Scolaris Content Display Scolaris Content Display

Intervenciones para la prevención y el tratamiento de las afecciones renales en la vasculitis por IgA

Contraer todo Desplegar todo

Antecedentes

La vasculitis por IgA (VIgA), antes conocida como la púrpura de Schönlein‐Henoch, es la vasculitis más frecuente de la infancia, aunque puede darse también en adultos. Esta vasculitis de vasos pequeños se caracteriza por púrpura palpable, dolor abdominal, artritis o artralgia y afectación renal. Esta es una actualización de una revisión publicada por primera vez en 2009 y actualizada en 2015.

Objetivos

Evaluar los efectos beneficiosos y perjudiciales de diferentes agentes (utilizados solos o combinados) en comparación con placebo, ningún tratamiento o cualquier otro producto para (1) la prevención de la enfermedad renal grave en personas con VIgA con o sin afectación renal al inicio, (2) el tratamiento de la enfermedad renal grave establecida (hematuria macroscópica, proteinuria, síndrome nefrítico, síndrome nefrótico con o sin insuficiencia renal aguda) en la VIgA, y (3) la prevención de episodios recurrentes de enfermedad renal asociada a VIgA.

Métodos de búsqueda

Se realizaron búsquedas en el registro de estudios del Grupo Cochrane de Riñón y trasplante (Cochrane Kidney and Transplant) hasta el 2 de febrero de 2023, mediante el contacto con el documentalista y el uso de términos de búsqueda relevantes para esta revisión. Los estudios en el registro se identifican mediante búsquedas en CENTRAL, MEDLINE y EMBASE, en resúmenes de congresos, en el portal de búsqueda de la Plataforma de registros internacionales de ensayos clínicos (ICTRP) y en ClinicalTrials.gov.

Criterios de selección

Se incluyeron los ensayos controlados aleatorizados (ECA) que compararon las intervenciones para prevenir o tratar las afecciones renales en la VIgA con placebo, ningún tratamiento u otros agentes.

Obtención y análisis de los datos

Dos autores de la revisión determinaron de forma independiente la elegibilidad de los estudios, evaluaron el riesgo de sesgo y extrajeron los datos de cada estudio. Los análisis estadísticos se realizaron con un modelo de efectos aleatorios, y los resultados se expresaron como razones de riesgos (RR) para los desenlaces dicotómicos y diferencia de medias (DM) para los desenlaces continuos, con intervalos de confianza (IC) del 95%. La confianza en la evidencia se evaluó mediante el método GRADE (Grading of Recommendations Assessment, Development and Evaluation).

Resultados principales

Se identificaron 20 estudios (1963 participantes inscritos); un estudio de tres grupos se evaluó como dos estudios. Nueve estudios se consideraron con bajo riesgo de sesgo para la generación de la secuencia y (sesgo de selección) y nueve estudios se consideraron con bajo riesgo de sesgo para la ocultación de la asignación (sesgo de selección). El cegamiento de los participantes y del personal (sesgo de realización) y la evaluación de los desenlaces (sesgo de detección) tuvieron un riesgo bajo de sesgo en cuatro y siete estudios, respectivamente. Nueve estudios proporcionaron los datos completos de los desenlaces (sesgo de desgaste), mientras que 10 estudios proporcionaron los desenlaces esperados, por lo que tuvieron bajo riesgo de sesgo de notificación. Cinco estudios tuvieron riesgo bajo de otros sesgos.

Once estudios evaluaron el tratamiento para prevenir la enfermedad renal persistente en la VIgA con o sin afectación renal en el momento de la visita. Es probable que no hubiera diferencias significativas en el riesgo de afecciones renales persistentes en ningún momento después del tratamiento (cinco estudios, 746 niños: RR 0,74; IC del 95%: 0,42 a 1,32), ni al mes, a los 3, 6 y 12 meses en niños que recibieron prednisona durante 14 a 28 días en el momento de la aparición de la VIgA en comparación con placebo o tratamiento complementario (evidencia de certeza moderada). Podría no haber diferencias en el riesgo de cualquier enfermedad renal persistente con el tratamiento antiagregante plaquetario (tres estudios) o la heparina (dos estudios) en niños con o sin cualquier enfermedad renal al inicio del estudio, aunque la heparina podría reducir el riesgo de proteinuria en tres meses en comparación con el placebo o ningún tratamiento específico (dos estudios, 317 niños: RR 0,47; IC del 95%: 0,31 a 0,73). Un estudio que comparó montelukast con placebo no encontró diferencias en los desenlaces evaluados por las puntuaciones de la escala de gravedad.

Nueve estudios examinaron el tratamiento de las enfermedades renales graves asociadas con la VIgA. En dos estudios (uno con 56 niños y otro con 54 adultos), es posible que no haya diferencias en los desenlaces de eficacia ni en los efectos adversos con la ciclofosfamida en comparación con el placebo o el tratamiento complementario. En dos estudios, es posible que no haya diferencias en el número de niños que logran la remisión de la proteinuria con ciclofosfamida intravenosa (i.v.) en comparación con micofenolato mofetilo (MMF) (65 niños evaluados) o tacrólimus (142 niños evaluados). En tres estudios pequeños que compararon ciclosporina con metilprednisolona (15 niños), MMF con azatioprina (26 niños) o MMF con leflunomida (19 niños), no está claro si el tratamiento tuvo algún efecto sobre el número de remisiones o el grado de proteinuria entre los grupos de tratamiento debido al pequeño número de participantes incluidos. En un estudio en el que se comparó la plasmaféresis, la ciclofosfamida y la metilprednisolona con la ciclofosfamida y la metilprednisolona, podría no haber diferencias en el número de pacientes que alcanzaron la remisión. Un estudio comparó el fosinopril con ningún tratamiento específico e informó que el fosinopril redujo el número de participantes con proteinuria. No se identificaron estudios que evaluaran la eficacia del tratamiento en las afecciones renales de los participantes con episodios recurrentes de VIgA.

Conclusiones de los autores

No hay cambios sustanciales en las conclusiones de esta actualización en comparación con la revisión inicial ni con la anterior actualización a pesar de que se han añadido cinco estudios. A partir de evidencia generalmente de certeza baja a moderada, se observó que podría haber poco o ningún efecto beneficioso del uso de corticosteroides o antiagregantes plaquetarios para prevenir la enfermedad renal persistente en niños con VIgA, en participantes sin afectación renal o con afectación renal mínima en el momento de la consulta. No se encontró ningún estudio que evaluara los corticosteroides en niños que presentaban VIgA y síndrome nefrítico o nefrótico, aunque las guías recomiendan los corticosteroides en esta población. Aunque la heparina podría ser eficaz para reducir la proteinuria, este tratamiento potencialmente peligroso no está justificado para prevenir afecciones renales graves cuando unos pocos niños con VIga desarrollan enfermedad renal grave. Es posible que la ciclofosfamida no aporte ningún beneficio en comparación con ningún tratamiento específico o con los corticosteroides. Aunque podría no haber beneficio en la eficacia del MMF o el tacrólimus en comparación con la ciclofosfamida i.v. en niños o adultos con VIgA y enfermedad renal grave, los efectos adversos, en concreto las infecciones, podrían ser menores en los niños tratados con MMF o tacrólimus. Debido a que la baja cifra de pacientes y eventos producen imprecisiones en los resultados, aún no se sabe si la ciclosporina, el MMF o la leflunomida tienen alguna función en el tratamiento de niños con VIgA y enfermedad renal grave. No se identificó ningún estudio que evaluara los corticosteroides.

PICO

Population
Intervention
Comparison
Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Intervenciones para la prevención y el tratamiento de las afecciones renales en la vasculitis por IgA (púrpura de Schönlein‐Henoch)

¿Cuál es el problema?

La vasculitis por IgA (VIgA), antes conocida como púrpura de Schönlein‐Henoch, provoca la inflamación de pequeños vasos sanguíneos en niños y, rara vez, en adultos. Los síntomas y signos incluyen erupción cutánea de pequeñas manchas rojas y hematomas más grandes, sobre todo en las nalgas y las piernas, dolor de barriga, dolor e hinchazón de las articulaciones y, ocasionalmente, hemorragias intestinales. Alrededor de un tercio de los niños presentan afectación renal, con presencia de sangre y proteínas en la orina en los análisis. En la mayoría de los casos, la afectación renal es leve (solo pequeñas cantidades de sangre y proteína en la orina) y se resuelve por completo, aunque unos pocos niños presentan enfermedad renal persistente que podría progresar a insuficiencia renal.

¿Qué se hizo?

Se analizó la información de 20 ensayos controlados aleatorizados (ECA), que incluyeron a 1963 participantes. Once estudios incluyeron niños con VIgA con afectación renal leve o nula. Cinco estudios compararon comprimidos de prednisona administrados durante 14 a 28 días con comprimidos de placebo o ningún tratamiento, cinco estudios compararon medicamentos que reducen la coagulación de la sangre y un estudio comparó montelukast (un medicamento utilizado habitualmente en niños con asma) con un placebo. Nueve estudios incluyeron niños con afectación renal moderada o grave. Cinco estudios compararon diferentes medicamentos que deprimen el sistema inmunitario (ciclofosfamida, micofenolato mofetilo, tacrólimus, ciclosporina, leflunomida, azatioprina). Un estudio comparó el recambio plasmático (en el que se extrae el plasma del paciente y se sustituye por plasma normal) y la ciclofosfamida y la metilprednisolona con la ciclofosfamida y la metilprednisolona solas. El último estudio comparó el fosinopril, que reduce la cantidad de proteínas en la orina, con ningún tratamiento.

¿Qué se encontró?

Se quiso averiguar si los tratamientos evaluados prevenían o trataban la enfermedad renal persistente entre 6 y 12 meses después de la aparición de la VIgA. No se encontraron beneficios definitivos de la prednisona u otros tratamientos en la prevención de una afectación renal más grave en niños sin afectación renal o con afectación renal leve al inicio del estudio. No se encontraron estudios que evaluaran la prednisona en niños con VIgA y afectación renal grave, aunque está recomendada para estos niños en las guías de tratamiento. En los niños con afectación renal grave, no se encontraron beneficios de ningún medicamento que deprima el sistema inmunitario ni del recambio plasmático en el tratamiento de la afectación renal en la VIgA. Como en otras enfermedades renales, se observó que el inhibidor de la enzima convertidora de la angiotensina, el fosinopril, reducía el número de niños con proteínas en la orina.

Conclusiones

Existen pocos datos de ECA que examinen las intervenciones para prevenir o tratar la enfermedad renal en personas con VIgA. No se encontraron pruebas de que la administración de prednisona en el momento de aparición de la VIgA reduzca el riesgo de enfermedad renal grave posteriormente. No se encontraron pruebas de que algunos medicamentos sean más eficaces que otros en el tratamiento de la afectación renal cuando esta se produce. Sin embargo, el número de personas estudiadas fue demasiado bajo para excluir completamente un efecto beneficioso del tratamiento, por lo que se necesitan más estudios. No se observaron efectos secundarios graves.

Authors' conclusions

Implications for practice

Prevention of kidney disease in IgAV

  • Corticosteroids probably do not prevent serious kidney disease in children with IgAV with or without minor kidney abnormalities at presentation (moderate certainty evidence).

  • Antiplatelet agents may not have any benefit in preventing serious kidney disease, but the certainty of the evidence is low.

  • Two studies of heparin came to different conclusions. Tian 2015 only partially supported the conclusions of He 2002 that heparin may reduce the risk for kidney disease in IgAV. The certainty of the evidence was low in both studies. The use of such a potentially harmful treatment cannot be justified when only a third of children with IgAV develop kidney disease, and most have spontaneous resolution of their kidney involvement.

Treatment of serious kidney disease in IgAV

  • Cyclophosphamide treatment compared with supportive therapy or corticosteroids in children and adults with IgAV and severe kidney disease may not increase the number of participants with improvement in outcomes.

  • It remains unclear whether cyclosporin is more effective than methylprednisolone in children with IgAV and severe kidney disease; further studies with longer follow‐up are required.

  • Tacrolimus and MMF may be as effective as cyclophosphamide in the treatment of severe IgAV‐associated kidney disease at two years, but longer follow‐up is required to confirm efficacy.

  • The addition of plasmapheresis to cyclophosphamide and methylprednisolone may not improve outcomes.

  • No studies addressing the management of kidney disease in participants with recurrent episodes of IgAV were identified.

Implications for research

Prevention of serious kidney disease in IgAV

  • While short‐term prednisone may not prevent the development of IgAV nephritis, it remains possible that prednisone therapy has a role in children with risk factors for developing kidney disease, including older age (Shin 2006), severe abdominal pain (Ronkainen 2006aShin 2006), persistent (Ronkainen 2006aShin 2006) or recurrent purpura (Shin 2006) so a further RCT in this group of children may be warranted. However, recruitment to a placebo‐controlled RCT may be difficult since Ronkainen 2006a has demonstrated that short‐course prednisone significantly reduces the severity and duration of abdominal pain in children with IgAV, making it unlikely that clinicians would be prepared to withhold prednisone from children with severe IgAV‐associated abdominal pain.

Treatment of serious kidney disease in IgAV

  • Further adequately powered and well‐designed RCTs with at least five‐year follow‐up periods are needed in children with IgAV associated with kidney involvement, including nephritic syndrome and/or nephrotic syndrome.

  • The study treatment investigated should be adapted according to the severity of kidney disease and should be started early after the onset of IgAV (Davin 2011Delbert 2021).

  • Treatment regimens requiring further evaluation in RCTs include the following in combination with corticosteroids:

    • Calcineurin inhibitors

    • MMF

    • Rituximab and other biological agents.

Summary of findings

Open in table viewer
Summary of findings 1. Prednisone versus placebo or supportive treatment for preventing persistent kidney disease in patients with IgAV (Henoch‐ Schönlein Purpura)

Prednisone versus placebo or supportive treatment for preventing persistent kidney disease in patients with IgAV (Henoch‐Schönlein Purpura)

Patient or population: patients with IgAV
Settings: all settings
Intervention: prednisone
Comparison: placebo or supportive treatment

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Certainty of the evidence
(GRADE)

Assumed risk

Corresponding risk

Placebo or supportive treatment

Prednisone

Persistent kidney disease at any time after treatment

143 per 1000

106 per 1000
(60 to 189)

RR 0.74 
(0.42 to 1.32)

746 (5)

⊕⊕⊕⊝
Moderate1

Children with any continuing kidney disease at 3 months

199 per 1000

165 per 1000
(92 to 303)

RR 0.83 
(0.46 to 1.52)

655 (4)

⊕⊕⊕⊝
Moderate2

Children with any continuing kidney disease at 6 months

100 per 1000

51 per 1000
(24 to 111)

RR 0.51 
(0.24 to 1.11)

379 (3)

⊕⊕⊕⊝
Moderate2

Children with any continuing kidney disease at 12 months

84 per 1000

89 per 1000
(32 to 244)

RR 1.06 
(0.38 to 2.91)

455 (3)

⊕⊕⊝⊝
Low2,3

Any continuing kidney disease at 3 months

(study with high risk of bias excluded)

243 per 1000

238 per 1000
(170 to 330)

RR 0.98 
(0.70 to 1.36)

487 (3)

⊕⊕⊕⊕
High

Any continuing kidney disease at 12 months

(study with high risk of bias excluded)

105 per 1000

146 per 1000
(79 to 272)

RR 1.39 
(0.75 to 2.59)

287 (2)

⊕⊕⊕⊝
Moderate3,4

Number developing severe kidney disease

14 per 1000

22 per 1000
(6 to 85)

RR 1.58 
(0.42 to 6)

418 (2)

⊕⊕⊝⊝
Low3,5

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) is based on the 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 evidence
High certainty: Further research is very unlikely to change our confidence in the estimate of effect
Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low certainty: 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
Very low certainty: We are very uncertain about the estimate
 

1 Two studies had unclear or biased allocation concealment & were not blinded
2 One study had inadequate allocation concealment & no blinding & one study had large loss to follow‐up
3 30% loss to follow‐up in largest included study
4 Small numbers of patients and events
5 Small numbers of events

Background

Description of the condition

IgA vasculitis (previously known as Henoch‐Schönlein Purpura) is a primary non‐thrombocytopenic small vessel, non‐granulomatous vasculitis that typically presents acutely. It is the most common systemic vasculitis in children occurring between the ages of three and 15 years, with an incidence of 3 to 27 cases per 100,000 child population (Piram 2017Ruperto 2010). Clinically the disease is characterised by a tetrad of features, including palpable purpura, arthritis or arthralgia, abdominal pain and kidney disease (Saulsbury 1999). IgA vasculitis (IgAV) is classified as vasculitis with IgA1‐ dominant immune deposits affecting small vessels, predominantly capillaries, venules or arterioles (Jennette 2013). Kidney involvement, which occurs in 40% to 50% of children with IgAV, is the most important complication of IgAV since it is the only complication associated with long‐term morbidity in children and adults. Kidney involvement is clinically manifested by microscopic or macroscopic haematuria, proteinuria, nephrotic syndrome and reduced kidney function. In a systematic review of studies of unselected patients with IgAV (Narchi 2005), kidney involvement occurred in 34% of children; 80% had isolated haematuria, proteinuria or both, while 20% had acute nephritic syndrome or nephrotic syndrome. Kidney disease, if it did occur, developed early ‐ by four weeks in 85% and by six months in nearly all children. Persistent kidney disease (hypertension, reduced function, nephrotic or nephritic syndrome) occurred in 1.8% of children overall, but the incidence varied with the severity of the kidney disease at presentation. In general, the prognosis for long‐term kidney function in IgAV is excellent in children with microscopic or macroscopic haematuria alone. However, patients with nephrotic syndrome and reduced kidney function frequently show a progressive course to end‐stage kidney disease (ESKD). In a study of 78 children with IgAV and kidney involvement presenting to two paediatric nephrology services, 44% of children presenting with acute nephritic syndrome, nephrotic syndrome or both, compared with 13% presenting with haematuria, proteinuria, or both, had hypertension or impaired kidney function at a mean follow‐up of 23.4 years (Goldstein 1992).

Description of the intervention

Corticosteroid therapy may be used in the acute phase of IgAV largely to manage severe abdominal pain. Controversy has existed as to whether corticosteroids can prevent the development of kidney involvement, reduce its severity, or both in IgAV. An earlier systematic review concluded that early corticosteroid therapy might reduce the risk of developing persistent kidney disease (Weiss 2007), but two other reviews concluded that the benefit of corticosteroids in preventing persistent kidney disease remained unproven (Wyatt 2001Zaffanello 2007). There is also considerable uncertainty about the efficacy of therapies to prevent progression to chronic or ESKD in children with IgAV‐associated acute nephritis or nephrotic syndrome. Corticosteroid therapy, azathioprine, mycophenolate mofetil (MMF), cyclophosphamide, calcineurin inhibitors (cyclosporin, tacrolimus), antiplatelet therapy, anticoagulants, and plasmapheresis have been used in such patients (Bergstein 1998Du 2012Flynn 2001Foster 2000Iijima 1998Niaudet 1998Ronkainen 2003Shenoy 2007) with varying results. However, the data came largely from observational studies rather than from randomised controlled trials (RCTs). Recently European consensus guidelines have been developed for the management of IgAV, including the management of IgAV nephritis (Ozen 2019). These guidelines separate kidney involvement in IgAV into mild, moderate and severe degrees of IgAV nephritis. Corticosteroids are recommended as the primary treatment for IgAV nephritis for mild or moderate nephritis, with corticosteroids with intravenous (IV) cyclophosphamide recommended for severe nephritis.

How the intervention might work

IgAV nephritis is due to a systemic vasculitis with deposition of immune deposits of IgA1 in the mesangium, activation of the alternative complement pathway and inflammation. Therefore, it has been argued that medications which treat other immune diseases, including kidney diseases, would have a role in preventing or treating IgAV nephritis. In particular, it was postulated that corticosteroids could prevent the development of significant IgAV nephritis in children presenting with IgAV (Ozen 2019). The use of other immunosuppressive agents is based on their efficacy in treating other immune complex diseases such as systemic lupus erythematosus. Urokinase, dipyridamole and warfarin have been used because of their roles in inhibiting the mediators of glomerular damage (Kawasaki 2004). Angiotensin‐converting enzyme inhibitors (ACEi) and angiotensin‐receptor blockers (ARB) would be expected to reduce proteinuria via effects on intraglomerular haemodynamics (Ozen 2019).

Why it is important to do this review

Although multiple treatment modalities have been used to prevent or treat IgAV nephritis, there is no consensus on the efficacy of various therapies. The aims of this systematic review were to determine the benefits and harms of different interventions used to prevent or treat persistent kidney disease in IgAV in children and adults. The scope was deliberately broad because RCTs in IgAV are few, and variability in the spectrum of kidney disease included in the relevant studies was very likely. This update of this systematic review, originally published in 2009 (Chartapisak 2009) and updated in 2015 (Hahn 2015), aimed to incorporate any further data from RCTs to provide additional evidence for or against the use of corticosteroids or other therapies to prevent IgAV nephritis, for or against the use of immunosuppressive agents to treat established IgAV nephritis and to determine the efficacy of ACEi or ARB in reducing proteinuria in IgAV nephritis.

Objectives

To evaluate the benefits and harms of different agents (used singularly or in combination) compared with placebo, no treatment or any other agent for:

  • The prevention of severe kidney disease in patients with IgAV without kidney disease at presentation.

  • The prevention of severe kidney disease in patients with IgAV and minor kidney disease (microscopic haematuria, mild proteinuria) at presentation.

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

  • The prevention of recurrent episodes of IgAV‐associated kidney disease.

Methods

Criteria for considering studies for this review

Types of studies

All RCTs and quasi‐RCTS (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) looking at the benefits and harms of different therapeutic modalities for the prevention or treatment of kidney disease in IgAV. If cross‐over studies were identified, the first period of randomised cross‐over studies was to be included.

Types of participants

Inclusion criteria

Patients of any age with IgAV with or without kidney disease manifestations (microscopic haematuria, macroscopic haematuria, proteinuria, nephrotic syndrome, acute nephritic syndrome, reduced function, acute kidney failure).

Exclusion criteria

Patients with other forms of primary or secondary glomerulonephritis (GN), such as IgA nephropathy, mesangiocapillary GN, membranous GN, systemic lupus erythematosus, rapidly progressive GN not associated with IgAV, other systemic vasculitides.

Types of interventions

Inclusion criteria

  • Immunosuppressive agents, including corticosteroids, alkylating agents (cyclophosphamide, chlorambucil), azathioprine, MMF, cyclosporin, tacrolimus and rituximab

  • Anticoagulants and antiplatelet agents, including warfarin, dipyridamole, aspirin, heparin

  • ACEi and ARB

  • Fish oil

  • Immunoglobulin G, plasma exchange, antibody therapy

The above agents used individually or in combination were compared with placebo or no specific therapy or compared with other agents

  • Different durations, frequencies or modes of delivery of the same interventions.

Exclusion criteria

Studies of therapies with Traditional Chinese Medicines and non‐pharmacological interventions were excluded.

Types of outcome measures

  1. ESKD (including dialysis and transplantation)

  2. Significant increase in serum creatinine (SCr) as defined by the investigators

  3. Significant reduction in glomerular filtration rate (GFR) as defined by the investigators

  4. Hypertension due to IgAV‐associated kidney disease

  5. Development, persistence or worsening of proteinuria as defined by the investigators

  6. The development or persistence of nephrotic syndrome, nephritic syndrome, acute kidney insufficiency

  7. Death

  8. Biopsy results including per cent of crescent formation, chronicity index, sclerosis, and fibrosis

  9. Quality of life (QoL)

  10. Complications of therapy e.g. infection, bleeding, neutropenia, hypertension.

Primary outcomes

  1. Reduction in kidney function including ESKD, acute kidney insufficiency or significant increase in SCr, significant reduction in GFR or both as defined by the investigators

  2. Development, persistence or worsening of proteinuria, development of nephrotic syndrome or acute nephritic syndrome as defined by the investigators

  3. Complications of therapy e.g. infection, bleeding, leucopenia, hypertension.

Secondary outcomes

  1. Biopsy results, including per cent of crescent formation, chronicity index, sclerosis, and fibrosis

  2. QoL

  3. Hypertension due to IgAV‐associated kidney disease

  4. Death

Search methods for identification of studies

Electronic searches

We searched the Cochrane Kidney and Transplant Register of Studies up to 2 February 2023 through contact with the Information Specialist using search terms relevant to this review. The Register contains studies identified from the following sources:

  1. Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)

  2. Weekly searches of MEDLINE OVID SP

  3. Handsearching of kidney‐related journals and the proceedings of major kidney conferences

  4. Searching the current year of EMBASE OVID SP

  5. Weekly current awareness alerts for selected kidney and transplant journals

  6. Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Studies contained in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE based on the scope of Cochrane Kidney and Transplant. Details of search strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available in the Specialised Register section of information about Cochrane Kidney and Transplant.

See Appendix 1 for search terms used in strategies for this review.

Searching other resources

  1. Reference lists of review articles, relevant studies and clinical practice guidelines.

  2. Letters seeking information about unpublished or incomplete trials to investigators known to be involved in previous studies.

Data collection and analysis

Selection of studies

The search strategy described was used to obtain titles and abstracts of studies that might be relevant to the review. The titles and abstracts were screened independently by two authors, who discarded studies that were not applicable. However, studies and reviews that might have included relevant data or information on studies were retained initially. Three authors independently assessed retrieved abstracts and, if necessary, the full text of these studies to determine which studies satisfied the inclusion criteria.

Data extraction and management

Data extraction was carried out independently by three authors using standard data extraction forms. Studies reported in non‐English language journals were translated before assessment. When more than one publication of one study was identified, reports were grouped together, and the publication with the most complete data was used in the analyses. Where relevant outcomes were only published in earlier versions, these data were used. Any discrepancy between published versions was highlighted. Where necessary, authors were contacted for additional information about their studies. Disagreements were resolved by discussion.

Assessment of risk of bias in included studies

The following items were assessed independently by two authors using the risk of bias assessment tool (Higgins 2022) (Appendix 2).

  • Was there adequate sequence generation (selection bias)?

  • Was allocation adequately concealed (selection bias)?

  • Was knowledge of the allocated interventions adequately prevented during the study?

    • Participants and personnel (performance bias)

    • Outcome assessors (detection bias)

  • Were incomplete outcome data adequately addressed (attrition bias)?

  • Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?

  • Was the study apparently free of other problems that could put it at risk of bias?

Measures of treatment effect

For dichotomous outcomes (number with any kidney disease), results were expressed as risk ratio (RR) with 95% confidence intervals (CI). For continuous outcomes (severity or duration of haematuria or proteinuria, SCr, GFR), the mean difference (MD) with 95% CI were calculated.

Unit of analysis issues

We planned to include data from the first part of any cross‐over study if the data could be separated. However no cross‐over studies were identified.

Dealing with missing data

Any further information required from the original author was requested by written correspondence, and any relevant information obtained was included in the review. We aimed to analyse available data in meta‐analyses using the intention‐to‐treat (ITT) data. However, where ITT data were only available graphically or were not provided, and additional information could not be obtained from the authors, available data were used in analyses. Attrition rates (e.g. drop‐outs), losses to follow‐up and withdrawals were assessed.

Assessment of heterogeneity

We first assessed the heterogeneity by visual inspection of the forest plot. We then quantified statistical heterogeneity using the I² statistic, which describes the percentage of total variation across studies that is due to heterogeneity rather than sampling error (Higgins 2003). A guide to the interpretation of I² values was as follows:

  • 0% to 40%: might not be important

  • 30% to 60%: may represent moderate heterogeneity

  • 50% to 90%: may represent substantial heterogeneity

  • 75% to 100%: considerable heterogeneity.

The importance of the observed value of I² depends on the magnitude and direction of treatment effects and the strength of evidence for heterogeneity (e.g. P‐value from the Chi² test or a CI for I²) (Higgins 2022).

Assessment of reporting biases

We planned to assess for reporting bias using funnel plots. However we did not identify sufficient studies on any intervention to allow this assessment.

Data synthesis

We pooled data using the random effects model but we also analysed the fixed effect model to ensure robustness of the model chosen.

Subgroup analysis and investigation of heterogeneity

We planned subgroup analyses to explore possible sources of heterogeneity among participants (severity of kidney disease, kidney pathology, age), interventions (agent, dose and duration of treatment) or associated risk of bias that might explain any observed heterogeneity of treatment effects. Examination of these possible between‐study differences by subgroup analysis was not possible because of insufficient study data.

Sensitivity analysis

Sensitivity analysis was undertaken where significant heterogeneity among studies existed, and single studies appeared to be responsible for this heterogeneity. Where required, results were reported with and without the inclusion of such single studies.

Summary of findings and assessment of the certainty of the evidence

We presented the main results of the review in a Summary of findings table. This table presents key information concerning the certainty of the evidence, the magnitude of the effects of the interventions examined, and the sum of the available data for the main outcomes (Schunemann 2022a). The Summary of findings table also includes an overall grading of the evidence related to each of the main outcomes using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach (GRADE 2008; GRADE 2011). The GRADE approach defines the certainty of a body of evidence as the extent to which one can be confident that an estimate of effect or association is close to the true quantity of specific interest. The certainty of a body of evidence involves consideration of within‐trial risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias (Schunemann 2022b). We presented the following outcomes in the Summary of findings table.

  • Number with any persistent kidney involvement at different time points

  • Number with severe kidney involvement

Results

Description of studies

Results of the search

In the 2009 review, 909 reports were identified. After screening titles and abstracts, 13 reports underwent full‐text review. Ten studies (11 reports) were included (Dudley 2013He 2002Huber 2004Islek 1999Jauhola 2010Mollica 1992Peratoner 1990Ronkainen 2006aTarshish 2004); and one three‐armed study was listed as two studies for analysis purposes (Yoshimoto 1987aYoshimoto 1987b). Two studies were excluded (Hui‐Lan 2001Jin 2003).

In the 2015 update, 37 new reports were identified. There were six reports of three new studies (CESAR 2010Fuentes 2010Xu 2009) and 11 reports of five already included studies (Dudley 2013He 2002Jauhola 2010Ronkainen 2006aTarshish 2004). Sixteen new studies (16 reports) were excluded. Four studies (4 reports) were identified prior to publication, but no data were available and were listed as awaiting classification. Additional information was obtained for four studies (Dudley 2013Fuentes 2010Jauhola 2010Ronkainen 2006a).

For this 2023 update, we searched the Cochrane Kidney and Transplant Register of Studies up to 2 February 2023 and identified 30 new reports. There were five reports of five new studies (Du 2016Geng 2021Liu 2019eTian 2015Zhang 2021a) and three reports of two already included studies (CESAR 2010Fuentes 2010). Three reports of three new ongoing studies were identified (NCT02532777NCT02532790NCT02540720), and 19 new studies were excluded (19 reports).

We reassessed and reclassified three studies awaiting classification: one study was included (Wu 2014c), one study was excluded (Ding 2014), and one study was deleted (not randomised). NCT00301613 was completed in 2006; however, no publication of the results has been identified. One previously excluded study was deleted as it was not randomised.

A total of 19 studies (34 reports), 1963 randomised participants (Figure 1) were included, 37 studies were excluded, one study is awaiting classification, and there are three ongoing studies.


Flow diagram of study selection

Flow diagram of study selection

Included studies

In this 2023 update, a total of 20 studies (36 reports) enrolling 1963 participants were included (CESAR 2010Du 2016 Dudley 2013Fuentes 2010Geng 2021He 2002Huber 2004Islek 1999Jauhola 2010Liu 2019e Mollica 1992Peratoner 1990Ronkainen 2006aTarshish 2004Tian 2015Wu 2014cXu 2009Yoshimoto 1987aYoshimoto 1987bZhang 2021a). One study (Yoshimoto 1987aYoshimoto 1987b) compared two different interventions with a single control intervention and was treated as two studies for this review. CESAR 2010 included 54 adult patients, but the other studies only included children. Five studies were available in abstract form only (Du 2016Fuentes 2010Islek 1999He 2002Yoshimoto 1987aYoshimoto 1987b). Eighteen studies were published in English; two studies published in Chinese were translated before assessment.

Eleven studies (1432 participants) examined the prevention of progressive kidney disease in participants with IgAV with or without kidney involvement at presentation. Five studies (856 enrolled participants) examined the effects of short‐duration corticosteroids (14 to 28 days) on preventing persistent IgAV‐associated kidney disease at six to 12 months after presentation in comparison with placebo (Dudley 2013Huber 2004Ronkainen 2006a) or supportive treatment (Islek 1999Mollica 1992). Three studies included children with kidney disease at randomisation (Dudley 2013Huber 2004Ronkainen 2006a). Participants considered to have established IgAV‐associated kidney disease (proteinuria > 300 mg/L or haematuria > 10 red blood cells/high power field) were excluded from Ronkainen 2006a, while Dudley 2013 and Huber 2004 included children with any degree of kidney disease at randomisation. Islek 1999 and Mollica 1992 only included children who had no haematuria or proteinuria at presentation.

Three studies (Peratoner 1990Yoshimoto 1987aYoshimoto 1987b) with 129 participants (all children) compared antiplatelet agents (dipyridamole, cyproheptadine and salicylates) with supportive treatment, and two studies (He 2002Tian 2015) (317 children) compared heparin with placebo or no specific treatment. Peratoner 1990 provided outcome data separately for children with and without kidney disease at presentation. Tian 2015 included participants with kidney involvement but did not specify the severity, while the other studies only included children with no kidney disease at randomisation.

Dudley 2013 used urinary protein‐creatinine ratio (UPCR) as the primary endpoint, while in nine other studies, the primary endpoint of kidney disease was defined by a composite of haematuria and proteinuria. The primary outcome in Dudley 2013 at 12 months was only available in 247 of the 296 children who had a 12‐month follow‐up visit. Data on the number of children with haematuria or proteinuria were used in analyses at one and three months. At each time point, the number of children with available data was less than the number undergoing follow‐up.

Wu 2014c compared montelukast sodium with placebo in 84 children with IgAV without kidney involvement and in 46 children with IgAV with haematuria and proteinuria and reported results according to a symptom severity score.

Nine studies (531 participants) examined the treatment of severe IgAV‐associated kidney disease (nephrotic range proteinuria, ISKDC grade II‐IV changes on biopsy).

  • Tarshish 2004 (56 children entered/evaluated) compared cyclophosphamide with no specific treatment.

  • Jauhola 2010 (15 children entered/evaluated) compared cyclosporin with methylprednisolone.

  • CESAR 2010 (54 adults) compared cyclophosphamide and prednisone with prednisone alone in adults with severe biopsy‐proven IgAV kidney disease.

  • Fuentes 2010 (26 children entered/evaluated) compared MMF with azathioprine; both treatment groups received prednisone.

  • Du 2016 (18 children entered/evaluated) compared MMF with leflunomide.

  • Liu 2019e (60 children entered/evaluated) compared double filtration plasmapheresis together with cyclophosphamide and corticosteroids with cyclophosphamide and corticosteroids alone.

  • Geng 2021 (65 children entered/evaluated) compared MMF with IV cyclophosphamide, with both groups receiving corticosteroids.

  • Zhang 2021a (186 children entered/170 evaluated) compared tacrolimus with IV cyclophosphamide with all three groups receiving corticosteroids; participants in the third arm of Zhang 2021a were excluded from analyses as they received tacrolimus with tripterygium glycosides (Chinese medicines were excluded from this review).

  • Xu 2009 (48 children) compared fosinopril with supportive treatment, with the primary endpoint being the number with remission of proteinuria.

In the nine studies evaluating interventions for severe IgAV‐associated kidney disease, the primary endpoint was defined by a composite of proteinuria and reduced kidney function in three studies (Jauhola 2010Liu 2019eTarshish 2004), while CESAR 2010 used a Birmingham Vascular Activity Score (BVAS) of zero at six months as indicating complete disease remission. In the remaining five studies (Du 2016Fuentes 2010Geng 2021Liu 2019eZhang 2021a), the primary endpoint was remission of proteinuria, usually measured by 24‐hour urinary protein excretion. Jauhola 2010 reported data on included randomised and non‐randomised patients. Using information obtained from the authors, only randomised patients were included in the study analyses.

Outcomes were assessed at six to at least 12 months in nine studies (CESAR 2010Dudley 2013Fuentes 2010Huber 2004Jauhola 2010Mollica 1992Peratoner 1990Ronkainen 2006aWu 2013b), at 15 months in one study (Geng 2021) and at two years in two studies (Jauhola 2010Zhang 2021a). Tarshish 2004 reported the outcomes at the end of the study without providing detailed information on the duration of the study. Ronkainen 2006a provided a further long‐term outcome at eight years. The remaining seven studies did not specify the timing of the outcome assessment (Du 2016He 2002Islek 1999Liu 2019eTian 2015Xu 2009Yoshimoto 1987aYoshimoto 1987b).

No studies examining warfarin, ARB alone, fish oil, immunoglobulin G, rituximab or dapsone were identified.

Excluded studies

Thirty‐seven studies were excluded. Reasons for exclusion included:

Risk of bias in included studies

Figure 2 and Figure 3 describe the graphical representation of the risk of bias assessment for all studies.


Risk of bias: Review authors' judgements about each methodological quality item presented as percentages across all included studies.

Risk of bias: Review authors' judgements about each methodological quality item presented as percentages across all included studies.


Risk of bias: Review authors' judgements about each risk of bias item for each included study

Risk of bias: Review authors' judgements about each risk of bias item for each included study

Allocation

Nine studies (CESAR 2010Dudley 2013Fuentes 2010Geng 2021Huber 2004Jauhola 2010Ronkainen 2006aWu 2014cZhang 2021a) were determined to be at low risk of bias for random sequence generation; the risk of bias was unclear in the remaining 11 studies.

Nine studies (CESAR 2010Dudley 2013Fuentes 2010Huber 2004Jauhola 2010Ronkainen 2006aTarshish 2004Wu 2014cZhang 2021a) were determined to be a low risk of bias for allocation concealment, one study was at high risk of bias (Mollica 1992), and the remaining 11 studies had unclear risk of bias.

Blinding

Performance bias was at low risk in four studies (Dudley 2013Huber 2004Ronkainen 2006aWu 2014c), at unclear risk in one study (He 2002), and at high risk of bias in the remaining 12 studies.

Detection bias was at low risk in seven studies (Du 2016Dudley 2013Geng 2021Huber 2004Liu 2019eRonkainen 2006aZhang 2021a), at high risk in five studies (CESAR 2010Fuentes 2010Jauhola 2010Tian 2015Xu 2009) and at unclear risk in the remaining seven studies.

Incomplete outcome data

Nine studies were considered to be at low risk of attrition bias (CESAR 2010Fuentes 2010Geng 2021Huber 2004Liu 2019eRonkainen 2006aTian 2015Xu 2009Zhang 2021a). Three studies were at high risk of attrition bias (Dudley 2013Jauhola 2010Mollica 1992) because of loss to follow‐up or exclusion of data from analyses. In the eight remaining studies, there was insufficient information provided to determine whether all patients entering the study were included in the analysis, so the risk of bias was unclear.

Selective reporting

Reporting included all important kidney outcomes and adverse effects of medications in 10 studies (CESAR 2010Dudley 2013Fuentes 2010Geng 2021He 2002Huber 2004Jauhola 2010Mollica 1992Peratoner 1990Tarshish 2004). Seven studies were considered at high risk of reporting bias because they did not report all expected outcomes (Du 2016Mollica 1992Peratoner 1990Tian 2015Zhang 2021a) or provided outcomes in a graphical form that could not be included in meta‐analyses (Ronkainen 2006aWu 2014c). In the remaining three studies, it was unclear whether important kidney outcomes, including nephrotic syndrome, reduced kidney function, and adverse effects of medications, had not occurred or had not been reported.

Other potential sources of bias

Five studies appeared free of other potential sources of bias (CESAR 2010Dudley 2013Huber 2004Ronkainen 2006aWu 2014c). One author in Fuentes 2010 was a consultant for a pharmaceutical company, so this study was judged to be at high risk of bias. Five studies (Du 2016Fuentes 2010Islek 1999Yoshimoto 1987aYoshimoto 1987b) were only available as conference abstracts with no full‐text reports identified, so they were judged to be at high risk of bias. In the remaining studies, there was insufficient information provided to determine if there were other potential sources of bias.

Effects of interventions

See: Summary of findings 1 Prednisone versus placebo or supportive treatment for preventing persistent kidney disease in patients with IgAV (Henoch‐ Schönlein Purpura)

Preventing persistent kidney disease

Eleven studies enrolled participants with no kidney involvement or mild degrees of haematuria and proteinuria (Dudley 2013He 2002Huber 2004Islek 1999Mollica 1992Peratoner 1990Ronkainen 2006aTian 2015Wu 2014cYoshimoto 1987aYoshimoto 1987b).

Prednisone versus placebo or supportive treatment

In children with newly diagnosed IgAV and without significant kidney disease, prednisone treatment compared with placebo or supportive treatment probably makes little or no difference to the risk of any kidney disease (Analysis 1.1 (5 studies, 746 children): RR 0.73, 95% CI 0.43 to 1.24; I² = 44%; moderate certainty evidence).

Prednisone compared with placebo or supportive therapy probably makes little or no difference to the risk of development or persistence of kidney involvement at one (Analysis 1.2.1 (4 studies, 655 children): RR 0.80, 95% CI 0.34 to 1.84; I² = 72%), three (Analysis 1.2.2 (4 studies, 655 children): RR 0.83, 95% CI 0.46 to 1.52; I² = 44%) and six months (Analysis 1.2.3 (3 studies, 379 children): RR 0.51, 95% CI 0.24 to 1.11; I² = 0%; moderate certainty evidence). At 12 months, prednisone may make little or no difference to the development or persistence of kidney involvement (Analysis 1.2.4 (3 studies, 455 children): RR 1.06, 95% CI 0.38 to 2.91; I² = 32%; low certainty evidence). There was substantial heterogeneity in study outcomes at one, three and 12 months, which was largely due to Mollica 1992. This study, which was at high risk of bias due to inadequate allocation concealment, showed a large benefit of prednisone in contrast to the other three studies. Sensitivity analysis with the exclusion of this study eliminated the heterogeneity except at one month with no change to significance (Analysis 1.3). Removal of this study from the analysis indicated that prednisone compared with placebo, makes little difference to the risk of development or persistence of kidney involvement at three months or 12 months (high certainty evidence at 3 months; moderate certainty evidence at 12 months) (summary of findings Table 1).

In Ronkainen 2006a, a post hoc subgroup analysis of 71 children with kidney disease at or within one month of randomisation found that kidney disease may be less common at six months after prednisone therapy compared with placebo (Analysis 1.4.3: RR 0.45, 95% CI 0.21 to 0.98).

Two studies (Dudley 2013Ronkainen 2006a) reported the number of children who developed severe kidney disease with nephrotic range proteinuria, hypertension or reduced kidney function. There may be little or no difference in the risk of severe kidney disease between children treated with prednisone or placebo (Analysis 1.5 (2 studies, 418 children): RR 1.58, 95% CI 0.42 to 6.00; I² = 0%). However, there was considerable imprecision in the results.

Islek 1999 assessed the duration of haematuria and proteinuria and found that there may be little or no difference in the duration of haematuria (Analysis 1.6.1 (33 children): MD ‐1.00, 95% CI ‐10.26 to 8.26) or proteinuria (Analysis 1.6.2 (33 children): MD ‐1.60, 95% CI ‐15.62 to 12.42) between treatment groups.

The risk of gastrointestinal involvement requiring hospital admission may not differ between prednisone and placebo or supportive treatment (Analysis 1.7 (3 studies, 517 participants): RR 0.56, 95% CI 0.25 to 1.23; I² = 0%). In Huber 2004, two children in the placebo group required surgery for intussusception and were withdrawn from the study. Based on patient diary records in Ronkainen 2006a, children on prednisone may have had less abdominal pain and joint pain based on lower pain severity scores for abdominal or joint pain. They also may have shorter durations of abdominal pain but not joint pain compared with placebo.

Ronkainen 2006a completed an eight‐year follow‐up on 138/176 children originally randomised. They reported minor abnormalities after two clinical screenings in 10 children; eight who had received prednisone and two who received placebo. There may be no differences in haematuria (Analysis 1.8.1: RR 4.86, 95% CI 0.24 to 99.39), proteinuria (Analysis 1.8.2: RR 2.92, 95% CI 0.12 to 70.35), haematuria and proteinuria (Analysis 1.8.3: RR 2.92, 95% CI 0.12 to 70.35), hypertension (Analysis 1.8.4: RR 0.97, 95% CI 0.14 to 6.70), and decreased GFR by Schwartz formula (Analysis 1.8.5: RR 4.86, 95% CI 0.24 to 99.39) but there was considerable imprecision in the results.

Huber 2004 and Ronkainen 2006a reported no serious adverse effects caused by prednisone or placebo. In Ronkainen 2006a, children receiving prednisone had a 1 kg greater increase in weight and a 4 mm Hg increase in diastolic blood pressure during treatment. In Dudley 2013, one child developed behavioural problems, and one had an infection; these were considered related to prednisone therapy, while one child developed abdominal pain in the placebo group. Adverse effects were not recorded in either Islek 1999 or Mollica 1992.

Antiplatelet agents versus supportive treatment

Treatment with antiplatelet agents compared with supportive treatment may make little or no difference to the risk of kidney disease occurring at any time during follow‐up in children without kidney disease at entry (Analysis 2.1.1 (2 studies, 101 children): RR 1.16, 95% CI 0.46 to 2.95; I² = 0%) or with kidney disease at study entry (Analysis 2.1.2 (19 children): RR 0.92, 95% CI 0.23 to 3.72) (low certainty evidence).

It is unclear whether aspirin compared with supportive therapy makes any difference to the risk of kidney disease as the certainty of the evidence is very low (Yoshimoto 1987a) (Analysis 2.1.3 (18 children): RR 0.14, 95% CI 0.01 to 2.42).

Duration of follow‐up and adverse effects were not recorded in these studies.

Heparin versus placebo or conventional treatment

Two studies (He 2002Tian 2015) reported heparin may reduce proteinuria (Analysis 3.2.2 (2 studies, 317 children): RR 0.47, 95% CI 0.31 to 0.73; I² = 0%). However, for the outcomes of any kidney disease (Analysis 3.1 (2 studies, 317 children): RR 0.48, 95% CI 0.15 to 1.54; I² = 89%) and haematuria (Analysis 3.2.1 (2 studies, 317 children): RR 0.39, 95% CI 0.07 to 2.21; I² = 82%), there was considerable heterogeneity between studies so that it is uncertain whether heparin has any effect on the outcomes. The risk for nephrotic syndrome in He 2002 may not differ between the groups, but event numbers were small, resulting in imprecision (Analysis 3.2.3 (228 children): RR 0.31, 95% CI 0.03 to 2.89). The development of kidney disease may be delayed in the heparin group compared with placebo in He 2002 (Analysis 3.3 (228 children): MD 47.3 days, 95% CI 34.24 to 60.36). No child developed severe bleeding.

Montelukast sodium versus placebo

Wu 2014c compared montelukast sodium with placebo in 84 children with IgAV without nephritis and in 46 children with IgAV with haematuria and proteinuria. In children with nephritis, the authors reported that montelukast compared with placebo may reduce the severity scale scores for proteinuria and haematuria at four weeks and at the end of treatment at three months, but scores may increase at six months in both groups. The data were shown graphically only, so meta‐analysis could not be performed. One child experienced irritability, and one reported dizziness. Clinical features of IgAV may be reduced at one, two and three weeks in children with and without nephritis. Montelukast did not alter the outcome of nephritis at three years in children with nephritis at study onset.

Treating severe kidney disease

Nine studies enrolled participants with more severe kidney disease (CESAR 2010Du 2016Fuentes 2010Geng 2021Jauhola 2010Liu 2019eTarshish 2004Xu 2009Zhang 2021a).

Cyclophosphamide versus supportive treatment

In Tarshish 2004, a study of children with significant IgAV‐associated kidney disease (proteinuria, reduced kidney function, crescents, segmental lesions or both on kidney biopsy) treated within three months of the onset of IgAV, cyclophosphamide compared with supportive treatment may make little difference to the risk of persistent kidney disease of any severity (Analysis 4.1 (56 children): RR 1.07, 95% CI 0.65 to 1.78), severe kidney disease (heavy proteinuria, reduced GFR, ESKD) (Analysis 4.2 (56 children): RR 0.88, 95% CI 0.37 to 2.09), or ESKD (Analysis 4.3 (56 children): RR 0.75, 95% CI 0.18 to 3.05) during follow‐up (low certainty evidence). Adverse effects of cyclophosphamide were not reported.

Cyclophosphamide plus steroids versus steroids

CESAR 2010 compared cyclophosphamide and methylprednisolone followed by prednisone with methylprednisolone and prednisone in adults. With treatment, there may be no difference in the number of adults who achieved a BVAS of zero by six months (Analysis 5.1.1 (54 adults): RR 1.16, 95% CI, 0.26 to 5.24) or in the number whose BVAS score improved by six months (Analysis 5.1.2 (54 adults): RR 0.98, 95% CI 0.81 to 1.19). There may be no differences in the secondary outcomes, including hypertension, reduced GFR, proteinuria, improvement in kidney function and ESKD at 12 months (Analysis 5.2). There may be no difference in death between treatment groups (Analysis 5.2.7 (54 adults): RR 0.19, 95% CI 0.02 to 1.50). These deaths were not considered to be related to the treatments received, and the authors noted that those in the prednisone group had more severe disease at baseline based on BVAS scores. There may be no differences in adverse effects (Analysis 5.3) (low certainty evidence).

Tacrolimus versus IV cyclophosphamide

Zhang 2021a compared tacrolimus with IV cyclophosphamide, with both groups receiving prednisolone. Since tripterygium glycosides is an excluded intervention for this systematic review, only the data comparing tacrolimus with IV cyclophosphamide were included in this review. The number of children without proteinuria (Analysis 6.1.1 (170 children): RR 1.13, 95% CI 0.99 to 1.30) or haematuria Analysis 6.1.2 (170 children): RR 1.18, 95% CI 1.02 to 1.37) may be slightly increased at two years following tacrolimus compared with IV cyclophosphamide. At two years, the number of children with recurrence of proteinuria or haematuria may not differ between treatment groups (Analysis 6.2). Twenty‐four‐hour urinary protein excretion at three months (end of treatment) (Analysis 6.3.3 (170 children): MD ‐0.31, 95% CI ‐0.40 to ‐0.22) and at six months (Analysis 6.3.4 (170 children): MD ‐0.20, 95% CI ‐0.24 to ‐0.16) may be slightly lower in children treated with tacrolimus compared with cyclophosphamide. Urine red blood cell excretion may be lower in tacrolimus‐treated children compared with cyclophosphamide at three months (Analysis 6.3.5) and six months (Analysis 6.3.6) (low certainty evidence).

Respiratory infections (Analysis 6.4.2 (68 children): RR 0.55, 95% CI 0.38 to 0.82) and other severe adverse effects (including hypertension, diabetes, ocular hypertension, lipid abnormalities) may be less common with tacrolimus compared with IV cyclophosphamide (Analysis 6.4.6 (170 children): RR 0.45, 95% CI 0.20 to 0.98). Other adverse effects (leucopenia, abnormal liver function tests, urinary tract infections and poor appetite) may not differ between treatment groups (Analysis 6.4).

Cyclosporin versus methylprednisolone

Jauhola 2010 compared cyclosporin with methylprednisolone in children with severe kidney disease. All seven children treated with cyclosporin compared with 4/8 treated with methylprednisolone were in remission by three months. Because of the small numbers, it is unclear whether the number with remission differs between groups (Analysis 7.1 (15 children): RR 1.88, 95% CI 0.95 to 3.69). At the two‐year follow‐up, 23 children were assessed, including eight non‐randomised children; the remission rate was 70% in children treated with cyclosporin and 58% in children treated with methylprednisolone. At final follow‐up at a mean of 6.3 years, it is unclear whether there is any difference in efficacy with 6/7 children treated with cyclosporin compared with 5/8 treated with methylprednisolone in remission (Analysis 7.2 (15 children): RR 1.37, 95% CI 0.74 to 2.54) (all low certainty evidence). Adverse effects related to cyclosporin and methylprednisolone were not reported separately for the randomised children.

Mycophenolate mofetil versus IV cyclophosphamide

Geng 2021 compared MMF with IV cyclophosphamide. Both groups received prednisone, and most received three pulses of IV methylprednisolone. The number of children with complete remission at three months (Analysis 8.1.1 (68 children): RR 1.20, 95% CI 0.72 to 1.99), six months (Analysis 8.1.2 (68 children): RR 1.02, 95% CI 0.78 to 1.34), and 12 months (Analysis 8.1.3 (68 children): RR 1.06, 95% CI 0.83 to 1.35) may not differ between groups. Similarly, the number of children with complete or partial remission at three months (Analysis 8.2.1), six months (Analysis 8.2.2), and 12 months ( Analysis 8.2.3) may not differ between treatment groups. Adverse effects may not differ between treatment groups (Analysis 8.3) (all low certainty evidence).

Mycophenolate mofetil versus azathioprine

Fuentes 2010 compared AZA versus MMF in children with biopsy‐proven IgAV (class I‐III); both groups received prednisone. There may be little or no difference in the numbers with protein remission between the two groups (Analysis 9.1 (26 children): RR 1.32, 95% CI 0.86 to 2.02). There may be little or no difference in the number of children with improvement in kidney histology between treatment groups (Analysis 9.2 (26 children): RR 1.24,95% CI 0.66 to 2.36), in the number with relapse of IgAV (Analysis 9.3) or the GFR (Analysis 9.4) between groups (all low certainty evidence).

Mycophenolate mofetil versus leflunomide

Du 2016 compared leflunomide with MMF. Both groups received tapering prednisone and ACEi. There may be little or no difference in proteinuria between groups at three months (Analysis 10.1.1 (19 participants): MD 360 mg/day, 95% CI ‐43.35 to 763.35) and nine months (Analysis 10.1.2 (19 participants): MD 49.00 mg/day, 95% CI 3.09 to 94.91) (all low certainty evidence).

Double filtration plasmapheresis with cyclophosphamide and methylprednisolone compared with cyclophosphamide and methylprednisolone alone

In Liu 2019e, double filtration plasmapheresis with cyclophosphamide and methylprednisolone compared with cyclophosphamide and methylprednisolone alone may make little or no difference to the numbers of children with complete remission (Analysis 11.1.1 (60 participants): RR 1.43, 95% CI 0.63 to 3.25), the numbers with complete and partial remission after three cycles of treatment (Analysis 11.1.2 (60 participants): RR 1.26, 95% CI 0.91 to 1.75) or for to the numbers with complete remission at six months (Analysis 11.1.3 (60 participants) RR 1.13, 95% CI 0.89 to 1.44). Adverse effects were uncommon and may not differ between treatment groups (Analysis 11.2) (all low certainty evidence).

Fosinopril plus supportive treatment versus supportive treatment alone

Xu 2009 reported fosinopril given for two months may increase the number of children with complete remission of proteinuria compared with supportive treatment (Analysis 12.1 (48 children): RR 5.83, 95% CI 1.50 to 22.74) (low certainty evidence).

Other outcomes

In most studies, the severity of haematuria and proteinuria, the degree of kidney dysfunction and the presence of hypertension were not specified. Dudley 2013 provided information on UPCR, and Tarshish 2004 provided separate information on ESKD.

Discussion

Summary of main results

In this 2023 update of a review first published in 2008 and updated in 2015, we identified 20 studies involving 1963 participants with IgAV.

  • Eleven studies examined the efficacy of therapies to prevent persistent kidney disease in IgAV.

  • Nine studies examined the efficacy of therapies to treat kidney disease in IgAV.

Prevention of persistent kidney disease in IgAV with prednisone therapy

  • Five studies with 746 evaluated children found that prednisone therapy compared with placebo or supportive therapy may have little or no effect in preventing persistent kidney disease at any time up to one year.

  • Two of the five studies with 418 evaluated children found that prednisone therapy compared with placebo or supportive therapy may make little or no difference in the number of children with severe kidney disease at one year.

Prevention of persistent kidney disease in IgAV with antiplatelet therapy or heparin

  • Three small studies found that antiplatelet therapies (dipyridamole, cyproheptadine, aspirin) compared with supportive therapy may make little or no difference to the number of children with any kidney involvement.

  • Two studies suggested that heparin may reduce proteinuria at three months after presentation in children with IgAV and kidney involvement.

Prevention of persistent kidney disease in IgAV with other treatments

  • One study reported montelukast sodium compared with placebo may reduce clinical symptoms in IgAV.

Treatment of severe kidney disease in IgAV with immunosuppressive therapy

  • One study in children (56 evaluated children) and one study in adults (54 evaluated adults) found that cyclophosphamide compared with corticosteroids may make little or no difference to any persistent kidney disease or ESKD in IgAV.

  • One study (170 evaluated children) reported that tacrolimus compared with IV cyclophosphamide may slightly reduce 24‐hour urine excretion of protein and red cells at six months, may slightly increase the number with resolution of proteinuria and haematuria by two years, but may not reduce the number with recurrence of disease by two years in IgAV. Adverse effects, particularly infections, may be fewer with tacrolimus.

  • It is unclear from one study with only 15 children enrolled whether cyclosporin compared with methylprednisolone makes any difference to the outcomes of IgAV nephritis.

  • MMF has been evaluated in three studies compared with IV cyclophosphamide (68 children), azathioprine (26 children) and leflunomide (19 children).

    • MMF compared with IV cyclophosphamide, may make little or no difference to any persistent kidney disease in IgAV.

    • MMF compared with azathioprine may make little or no difference to persistent kidney disease in IgAV.

    • MMF compared with leflunomide may make little or no difference to persistent kidney disease in IgAV.

  • One study (60 children) reported that double filtration plasmapheresis with IV cyclophosphamide and methylprednisolone compared with IV cyclophosphamide and methylprednisolone may make little or no difference to persistent kidney disease in IgAV.

  • One study reported that proteinuria in IgAV may be reduced with the ACEi (fosinopril) in children with IgAV and kidney involvement.

Overall completeness and applicability of evidence

Twenty studies enrolling 1963 participants were included in this review update; five studies were only available in abstract form, and several studies included small numbers of participants with incomplete outcome data, which could result in incomplete information being included in this systematic review.

Three well‐designed, placebo‐controlled studies (Dudley 2013Huber 2004Ronkainen 2006a) have provided data from over 400 children. There is no demonstrable benefit of prednisone therapy at six to 12 months in children with IgAV, with no or minor kidney involvement at presentation, in preventing subsequent important kidney involvement. In addition, eight‐year follow‐up data in Ronkainen 2006a found no longer‐term benefit. Therefore, further RCTs to evaluate prednisone to prevent kidney disease in this group of children presenting with IgAV are unlikely to be justified. In the studies evaluating prednisone therapy, the outcomes reported were poorly defined except for Dudley 2013, which used UPCR as the primary outcome. The potential significance for long‐term kidney function of any residual urinary abnormalities could not be assessed in the other studies since they reported the endpoint as the presence of haematuria or proteinuria or both without measuring the degree of proteinuria.

Persistent proteinuria with or without reduction in GFR places the child with IgAV at risk of progression to chronic kidney disease and is considered by paediatric rheumatologists and nephrologists to require treatment with some urgency since delay in treatment may result in more chronic histological changes (Davin 2011KDIGO 2021). Observational studies (Niaudet 1998) support the use of corticosteroids, including IV methylprednisolone followed by oral prednisone, in patients with nephrotic range proteinuria and no reduction in kidney function. The European Consensus Guidelines on IgAV (Ozen 2019) recommend oral prednisolone for mild IgAV nephritis (normal GFR with mild to moderate proteinuria) and IV methylprednisolone followed by oral prednisone for moderate IgAV nephritis (persistent proteinuria ± reduced GFR with kidney biopsy evidence of < 50% crescents). However, there are no adequately powered RCTs that have evaluated corticosteroid therapy (prednisolone, methylprednisolone) in children with moderate or severe IgAV‐associated nephritis.

The European Consensus Guidelines (Ozen 2019) and KDIGO (KDIGO 2021) suggest that children with IgAV and severe kidney involvement (> 50% crescents on kidney biopsy, impaired GFR and nephrotic range proteinuria) should be treated similarly to systemic small vessel vasculitis with kidney involvement using IV cyclophosphamide and high dose corticosteroids. We identified four studies that compared oral or IV cyclophosphamide with supportive therapy (Tarshish 2004), corticosteroids (CESAR 2010), tacrolimus (Zhang 2019b) and MMF (Geng 2021). Tacrolimus or MMF may achieve similar degrees of improvement to IV cyclophosphamide (Geng 2021Zhang 2021a), suggesting that these agents could be used in preference to IV cyclophosphamide. Small studies found no benefit of cyclosporin over methylprednisolone (Jauhola 2010) or MMF over azathioprine (Fuentes 2010) or leflunomide (Du 2016). Plasma exchange is also used in patients with IgAV and severe kidney involvement. A single study found no increased benefit of plasmapheresis with IV cyclophosphamide and corticosteroids over IV cyclophosphamide and corticosteroids alone (Liu 2019e). Limited reporting revealed small numbers of adverse events in all studies with no significant difference between interventions. No studies were identified that evaluated therapy to prevent or treat persistent kidney disease in participants with recurrent episodes of IgAV.

A single study showed that the ACEi, fosinopril, reduced the number of children with proteinuria associated with IgAV. Both the European Consensus Guidelines (Ozen 2019) and the KDIGO guidelines (KDIGO 2021) state that these children should be treated with ACEi or ARBs.

No RCTs were identified that examined IV immunoglobulin, rituximab, fish oil or ARB. No studies specifically addressing whether therapy reduced the risk of recurrent episodes of IgAV were identified.

Quality of the evidence

Sequence generation and allocation concealment were at low risk of bias in nine studies (45%). This may be attributed to poorer reporting of these parameters in the earlier studies as well as the inclusion of studies only available as abstracts. Blinding of participants and investigators was reported in four studies while seven studies were at low risk of detection bias, reflecting a high risk of bias in the remaining studies since knowledge of treatment groups could influence patient management and reporting. Only nine studies were at low risk of attrition bias. The otherwise robust study of Dudley 2013 was at high risk of attrition bias due to a significant dropout rate, with only 72% (123/171) reporting the primary outcome. Ten studies were at low risk of selective reporting. Studies with a high risk of bias are associated with an increased likelihood of results favouring the study intervention (Schulz 1995Wood 2008). The exclusion of one study at high risk of bias removed heterogeneity between studies without altering the overall result but reinforcing the strength of the evidence suggesting that short courses of prednisone do not prevent serious kidney disease in children with IgAV (Analysis 1.3).

Only the five studies comparing prednisone with placebo or supportive treatment for the prevention of persistent kidney disease in IgAV could be assessed in a summary of findings table (summary of findings Table 1). The overall certainty of the studies was considered moderate for the persistence of kidney disease at any time after treatment and for the number of children with continuing kidney disease at varying time points. With the removal of one study, which had inadequate allocation concealment and no blinding, the remaining three studies were graded as of high certainty at the three‐month interval but only moderate at 12 months because of the small number of events and high loss to follow‐up in Dudley 2013. The number developing severe kidney disease was graded as low in two studies as a result of a significant loss to follow‐up in the largest included study and small numbers of events.

The remaining studies could not be included in summary of findings tables as they were single studies, or study data could not be included in meta‐analyses.

Potential biases in the review process

A thorough search utilising Cochrane Kidney and Transplant's Specialised Register was completed in February 2023.

The Specialised Register includes published studies and conference abstracts with no restriction on language. The omission of eligible studies was therefore minimised. However, 30% of study reports in the Specialised Register have been identified by handsearching of conference proceedings so it remains possible that further studies of therapy to prevent or treat serious kidney disease in IgAV will be identified as conference proceedings from different congresses are searched.

Five (25%) of the included studies were only available in the abstract form, thus limiting information on study methods and outcomes. Four of the studies were published prior to 2000 before the CONSORT checklist (first published in 1996) would influence trial methodology and reporting. Incomplete reporting of these studies may result in incomplete information being included in this systematic review.

Two authors independently undertook all the steps of this review, thereby minimising risks of errors in determining study eligibility, data extraction and risk of bias assessment and data synthesis.

Agreements and disagreements with other studies or reviews

Three earlier systematic reviews assessed the effects of corticosteroid therapy to prevent or alter the course of kidney disease in IgAV (Weiss 2007Wyatt 2001Zaffanello 2007). All three included data from RCTs and observational studies. Two reviews determined that it remained unclear whether corticosteroid therapy prevented or altered the course of IgAV‐associated kidney disease (Wyatt 2001Zaffanello 2007). The third review concluded that corticosteroids decreased the likelihood of developing persistent kidney disease but did not prevent kidney disease (Weiss 2007). However, in a further study (Dudley 2013), there was probably no benefit of corticosteroid therapy to prevent the development or persistence of kidney disease in IgAV, so corticosteroids are not recommended in children with IgAV to prevent kidney involvement.

We identified no randomised studies evaluating the use of corticosteroids in treating established kidney involvement of any severity in IgAV though most clinicians will use them and report some benefit. Despite the lack of supporting data, recent recommendations for the treatment of nephritis in IgAV recommend that corticosteroids should be used without delay in children presenting with moderate or severe nephritis (Delbert 2021KDIGO 2021Ozen 2019).

An earlier systematic review also evaluated immunosuppressive and other therapies in IgAV nephritis (Zaffanello 2007). It concluded, based on observational studies, that cyclophosphamide was of value in treating IgAV‐associated kidney disease. Studies evaluating cyclophosphamide compared with corticosteroids or supportive treatment in this review may not show any benefit of cyclophosphamide (CESAR 2010Tarshish 2004), with both interventions associated with improvements in kidney involvement in some participants. While earlier studies comparing cyclosporin with methylprednisolone and MMF with azathioprine were too small to establish whether or not these treatments may be effective (Fuentes 2010Jauhola 2010), two larger studies found that tacrolimus (Zhang 2021a) or MMF (Geng 2021) may be as effective as IV cyclophosphamide in IgAV associated nephritis. These studies support recent recommendations for the use of MMF or tacrolimus in IgAV nephritis (Delbert 2021). This review did not identify any studies evaluating rituximab. However, rituximab has been reported to be effective in case reports of patients with IgAV nephritis (Delbert 2021).

Guidelines (Delbert 2021KDIGO 2021Ozen 2019) recommend treatment of nephritis in IgAV with ACEi or ARB based largely on observational studies. This review identified one small study (Xu 2009), which demonstrated that fosinopril may result in complete remission of proteinuria in children with IgAV.

Flow diagram of study selection

Figuras y tablas -
Figure 1

Flow diagram of study selection

Risk of bias: Review authors' judgements about each methodological quality item presented as percentages across all included studies.

Figuras y tablas -
Figure 2

Risk of bias: Review authors' judgements about each methodological quality item presented as percentages across all included studies.

Risk of bias: Review authors' judgements about each risk of bias item for each included study

Figuras y tablas -
Figure 3

Risk of bias: Review authors' judgements about each risk of bias item for each included study

Comparison 1: Prednisone versus placebo/supportive treatment for preventing persistent kidney disease, Outcome 1: Persistent kidney disease at any time after treatment

Figuras y tablas -
Analysis 1.1

Comparison 1: Prednisone versus placebo/supportive treatment for preventing persistent kidney disease, Outcome 1: Persistent kidney disease at any time after treatment

Comparison 1: Prednisone versus placebo/supportive treatment for preventing persistent kidney disease, Outcome 2: Number of children with any continuing kidney disease at different time points

Figuras y tablas -
Analysis 1.2

Comparison 1: Prednisone versus placebo/supportive treatment for preventing persistent kidney disease, Outcome 2: Number of children with any continuing kidney disease at different time points

Comparison 1: Prednisone versus placebo/supportive treatment for preventing persistent kidney disease, Outcome 3: Any continuing kidney disease at different time points (study with high risk of bias excluded)

Figuras y tablas -
Analysis 1.3

Comparison 1: Prednisone versus placebo/supportive treatment for preventing persistent kidney disease, Outcome 3: Any continuing kidney disease at different time points (study with high risk of bias excluded)

Comparison 1: Prednisone versus placebo/supportive treatment for preventing persistent kidney disease, Outcome 4: Number of children with kidney disease in first month/with kidney disease at follow‐up

Figuras y tablas -
Analysis 1.4

Comparison 1: Prednisone versus placebo/supportive treatment for preventing persistent kidney disease, Outcome 4: Number of children with kidney disease in first month/with kidney disease at follow‐up

Comparison 1: Prednisone versus placebo/supportive treatment for preventing persistent kidney disease, Outcome 5: Number developing severe kidney disease

Figuras y tablas -
Analysis 1.5

Comparison 1: Prednisone versus placebo/supportive treatment for preventing persistent kidney disease, Outcome 5: Number developing severe kidney disease

Comparison 1: Prednisone versus placebo/supportive treatment for preventing persistent kidney disease, Outcome 6: Duration of kidney disease

Figuras y tablas -
Analysis 1.6

Comparison 1: Prednisone versus placebo/supportive treatment for preventing persistent kidney disease, Outcome 6: Duration of kidney disease

Comparison 1: Prednisone versus placebo/supportive treatment for preventing persistent kidney disease, Outcome 7: Gastrointestinal complications requiring hospital admission

Figuras y tablas -
Analysis 1.7

Comparison 1: Prednisone versus placebo/supportive treatment for preventing persistent kidney disease, Outcome 7: Gastrointestinal complications requiring hospital admission

Comparison 1: Prednisone versus placebo/supportive treatment for preventing persistent kidney disease, Outcome 8: Eight‐year outcomes

Figuras y tablas -
Analysis 1.8

Comparison 1: Prednisone versus placebo/supportive treatment for preventing persistent kidney disease, Outcome 8: Eight‐year outcomes

Comparison 2: Antiplatelet agents versus supportive treatment for preventing persistent kidney disease, Outcome 1: Kidney disease at any time

Figuras y tablas -
Analysis 2.1

Comparison 2: Antiplatelet agents versus supportive treatment for preventing persistent kidney disease, Outcome 1: Kidney disease at any time

Comparison 3: Heparin versus placebo for preventing persistent kidney disease, Outcome 1: Any kidney disease at 2 to 3 months after onset or relapse

Figuras y tablas -
Analysis 3.1

Comparison 3: Heparin versus placebo for preventing persistent kidney disease, Outcome 1: Any kidney disease at 2 to 3 months after onset or relapse

Comparison 3: Heparin versus placebo for preventing persistent kidney disease, Outcome 2: Type of kidney disease at 2 to 3 months or more after onset or relapse

Figuras y tablas -
Analysis 3.2

Comparison 3: Heparin versus placebo for preventing persistent kidney disease, Outcome 2: Type of kidney disease at 2 to 3 months or more after onset or relapse

Comparison 3: Heparin versus placebo for preventing persistent kidney disease, Outcome 3: Time to development of kidney disease

Figuras y tablas -
Analysis 3.3

Comparison 3: Heparin versus placebo for preventing persistent kidney disease, Outcome 3: Time to development of kidney disease

Comparison 4: Cyclophosphamide versus supportive treatment for treating severe kidney disease, Outcome 1: Persistent kidney disease

Figuras y tablas -
Analysis 4.1

Comparison 4: Cyclophosphamide versus supportive treatment for treating severe kidney disease, Outcome 1: Persistent kidney disease

Comparison 4: Cyclophosphamide versus supportive treatment for treating severe kidney disease, Outcome 2: Persistent severe kidney disease

Figuras y tablas -
Analysis 4.2

Comparison 4: Cyclophosphamide versus supportive treatment for treating severe kidney disease, Outcome 2: Persistent severe kidney disease

Comparison 4: Cyclophosphamide versus supportive treatment for treating severe kidney disease, Outcome 3: ESKD

Figuras y tablas -
Analysis 4.3

Comparison 4: Cyclophosphamide versus supportive treatment for treating severe kidney disease, Outcome 3: ESKD

Comparison 5: Cyclophosphamide + steroids versus steroids for treating severe kidney disease, Outcome 1: Primary outcome: BVAS at 6 months

Figuras y tablas -
Analysis 5.1

Comparison 5: Cyclophosphamide + steroids versus steroids for treating severe kidney disease, Outcome 1: Primary outcome: BVAS at 6 months

Comparison 5: Cyclophosphamide + steroids versus steroids for treating severe kidney disease, Outcome 2: Secondary endpoints at 12 months

Figuras y tablas -
Analysis 5.2

Comparison 5: Cyclophosphamide + steroids versus steroids for treating severe kidney disease, Outcome 2: Secondary endpoints at 12 months

Comparison 5: Cyclophosphamide + steroids versus steroids for treating severe kidney disease, Outcome 3: Adverse effects

Figuras y tablas -
Analysis 5.3

Comparison 5: Cyclophosphamide + steroids versus steroids for treating severe kidney disease, Outcome 3: Adverse effects

Comparison 6: Tacrolimus versus IV cyclophosphamide for treating severe kidney disease, Outcome 1: Number with resolution of proteinuria and haematuria at 2 years

Figuras y tablas -
Analysis 6.1

Comparison 6: Tacrolimus versus IV cyclophosphamide for treating severe kidney disease, Outcome 1: Number with resolution of proteinuria and haematuria at 2 years

Comparison 6: Tacrolimus versus IV cyclophosphamide for treating severe kidney disease, Outcome 2: Number with recurrence of proteinuria and haematuria at 2 years

Figuras y tablas -
Analysis 6.2

Comparison 6: Tacrolimus versus IV cyclophosphamide for treating severe kidney disease, Outcome 2: Number with recurrence of proteinuria and haematuria at 2 years

Comparison 6: Tacrolimus versus IV cyclophosphamide for treating severe kidney disease, Outcome 3: Laboratory parameters

Figuras y tablas -
Analysis 6.3

Comparison 6: Tacrolimus versus IV cyclophosphamide for treating severe kidney disease, Outcome 3: Laboratory parameters

Comparison 6: Tacrolimus versus IV cyclophosphamide for treating severe kidney disease, Outcome 4: Adverse effects

Figuras y tablas -
Analysis 6.4

Comparison 6: Tacrolimus versus IV cyclophosphamide for treating severe kidney disease, Outcome 4: Adverse effects

Comparison 7: Cyclosporin versus methylprednisolone for treating severe kidney disease, Outcome 1: Number with remission at 3 months

Figuras y tablas -
Analysis 7.1

Comparison 7: Cyclosporin versus methylprednisolone for treating severe kidney disease, Outcome 1: Number with remission at 3 months

Comparison 7: Cyclosporin versus methylprednisolone for treating severe kidney disease, Outcome 2: Number with remission at last follow‐up (mean 6.3 years)

Figuras y tablas -
Analysis 7.2

Comparison 7: Cyclosporin versus methylprednisolone for treating severe kidney disease, Outcome 2: Number with remission at last follow‐up (mean 6.3 years)

Comparison 8: Mycophenolate mofetil versus IV cyclophosphamide for treating severe kidney disease, Outcome 1: Number with complete remission

Figuras y tablas -
Analysis 8.1

Comparison 8: Mycophenolate mofetil versus IV cyclophosphamide for treating severe kidney disease, Outcome 1: Number with complete remission

Comparison 8: Mycophenolate mofetil versus IV cyclophosphamide for treating severe kidney disease, Outcome 2: Number with complete or partial remission

Figuras y tablas -
Analysis 8.2

Comparison 8: Mycophenolate mofetil versus IV cyclophosphamide for treating severe kidney disease, Outcome 2: Number with complete or partial remission

Comparison 8: Mycophenolate mofetil versus IV cyclophosphamide for treating severe kidney disease, Outcome 3: Adverse effects

Figuras y tablas -
Analysis 8.3

Comparison 8: Mycophenolate mofetil versus IV cyclophosphamide for treating severe kidney disease, Outcome 3: Adverse effects

Comparison 9: Mycophenolate mofetil versus azathioprine for treating severe kidney disease, Outcome 1: Remission of proteinuria at 1 year

Figuras y tablas -
Analysis 9.1

Comparison 9: Mycophenolate mofetil versus azathioprine for treating severe kidney disease, Outcome 1: Remission of proteinuria at 1 year

Comparison 9: Mycophenolate mofetil versus azathioprine for treating severe kidney disease, Outcome 2: Regression of histological lesions at 1 year

Figuras y tablas -
Analysis 9.2

Comparison 9: Mycophenolate mofetil versus azathioprine for treating severe kidney disease, Outcome 2: Regression of histological lesions at 1 year

Comparison 9: Mycophenolate mofetil versus azathioprine for treating severe kidney disease, Outcome 3: Relapse of IgAV

Figuras y tablas -
Analysis 9.3

Comparison 9: Mycophenolate mofetil versus azathioprine for treating severe kidney disease, Outcome 3: Relapse of IgAV

Comparison 9: Mycophenolate mofetil versus azathioprine for treating severe kidney disease, Outcome 4: Glomerular filtration rate

Figuras y tablas -
Analysis 9.4

Comparison 9: Mycophenolate mofetil versus azathioprine for treating severe kidney disease, Outcome 4: Glomerular filtration rate

Comparison 10: Mycophenolate mofetil versus leflunomide for treating severe kidney disease, Outcome 1: 24‐hour urine proteinuria

Figuras y tablas -
Analysis 10.1

Comparison 10: Mycophenolate mofetil versus leflunomide for treating severe kidney disease, Outcome 1: 24‐hour urine proteinuria

Comparison 11: Double filtration plasmapheresis versus no plasmapheresis for treating severe kidney disease, Outcome 1: Remission

Figuras y tablas -
Analysis 11.1

Comparison 11: Double filtration plasmapheresis versus no plasmapheresis for treating severe kidney disease, Outcome 1: Remission

Comparison 11: Double filtration plasmapheresis versus no plasmapheresis for treating severe kidney disease, Outcome 2: Adverse effects

Figuras y tablas -
Analysis 11.2

Comparison 11: Double filtration plasmapheresis versus no plasmapheresis for treating severe kidney disease, Outcome 2: Adverse effects

Comparison 12: Fosinopril + supportive treatment versus supportive treatment for treating proteinuria in IgAV, Outcome 1: Proteinuria

Figuras y tablas -
Analysis 12.1

Comparison 12: Fosinopril + supportive treatment versus supportive treatment for treating proteinuria in IgAV, Outcome 1: Proteinuria

Summary of findings 1. Prednisone versus placebo or supportive treatment for preventing persistent kidney disease in patients with IgAV (Henoch‐ Schönlein Purpura)

Prednisone versus placebo or supportive treatment for preventing persistent kidney disease in patients with IgAV (Henoch‐Schönlein Purpura)

Patient or population: patients with IgAV
Settings: all settings
Intervention: prednisone
Comparison: placebo or supportive treatment

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Certainty of the evidence
(GRADE)

Assumed risk

Corresponding risk

Placebo or supportive treatment

Prednisone

Persistent kidney disease at any time after treatment

143 per 1000

106 per 1000
(60 to 189)

RR 0.74 
(0.42 to 1.32)

746 (5)

⊕⊕⊕⊝
Moderate1

Children with any continuing kidney disease at 3 months

199 per 1000

165 per 1000
(92 to 303)

RR 0.83 
(0.46 to 1.52)

655 (4)

⊕⊕⊕⊝
Moderate2

Children with any continuing kidney disease at 6 months

100 per 1000

51 per 1000
(24 to 111)

RR 0.51 
(0.24 to 1.11)

379 (3)

⊕⊕⊕⊝
Moderate2

Children with any continuing kidney disease at 12 months

84 per 1000

89 per 1000
(32 to 244)

RR 1.06 
(0.38 to 2.91)

455 (3)

⊕⊕⊝⊝
Low2,3

Any continuing kidney disease at 3 months

(study with high risk of bias excluded)

243 per 1000

238 per 1000
(170 to 330)

RR 0.98 
(0.70 to 1.36)

487 (3)

⊕⊕⊕⊕
High

Any continuing kidney disease at 12 months

(study with high risk of bias excluded)

105 per 1000

146 per 1000
(79 to 272)

RR 1.39 
(0.75 to 2.59)

287 (2)

⊕⊕⊕⊝
Moderate3,4

Number developing severe kidney disease

14 per 1000

22 per 1000
(6 to 85)

RR 1.58 
(0.42 to 6)

418 (2)

⊕⊕⊝⊝
Low3,5

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) is based on the 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 evidence
High certainty: Further research is very unlikely to change our confidence in the estimate of effect
Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low certainty: 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
Very low certainty: We are very uncertain about the estimate
 

1 Two studies had unclear or biased allocation concealment & were not blinded
2 One study had inadequate allocation concealment & no blinding & one study had large loss to follow‐up
3 30% loss to follow‐up in largest included study
4 Small numbers of patients and events
5 Small numbers of events

Figuras y tablas -
Summary of findings 1. Prednisone versus placebo or supportive treatment for preventing persistent kidney disease in patients with IgAV (Henoch‐ Schönlein Purpura)
Comparison 1. Prednisone versus placebo/supportive treatment for preventing persistent kidney disease

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1.1 Persistent kidney disease at any time after treatment Show forest plot

5

746

Risk Ratio (M‐H, Random, 95% CI)

0.74 [0.42, 1.32]

1.2 Number of children with any continuing kidney disease at different time points Show forest plot

4

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.2.1 One month

4

655

Risk Ratio (M‐H, Random, 95% CI)

0.80 [0.34, 1.84]

1.2.2 Three months

4

655

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.46, 1.52]

1.2.3 Six months

3

379

Risk Ratio (M‐H, Random, 95% CI)

0.51 [0.24, 1.11]

1.2.4 Twelve months

3

455

Risk Ratio (M‐H, Random, 95% CI)

1.06 [0.38, 2.91]

1.3 Any continuing kidney disease at different time points (study with high risk of bias excluded) Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.3.1 One month

3

487

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.54, 1.93]

1.3.2 Three months

3

487

Risk Ratio (M‐H, Random, 95% CI)

0.98 [0.70, 1.36]

1.3.3 Six months

2

211

Risk Ratio (M‐H, Random, 95% CI)

0.59 [0.23, 1.50]

1.3.4 Twelve months

2

287

Risk Ratio (M‐H, Random, 95% CI)

1.39 [0.75, 2.59]

1.4 Number of children with kidney disease in first month/with kidney disease at follow‐up Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

1.4.1 One month

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

1.4.2 Three months

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

1.4.3 Six months

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

1.5 Number developing severe kidney disease Show forest plot

2

418

Risk Ratio (M‐H, Random, 95% CI)

1.58 [0.42, 6.00]

1.6 Duration of kidney disease Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

1.6.1 Haematuria

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

1.6.2 Proteinuria

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

1.7 Gastrointestinal complications requiring hospital admission Show forest plot

3

517

Risk Ratio (M‐H, Random, 95% CI)

0.56 [0.25, 1.23]

1.8 Eight‐year outcomes Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

1.8.1 Haematuria

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

1.8.2 Proteinuria

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

1.8.3 Haematuria and proteinuria

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

1.8.4 Hypertension

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

1.8.5 Decreased GFR (Schwartz formula)

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

Figuras y tablas -
Comparison 1. Prednisone versus placebo/supportive treatment for preventing persistent kidney disease
Comparison 2. Antiplatelet agents versus supportive treatment for preventing persistent kidney disease

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

2.1 Kidney disease at any time Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1.1 Dipyridamole ± cyproheptadine in children without kidney disease at entry

2

101

Risk Ratio (M‐H, Random, 95% CI)

1.16 [0.46, 2.95]

2.1.2 Dipyridamole ± cyproheptadine in children with kidney disease at entry

1

19

Risk Ratio (M‐H, Random, 95% CI)

0.92 [0.23, 3.72]

2.1.3 Aspirin versus supportive treatment

1

18

Risk Ratio (M‐H, Random, 95% CI)

0.14 [0.01, 2.42]

Figuras y tablas -
Comparison 2. Antiplatelet agents versus supportive treatment for preventing persistent kidney disease
Comparison 3. Heparin versus placebo for preventing persistent kidney disease

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

3.1 Any kidney disease at 2 to 3 months after onset or relapse Show forest plot

2

317

Risk Ratio (M‐H, Random, 95% CI)

0.48 [0.15, 1.54]

3.2 Type of kidney disease at 2 to 3 months or more after onset or relapse Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3.2.1 Haematuria

2

317

Risk Ratio (M‐H, Random, 95% CI)

0.39 [0.07, 2.21]

3.2.2 Proteinuria

2

317

Risk Ratio (M‐H, Random, 95% CI)

0.47 [0.31, 0.73]

3.2.3 Nephrotic syndrome

1

228

Risk Ratio (M‐H, Random, 95% CI)

0.31 [0.03, 2.89]

3.3 Time to development of kidney disease Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

Figuras y tablas -
Comparison 3. Heparin versus placebo for preventing persistent kidney disease
Comparison 4. Cyclophosphamide versus supportive treatment for treating severe kidney disease

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

4.1 Persistent kidney disease Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4.2 Persistent severe kidney disease Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4.3 ESKD Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Figuras y tablas -
Comparison 4. Cyclophosphamide versus supportive treatment for treating severe kidney disease
Comparison 5. Cyclophosphamide + steroids versus steroids for treating severe kidney disease

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

5.1 Primary outcome: BVAS at 6 months Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

5.1.1 BVAS = 0 at 6 months

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

5.1.2 Improvement in BVAS score

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

5.2 Secondary endpoints at 12 months Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

5.2.1 BP > 125/75 mm Hg

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

5.2.2 eGFR < 60 mL/min

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

5.2.3 Proteinuria > 1 g/day

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

5.2.4 RAS blockers

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

5.2.5 Kidney function improvement > 50%

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

5.2.6 ESKD

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

5.2.7 Death

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

5.3 Adverse effects Show forest plot

1

Risk Difference (M‐H, Random, 95% CI)

Totals not selected

5.3.1 infection

1

Risk Difference (M‐H, Random, 95% CI)

Totals not selected

5.3.2 Newly diagnosed or deterioration in existing diabetes

1

Risk Difference (M‐H, Random, 95% CI)

Totals not selected

5.3.3 Depression/anxiety

1

Risk Difference (M‐H, Random, 95% CI)

Totals not selected

5.3.4 Alopecia

1

Risk Difference (M‐H, Random, 95% CI)

Totals not selected

5.3.5 Insomnia

1

Risk Difference (M‐H, Random, 95% CI)

Totals not selected

Figuras y tablas -
Comparison 5. Cyclophosphamide + steroids versus steroids for treating severe kidney disease
Comparison 6. Tacrolimus versus IV cyclophosphamide for treating severe kidney disease

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

6.1 Number with resolution of proteinuria and haematuria at 2 years Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

6.1.1 Number without proteinuria

1

170

Risk Ratio (M‐H, Random, 95% CI)

1.13 [0.99, 1.30]

6.1.2 Number without haematuria

1

170

Risk Ratio (M‐H, Random, 95% CI)

1.18 [1.02, 1.37]

6.2 Number with recurrence of proteinuria and haematuria at 2 years Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

6.2.1 Number with proteinuria

1

170

Risk Ratio (M‐H, Random, 95% CI)

0.72 [0.45, 1.15]

6.2.2 Number with haematuria

1

170

Risk Ratio (M‐H, Random, 95% CI)

0.95 [0.61, 1.48]

6.3 Laboratory parameters Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

6.3.1 Serum creatinine at 3 months

1

170

Mean Difference (IV, Random, 95% CI)

‐1.00 [‐2.80, 0.80]

6.3.2 Serum creatinine at 6 months

1

170

Mean Difference (IV, Random, 95% CI)

‐1.00 [‐2.06, 0.06]

6.3.3 24‐hour urinary protein at 3 months

1

170

Mean Difference (IV, Random, 95% CI)

‐0.31 [‐0.40, ‐0.22]

6.3.4 24‐hour urinary protein at 6 months

1

170

Mean Difference (IV, Random, 95% CI)

‐0.20 [‐0.24, ‐0.16]

6.3.5 Urine RBC/HPF at 3 months

1

170

Mean Difference (IV, Random, 95% CI)

‐2.62 [‐3.79, ‐1.45]

6.3.6 Urine RBC/HPF at 6 months

1

170

Mean Difference (IV, Random, 95% CI)

‐2.45 [‐2.90, ‐2.00]

6.4 Adverse effects Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

6.4.1 Leucopenia

1

170

Risk Ratio (M‐H, Random, 95% CI)

0.64 [0.19, 2.17]

6.4.2 Respiratory infections

1

170

Risk Ratio (M‐H, Random, 95% CI)

0.55 [0.38, 0.82]

6.4.3 Abnormal liver function tests

1

170

Risk Ratio (M‐H, Random, 95% CI)

0.92 [0.58, 1.45]

6.4.4 Urinary tract infection

1

170

Risk Ratio (M‐H, Random, 95% CI)

0.56 [0.27, 1.15]

6.4.5 Poor appetite

1

170

Risk Ratio (M‐H, Random, 95% CI)

0.82 [0.47, 1.42]

6.4.6 Other serious adverse effect

1

170

Risk Ratio (M‐H, Random, 95% CI)

0.45 [0.20, 0.98]

Figuras y tablas -
Comparison 6. Tacrolimus versus IV cyclophosphamide for treating severe kidney disease
Comparison 7. Cyclosporin versus methylprednisolone for treating severe kidney disease

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

7.1 Number with remission at 3 months Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

7.2 Number with remission at last follow‐up (mean 6.3 years) Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

Figuras y tablas -
Comparison 7. Cyclosporin versus methylprednisolone for treating severe kidney disease
Comparison 8. Mycophenolate mofetil versus IV cyclophosphamide for treating severe kidney disease

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

8.1 Number with complete remission Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

8.1.1 Three months

1

68

Risk Ratio (M‐H, Random, 95% CI)

1.20 [0.72, 1.99]

8.1.2 Six months

1

68

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.78, 1.34]

8.1.3 Twelve months

1

68

Risk Ratio (M‐H, Random, 95% CI)

1.06 [0.83, 1.35]

8.2 Number with complete or partial remission Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

8.2.1 Three months

1

68

Risk Ratio (M‐H, Random, 95% CI)

0.87 [0.75, 1.02]

8.2.2 Six months

1

68

Risk Ratio (M‐H, Random, 95% CI)

0.87 [0.75, 1.02]

8.2.3 Twelve months

1

68

Risk Ratio (M‐H, Random, 95% CI)

0.87 [0.75, 1.02]

8.3 Adverse effects Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

8.3.1 Cerebral abscess

1

68

Risk Ratio (M‐H, Random, 95% CI)

0.35 [0.01, 8.37]

8.3.2 Abnormal LFTS requiring treatment change

1

68

Risk Ratio (M‐H, Random, 95% CI)

5.29 [0.26, 106.33]

8.3.3 Infection

1

68

Risk Ratio (M‐H, Random, 95% CI)

0.71 [0.37, 1.35]

8.3.4 Gastrointestinal upsets

1

68

Risk Ratio (M‐H, Random, 95% CI)

3.18 [0.35, 29.08]

Figuras y tablas -
Comparison 8. Mycophenolate mofetil versus IV cyclophosphamide for treating severe kidney disease
Comparison 9. Mycophenolate mofetil versus azathioprine for treating severe kidney disease

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

9.1 Remission of proteinuria at 1 year Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

9.2 Regression of histological lesions at 1 year Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

9.3 Relapse of IgAV Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

9.4 Glomerular filtration rate Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

Figuras y tablas -
Comparison 9. Mycophenolate mofetil versus azathioprine for treating severe kidney disease
Comparison 10. Mycophenolate mofetil versus leflunomide for treating severe kidney disease

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

10.1 24‐hour urine proteinuria Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

10.1.1 Three months

1

18

Mean Difference (IV, Random, 95% CI)

360.00 [‐48.50, 768.50]

10.1.2 Nine months

1

18

Mean Difference (IV, Random, 95% CI)

49.00 [2.78, 95.22]

Figuras y tablas -
Comparison 10. Mycophenolate mofetil versus leflunomide for treating severe kidney disease
Comparison 11. Double filtration plasmapheresis versus no plasmapheresis for treating severe kidney disease

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

11.1 Remission Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

11.1.1 Complete remission after 3 courses of treatment

1

60

Risk Ratio (M‐H, Random, 95% CI)

1.43 [0.63, 3.25]

11.1.2 Complete and partial remission after 3 courses of treatment

1

60

Risk Ratio (M‐H, Random, 95% CI)

1.26 [0.91, 1.75]

11.1.3 Complete remission at 6 months

1

60

Risk Ratio (M‐H, Random, 95% CI)

1.13 [0.89, 1.44]

11.2 Adverse effects Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

11.2.1 Hypertension

1

60

Risk Ratio (M‐H, Random, 95% CI)

0.78 [0.33, 1.82]

11.2.2 Leucopenia

1

60

Risk Ratio (M‐H, Random, 95% CI)

3.00 [0.13, 70.83]

11.2.3 Need for haemodialysis

1

60

Risk Ratio (M‐H, Random, 95% CI)

0.55 [0.23, 1.28]

11.2.4 Respiratory infections

1

60

Risk Ratio (M‐H, Random, 95% CI)

1.33 [0.53, 3.38]

11.2.5 GIT disturbances

1

60

Risk Ratio (M‐H, Random, 95% CI)

1.22 [0.59, 2.51]

Figuras y tablas -
Comparison 11. Double filtration plasmapheresis versus no plasmapheresis for treating severe kidney disease
Comparison 12. Fosinopril + supportive treatment versus supportive treatment for treating proteinuria in IgAV

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

12.1 Proteinuria Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

12.1.1 Complete remission of proteinuria < 150 mg/day

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

12.1.2 Partial remission

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

12.1.3 Minimal response/no response

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

Figuras y tablas -
Comparison 12. Fosinopril + supportive treatment versus supportive treatment for treating proteinuria in IgAV