurred or had notbeen reported.

Other potential sources of bias

Three studies appeared free of other problems that could put itat risk of bias (Dudley 2007; Huber 2004; Ronkainen 2006a ). Inthe remaining studies there was insufcient information providedto determine if there were other potential sources of bias.

Effects of interventions

See:Summary of ndings for the main comparison Prednisonesummary of ndings; Summary of ndings 2 Antiplateletsummary of ndings; Summary of ndings 3 Heparin summary of ndings; Summary of ndings 4 Cyclophosphamide summary of ndings; Summary of ndings 5 Cyclosporin summary of ndings

Prevention of persistent kidney disease

Prednisone compared with placebo/supportive treatmentIn children newly diagnosed with HSP and without signicantkidney disease, there was no signicant difference in the risk of any kidney disease followingprednisone treatment compared withplacebo or supportive treatment ( Analysis 1.1(5 studies, 789 chil-dren): RR 0.73, 95% CI 0.43 to 1.24).Four (Dudley 2007; Huber 2004; Mollica 1992; Ronkainen2006a ) of the ve studies, which evaluated prednisone therapy,reported outcomes at different time points up to one year. Thefth study did not report the time at which the end point was as-sessed (Islek 1999). There was no signicant difference in the risk of development or persistence of kidney disease at one (RR 0.80,95% CI 0.34 to 1.88), three (RR 0.82, 95% CI 0.45 to 1.50),six (RR 0.51, 95% CI 0.24 to 1.11) and 12 months (RR 1.02,95% CI 0.40 to 2.62) with prednisone compared with placeboor no specic treatment ( Analysis 1.2; Figure 2). There was sub-stantial variability in study outcomes at all time points, except atsix months, which was largely due to one study (Mollica 1992).This study, which had inadequate allocation concealment and wastherefore at high risk of bias, showed a large benet of prednisonein contrast to the other three studies. Exclusion of this study elimi-nated the heterogeneity except at one month ( Analysis 1.3; Figure3).



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Figure 3. Forest plot of comparison: 1 Prevention of persistent kidney disease - prednisone compared with

placebo/supportive treatment, outcome: 1.3 Continuing kidney disease at different time points - study withhigh risk of bias excluded.

In Ronkainen 2006a post hoc subgroup analysis of 71 children with kidney disease at or within one month of randomisationfound that kidney disease was signicantly less common at six months after prednisone therapycomparedwith placebo ( Analysis

1.4.3: RR 0.45, 95% CI 0.21 to 0.98).Two studies (Dudley 2007; Ronkainen 2006a ) reported thenumber of children, who developed severe kidney disease withnephrotic range proteinuria, hypertension or reducedkidney func-tion. Again there was no signicant difference in the risk of se-vere kidney disease between children treated with prednisone orplacebo ( Analysis 1.5: RR 1.92, 95% CI 0.57 to 6.50).Islek 1999 assessed the duration of haematuria and proteinuria and found no signicant difference in the duration of haematuria (120 children; MD -1.00, 95% CI -10.26 to 8.26) or proteinuria (MD -1.60, 95% CI -15.62 to 12.42) ( Analysis 1.6). However

condence intervals were very wide.The risk of gastrointestinal involvement requiring hospital ad-mission was not signicantly different between prednisone and

placebo ( Analysis 1.7 (2 studies, 211 patients): RR 0.58, 95% CI0.24 to 1.42). In Huber 2004, two children in the placebo grouprequiredsurgery for intussusception andwerewithdrawnfrom thestudy. Based on patient diary records in Ronkainen 2006a , chil-drenon prednisone had a signicantly lowerpain severity score forabdominal or joint pain and had signicantly shorter durations of abdominal pain but not joint pain compared with placebo.No adverse effects of prednisone were reported in Huber 2004and Ronkainen 2006a . In Ronkainen 2006a , children receiving prednisone had a 1 kg greater increase in weight and 4 mm Hg increase in diastolic blood pressure during treatment. One child



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had behavioural problems and one had infection, which werecon-

sidered related to prednisone therapy in Dudley 2007 while onechild developed abdominal pain related to therapy in the placebogroup. Adverse effects were not reported in Islek 1999 or Mollica 1992.

Dipyridamole, cyproheptadine, salicylates versus supportivetreatment

In children treated with antiplatelet agents (dipyridamole with/ without cyproheptadine, salicylates) or no specic therapies, there was no signicantdifference in the risk of kidney disease occurring or persisting at any time during follow-up in children withoutkidney disease at entry ( Analysis 2.1.1 (2 studies, 101 children):

RR 1.16, 95% CI 0.46 to 2.95) or in children with kidney diseaseat entry ( Analysis 2.1.2 (1 study, 19 children; RR 0.92, 95% CI0.23 to 3.72).Ina singlesmallstudy, there wasno signicant difference in therisk of kidney disease with aspirin compared with no specic therapy ( Analysis 2.2 (1 study, 18 children): RR 0.14, 95% CI 0.01 to2.42). Duration of follow-up was not reported. Adverse effects were not reported in these studies.

Heparin compared with placebo

A single study found that kidney disease overall ( Analysis 3.1:RR 0.27, 95% CI 0.14 to 0.55), haematuria ( Analysis 3.2.1: RR

0.15, 95% CI 0.03 to 0.67) and proteinuria ( Analysis 3.2.2: RR 0.37, 95% CI 0.15 to 0.91) was signicantly less common inchildren treated with heparin compared with placebo injectionsat three months or more after the onset or relapse of HSP. Therisk for nephrotic syndrome did not differ signicantly betweengroups but eventnumbers were small resulting in wide condenceintervals ( Analysis 3.2.3: RR 0.31, 95% CI 0.03 to 2.89). Thedevelopment of kidney disease was signicantly delayed in theheparin treated group compared with placebo ( Analysis 3.3: MD47.3 days, 95% CI 34.24 to 60.36). No child developed severebleeding.

Treatment of severe kidney disease

Cyclophosphamide compared with supportive treatment

In a single study of 56 children (Tarshish 2004) with signicantHSP associated kidney disease (proteinuria, reduced kidney func-tion, crescents and/or segmental lesions on kidney biopsy) treated within three months of onset of HSP, there was no signicantdifference in the risk for persistent kidney disease of any severity ( Analysis 4.1: RR 1.07, 95% CI 0.65 to 1.78), severe kidney dis-ease (heavy proteinuria, reduced GFR, ESKD) ( Analysis 4.2: RR 0.88, 95% CI 0.37 to 2.09) or ESKD ( Analysis 4.3: RR 0.75,95% CI 0.18 to 3.05) during follow-up between patients treated with cyclophosphamide and those given supportive therapy. Ad-verse effects of cyclophosphamide were not reported.

Cyclosporin compared with methylprednisolone

In a single study (Ronkainen 2006b) involving children with se-vere kidney disease, all of 10 children treated with cyclosporincompared with 3/9 treated with methylprednisolone were in re-mission by three months but the difference was not signicant( Analysis 5.1: RR 0.08, 95% CI 0.01 to 1.31) due to small pa-tient numbers. At nal follow-up 7/10 children compared with 2/9 treated with methylprednisolone were in remission. The differ-

ence was not signicant ( Analysis 5.2: RR 0.39, 95% CI 0.14 to1.06). Adverse effects were not reported.

Other outcomes

In most studies the severity of haematuria and proteinuria, thedegree of kidney dysfunction and the presence of hypertension were not specied.Dudley 2007providedinformation on protein/creatinine ratios andTarshish 2004 provided separate informationon ESKD.



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A D D I T I O N A L S U M M A R Y O F F I N D I N G S [ Explanation ]

Antiplatelet agents (dipyridamole, cyproheptadine, salicylates) versus supportive therapy for preventing persistent kidney disease in He

Patient or population: patients with HSPSettings: secondary and tertiary paediatric and paediatric nephrology servicesIntervention: antiplatelet agents (dipyridamole, cyproheptadine, salicylates) versus supportive therapy



Quality(GRAD


Control antiplateletagents (dipyridamole,cyproheptadine, salicy-lates) versus supportivetherapy

Kidney disease at anytime - Dipyridamole +/ - cyproheptadine in chil-dren without kidney dis-ease at entry(follow-up: 12 months1)


101(2) low2, 3

210 per 1000 244 per 1000(97 to 620)

Kidney disease at anytime - Dipyridamole +/ - cyproheptadine in chil-dren with kidney diseaseat entry(follow-up: 12 months)


19(1) low2, 3

333 per 1000 306 per 1000(77 to 1239)

Kidney disease at anytime - Aspirin comparedwith supportive treat-ment


18(1) low2, 3

1 5


http://www.thecochranelibrary.com/view/0/SummaryFindings.htmlhttp://www.thecochranelibrary.com/view/0/SummaryFindings.html


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333 per 1000 47 per 1000(3 to 806)




1 Yoshimoto 1987 did not specify duration of follow-up2 Small studies with unclear allocation concealment and no blinding3

Wide confidence intervals

1 6




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Cyclophosphamide versus supportive treatment for treating severe kidney disease in Henoch-Schonlein Purpura (HSP)

Patient or population: patients with HSP

Settings: tertiary paediatric nephrology servicesIntervention: cyclophosphamide versus supportive treatment



Quality(GRAD


Control cyclophosphamide ver-sus supportive treat-ment

Persistent kidney dis-

ease(follow-up: mean 4-7years1)

Medium risk population RR 1.07

(0.65 to 1.78)

56

(1) modera300 per 1000 321 per 1000

(195 to 534)

Persistent severe kidneydisease(follow-up: mean 4-7years1)


56(1) modera

300 per 1000 264 per 1000(111 to 627)




1 Mean duration of follow-up varied according to end-point and ranged between 4 and 7 years1 8




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2 Unclear allocation concealment and duration of follow-up. No blinding.

xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx

1 9




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Cyclosporin versus methylprednisolone for treating severe kidney disease in Henoch-Schonlein Purpura (HSP)

Patient or population: patients with HSPSettings: tertiary paediatric nephrology serviceIntervention: cyclosporin versus methylprednisolone



Quality(GRAD


Control cyclosporin versusmethylprednisolone

Number without remis-sion at last follow-up(follow-up: mean 2.9years)


19(1) low1, 2

300 per 1000 117 per 1000(42 to 318)




1 Unclear allocation concealment and no blinding2 Small number of patients in study

2 0




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D I S C U S S I O N

Summary of main results

We identied 10 RCTs of which eight examined the efcacy of therapies to prevent persistent kidney disease in HSP and twoexamined therapies to treat established severe kidney disease.

Prevention of persistent kidney disease - prednisone

Fivestudies including threewell designedplacebo controlledRCTsexamined the use of prednisone to prevent persistent kidney dis-ease. Overall no signicant difference in the number of chil-dren with persistent kidney disease was identied among chil-dren treated for 14 to 28 days with prednisone at presentation

of HSP compared with placebo or no specic therapy. Basedon the absolute risk of kidney disease seen in the control groupof 105/1000 children, the corresponding risk of kidney diseasein prednisone treated patients did not differ signicantly at 77/1000 children (95% CI 45 to 130) Summary of ndings for themain comparison. Data at specied time points after presenta-tion (Figure 2) revealed no signicant difference in the number of children with persistent kidney disease at one, three, six and 12months. Sensitivity analysis, in which the study with a high risk of bias was excluded, removed heterogeneity between studies andtended to make the summary result less favourable towards cor-ticosteroids (Figure 3). Because of the wide condence intervalsresulting in imprecision of results and heterogeneity, the overall

quality of evidence (GRADE) was considered moderate.Only twostudies assessed theuse of prednisone inpatients with se-vere kidney disease and identied no evidence of benet. Becauseof small numbers of events resulting in wide condence intervalsand inadequate denition of severe disease, there remains uncer-tainty as to the efcacy of prednisone in preventing severe HSPassociated kidney disease and the quality of evidence (GRADE) was considered low.The lack of signicant differences between prednisone andplacebo/supportive therapy in the numbers with kidney diseaseat one, three and six months suggests that prednisone did not re-sult in more rapid resolution of kidney disease overall. HoweverRonkainen 2006a presented a post hoc analysis of 71 children,

who had kidney disease at or within one month of presentation.Prednisone therapy for 28 days signicantly reduced the numberof children with persistent kidney disease at sixmonths. The study was not stratied before randomisation for the presence or ab-sence of kidney disease and the sample size was small so the resultscan only be considered as hypothesis-generating. The study only provided outcome data to six months after randomisation so itis unclear whether prednisone treatment reduced the number of patients with persistent HSP associated kidney disease overall orpromoted more rapid resolution of kidney disease compared withplacebo. In addition, children considered to have established kid-ney disease at randomisation were not included in this study. Inthe other two well designed studies (Dudley 2007; Huber 2004)

of prednisone therapy, children with any severity of kidney disease

at presentation were potentially included and a meta-analysis of these studies showed no signicant difference in the risk for per-sistent HSP associated kidney disease at 12 months.Two studies found no signicant difference in the number of children with abdominal complications of HSP (Huber 2004;Ronkainen 2006a ). HoweverRonkainen 2006a ) reportedthat theseverity and duration of abdominal pain as well as the durationof joint pain were signicantly less severe in children treated withprednisone.

Prevention of persistent kidney disease -dipyridamole, cyproheptadine, salicylates and heparin

No signicant benet of antiplatelet agents was demonstrated intwo small studies suggesting that these agents have no role in pre-ventingkidney disease inHSP. The studies enrolled smallnumbersof patients with few events leading to imprecision of results. They demonstrated unclear allocation concealment and no blinding sothe quality of evidence (GRADE) was considered low (Summary of ndings 2). Yanyan 2001, availableinabstractonly, demonstrated thatheparinreduced the number of children with kidney disease. However nodetails on study methodology were available. Heparin or placebo were administered to children at onset of disease and at relapse andit was not possible to determine how many children in each groupreceived more than one period of treatment. Because of these un-

certainties of study design, the quality of evidence (GRADE) wasconsidered low (Summary of ndings 3). Though bleeding wasnot reported in this study, the use of such a potentially danger-ous therapy is not justied when only about a third of children with HSP develop kidney disease and less than 2% develop severekidney disease (nephrotic syndrome, nephritic syndrome, kidney failure) (Narchi 2005).

Treatment of severe kidney disease -cyclophosphamide and cyclosporin

Children with signicant proteinuria, macroscopic haematuria,nephrotic syndrome, reduced kidney function are more likely to

progress to ESKD so that treatment has been largely directed towards these children. However only two studies, which examinedthe treatment of severe established kidney disease in HSP, wereidentied. In children with HSP and nephrotic range proteinuria,Tarshish 2004 reported no signicant benet of cyclophospha-mide alone compared with no specic therapy. Because of defectsin study design (unclear allocation concealment, lack of blind-ing and unclear duration of follow-up), the quality of evidence(GRADE) was considered to be moderate (Summary of ndings4).Ronkainen 2006b suggested that cyclosporin may be more effec-tive than methylprednisolone and prednisone in inducing remis-sion in children with HSP and nephrotic range proteinuria, but



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numbers were too small to achieve statistical signicance. Because

of small patient numbers resulting in wide condence intervals,unclear allocation concealment and lack of blinding, the quality of the evidence (GRADE) was considered to be low (Summary of ndings 5).

Overall completeness and applicability of evidence

Corticosteroids are commonly administered for abdominal painin HSPbutopinions differ as to whether they are indicated to pre-vent the development of persistent kidney disease. We identiedve studies involving 789 children which examined the efcacy of short course prednisone in the prevention of persistent kidney disease. In meta-analysis of these studies, no signicant benetof prednisone was identied. However there remains considerableresidual imprecision in the results as indicated by wide condenceintervals. For example compared with the number with persistentkidney disease at one year in the control group (103/1000 chil-dren), the number treated with prednisone with persistent kid-ney disease was 105/1000 children (RR 1.02). However the widecondence intervals (41 to 270) indicate that prednisone couldreduce the number of children with kidney disease to 41/1000or increase it to 270/1000 children (Summary of ndings for themain comparison). In addition, the potential signicance for long term kidney function of residual urinary abnormalities could notbe assessed in 3/4 studies, which reported the end point as thepresence of haematuria and/or proteinuria without measuring thedegree of proteinuria by protein/creatinine ratio or 24 hour uri-nary protein excretion.Immunosuppressive agents are commonly used in an attempt totreat established severe kidney disease in HSP with observationalstudies suggesting benet of methylprednisolone (Niaudet 1993)azathioprine (Bergstein 1998), cyclophosphamide (Flynn 2001;Iijima 1998; Tanaka 2003) and cyclosporin (Ronkainen 2003).Two studies were identied which evaluated therapies for estab-lished severe kidney disease. No benet of cyclophosphamide wasidentied (Tarshish 2004). The studycomparing cyclosporin withmethylprednisolone was too small to establish whether or not cy-closporin was more effective (Ronkainen 2006b).No studies examining intravenous methylprednisolone alone orin combination with other medications or of azathioprine, my-cophenolate, immunoglobulin or plasma exchange were identi-ed. No studies examining sh oil, ACEi or ARB or dapsone wereidentied. No studies which included adults with HSP or whichspecically addressed whether therapy reduced the risk of recur-rent episodes of HSP were identied.

Quality of the evidence

Two of the ve included studies evaluating prednisone were at a

high risk of bias with unclear or inadequate allocation conceal-ment, no blinding andunclear duration of follow-up. Studies witha high risk of bias (inadequate or unclear allocation concealment,no blinding of participants, investigators or outcome assessors)are associated with an increased likelihood of results favouring thestudy intervention (Schulz 1995; Wood 2008). Exclusion of stud-ies with a high risk of bias removed heterogeneity between stud-ies without altering the overall result reinforcing the strength of the evidence suggesting that prednisone does not prevent seriouskidney disease in children with HSP. However the overall quality of evidence was considered moderate because of residual impreci-sion.Three studies assessed theefcacy of antiplatelet agents or heparinto prevent kidney disease. All studies were at a high risk of bias sothe quality of the evidence was low.Two studies assessed the efcacy of immunosuppressive agents(cyclophosphamide, cyclosporin) to treat serious kidney disease.Both studies were small and at risk of bias limiting theapplicability of the results to patient management.

Potential biases in the review process

We identied ten studies of which ve were available in abstractform only although some additional information was obtainedfrom study authors of two studies. Incomplete reporting of these

studies may result in incomplete information being included inthissystematicreview. Further publicationsof two studies (Dudley 2007; Ronkainen 2006b) could lead to additional informationavailable for this review or for changes to the information in thisreview. Since the protocol was published, the literature search hasbeen run several times up to November 2008 making it unlikely that any studies have been missed. However 40% of study reportsin the Cochrane Renal Groups specialised trials register have beenidentied by handsearching of conference proceedings so it re-mains possible that further studies of therapy to prevent or treatserious kidney disease in HSP will be identied as conference pro-ceedings from different congresses are searched.

Agreements and disagreements with other studies or reviews

Three systematic reviews have previously assessed the effects of corticosteroid therapy to prevent or alter the course of kidney dis-ease in HSP ( Weiss 2007; Wyatt 2001; Zaffanello 2007). All threeincluded data from RCTs and observational studies. Conclusionsbased on non-randomised study designs are more likely to be bi-ased towards a benet of treatment (Chalmers 1983). Two reviewsdetermined that it remained unclear whether corticosteroid ther-apy prevented or altered the course of HSP associated kidney dis-ease ( Wyatt 2001; Zaffanello 2007). The third review concluded



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that corticosteroids decreased the likelihood of developing per-

sistent kidney disease but did not prevent kidney disease ( Weiss2007). This conclusion was based on a meta-analysis of the adhoc subgroup of children with kidney abnormalities within onemonth of presentation from Ronkainen 2006a combined withdata from two other studies (Huber 2004; Mollica 1992). Theinclusion in this Cochrane review of the most recent large study (Dudley 2007) which showed no benet of corticosteroid therapy increases the evidence base from RCTs to support the conclusionthat corticosteroids do not appear to alter the course of kidney disease in HSP. Onereview alsoevaluated immunosuppressive andother therapies in HSP (Zaffanello 2007). It concluded based onobservational studies that cyclophosphamide was of value in treat-ing HSP associated kidney disease. The single study evaluatingcy-clophosphamide in the Cochrane review did not show any benetof cyclophosphamide (Tarshish 2004).

A U T H O R S C O N C L U S I O N S

Implications for practice

Prevention of kidney disease in HSP

No evidence of benet has been identied from RCTs forthe use of prednisone to prevent serious kidney disease inchildren with HSP. The quality of the evidence is moderatesuggesting that further research could have an important impacton our condence in the estimate of effect and could change theestimate of effect.

Small studies examining antiplatelet agents have notdemonstrated any benet in preventing serious kidney diseasebut the quality of evidence is low.

In a single study heparin reduced the risk for kidney diseasebut the quality of evidence is low and the use of such a potentially harmful treatment cannot be justied when only a third of children with HSP develop kidney disease and mostresolve spontaneously.

Treatment of serious kidney disease in HSP

No evidence of benet has been found for treatment withcyclophosphamide treatment in children with HSP and severekidney disease. The quality of evidence is moderate.

It remains unclear whether cyclosporin is more effectivethan methylprednisolone in children with HSP and severekidney disease and further studies with longer follow-up arerequired. The quality of the evidence is low.

Implications for research

Prevention of serious kidney disease

A further adequately powered RCT of short termprednisone therapy compared with placebo should be consideredin children, who have or develop kidney disease with HSP orhave risk factors for developing kidney disease including olderage (Shin 2006), severe abdominal pain (Ronkainen 2006a ; Shin2006), persistent (Ronkainen 2006a ; Shin 2006) or recurrentpurpura (Shin 2006) with clearly dened end points for kidney function (GFR), proteinuria (protein/creatinine ratios or timed

urine collections), microscopic and macroscopic haematuria andhypertension. However recruitment to a placebo controlled RCTmay be difcult since Ronkainen 2006a has demonstrated thatshort-course prednisone signicantly reduces the severity andduration of abdominal pain in children with HSP making itunlikely that clinicians will be prepared to withhold prednisonefrom children with severe HSP-associated abdominal pain.

Treatment of serious kidney disease in HSP

Adequately powered well designed RCTs with at least veyear follow-up periods are particularly needed in children withHSP-associated nephritic syndrome and/or nephrotic syndrome.

A multicentre RCT comparing, for example, a six monthcourse of corticosteroids with short duration corticosteroids (28days) in children with moderately severe kidney disease (acutenephritic syndrome or nephrotic syndrome with normal kidney function, mesangial proliferative GN and < 50% crescents orsclerosing lesions on biopsy) should be considered.

Based on the data from Ronkainen 2006b comparing cyclosporin and methylprednisolone, a multicentre RCT shouldbe set up to compare cyclosporin (with or without prednisone) with methylprednisolone/prednisone in treating children withHSP and severe kidney disease (50% or more crescents orsclerosing lesions on biopsy with or without reduced kidney function). Clinicians are likely to be reluctant to enter children with HSP and crescentic GN involving more than 50% of glomeruli into RCTs with a placebo arm even though currently no therapy has been shown to be effective in an RCT in suchchildren.

A C K N O W L E D G E M E N T S

We thank Dr Dudley, Dr Smith and Dr Tizard foradditional information on their RCT. We thank Dr Ronkainenand Dr Nuutinen for additional information on their RCTs.



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We would like to thank Drs Michael Dillon, Matti

Nuutinen and Lesley Rees for their editorial advice during thepreparation of this review

This work has been presented in part at the 42nd AnnualScientic Meeting of the Australian and New Zealand Society of Nephrology (Melbourne 2006).

R E F E R E N C E S

References to studies included in this review

Dudley 2007 {published and unpublished data}

Dudley J, Smith G, Llewellyn-Edwards A, Tizard EJ. Randomisedplacebo controlled trial to assess the role of early prednisolone onthe development and progression of Henoch-Schonlein Purpura Nephritis [abstract]. Pediatric Nephrology 2007;22:1457.Smith G. Randomised, double-blind, placebo controlled study todetermine whether steroids reduce the development of nephropathy in Henoch-Schonlein purpura. National Research Register, UK [https://portal.nihr.ac.uk/Proles/NRR.aspx?PublicationID=M0048086115] 2002. [CENTRAL: CN00449954]

Huber 2004 {published data only}Huber AM, King J, McLaine P, Klassen T, Pothos M. A

randomized, placebo-controlled trial of prednisolone in early Henoch Schonlein purpura [ISRCTN85109383]. BMC Medicine2004; Vol. 2, issue 7. [DOI: 10.1186/1741-7015-2-7]

Islek 1999 {published data only}Islek I, Sezer T, Totan M, Cakir M, Kucukoduk S. The effect of

prolactic prednisolon therapy on renal involvement in henochschoenlein vasculitis. XXXVI Congress of the European Renal Association European Dialysis & Transplant Association; 1999 Sep5-8; Madrid (Spain). 1999:103. [CENTRAL: CN00484464]

Mollica 1992 {published data only}Mollica F, Li VS, Garozzo R, Russo G. Effectiveness of early

prednisone treatment in preventing the development of nephropathy in anaphylactoid purpura. European Journal of Pediatrics 1992;151(2):1404. [MEDLINE: 1343079]

Peratoner 1990 {published data only}Peratoner L, Longo F, Lepore L, Freschi P. Prophylaxis and

therapy of glomerulonephritis in the course of anaphylactoidpurpura. The results of a polycentric clinical trial. Acta Paediatrica Scandinavica 1990;79(10):9767. [MEDLINE: 2264475]

Ronkainen 2006a {published and unpublished data}Ronkainen J, Koskimies O, Ala-Houhala M, Antkainen M,

Merenmies J, Rajantie J, et al.Early prednisone therapy in Henoch-Schonlein purpura: a randomized double-blind, placebo-controlledtrial. Journal of Pediatrics 2006;149(2):2417. [MEDLINE:16887443]

Ronkainen 2006b {published and unpublished data}Ronkainen J, Ala-Houhala M, Antkainen M, Jahnukainen T,

Koskimies O, Merenmies J, et al.Cyclosporine A (CyA) versus MPpulses (MP) in the treatment of severe Henoch-Schonlein Nephritis(HSN) [abstract]. Pediatric Nephrology 2006;21(10):1531.

Tarshish 2004 {published data only}Tarshish P, Bernstein J, Edelmann CM Jr. Henoch-Schonlein

purpura nephritis: course of disease and efcacy of

cyclophosphamide. Pediatric Nephrology 2004;19(1):516.[MEDLINE: 14634864] Yanyan 2001 {published data only}

Yanyan H, Hongmei S, Lihua S, Min W. Preventive value of heparin on the occurrence of nephropathy in Henoch-SchoenleinPurpura: a randomized controlled clinical trial [abstract]. 23rdInternational Congress of Paediatrics; 2001 Sep 9-14; Beijing (China). 2001. [CENTRAL: CN00462028]

Yoshimoto 1987a {published data only} Yoshimoto M, Ito H, Shindo S, Yamashita F. Evaluation of the

preventive role of dipyridamoleant aspirin against renalcomplication in Schonlein-Henoch purpura [abstract]. Pediatric Nephrology 1987;1(1):C47. [CENTRAL: CN00445875]

Yoshimoto 1987b {published data only} Yoshimoto M, Ito H, Shindo S, Yamashita F. Evaluation of the

preventive role of dipyridamole and aspirin against renalcomplication in Schonlein-Henoch purpura [abstract]. Pediatric Nephrology 1987;1:C47. [CENTRAL: CN00445875]

References to studies excluded from this review

Jin 2003 {published data only} Jin ZD, Wang SC, Sun YQ, et al.Effect of Danshao granule onserum superoxide dismutase activity and malonyldialdehydecontent in children with Henoch-Schonlein purpura nephritis. Zhongguo Zhongxiyi Jiehe Zqzhi [Chinese Journal of Integrated Traditional & Western Medicine] 2003;23(12):9057.

Yu 2001 {published data only}

Yu YH. Treatment of purpuric nephritis in children withTripterygium Wilfordii Polyglucoside and Radix SalviaeMiltiorrhizae [abstract]. Pediatric Nephrology 2001;16:C78.

Additional references

Bergstein 1998Bergstein J, Leiser J, Andreoli SP. Response of crescentic Henoch-Schoenlein purpura nephritis to corticosteroid and azathioprinetherapy. Clinical Nephrology 1998;49(1):914. [MEDLINE:9491279]

Chalmers 1983Chalmers TC, Celano P, Sacks HS, Smith H. Bias in treatmentassignment in controlled clinical trials. New England Journal of Medicine 1983;309(22):135861. [MEDLINE: 6633598]



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Flynn 2001

Flynn JT, Smoyer WE, Bunchman TE, Kershaw DB, Sedman AB.Treatment of Henoch-Schonlein Purpura glomerulonephritis inchildren with high-dose corticosteroids plus oralcyclophosphamide. American Journal of Nephrology 2001;18(4):34750. [MEDLINE: 11359020]

Foster 2000Foster BJ, Bernard C, Drummond KN, Sharma AK. Effectivetherapy for severe Henoch-Schonlein purpura nephritis withprednisone and azathioprine: a clinical and histopathologic study. Journal of Pediatrics 2000;136(3):3705. [MEDLINE: 10700695]

Gardner-Medwin 2002Garner-Medwin JM, Dolezalova P, Cummins C, Southwood TR.Incidence of Henoch-Schonlein purpura, Kawasaki disease, andrare vasculitides in children of different ethnic origins. Lancet 2002;360(9341):1197202. [MEDLINE: 12401245]

Goldstein 1992Goldstein AR, White RHW, Akuse R, Chantler C. Long termfollow up of childhood Henoch Schonlein nephritis. Lancet 1992;339(8788):2802. [MEDLINE: 1346291]

Higgins 2003Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327(7414):55760.[MEDLINE: 12958120]

Higgins 2008Higgins JPT, Green S (editors). Cochrane Handbook forSystematic Reviews of Interventions Version 5.0.0 [updatedFebruary 2008]. The Cochrane Collaboration, 2008. Available

from www.cochrane-handbook.org.Iijima 1998

Iijima R, Ito-Kariya S, Nakamura H, Yoshikowa N. Multiplecombined therapy for severe Henoch Schonlein nephritis inchildren. Pediatric Nephrology 1998;12(3):2448. [MEDLINE:9630047]

Jennette 1994 Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross W, etal.Nomenclature of systemic vasculitides. Proposal of aninternational consensus conference. Arthritis & Rheumatism 1994;37(2):18792. [MEDLINE: 8129773]

Lefebvre 2008Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching forstudies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.0 (updatedFebruary 2008). The Cochrane Collaboration, 2008. Availablefrom www.cochrane-handbook.org.

Narchi 2005Narchi H. Risk of long term renal impairment and duration of follow up recommended for Henoch-Schonlein purpura withnormal or minimal urinary ndings: a systematic review. Archives of Disease in Childhood 2005;90(9):91620. [MEDLINE: 15871983]

Niaudet 1993Niaudet P, Murcia I, Beauls H, Broyer M, Habib R. Primary IgA nephropathies in children: prognosis and treatment. Advances inNephrology From the Necker Hospital 1993;2:12140. [MEDLINE:8427055]

Niaudet 1998

Niaudet P, Habib R. Methylprednisolone pulse therapy in thetreatment of severe forms of Schonlein-Henoch purpura nephritis.Pediatric Nephrology 1998;12(3):23843. [MEDLINE: 9630046]

Renal Group 2009 Willis NS, Mitchell R, Higgins GY, Webster AC, Craig JC.Cochrane Renal Group. About The Cochrane Collaboration(Cochrane Review Groups (CRGs)) 2009, Issue 1. Art. No.:RENAL (accessed March 2009).

Ronkainen 2003Ronkainen J, Ala- Houhala M, Huttunen NP, Jahnukainen T,Koskimies O, Ormala T, et al.Outcome of Henoch-Schoenleinnephritis with nephrotic-range proteinuria. Clinical Nephrology 2003;60(2):804. [MEDLINE: 12940608]

Saulsbury 1999Saulsbury FT. Henoch-Schonlein Purpura in children. Report of 100 patients and review of the literature. Medicine 1999;78(6):395409. [MEDLINE: 10575422]

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Shenoy 2007Shenoy M, Ognjanovic MV, Coulthard MG. Treating severeHenoch-Schonlein and IgA nephritis with plasmapheresis alone.Pediatric Nephrology 2007;22(8):116771. [MEDLINE:

17530298]Shin 2006

Shin JI, Park JM, Shin YH, Hwang DH, Kim JH, Lee JS.Predictive factors for nephritis, relapse, and signicant proteinuria in childhood Henoch-Schonlein purpura. Scandinavian Journal of Rheumatology 2006;35(1):5660. [MEDLINE: 16467044]

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References to other published versions of this review

Chartapisak 2005

Chartapisak W, Opastirakul S, Hodson EM, Willis NS, Craig JC.Interventions for preventing and treating renal disease in Henoch-Schnlein Purpura (HSP). Cochrane Database of Systematic Reviews 2005, Issue 1. [DOI: 10.1002/14651858.CD005128]

Chartapisak 2008Chartapisak W, Opastirakul O, Willis NS, Craig JC, Hodson EM.Prevention and treatment of renal disease in Henoch-SchnleinPurpura: a systematic review. Archives of Disease in Childhood 2008;94(2):1327. [MEDLINE: 18701559]

Indicates the major publication for the study



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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Dudley 2007

Methods Country : UK Setting/Design : 25 Paediatric departments in secondary/tertiary hospital/parallel groupdesignTime frame: Jan 2001 to Jan 2005Follow-up period : One yearLoss to follow-up: 16 from treatment arm, 6 from placebo arm

Participants Inclusion criteria Children < 18 years enrolled/randomised within 7 days of onset of HSP rash HSP dened as: palpable purpura with arthritis, kidney disease, gut involvement Kidney disease dened as: P:Cr > 20 mg/mmol; positive dipstick for blood or

protein Patients with haematuria and/or proteinuria at study entry were included; 50/140

had proteinuria in treatment group and 43/140 had proteinuria in placebo group.Treatment group

Number : 181 entered; 145 analysed (16 lost to follow-up, 20 no specimen at 12months)

Age: 6.34 (median); range 1 to 15.7 years Sex (M/F): 93/88

Control group Number : 172; 145 analysed (6 lost to follow-up, 21 no specimen at 12 months) Age: 6.12 (median); range 0.5 to 13.9 years Sex (M/F): 100/72

Exclusion criteria Already on steroids or immunosuppressives, pre-existing kidney disease,

hypertension, immunodeciency, systemic infection, contraindications to steroids.

Interventions Treatment group Prednisolone 2 mg/kg/d orally for 7 days (max dose 80 mg); 1mg/kg/d for 7 days

Control group Placebo given in same regimen

Co-interventions Additional treatment for gut or kidney disease as steroids (4 prednisolone; 9 placebo); ACEi or ARBs (2 prednisolone; 3 placebo); other antihypertensives (3 prednisolone; 0placebo)

Outcomes P:Cr > 20 mg/mmol at 12 months Haematuria/proteinuria on dipstick at 4 and 12 weeks Gastrointestinal involvement, joint involvement, rash at 4 and 12 weeks BP at 4 weeks, 12 weeks and 12 months Need for additional therapy Adverse effects



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Dudley 2007 (Continued)

Notes Exclusions post randomisation but pre-intervention 10 in treatment group; 15 in placebo discontinued treatment but included

in nal analysis. 20 in treatment group and 21 in placebo group did not have end of study

urine P:Cr measurement so nal analysis involved 290/353 children (82%) 20 in treatment group and 21 in placebo group did not have end of study

urine P:Cr measurement so nal analysis involved 290/353 children (82%) Stop or end point/s : None Additional data requested from authors : Draft manuscript provided by authors

Risk of bias

Item Authors judgement Description

Adequate sequence generation? Yes Computer generated random number se-quence

Allocation concealment? Yes Plain sealed envelopes opened by researchpharmacist

Blinding? All outcomes

Yes Trial medications (active and placebo) sup-plied by same company. Identical bot-tles for active and placebo medicationscoded centrally with trial numbers. Pa-tients, parents, paediatricians, investigators were blinded to assignment.

Incomplete outcome data addressed? All outcomes

Yes Lost to follow-up: 16 in prednisone groupand 6 in placebo groupDiscontinuedtreatment butanalysedinap-propriate treatment groups: 10 in pred-nisone group and 15 in placebo groupTwelve month missing data for P:Cr in 20patients in prednisolone group and 21 pa-tients in placebo group. These patients ex-cluded from analysis.

Free of selective reporting? Yes Primary outcome pre-specied as P:Cr inNationalResearch Register of NHSin UK.Informationalsoprovided ondipstickanal-ysis of haematuria and proteinuria. Meansystolic and diastolic BP levels only pro-vided and no information providedon kid-ney function but these were not speciedas outcomes.

Free of other bias? Yes Appears to be free of other biases



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Huber 2004Methods Country : Canada

Setting/Design : Emergency department in tertiary hospital/parallel group designTime frame: Sep 1996 to Jan 2000Follow-up period : One yearLoss to follow-up: Three were withdrawn from placebo arm due to complications(intussusception 2, severe rash 1)

Participants Inclusion criteria Children 2 to 15 years within 7 days of onset of HSP HSP dened as: palpable purpura and 1 or more of arthritis, kidney disease or gut

involvement

Kidney disease dened as: haematuria 5 or more RBC/HPF or RBC casts,proteinuria 0.3g/L or more, hypertension 90th percentile for age/sex or above. Study included 4 children in prednisone group and 2 in placebo group with

kidney disease at study entry.Treatment group

Number : 21 Age: 5 (2 to 11) years Sex (M/F): 13/8

Control group Number : 19 Age: 6.1(3 to 15) years Sex (M/F): 7/12

Exclusion criteria

Known underlying systemic vasculitis, steroids in previous month, underlying kidney, gastrointestinal or immunodeciency illness, active infection, a life threatening complication of HSP.

Interventions Treatment group Prednisolone 2 mg/kg orally daily for 7 days; reducing dose over 7 days

Control group Placebo given in same regimen

Co-interventions : NS

Outcomes New or persistent kidney disease at one year Gastrointestinal involvement

Notes Exclusions post randomisation but pre-intervention : None Stop or end point/s : None Additional data requested from authors : None

Risk of bias


Adequate sequence generation? Yes Computer generated sequence of randomnumbers.



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Huber 2004 (Continued)

Allocation concealment? Yes Plain sealed numbered envelopes openedat subject randomisation by research phar-macist. Individuals directly involved in thestudy had no access to these envelopes.


Yes Prednisone and placebo groups receivedidentical number of pills and followed thesame schedule.Prednisone and placebo tablets placed inopaque tasteless gelatin capsules.


Yes One subject enrolled declined randomisa-tion.Three children withdrawn from theplacebo group but included in the analysis.

Free of selective reporting? Yes Reported that children with persistent kid-ney disease had haematuria and/or protein-uria and did not have hypertension or kid-ney insufciency.

Free of other bias? Yes The study appears to be free of othersources of bias

Islek 1999

Methods Country : Turkey Setting/Design : University paediatric clinic/parallel group designTime frame: Sep 1996 to Jan 2000Duration of follow-up : Unclear

Participants Inclusion criteria Children aged 9.2 2.7 years with HSP without haematuria/proteinuria on

admission. Sex (M/F): 69/48

Dened as non-thrombocytopenic purpura, arthritis and arthralgia, abdominalpain, gastrointestinal haemorrhage.Treatment group

Number : 70 Age: NS Sex (M/F): NS

Control group Number : 50 Age: NS Sex (M/F): NS

Exclusion criteria Kidney disease



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Islek 1999 (Continued)

Interventions Treatment group Prednisolone 1mg/kg/d for 10 days; tapered over 1 week and withdrawn

Control group No treatment

Co-interventions : NS

Outcomes Haematuria and/or proteinuria: No denitions provided

Notes Exclusions post randomisation but pre-intervention : NS Stop or end point/s : NS

Additional data requested from authors : None

Risk of bias


Adequate sequence generation? Unclear No information provided

Allocation concealment? Unclear No information provided


No No placebo tablets administered in the con-trol group. No information provided on whether outcome assessors were blinded.


Unclear Unclear whether all eligible patients en-tered and completed the trial and whethertherewasanymissing data. Allreportedpa-tients appeared to have completed study.

Free of selective reporting? Unclear Only outcomes reported were haematuria and proteinuria. No reports separately of more severe kidney disease (acute nephriticsyndrome, nephrotic syndrome, hyperten-sion).

Free of other bias? Unclear Insufcient information available to deter-mine



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Mollica 1992 (Continued)


No Control group did not receive placebomedications. No information provided on whether outcome assessors were blinded.


No 19 patients excluded because of insufcientor inadequate follow-up.

Free of selective reporting? Yes Information on the numbers with pro-teinuria, haematuria, hypertension and re-duced kidney f

Interventions for Kidney Disease in HSP

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