Corticosteroid therapy for nephrotic syndrome in children.

BACKGROUND: In nephrotic syndrome, protein leaks from the blood into the urine through the glomeruli, resulting in hypoproteinaemia and generalised oedema. While most children with nephrotic syndrome respond to corticosteroids, 80% experience a relapsing course. Corticosteroids have reduced the death rate to around 3%; however, corticosteroids have well-recognised potentially serious adverse events such as obesity, poor growth, hypertension, diabetes mellitus, osteoporosis, cataracts, glaucoma and behavioural disturbances. This is an update of a review first published in 2000 and updated in 2002, 2005, 2007, 2015 and 2020. OBJECTIVES: The aim of this review was to assess the benefits and harms of different corticosteroid regimens in children with steroid-sensitive nephrotic syndrome (SSNS). The benefits and harms of therapy were studied in two groups of children: 1) children in their initial episode of SSNS and 2) children who experience a relapsing course of SSNS. SEARCH METHODS: We contacted the Information Specialist and searched the Cochrane Kidney and Transplant Register of Studies up to 9 July 2024 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) performed in children (one to 18 years) during their initial or subsequent episode of SSNS, comparing different durations, total doses or other dose strategies using any corticosteroid agent. DATA COLLECTION AND ANALYSIS: Summary estimates of effects were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: In this 2024 update, we included five new studies, resulting in 54 studies randomising 4670 children. Risk of bias methodology was often poorly performed, with only 31 studies and 28 studies respectively assessed to be at low risk for random sequence generation and allocation concealment. Ten studies were at low risk of performance bias (blinding of participants and personnel), and 12 studies were at low risk of detection bias (blinding of outcome assessment); nine of these studies were placebo-controlled RCTs. Twenty-seven studies (fewer than 50%) were at low risk for attrition bias, and 26 studies were at low risk for reporting bias (selective outcome reporting). In studies at low risk of selection bias evaluating children in their initial episode of SSNS, there is little or no difference in the number of children with frequent relapses when comparing two months of prednisone with three months or more (RR 0.96, 95% CI 0.83 to 1.10; 755 children, 5 studies; I2 = 0%; high certainty evidence) or when comparing three months with five to seven months of therapy (RR 0.99, 95% CI 0.74 to 1.33; 376 children, 3 studies; I2 = 35%; high certainty evidence). In analyses of studies at low risk of selection bias, there is little or no difference in the number of children with any relapse by 12 to 24 months when comparing two months of prednisone with three months or more (RR 0.93, 95% CI 0.81 to 1.06; 808 children; 6 studies; I2 = 47%) or when comparing three months with five to seven months of therapy (RR 0.88, 95% CI 0.70 to 1.11; 377 children, 3 studies; I2 = 53%). Little or no difference was noted in adverse events between the different treatment durations. Amongst children with relapsing SSNS, four small studies (177 children) utilising lower doses of prednisone compared with standard regimens found little or no differences between groups in the numbers with relapse (RR 1.01, 95% CI 0.85 to 1.20; I2 = 0%). A fifth study (117 children) reported little or no difference between two weeks and four weeks of alternate-day prednisone after remission with daily prednisone. A recent large, well-designed study with 271 children found that administering daily prednisone compared with alternate-day prednisone or no prednisone during viral infection did not reduce the risk of relapse. In contrast, four previous small studies in children with frequently relapsing disease had reported that daily prednisone during viral infections compared with alternate-day prednisone or no treatment reduced the risk of relapse. AUTHORS' CONCLUSIONS: There are four well-designed studies randomising 823 children, which have demonstrated that there is no benefit of prolonging prednisone therapy beyond two to three months in the first episode of SSNS. Small studies in children with relapsing disease have identified no differences in efficacy using lower induction doses or shorter durations of prednisone therapy. Large, well-designed studies are required to confirm these findings. While previous small studies had suggested that changing from alternate-day to daily prednisone therapy at the onset of infection reduced the likelihood of relapse, a much larger and well-designed study found no reduction in the number relapsing when administering daily prednisone at the onset of infection.

Interventions for renal vasculitis in adults.

BACKGROUND: Renal vasculitis presents as rapidly progressive glomerulonephritis and comprises of a group of conditions characterised by acute kidney injury (AKI), haematuria and proteinuria. Treatment of these conditions involve the use of steroid and non-steroid agents in combination with plasma exchange. Although immunosuppression overall has been very successful in treatment of these conditions, many questions remain unanswered in terms of dose and duration of therapy, the use of plasma exchange and the role of new therapies. This 2019 publication is an update of a review first published in 2008 and updated in 2015. OBJECTIVES: To evaluate the benefits and harms of any intervention used for the treatment of renal vasculitis in adults. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 21 November 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials investigating any intervention for the treatment of renal vasculitis in adults. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. Statistical analyses were performed using a random effects model and results expressed as risk ratio (RR) with 95% confidence intervals (CI) for dichotomous outcomes or mean difference (MD) for continuous outcomes. MAIN RESULTS: Forty studies (3764 patients) were included. Studies conducted earlier tended to have a higher risk of bias due to poor (or poorly reported) study design, broad inclusion criteria, less well developed disease definitions and low patient numbers. Later studies tend to have improved in all areas of quality, aided by the development of large international study groups. Induction therapy: Plasma exchange as adjunctive therapy may reduce the need for dialysis at three (2 studies: RR 0.43, 95% CI 0.23 to 0.78; I2 = 0%) and 12 months (6 studies: RR 0.45, 95% CI 0.29 to 0.72; I2 = 0%) (low certainty evidence). Plasma exchange may make little or no difference to death, serum creatinine (SCr), sustained remission or to serious or the total number of adverse events. Plasma exchange may increase the number of serious infections (5 studies: RR 1.26, 95% CI 1.03 to 1.54; I2 = 0%; low certainty evidence). Remission rates for pulse versus continuous cyclophosphamide (CPA) were equivalent but pulse treatment may increase the risk of relapse (4 studies: RR 1.79, 95% CI 1.11 to 2.87; I2 = 0%) (low certainty evidence) compared with continuous cyclophosphamide. Pulse CPA may make little or no difference to death at final follow-up, or SCr at any time point. More patients required dialysis in the pulse CPA group. Leukopenia was less common with pulse treatment; however, nausea was more common. Rituximab compared to CPA probably makes little or no difference to death, remission, relapse, severe adverse events, serious infections, or severe adverse events. Kidney function and dialysis were not reported. A single study reported no difference in the number of deaths, need for dialysis, or adverse events between mycophenolate mofetil (MMF) and CPA. Remission was reported to improve with MMF however more patients relapsed. A lower dose of steroids was probably as effective as high dose and may be safer, causing fewer infections; kidney function and relapse were not reported. There was little of no difference in death or remission between six and 12 pulses of CPA. There is low certainty evidence that there were less relapses with 12 pulses (2 studies: RR 1.57, 95% CI 0.96 to 2.56; I2 = 0%), but more infections (2 studies: RR 0.79, 95% CI 0.36 to 1.72; I2 = 45%). One study reported severe adverse events were less in patients receiving six compared to 12 pulses of CPA. Kidney function and dialysis were not reported. There is limited evidence from single studies about the effectiveness of intravenous immunoglobulin, avacopan, methotrexate, immunoadsorption, lymphocytapheresis, or etanercept. Maintenance therapy: Azathioprine (AZA) has equivalent efficacy as a maintenance agent to CPA with fewer episodes of leucopenia. MMF resulted in a higher relapse rate when tested against azathioprine in remission maintenance. Rituximab is an effective remission induction and maintenance agent. Oral co-trimoxazole did not reduce relapses in granulomatosis with polyangiitis. There were fewer relapses but more serious adverse events with leflunomide compared to methotrexate. There is limited evidence from single studies about the effectiveness of methotrexate versus CPA or AZA, cyclosporin versus CPA, extended versus standard AZA, and belimumab. AUTHORS' CONCLUSIONS: Plasma exchange was effective in patients with severe AKI secondary to vasculitis. Pulse cyclophosphamide may result in an increased risk of relapse when compared to continuous oral use but a reduced total dose. Whilst CPA is standard induction treatment, rituximab and MMF were also effective. AZA, methotrexate and leflunomide were effective as maintenance therapy. Further studies are required to more clearly delineate the appropriate place of newer agents within an evidence-based therapeutic strategy.

Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children.

BACKGROUND: About 80% of children with steroid-sensitive nephrotic syndrome (SSNS) have relapses. Of these children, half relapse frequently, and are at risk of adverse effects from corticosteroids. While non-corticosteroid immunosuppressive medications prolong periods of remission, they have significant potential adverse effects. Currently, there is no consensus about the most appropriate second-line agent in children who are steroid sensitive, but who continue to relapse. In addition, these medications could be used with corticosteroids in the initial episode of SSNS to prolong the period of remission. This is the fourth update of a review first published in 2001 and updated in 2005, 2008 and 2013. OBJECTIVES: To evaluate the benefits and harms of non-corticosteroid immunosuppressive medications in SSNS in children with a relapsing course of SSNS and in children with their first episode of nephrotic syndrome. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 10 March 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs were included if they involved children with SSNS and compared non-corticosteroid immunosuppressive medications with placebo, corticosteroids (prednisone or prednisolone) or no treatment; compared different non-corticosteroid immunosuppressive medications or different doses, durations or routes of administration of the same non-corticosteroid immunosuppressive medication. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study eligibility, risk of bias of the included studies and extracted data. Statistical analyses were performed using a random-effects model and results expressed as risk ratio (RR) for dichotomous outcomes or mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). The certainty of the evidence was assessed using GRADE. MAIN RESULTS: We identified 43 studies (91 reports) and included data from 2428 children. Risk of bias assessment indicated that 21 and 24 studies were at low risk of bias for sequence generation and allocation concealment respectively. Nine studies were at low risk of performance bias and 10 were at low risk of detection bias. Thirty-seven and 27 studies were at low risk of incomplete and selective reporting respectively. Rituximab (in combination with calcineurin inhibitors (CNI) and prednisolone) versus CNI and prednisolone probably reduces the number of children who relapse at six months (5 studies, 269 children: RR 0.23, 95% CI 0.12 to 0.43) and 12 months (3 studies, 198 children: RR 0.63, 95% CI 0.42 to 0.93) (moderate certainty evidence). At six months, rituximab resulted in 126 children/1000 relapsing compared with 548 children/1000 treated with conservative treatments. Rituximab may result in infusion reactions (4 studies, 252 children: RR 5.83, 95% CI 1.34 to 25.29). Mycophenolate mofetil (MMF) and levamisole may have similar effects on the number of children who relapse at 12 months (1 study, 149 children: RR 0.90, 95% CI 0.70 to 1.16). MMF may have a similar effect on the number of children relapsing compared to cyclosporin (2 studies, 82 children: RR 1.90, 95% CI 0.66 to 5.46) (low certainty evidence). MMF compared to cyclosporin is probably less likely to result in hypertrichosis (3 studies, 140 children: RR 0.23, 95% CI 0.10 to 0.50) and gum hypertrophy (3 studies, 144 children: RR 0.09, 95% CI 0.07 to 0.42) (low certainty evidence). Levamisole compared with steroids or placebo may reduce the number of children with relapse during treatment (8 studies, 474 children: RR 0.52, 95% CI 0.33 to 0.82) (low certainty evidence). Levamisole compared to cyclophosphamide may make little or no difference to the risk for relapse after 6 to 9 months (2 studies, 97 children: RR 1.17, 95% CI 0.76 to 1.81) (low certainty evidence). Cyclosporin compared with prednisolone may reduce the number of children who relapse (1 study, 104 children: RR 0.33, 95% CI 0.13 to 0.83) (low certainty evidence). Alkylating agents compared with cyclosporin may make little or no difference to the risk of relapse during cyclosporin treatment (2 studies, 95 children: RR 0.91, 95% CI 0.55 to 1.48) (low certainty evidence) but may reduce the risk of relapse at 12 to 24 months (2 studies, 95 children: RR 0.51, 95% CI 0.35 to 0.74), suggesting that the benefit of the alkylating agents may be sustained beyond the on-treatment period (low certainty evidence). Alkylating agents (cyclophosphamide and chlorambucil) compared with prednisone probably reduce the number of children, who experience relapse at six to 12 months (6 studies, 202 children: RR 0.44, 95% CI 0.32 to 0.60) and at 12 to 24 months (4 studies, 59 children: RR 0.20, 95% CI 0.09 to 0.46) (moderate certainty evidence). IV cyclophosphamide may reduce the number of children with relapse compared with oral cyclophosphamide at 6 months (2 studies, 83 children: RR 0.54, 95% CI 0.34 to 0.88), but not at 12 to 24 months (2 studies, 83 children: RR 0.99, 95% CI 0.76 to 1.29) and may result in fewer infections (2 studies, 83 children: RR 0.14, 95% CI 0.03 to 0.72) (low certainty evidence). Cyclophosphamide compared to chlorambucil may make little or no difference in the risk of relapse after 12 months (1 study, 50 children: RR 1.31, 95% CI 0.80 to 2.13) (low certainty evidence). AUTHORS' CONCLUSIONS: New studies incorporated in this review indicate that rituximab is a valuable additional agent for managing children with steroid-dependent nephrotic syndrome. However, the treatment effect is temporary, and many children will require additional courses of rituximab. The long-term adverse effects of this treatment are not known. Comparative studies of CNIs, MMF, levamisole and alkylating agents have demonstrated little or no differences in efficacy but, because of insufficient power; clinically important differences in treatment effects have not been completely excluded.

Corticosteroid therapy for nephrotic syndrome in children.

BACKGROUND: In nephrotic syndrome protein leaks from blood into the urine through the glomeruli resulting in hypoproteinaemia and generalised oedema. While most children with nephrotic syndrome respond to corticosteroids, 80% experience a relapsing course. Corticosteroids have reduced the death rate to around 3%. However, corticosteroids have well recognised potentially serious adverse effects such as obesity, poor growth, hypertension, diabetes mellitus, osteoporosis, and behavioural disturbances. This is an update of a review first published in 2000 and updated in 2002, 2005, 2007, and 2015. OBJECTIVES: The aim of this review was to assess the benefits and harms of different corticosteroid regimens in children with steroid-sensitive nephrotic syndrome (SSNS). The benefits and harms of therapy were studied in two groups of children 1) children in their initial episode of SSNS, and 2) children who experience a relapsing course of SSNS. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 30 May 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) performed in children (one to 18 years) in their initial or subsequent episode of SSNS, comparing different durations, total doses or other dose strategies using any corticosteroid agent. DATA COLLECTION AND ANALYSIS: Two authors independently assessed risk of bias and extracted data. Results were expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). MAIN RESULTS: In this 2020 review update 16 new included studies were identified providing a total of 48 included studies with 3941 randomised participants. Risk of bias methodology was often poorly performed with only 25 studies and 22 studies respectively assessed to be at low risk for random sequence generation and allocation concealment. Only nine studies (19%) were at low risk of bias for performance (blinding of participants and personnel) and 11 studies were at low risk of detection bias (blinding of outcome assessment); nine of these studies were placebo-controlled RCTs. Twenty-two studies (fewer than 50%) were at low risk for attrition bias and 23 studies were at low risk for reporting bias (selective outcome reporting). In seven studies, which evaluated children in their initial episode of SSNS and were at low risk of bias for selection bias, there is little or no difference in the number of children with frequent relapses when comparing two months of prednisone with three months or more (RR 0.99, 95% CI 0.82 to 1.19; 585 participants, 4 studies; I2 = 0%) or when comparing three months with five to seven months of therapy (RR 0.99, 95% CI 0.74 to 1.33; 376 participants, 3 studies; I2 = 35%; high certainty evidence). In analyses of eight studies at low risk of selection bias, there is little or no difference in the number of children with any relapse by 12 to 24 months when comparing two months of prednisone with three months or more (RR 0.91, 95% CI 0.78 to 1.06; 637 participants; 5 studies; I2 = 47%) or when comparing three months with five to seven months of therapy (RR 0.88, 95% CI 0.70 to 1.11; 377 participants, 3 studies; I2 = 53%). Little or no difference was noted in adverse effects between the different treatment durations. Among children with relapsing SSNS, two small studies showed that time to remission did not differ between prednisone doses of 1 mg/kg compared with the conventional dose of 2 mg/kg (MD 0.71 days, 95% CI -0.43 to 1.86; 79 participants) and that the total prednisone dose administered was lower (MD -20.60 mg/kg, 95% CI -25.65 to -15.55; 20 participants). Two studies found little or no difference in the number with relapse at six months when comparing dosing by weight with dosing by surface area (RR 1.03, 95% CI 0.71 to 1.49; 146 participants). One study found a reduced risk of relapse with low daily dosing compared with alternate daily dosing (MD -0.90 number of relapses/year, 95% CI -1.33 to -0.47). Four studies found that in children with frequently relapsing disease, daily prednisone during viral infections compared with alternate-day prednisone or no treatment reduced the risk of relapse. AUTHORS' CONCLUSIONS: There are now four well designed studies randomising 823 children which have clearly demonstrated that there is no benefit of prolonging prednisone therapy beyond two to three months in the first episode of SSNS. Small studies in children with relapsing disease have identified no differences in the times to remission using half the conventional induction dose of 2 mg/kg or 60 mg/m2. It is imperative that a much larger study be carried out to confirm these findings. Lower dose prednisone therapy administered daily during an upper respiratory infection or other infection reduces the risk of relapse compared with continuing alternate-day prednisone or no prednisone based on four small studies. The results of a much larger RCT enrolling more than 300 children are awaited to determine the relative efficacies and adverse effects of using alternate-day compared with daily prednisone to prevent relapse in children with intercurrent infections.

Interventions for idiopathic steroid-resistant nephrotic syndrome in children.

BACKGROUND: The majority of children who present with their first episode of nephrotic syndrome achieve remission with corticosteroid therapy. Children who fail to respond to corticosteroids in the first episode of nephrotic syndrome (initial resistance) or develop resistance after one or more responses to corticosteroids (delayed resistance) may be treated with immunosuppressive agents including calcineurin inhibitors (CNI) (cyclosporin or tacrolimus) and with non-immunosuppressive agents such as angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). However, response to these agents is limited so newer agents are being assessed for efficacy. This is an update of a review first published in 2004 and updated in 2006, 2010 and 2016. OBJECTIVES: To evaluate the benefits and harms of different interventions used in children with idiopathic nephrotic syndrome, who do not achieve remission following four weeks or more of daily corticosteroid therapy. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies to 17 September 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs were included if they compared different immunosuppressive agents or non-immunosuppressive agents with placebo, prednisone or other agent given orally or parenterally in children aged three months to 18 years with steroid-resistant nephrotic syndrome (SRNS). Studies, which enrolled children and adults but in which paediatric data could not be separated from adult data, were also included. DATA COLLECTION AND ANALYSIS: Two authors independently searched the literature, determined study eligibility, assessed risk of bias and extracted data. For dichotomous outcomes, results were expressed as risk ratios (RR) and 95% confidence intervals (CI). For continuous outcomes, results were expressed as mean difference (MD) and 95% CI. Data were pooled using the random effects model. The certainty of the evidence was assessed using the GRADE approach. MAIN RESULTS: Twenty-five studies (1063 participants) were included. Fourteen studies were at low risk of bias for sequence generation and allocation concealment. Five and 19 studies were at low risk of performance and detection bias. Fourteen, 14 and 13 studies were at low risk of attrition bias, reporting bias and other bias respectively. Cyclosporin compared with placebo or no treatment may increase the number of participants who achieve complete remission (4 studies, 74 participants: RR 3.50, 95% CI 1.09 to 11.20) or complete or partial remission (4 studies, 74 children: RR 3.15, 95% CI 1.04 to 9.57) by 6 months (low certainty evidence). It is uncertain whether cyclosporin increases the likelihood of worsening hypertension or reduces the likelihood of end-stage kidney disease (very low certainty evidence). CNI compared with IV cyclophosphamide (CPA) may increase the number of participants with complete or partial remission at 3 to 6 months (2 studies, 156 children: RR 1.98, 95% CI 1.25 to 3.13) (low certainty evidence) and probably reduces the number with treatment failure (non response, serious infection, persistently elevated creatinine (1 study, 124 participants: RR 0.32, 95% CI 0.18 to 0.58) (moderate certainty evidence) with little or no increase in serious infections (1 study, 131 participants: RR 0.49, 95% CI 0.16 to 1.56) (moderate certainty evidence). Tacrolimus compared with cyclosporin may make little or no difference to the number who achieve complete or partial remission (2 studies, 58 participants: RR 1.05, 95% CI 0.87 to 1.25) (low certainty evidence) or in the number with worsening hypertension (2 studies, 58 participants: RR 0.41, 95% CI 0.08 to 2.15) (low certainty evidence). Cyclosporin compared with mycophenolate mofetil (MMF) and dexamethasone probably makes little or no difference to the number who achieve complete or partial remission (1 study, 138 participants: RR 2.14, 95% CI 0.87 to 5.24) (moderate certainty evidence) and makes little or no difference to the number dying (1 study, 138 participants: RR 2.14, 95% CI 0.87 to 5.24) or with 50% reduction in glomerular filtration rate (GFR) (1 study, 138 participants: RR 2.29, 95% CI 0.46 to 11.41) (low certainty evidence). Among children, who have achieved complete remission, tacrolimus compared with MMF may increase the number of children who maintain complete or partial response for 12 months (1 study, 60 children: RR 2.01, 95% CI 1.32 to 3.07) (low certainty evidence). Oral CPA with prednisone compared with prednisone alone may make little or no difference to the number who achieve complete remission (2 studies, 84 children: RR 1.06, 95% CI 0.61 to 1.87) (low certainty evidence). IV CPA compared with oral CPA (2 studies, 61 children: RR 1.58, 95% CI 0.65 to 3.85) and IV compared with oral CPA plus IV dexamethasone (1 study, 49 children: RR 1.13, 95% CI 0.65 to 1.96) may make little or no difference to the number who achieve complete remission (low certainty evidence). It is uncertain whether rituximab and cyclosporin compared with cyclosporin increases the likelihood of remission because the certainty of the evidence is very low. It is uncertain whether adalimumab or galactose compared with conservative therapy increases the likelihood of remission because the certainty of the evidence is very low. Two studies reported that ACEi may reduce proteinuria in children with SRNS. One study reported that the dual angiotensin II and endothelin Type A receptor antagonist, sparsentan, may reduce proteinuria more effectively than the angiotensin receptor blocker, irbesartan. AUTHORS' CONCLUSIONS: To date RCTs have demonstrated that CNIs may increase the likelihood of complete or partial remission compared with placebo/no treatment or CPA. For other regimens assessed, it remains uncertain whether the interventions alter outcomes because the certainty of the evidence is low. Further adequately powered, well designed RCTs are needed to evaluate other regimens for children with idiopathic SRNS. Since SRNS represents a spectrum of diseases, future studies should enrol children from better defined groups of patients with SRNS.

Interventions for idiopathic steroid-resistant nephrotic syndrome in children.

BACKGROUND: The majority of children who present with their first episode of nephrotic syndrome achieve remission with corticosteroid therapy. Children who fail to respond may be treated with immunosuppressive agents including calcineurin inhibitors (cyclosporin or tacrolimus) and with non-immunosuppressive agents such as angiotensin-converting enzyme inhibitors (ACEi). Optimal combinations of these agents with the least toxicity remain to be determined. This is an update of a review first published in 2004 and updated in 2006 and 2010. OBJECTIVES: To evaluate the benefits and harms of different interventions used in children with idiopathic nephrotic syndrome, who do not achieve remission following four weeks or more of daily corticosteroid therapy. SEARCH METHODS: We searched Cochrane Kidney and Transplant's Specialised Register (up to 2 March 2016) through contact with the Information Specialist using search terms relevant to this review. SELECTION CRITERIA: RCTs and quasi-RCTs were included if they compared different immunosuppressive agents or non-immunosuppressive agents with placebo, prednisone or other agent given orally or parenterally in children aged three months to 18 years with SRNS. DATA COLLECTION AND ANALYSIS: Two authors independently searched the literature, determined study eligibility, assessed risk of bias and extracted data. For dichotomous outcomes, results were expressed as risk ratios (RR) and 95% confidence intervals (CI). Data were pooled using the random effects model. MAIN RESULTS: Nineteen RCTs (820 children enrolled; 773 evaluated) were included. Most studies were small. Eleven studies were at low risk of bias for allocation concealment and only four studies were at low risk of performance bias. Fifteen, eight and 10 studies were at low risk of detection bias, attrition bias and reporting bias respectively. Cyclosporin when compared with placebo or no treatment significantly increased the number of children who achieved complete remission. However this was based on only eight children who achieved remission with cyclosporin compared with no children who achieved remission with placebo/no treatment in three small studies (49 children: RR 7.66, 95% CI 1.06 to 55.34). Calcineurin inhibitors significantly increased the number with complete or partial remission compared with IV cyclophosphamide (2 studies, 156 children: RR 1.98, 95% CI 1.25 to 3.13; I2 = 20%). There was no significant differences in the number who achieved complete remission between tacrolimus versus cyclosporin (1 study, 41 children: RR 0.86, 95% CI 0.44 to 1.66), cyclosporin versus mycophenolate mofetil plus dexamethasone (1 study, 138 children: RR 2.14, 95% CI 0.87 to 5.24), oral cyclophosphamide with prednisone versus prednisone alone (2 studies, 91 children: RR 1.06, 95% CI 0.61 to 1.87), IV versus oral cyclophosphamide (1 study, 11 children: RR 3.13, 95% CI 0.81 to 12.06), IV cyclophosphamide versus oral cyclophosphamide plus IV dexamethasone (1 study, 49 children: RR 1.13, 95% CI 0.65 to 1.96), and azathioprine with prednisone versus prednisone alone (1 study, 31 children: RR 0.94, 95% CI 0.15 to 5.84). One study found no significant differences between three agents (cyclophosphamide, mycophenolate mofetil, leflunomide) used in combination with tacrolimus and prednisone. One study found no significant difference in the percentage reduction in proteinuria (31 children: -12; 95% CI -73 to 110) between rituximab with cyclosporin/prednisolone and cyclosporin/prednisolone alone. Two studies reported ACEi significantly reduced proteinuria. AUTHORS' CONCLUSIONS: To date RCTs have demonstrated that calcineurin inhibitors increase the likelihood of complete or partial remission compared with placebo/no treatment or cyclophosphamide. For other regimens assessed, it remains uncertain whether the interventions alter outcomes because the certainty of the evidence is low. Further adequately powered, well designed RCTs are needed to evaluate other regimens for children with idiopathic SRNS. Since SRNS represents a spectrum of diseases, future studies should enrol children from better defined groups of patients with SRNS.

Interventions for renal vasculitis in adults.

BACKGROUND: Renal vasculitis presents as rapidly progressive glomerulonephritis which comprises of a group of conditions characterised by acute kidney injury (AKI), haematuria and proteinuria. Treatment of these conditions comprises steroid and non-steroid agents in combination with plasma exchange. Although immunosuppression overall has been very successful in treatment of these conditions, many questions remain unanswered in terms of dose and duration of therapy, the use of plasma exchange and the role of new therapies. This an update of a review first published in 2008. OBJECTIVES: To evaluate the benefits and harms of any intervention used for the treatment of renal vasculitis in adults. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register up to 27 July 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: Randomised controlled trials investigating any intervention for the treatment of renal vasculitis in adults. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. Statistical analyses were performed using a random effects model and results expressed as risk ratio (RR) with 95% confidence intervals (CI) for dichotomous outcomes or mean difference (MD) for continuous outcomes. MAIN RESULTS: Thirty one studies (2217 patients) were included. Studies conducted earlier tended to have a higher risk of bias due to poor (or poorly reported) study design, broad inclusion criteria, less well developed disease definitions and low patient numbers. Later studies tend to have improved in all areas of quality, aided by the development of large transnational study groups.Plasma exchange as adjunctive therapy significantly reduces the risk of end-stage kidney disease at three months (2 studies: RR 0.43, 95% CI 0.23 to 0.78) and 12 months (6 studies: RR 0.45, 95% CI 0.29 to 0.72). Four studies (300 patients) compared the use of pulse and continuous administration of cyclophosphamide. Remission rates were equivalent but pulse treatment causes an increased risk of relapse (4 studies: RR 1.79, 95% CI 1.11 to 2.87) compared with continuous cyclophosphamide. Azathioprine has equivalent efficacy as a maintenance agent to cyclophosphamide with fewer episodes of leucopenia. Mycophenolate mofetil may be equivalent to cyclophosphamide as an induction agent but resulted in a higher relapse rate when tested against azathioprine in remission maintenance. Rituximab is an effective remission induction agent. Methotrexate or leflunomide are potential choices in remission maintenance therapy. Oral co-trimoxazole did not reduce relapses significantly in granulomatosis with polyangiitis. AUTHORS' CONCLUSIONS: Plasma exchange was effective in patients with severe AKI secondary to vasculitis. Pulse cyclophosphamide results in an increased risk of relapse when compared to continuous oral use but a reduced total dose. Whilst cyclophosphamide is standard induction treatment, rituximab and mycophenolate mofetil were also effective. Azathioprine, methotrexate and leflunomide were effective as maintenance therapy. Further studies are required to more clearly delineate the appropriate place of newer agents within an evidence-based therapeutic strategy.

Corticosteroid therapy for nephrotic syndrome in children.

BACKGROUND: In nephrotic syndrome protein leaks from the blood to the urine through the glomeruli resulting in hypoproteinaemia and generalised oedema. While most children with nephrotic syndrome respond to corticosteroids, 80% experience a relapsing course. Corticosteroids have reduced the mortality rate to around 3%. However corticosteroids have well recognised potentially serious adverse effects such as obesity, poor growth, hypertension, diabetes mellitus, osteoporosis and behavioural disturbances. This is an update of a review first published in 2000 and updated in 2003, 2005 and 2007. OBJECTIVES: The aim of this review was to assess the benefits and harms of different corticosteroid regimens in children with steroid-sensitive nephrotic syndrome (SSNS). The benefits and harms of therapy were studied in two groups of children 1) children in their initial episode of SSNS, and 2) children who experience a relapsing course of SSNS. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register to 26 February 2015 through contact with the Trials Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: Randomised controlled trials (RCTs) performed in children (three months to 18 years) in their initial or subsequent episode of SSNS, comparing different durations, total doses or other dose strategies using any corticosteroid agent. DATA COLLECTION AND ANALYSIS: Two authors independently assessed risk of bias and extracted data. Results were expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). MAIN RESULTS: Ten new studies were identified so a total of 34 studies (3033 total participants) were included in the 2015 review update. The risk of bias attributes were frequently poorly performed. Low risk of bias was reported in 18 studies for sequence generation, 16 studies for allocation concealment, seven for performance and detection bias, 15 for incomplete reporting and 16 for selective reporting. Three months or more of prednisone significantly reduced the risk of frequently relapsing nephrotic syndrome (FRNS) (6 studies, 582 children: RR 0.68, 95% CI 0.47 to 1.00) and of relapse by 12 to 24 months (8 studies, 741 children: RR 0.80, 95% CI 0.64 to 1.00) compared with two months. Five or six months of prednisone significantly reduced the risk of relapse (7 studies, 763 children: RR 0.62, 95% CI 0.45 to 0.85) but not FRNS (5 studies, 591 children: RR 0.78, 95% CI 0.50 to 1.22) compared with three months. However there was significant heterogeneity in the analyses. Subgroup analysis stratified by risk of bias for allocation concealment showed that the risk for FRNS did not differ significantly between two or three months of prednisone and three to six months among studies at low risk of bias but was significantly reduced in extended duration studies compared with two or three months in studies at high risk or unclear risk of bias. There were no significant differences in the risk of adverse effects between extended duration and two or three months of prednisone. Four studies found that in children with FRNS, daily prednisone during viral infections compared with alternate-day prednisone or no treatment significantly reduced the rate of relapse. AUTHORS' CONCLUSIONS: In this 2015 update the addition of three well-designed studies has changed the conclusion of this review. Studies of long versus shorter duration of corticosteroids have heterogeneous treatment effects, with the older high risk of bias studies tending to over-estimate the effect of longer course therapy, compared with more recently published low risk of bias studies. Among studies at low risk of bias, there was no significant difference in the risk for FRNS between prednisone given for two or three months and longer durations or total dose of therapy indicating that there is no benefit of increasing the duration of prednisone beyond two or three months in the initial episode of SSNS.The risk of relapse in children with FRNS is reduced by the administration of daily prednisone at onset of an upper respiratory tract or viral infection. Three additional studies have increased the evidence supporting this conclusion. This management strategy may be considered for children with FRNS. A paucity of data on prednisone use in relapsing nephrotic syndrome remains. In particular there are no data from RCTs evaluating the efficacy and safety of prolonged courses of low dose alternate-day prednisone although this management strategy is recommended in current guidelines.

Interventions for preventing and treating kidney disease in Henoch-Schönlein Purpura (HSP).

BACKGROUND: Henoch-Schönlein purpura (HSP) is the most common vasculitis of childhood but may occur in adults. This small vessel vasculitis is characterised by palpable purpura, abdominal pain, arthritis or arthralgia and kidney involvement. This is an update of a review first published in 2009. 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: (1) the prevention of severe kidney disease in patients with HSP without kidney disease at presentation; (2) the prevention of severe kidney disease in patients with HSP and minor kidney disease (microscopic haematuria, mild proteinuria) at presentation; (3) the treatment of established severe kidney disease (macroscopic haematuria, proteinuria, nephritic syndrome, nephrotic syndrome with or without acute kidney failure) in HSP; and (4) the prevention of recurrent episodes of HSP-associated kidney disease. SEARCH METHODS: We searched the Cochrane Kidney and Transplant's Specialised Register to 13 July 2015 through contact with the Trials Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing interventions used to prevent or treat kidney disease in HSP compared with placebo, no treatment or other agents were included. DATA COLLECTION AND ANALYSIS: Two authors independently determined study eligibility, assessed risk of bias and extracted data from each study. Statistical analyses were performed using the random effects model and the results were expressed as risk ratio (RR) or risk difference (RD) for dichotomous outcomes and mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). MAIN RESULTS: Thirteen studies (1403 enrolled patients) were identified. Risks of bias attributes were frequently poorly performed. Low risk of bias was reported in six studies (50%) for sequence generation (selection bias) and in seven (58%) for allocation concealment (selection bias). Blinding of participants and personnel (performance bias) and of outcome assessment (detection bias) was at low risk of bias in three studies. Five studies reported complete outcome data (attrition bias) while eight studies reported expected outcomes so were at low risk of reporting bias.Eight studies evaluated therapy to prevent persistent kidney disease in HSP. There was no significant difference in the risk of persistent kidney disease any time after treatment (5 studies, 746 children: RR 0.74, 95% CI 0.42 to 1.32), or at one, three, six and 12 months in children given prednisone for 14 to 28 days at presentation of HSP compared with placebo or supportive treatment. There were no significant differences in the risk of persistent kidney disease with antiplatelet therapy in children with or without kidney disease at entry. Heparin significantly reduced the risk of persistent kidney disease by three months compared with placebo (1 study, 228 children: RR 0.27, 95% CI 0.14 to 0.55); no significant bleeding occurred. Four studies examined the treatment of severe HSP-associated kidney disease. Two studies (one involving 56 children and the other involving 54 adults) compared cyclophosphamide with placebo or supportive treatment and found no significant benefit of cyclophosphamide. There were no significant differences in adverse effects. In one study comparing cyclosporin with methylprednisolone (15 children) there was no significant difference in remission at final follow-up at a mean of 6.3 years (RR 1.37, 95% CI 0.74 to 2.54). In one study (17 children) comparing mycophenolate mofetil with azathioprine, there was no significant difference in the remission of proteinuria at one year (RR 1.32, 95% CI 0.86 to 2.03). No studies were identified which evaluated the efficacy of therapy on kidney disease in participants with recurrent episodes of HSP. AUTHORS' CONCLUSIONS: There are no substantial changes in conclusions from this update compared with the initial review. From generally low quality evidence, we found no evidence of benefit from RCTs for the use of prednisone or antiplatelet agents to prevent persistent kidney disease in children with HSP. Though heparin appeared effective, this potentially dangerous therapy is not justified to prevent serious kidney disease when fewer than 2% of children with HSP develop severe kidney disease. No evidence of benefit has been found for cyclophosphamide treatment in children or adults with HSP and severe kidney disease. Because of small patient numbers and events leading to imprecision in results, it remains unclear whether cyclosporin and mycophenolate mofetil have any roles in the treatment of children with HSP and severe kidney disease.

Predictors of remission and relapse in idiopathic nephrotic syndrome: a prospective cohort study.

BACKGROUND: Although most children with idiopathic nephrotic syndrome will respond to corticosteroid therapy, 80-90 % suffer one or more relapses. METHODS: Using Cox proportional hazard models, we analyzed predictors of remission and relapse in 1-year follow-up data on children aged below 15 years with new-onset nephrotic syndrome. RESULTS: Of 129 children, 107 achieved remission with corticosteroid therapy and 86 subsequently relapsed. Boys achieved remission more often than girls (adjusted hazard ratio [AHR] 1.52, 95 % confidence interval (CI) 1.02-2.3). Boys relapsed significantly more frequently than girls (AHR 1.77, 95 % CI 1.11-2.83) and were more likely to have frequently relapsing disease (AHR 3.3, 95 % CI 1.18-9.23). The risk of first relapse increased with the number of days to first remission (AHR 1.02, 95 % CI 1.01-1.04). The risk for a frequently relapsing course increased with a shorter time from remission to first relapse (AHR 0.92, 95 % CI 0.87-0.97). CONCLUSIONS: In idiopathic nephrotic syndrome, boys are more likely to respond initially, more likely to relapse, and to be classified as having frequently relapsing nephrotic syndrome. A decrease in time from remission to first relapse predicts for a frequently relapsing course.

Antibiotics for acute pyelonephritis in children.

BACKGROUND: Urinary tract infection (UTI) is one of the most common bacterial infections in infants. The most severe form of UTI is acute pyelonephritis, which results in significant acute morbidity and may cause permanent kidney damage. There remains uncertainty regarding the optimum antibiotic regimen, route of administration and duration of treatment. This is an update of a review that was first published in 2003 and updated in 2005 and 2007. OBJECTIVES: To evaluate the benefits and harms of antibiotics used to treat children with acute pyelonephritis. The aspects of therapy considered were 1) different antibiotics, 2) different dosing regimens of the same antibiotic, 3) different duration of treatment, and 4) different routes of administration. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register, CENTRAL, MEDLINE, EMBASE, reference lists of articles and conference proceedings without language restriction to 10 April 2014. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing different antibiotic agents, routes, frequencies or durations of therapy in children aged 0 to 18 years with proven UTI and acute pyelonephritis were selected. DATA COLLECTION AND ANALYSIS: Four authors independently assessed study quality and extracted data. Statistical analyses were performed using the random-effects model and the results expressed as risk ratio (RR) for dichotomous outcomes or mean difference (MD) for continuous data with 95% confidence intervals (CI). MAIN RESULTS: This updated review included 27 studies (4452 children). This update included evidence from three new studies, and following re-evaluation, a previously excluded study was included because it now met our inclusion criteria.Risk of bias was assessed as low for sequence generation (12 studies), allocation concealment (six studies), blinding of outcome assessors (17 studies), incomplete outcome reporting (19 studies) and selective outcome reporting (13 studies). No study was blinded for participants or investigators. The 27 included studies evaluated 12 different comparisons. No significant differences were found in duration of fever (2 studies, 808 children: MD 2.05 hours, 95% CI -0.84 to 4.94), persistent UTI at 72 hours after commencing therapy (2 studies, 542 children: RR 1.10, 95% CI 0.07 to 17.41) or persistent kidney damage at six to 12 months (4 studies, 943 children: RR 0.82, 95% CI 0.59 to 1.12) between oral antibiotic therapy (10 to 14 days) and intravenous (IV) therapy (3 days) followed by oral therapy (10 days). Similarly, no significant differences in persistent bacteriuria at the end of treatment (4 studies, 305 children: RR 0.78, 95% CI 0.24 to 2.55) or persistent kidney damage (4 studies, 726 children: RR 1.01, 95% CI 0.80 to 1.29) were found between IV therapy (three to four days) followed by oral therapy and IV therapy (seven to 14 days). No significant differences in efficacy were found between daily and thrice daily administration of aminoglycosides (1 study, 179 children, persistent clinical symptoms at three days: RR 1.98, 95% CI 0.37 to 10.53). Adverse events were mild and uncommon and rarely resulted in discontinuation of treatment. AUTHORS' CONCLUSIONS: This updated review increases the body of evidence that oral antibiotics alone are as effective as a short course (three to four days) of IV antibiotics followed by oral therapy for a total treatment duration of 10 to 14 days for the treatment of acute pyelonephritis in children. When IV antibiotics are given, a short course (two to four days) of IV therapy followed by oral therapy is as effective as a longer course (seven to 10 days) of IV therapy. If IV therapy with aminoglycosides is chosen, single daily dosing is safe and effective. Insufficient data are available to extrapolate these findings to children aged less than one month of age or to children with dilating vesicoureteric reflux (grades III-V). Further studies are required to determine the optimal total duration of antibiotic therapy required for acute pyelonephritis.

Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children.

BACKGROUND: About 80% to 90% of children with steroid-sensitive nephrotic syndrome (SSNS) have relapses. Of these children, around half relapse frequently, and are at risk of adverse effects from corticosteroids. Non-corticosteroid immunosuppressive medications are used to prolong periods of remission in these children; however, these medications have significant potential adverse effects. Currently, there is no consensus about the most appropriate second line agent in children who are steroid sensitive, but who continue to relapse. This is the third update of a review first published in 2001 and updated in 2005 and 2008. OBJECTIVES: To evaluate the benefits and harms of non-corticosteroid immunosuppressive medications in relapsing SSNS in children. SEARCH METHODS: For this update we searched the Cochrane Renal Group's Specialised Register to June 2013. SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs were included if they compared non-corticosteroid immunosuppressive medications with placebo, prednisone or no treatment, different non-corticosteroid immunosuppressive medications and different doses, durations or routes of administration of the same non-corticosteroid immunosuppressive medication. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risk of bias of the included studies and extracted data. Statistical analyses were performed using a random-effects model and results expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). MAIN RESULTS: We identified 32 studies (1443 children) of which one study is still ongoing. In the 31 studies with data, risk of bias assessment indicated that 11 (37%) and 16 (53%) studies were at low risk of bias for sequence generation and allocation concealment respectively. Six (29%) studies were at low risk of performance and detection bias. Twenty seven (87%) and 19 (60%) studies were at low risk of incomplete and selective reporting respectively. Alkylating agents (cyclophosphamide and chlorambucil) significantly reduced the risk of relapse at six to 12 months (RR 0.43, 95% CI 0.31 to 0.60) and 12 to 24 months (RR 0.20, 95% CI 0.09 to 0.46) compared with prednisone alone. There was no significant difference in relapse risk at two years between chlorambucil and cyclophosphamide (RR 1.31, 95% CI 0.80 to 2.13). There was no significant difference at one year between intravenous and oral cyclophosphamide (RR 0.99, 95% CI 0.76 to 1.29). Cyclosporin was as effective as cyclophosphamide (RR 1.07, 95% CI 0.48 to 2.35) and chlorambucil (RR 0.82, 95% CI 0.44 to 1.53) at the end of therapy while levamisole (RR 0.47, 95% CI 0.24 to 0.89) was more effective than steroids alone. However the effects of cyclosporin and levamisole were not sustained once treatment was stopped. In one small study cyclosporin significantly reduced the relapse rate compared with mycophenolate mofetil (MD 0.75, 95% CI 0.01 to 1.49). Limited data from a cross-over study suggested that cyclosporin was more effective than mycophenolate mofetil in maintaining remission. In steroid- and cyclosporin-dependent disease, rituximab significantly reduced the risk of relapse at three months compared with conventional therapy. Mizoribine and azathioprine were no more effective than placebo or prednisone alone in maintaining remission. AUTHORS' CONCLUSIONS: Eight-week courses of cyclophosphamide or chlorambucil and prolonged courses of cyclosporin and levamisole reduce the risk of relapse in children with relapsing SSNS compared with corticosteroids alone. Limited data indicate that mycophenolate mofetil and rituximab are valuable additional medications for relapsing SSNS. However clinically important differences in efficacy are possible and further comparative studies are still needed.

Growth hormone for children with chronic kidney disease.

BACKGROUND: Growth retardation is a common complication of chronic kidney disease (CKD) in children and is of concern to families. Recombinant human growth hormone (rhGH) treatment has been used to help short children with CKD attain a height more in keeping with their age group. However there are concerns about the long-term benefits of rhGH in significantly improving adult height as well as concerns about potential adverse effects (deterioration in native kidney function, increased acute rejection in kidney transplant recipients, benign intracranial hypertension). OBJECTIVES: To evaluate the benefits and harms of rhGH treatment in children with CKD. SEARCH METHODS: Randomised controlled trials (RCTs) were identified from the Cochrane Renal Group's Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 12, 2011), MEDLINE (from 1966), EMBASE (from 1980), article reference lists and through contact with local and international experts in the field.Date of last search: December 29, 2011 SELECTION CRITERIA: RCTs were included if they were carried out in children aged zero to 18 years, diagnosed with CKD, who were pre-dialysis, on dialysis or post-transplant; if they compared rhGH treatment with placebo/no treatment or two doses of rhGH treatments; and if they included height outcomes. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for risk of bias and extracted data from eligible studies. Data was pooled using a random effects model with calculation of mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). MAIN RESULTS: Sixteen studies (enrolling 809 children) were identified. Risk of bias assessment indicated that study quality was poor or poorly reported with only four and five studies respectively reporting adequate allocation concealment or blinding of study participants and investigators. Treatment with rhGH (28 IU/m²/wk) compared with placebo or no specific therapy resulted in a significant increase in height standard deviation score (HSDS) at one year (8 studies, 391 children: MD 0.82, 95% CI 0.56 to 1.07), and a significant increase in height velocity at six months (2 studies, 27 children: MD 2.85 cm/6 mo, 95% CI 2.22 to 3.48) and one year (7 studies, 287 children: MD 3.88 cm/y, 95% CI 3.32 to 4.44). Height velocity, though reduced, remained significantly greater than untreated children during the second year of therapy (1 study, 82 children: MD 2.30 cm/y, 95% CI 1.39 to 3.21). Compared to the 14 IU/m²/wk group, there was a 1.18 cm/y increase in height velocity in the 28 IU/m²/wk group (3 studies, 150 children: 1.18 cm/y, 95% CI 0.52 to 1.84) . The frequency of reported side effects of rhGH was generally similar to that of the control group. AUTHORS' CONCLUSIONS: One year of 28 IU/m²/wk rhGH in children with CKD resulted in a 3.88 cm increase in height velocity above that of untreated patients. Studies were too short to determine if continuing treatment resulted in an increase in final adult height.

Interventions for idiopathic steroid-resistant nephrotic syndrome in children.

BACKGROUND: The majority of children who present with their first episode of nephrotic syndrome achieve remission with corticosteroid therapy. Children who fail to respond may be treated with immunosuppressive agents including calcineurin inhibitors (cyclosporin or tacrolimus) and with non-immunosuppressive agents such as angiotensin-converting enzyme inhibitors (ACEi). Optimal combinations of these agents with the least toxicity remain to be determined. OBJECTIVES: To evaluate the benefits and harms of interventions used to treat idiopathic steroid-resistant nephrotic syndrome (SRNS) in children. SEARCH STRATEGY: Randomised controlled trials (RCTs) were identified from the Cochrane Renal Group's specialised register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and reference lists of articles. SELECTION CRITERIA: RCTs and quasi-RCTs were included if they compared different immunosuppressive agents or non-immunosuppressive agents with placebo, prednisone or other agent given orally or parenterally in children aged three months to 18 years with SRNS. DATA COLLECTION AND ANALYSIS: Two authors independently searched the literature, determined study eligibility, assessed quality and extracted data. For dichotomous outcomes, results were expressed as risk ratios (RR) and 95% confidence intervals (CI). Data were pooled using the random effects model. MAIN RESULTS: Fourteen RCTs (449 children) were included. Cyclosporin when compared with placebo or no treatment significantly increased the number of children who achieved complete remission (three studies, 49 children: RR 7.66, 95% CI 1.06 to 55.34). Cyclosporin significantly increased the number with complete or partial remission compared with IV cyclophosphamide (one study, 32 children: RR 3.40, 95% CI 1.12 to 10.28). There was no significant difference in the number who achieved complete remission between oral cyclophosphamide with prednisone versus prednisone alone (two studies, 91 children: RR 1.06, 95% CI 0.61 to 1.87), IV versus oral cyclophosphamide (one study, 11 children: RR 3.13, 95% CI 0.81 to 12.06), IV cyclophosphamide versus oral cyclophosphamide with IV dexamethasone (one study, 49 children: RR 1.13, 95% CI 0.65 to 1.96), tacrolimus versus cyclosporin (one study, 41 children: RR 0.86, 95% CI 0.44 to 1.66) and azathioprine with prednisone versus prednisone alone (one study, 31 children: RR 0.94, 95% CI 0.15 to 5.84). ACEi significantly reduced proteinuria (two studies, 70 children). No studies were identified comparing high dose steroids and cyclosporin with single agents, placebo or no treatment. AUTHORS' CONCLUSIONS: Further adequately powered, well designed RCTs are needed to confirm the efficacy of cyclosporin and to evaluate other regimens for idiopathic SRNS including high dose steroids with cyclosporin.

Interleukin 2 receptor antagonists for kidney transplant recipients.

BACKGROUND: Interleukin 2 receptor antagonists (IL2Ra) are used as induction therapy for prophylaxis against acute rejection in kidney transplant recipients. Use of IL2Ra has increased steadily since their introduction, but the proportion of new transplant recipients receiving IL2Ra differs around the globe, with 27% of new kidney transplant recipients in the United States, and 70% in Australasia receiving IL2Ra in 2007. OBJECTIVES: To systematically identify and summarise the effects of using an IL2Ra, as an addition to standard therapy, or as an alternative to another immunosuppressive induction strategy. SEARCH STRATEGY: We searched the Cochrane Renal Group's specialised register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE to identify new records, and authors of included reports were contacted for clarification where necessary. SELECTION CRITERIA: Randomised controlled trials (RCTs) in all languages comparing IL2Ra to placebo, no treatment, other IL2Ra or other antibody therapy. DATA COLLECTION AND ANALYSIS: Data was extracted and assessed independently by two authors, with differences resolved by discussion. Dichotomous outcomes are reported as relative risk (RR) and continuous outcomes as mean difference (MD) with 95% confidence intervals (CI). MAIN RESULTS: We included 71 studies (306 reports, 10,537 participants). Where IL2Ra were compared with placebo (32 studies; 5,784 patients) graft loss including death with a functioning graft was reduced by 25% at six months (16 studies: RR 0.75, 95% CI 0.58 to 0.98) and one year (24 studies: RR 0.75, 95% CI 0.62 to 0.90), but not beyond this. At one year biopsy-proven acute rejection was reduced by 28% (14 studies: RR 0.72, 95% CI 0.64 to 0.81), and there was a 19% reduction in CMV disease (13 studies: RR 0.81, 95% CI 0.68 to 0.97). There was a 64% reduction in early malignancy within six months (8 studies: RR 0.36, 95% CI 0.15 to 0.86), and creatinine was lower (7 studies: MD -8.18 micromol/L 95% CI -14.28 to -2.09) but these differences were not sustained.When IL2Ra were compared to ATG (16 studies, 2211 participants), there was no difference in graft loss at any time point, or for acute rejection diagnosed clinically, but the was benefit of ATG therapy over IL2Ra for biopsy-proven acute rejection at one year (8 studies:, RR 1.30 95% CI 1.01 to 1.67), but at the cost of a 75% increase in malignancy (7 studies: RR 0.25 95% CI 0.07 to 0.87) and a 32% increase in CMV disease (13 studies: RR 0.68 95% CI 0.50 to 0.93). Serum creatinine was significantly lower for IL2Ra treated patients at six months (4 studies: MD -11.20 micromol/L 95% CI -19.94 to -2.09). ATG patients experienced significantly more fever, cytokine release syndrome and other adverse reactions to drug administration and more leucopenia but not thrombocytopenia. There were no significant differences in outcomes according to cyclosporine or tacrolimus use, azathioprine or mycophenolate, or to the study populations baseline risk for acute rejection. There was no evidence that effects were different according to whether equine or rabbit ATG was used. AUTHORS' CONCLUSIONS: Given a 38% risk of rejection, per 100 recipients compared with no treatment, nine recipients would need treatment with IL2Ra to prevent one recipient having rejection, 42 to prevent one graft loss, and 38 to prevent one having CMV disease over the first year post-transplantation. Compared with ATG treatment, ATG may prevent some experiencing acute rejection, but 16 recipients would need IL2Ra to prevent one having CMV, but 58 would need IL2Ra to prevent one having malignancy. There are no apparent differences between basiliximab and daclizumab. IL2Ra are as effective as other antibody therapies and with significantly fewer side effects.

How to write a Cochrane systematic review.

The Cochrane Collaboration is a global network whose aim is to improve health-care decision making through systematic reviews of the effects of health-care interventions. Cochrane systematic reviews are published in the Cochrane Database of Systematic Reviews within The Cochrane Library ( http://www.thecochranelibrary.com), and regularly updated as new evidence arises. Cochrane Reviews are undertaken by teams of volunteer authors, who have access to free training resources, reference texts and software for preparing and maintaining their review. Here we aim to describe the steps involved to undertake a new or update an existing Cochrane Review.

Interventions for renal vasculitis in adults. A systematic review.

BACKGROUND: Renal vasculitis presents as rapidly progressive glomerulonephritis and comprises of a group of conditions characterised by acute kidney failure, haematuria and proteinuria. Treatment of these conditions involves the use of steroid and non-steroid agents with or without adjunctive plasma exchange. Although immunosuppression has been successful, many questions remain unanswered in terms of dose and duration of therapy, the use of plasma exchange and the role of new therapies. This systematic review was conducted to determine the benefits and harms of any intervention for the treatment of renal vasculitis in adults. METHODS: We searched the Cochrane Central Register of Controlled Trials, the Cochrane Renal Group Specialised Register, MEDLINE and EMBASE to June 2009. Randomised controlled trials investigating any intervention for the treatment of adults were included. Two authors independently assessed study quality and extracted data. Statistical analyses were performed using a random effects model and results expressed as risk ratio with 95% confidence intervals for dichotomous outcomes or mean difference for continuous outcomes. RESULTS: Twenty two studies (1674 patients) were included. Plasma exchange as adjunctive therapy significantly reduces the risk of end-stage kidney disease at 12 months (five studies: RR 0.47, CI 0.30 to 0.75). Four studies compared the use of pulse and continuous administration of cyclophosphamide. Remission rates were equivalent but pulse treatment causes an increased risk of relapse (4 studies: RR 1.79, CI 1.11 to 2.87) compared with continuous cyclophosphamide. Azathioprine has equivalent efficacy as a maintenance agent to cyclophosphamide with fewer episodes of leukopenia. Mycophenolate mofetil may be equivalent to cyclophosphamide as an induction agent but resulted in a higher relapse rate when tested against Azathioprine in remission maintenance. Rituximab is an effective remission induction agent. Methotrexate or Leflunomide are potential choices in remission maintenance therapy. Oral co-trimoxazole did not reduce relapses significantly in Wegener's granulomatosis. CONCLUSIONS: Plasma exchange is effective in patients with severe ARF secondary to vasculitis. Pulse cyclophosphamide results in an increased risk of relapse when compared to continuous oral use but a reduced total dose. Whilst cyclophosphamide is standard induction treatment, rituximab and mycophenolate mofetil are also effective. Azathioprine, methotrexate and leflunomide are effective as maintenance therapy. Further studies are required to more clearly delineate the appropriate place of newer agents within an evidence-based therapeutic strategy.

Interventions for preventing and treating kidney disease in Henoch-Schönlein Purpura (HSP).

BACKGROUND: To determine the benefits and harms of therapies used to prevent or treat kidney disease in Henoch-Schönlein Purpura (HSP). OBJECTIVES: To evaluate the benefits and harms of different agents (used singularly or in combination) compared with placebo or no treatment or another agent for the prevention or treatment of kidney disease in patients with HSP. SEARCH STRATEGY: Randomised controlled trials (RCTs) and quasi-RCTs were identified from the Cochrane Renal Group's specialised register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE using optimally sensitive search strategies combined with search terms for HSP. SELECTION CRITERIA: RCTs comparing any intervention used to prevent or treat kidney disease in HSP compared with placebo, no treatment or other agents were included. DATA COLLECTION AND ANALYSIS: Three authors independently assessed trial quality and extracted data from each study. Statistical analyses were performed using the random effects model and the results were expressed as risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). MAIN RESULTS: Ten studies (1230 children) were identified. There was no significant difference in the risk of persistent kidney disease at six months (3 studies, 379 children: RR 0.51, 95% CI 0.24 to 1.11) and 12 months (3 studies, 498 children: RR 1.02, 95% CI 0.40 to 2.62) in children given prednisone for 14 to 28 days at presentation of HSP compared with placebo or supportive treatment. In children with severe kidney disease, there was no significant difference in the risk of persistent kidney disease with cyclophosphamide compared with supportive treatment (1 study, 56 children: RR 1.07, 95% CI 0.65 to 1.78) and with cyclosporin compared with methylprednisolone (1 study, 19 children: RR 0.39, 95% CI 0.14 to 1.06). AUTHORS' CONCLUSIONS: Data from RCTs for any intervention used in improve kidney outcomes in children with HSP are very sparse except for short-term prednisone. There was no evidence of benefit of prednisone in preventing serious long-term kidney disease in HSP.

Interventions for renal vasculitis in adults.

BACKGROUND: Renal vasculitis presents as rapidly progressive glomerulonephritis (RPGN) which comprises of a group of conditions characterised by acute kidney failure (AKF), haematuria and proteinuria. Treatment of these conditions comprises steroid and non-steroid agents in combination with plasma exchange in several situations. Although immunosuppression overall has been very successful in treatment of these conditions, many questions remain unanswered in terms of dose and duration of therapy and the use of plasma exchange. OBJECTIVES: To determine the benefits and harms of any intervention for the treatment of renal vasculitis in adults. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Renal Group Specialised Register, MEDLINE and EMBASE without language restriction, reference lists of articles and abstracts from conference proceedings. SELECTION CRITERIA: Randomised controlled trials investigating any intervention for the treatment of in adults. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. Statistical analyses were performed using a random effects model and results expressed as risk ratio (RR) with 95% confidence intervals for dichotomous outcomes or mean difference (MD) for continuous outcomes. MAIN RESULTS: Thirteen studies (702 patients) were included. Plasma exchange as adjunctive therapy significantly reduces the risk of end-stage kidney disease (ESKD) at three months (one study: RR 0.45, 95% CI 0.24 to 0.84) and 12 months (five studies: RR 0.47, CI 0.24 to 0.86). Three studies compared the use of pulse and continuous administration of cyclophosphamide (CPA). Overall analysis showed a significant increase in remission with pulse CPA (2 studies: RR 1.17; 95%CI 1.02-1.35) and fewer relapses with continuous CPA. A single study addressed the use of azathioprine (AZA) after three months of CPA therapy, showing no difference in outcome except for significantly less leukopenia in patients on AZA. One study into the use of antibiotics to prevent relapse in Wegener's granulomatosis failed to show a significant effect. AUTHORS' CONCLUSIONS: Plasma exchange is effective in patients with severe ARF secondary to vasculitis. On current data, the use of pulse CPA results in an increased risk of relapse when compared to continuous use but a reduced total dose. The use of cotrimoxazole is likely to be beneficial to prevent relapse of vasculitis. AZA is effective as maintenance therapy once remission has been achieved.

Immunosuppressive treatment for focal segmental glomerulosclerosis in adults.

BACKGROUND: Corticosteroids remain the mainstay of treatment in idiopathic nephrotic syndrome, including focal and segmental glomerulosclerosis (FSGS). However, only about 20% of patients with FSGS experience a partial or complete remission of nephrotic syndrome despite treatment. OBJECTIVES: To assess the effects of different immunomodulatory and immunosuppressive regimes in adults with FSGS. SEARCH STRATEGY: We searched MEDLINE, EMBASE and CENTRAL and handsearched congress reports of the American Society of Nephrology and the European Dialysis and Transplantation Association. Date of search: 31 January 2007. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs which examined the effects of different doses, dose strategies and duration of treatment of steroids, alkylating agents, cyclosporin A and antimetabolites in the treatment of FSGS in adults, where included. DATA COLLECTION AND ANALYSIS: At least two authors independently assessed abstracts and/or full text articles to determine which studies satisfied the inclusion criteria. Information was entered onto a separate data sheet for each identified study. Data relevant to outcomes (complete or partial remission of nephrotic syndrome, doubling of serum creatinine, adverse effects) from identified studies were included. Results were expressed as risk ratios (RR) with 95% confidence intervals (CI). MAIN RESULTS: Four studies (108 participants) were included. Three studies investigated cyclosporin A (CSA) with or without prednisone versus prednisone or no treatment and one compared chlorambucil plus prednisone versus no treatment. Outcome data was only available for complete or partial remission and doubling of serum creatinine. There was a significant increase in the number of participants who obtained complete or partial remission with CSA plus low dose prednisone versus prednisone alone (one study, 49 participants: RR 8.85, 95% CI 1.22 to 63.92). Pooled analyses were not performed due to the heterogeneity of the data. AUTHORS' CONCLUSIONS: Adult patients treated with CSA at an initial dose of 3.5-5 mg/kg/d in two divided doses perhaps in combination with oral prednisolone 0.15 mg/kg/d are more likely to achieve a partial remission of the nephrotic syndrome compared with symptomatic treatment or prednisolone alone. However, there is a probability of deterioration of kidney function due to the nephrotoxic effect of CSA in the long term. For CSA, a larger controlled trial with longer follow-up should be performed to prove the benefit of this regimen not only on proteinuria but also on the preservation of kidney function. Present available data do not support the general use of alkylating substances for the treatment of FSGS in adults.