Jonathan C. Craig

Background: Nephrotic syndrome is a condition in which the glomeruli of the kidney leak large amounts of protein from the blood into the urine. Most children who present with their first episode of nephrotic syndrome achieve remission with corticosteroids. 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 (cyclosporin or tacrolimus), and with non-immunosuppressive agents, such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. However, response to these agents is limited, so newer agents, including anti-CD20 antibodies (rituximab, ofatumumab) and dual endothelin-angiotensin receptor antagonists (sparsentan), are being assessed for efficacy and safety. This is an update of a review first published in 2004 and updated in 2006, 2010, 2016 and 2019. Objective: 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. Methods: The Cochrane Kidney and Transplant (CKT) Information Specialist searched the CKT Register of Studies to 28 January 2025 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. Methods: We included randomised controlled trials (RCTs) and quasi-RCTs that compared different immunosuppressive or non-immunosuppressive agents with placebo, prednisone or another agent given orally or parenterally in children aged three months to 18 years with steroid-resistant nephrotic syndrome (SRNS). We included studies that enrolled children and adults, in which paediatric data could not be separated from adult data. Methods: Two review authors independently screened the search results, determined study eligibility, assessed risk of bias and extracted study data. We expressed dichotomous outcomes as risk ratios (RRs) with 95% confidence intervals (CIs), and continuous outcomes as mean differences (MDs) with 95% CIs. We used a random-effects model to pool data, and GRADE to assess the certainty of the evidence. The main outcomes of interest were treatment response (complete, partial, or complete or partial remission), kidney failure and adverse events. Results: We included 29 studies (1248 evaluated children). Sixteen studies were at low risk of bias for sequence generation and allocation concealment. Seven and 21 studies were at low risk of performance and detection bias, respectively. Sixteen, 15 and 15 studies were at low risk of attrition bias, reporting bias and other bias, respectively. Compared with placebo, corticosteroid or no treatment, cyclosporin may increase the number who achieve complete remission (RR 3.50, 95% CI 1.09 to 11.20; 4 studies, 74 children) or complete or partial remission (RR 3.15, 95% CI 1.04 to 9.57; 4 studies, 74 children) by two to six months (low-certainty evidence). It is uncertain whether cyclosporin reduces the likelihood of kidney failure or increases the likelihood of worsening hypertension or infection (very low-certainty evidence). Compared with intravenous cyclophosphamide, calcineurin inhibitors may increase the number with complete remission (RR 3.43, 95% CI 1.84 to 6.41; 2 studies, 156 children) and complete or partial remission (RR 1.98, 95% CI 1.25 to 3.13; 2 studies, 156 children) at three to six months (low-certainty evidence), and probably reduces the number with treatment failure (no response, serious infection, persistently elevated creatinine) and medications ceased due to adverse events (moderate-certainty evidence), with little or no increase in serious infections (moderate-certainty evidence). Kidney failure was not reported. Tacrolimus may make little or no difference to the number who achieve complete, or complete or partial remission at six and 12 months compared with cyclosporin, but may reduce the number who relapse during treatment (RR 0.22, 95% CI 0.06 to 0.90; 1 study, 34 children) or the number with worsening hypertension (low-certainty evidence). Hypertrichosis and gingival hyperplasia probably increased with cyclosporin. Kidney failure was not reported. Compared with mycophenolate mofetil (MMF) and dexamethasone, cyclosporin probably makes little or no difference to complete, partial, or complete or partial remission (moderate-certainty evidence), and may make little or no difference to kidney failure, serious infection requiring hospitalisation or hypertension (low-certainty evidence). Among children who have achieved complete remission, tacrolimus compared with MMF may increase the number who maintain complete, partial, or complete or partial response for 12 months, but may make little or no difference to serious adverse events and serious infection (low-certainty evidence). Oral cyclophosphamide plus prednisone compared with prednisone alone may make little or no difference to the number who achieve complete remission (low-certainty evidence) and has uncertain effects on adverse events. Kidney failure was not reported. Compared with oral cyclophosphamide plus intravenous dexamethasone, intravenous cyclophosphamide may make little or no difference to complete, partial, or complete or partial remission at six months. There may be little or no difference in bacterial infections; however, hypertension may decrease (all low-certainty evidence). Kidney failure was not reported. It is uncertain whether rituximab/cyclosporin/prednisolone compared with cyclosporin/prednisolone increases the likelihood of remission or reduces adverse events because the certainty of the evidence is very low. Kidney failure was not reported. Conclusions: Calcineurin inhibitors may increase the likelihood of complete or partial remission compared with placebo/no treatment or cyclophosphamide. For other regimens, it remains unclear 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 people with SRNS.

Background: Nephrotic syndrome is a condition in which the glomeruli of the kidney leak large amounts of protein from the blood into the urine. Most children who present with their first episode of nephrotic syndrome achieve remission with corticosteroids. 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 (cyclosporin or tacrolimus), and with non-immunosuppressive agents, such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. However, response to these agents is limited, so newer agents, including anti-CD20 antibodies (rituximab, ofatumumab) and dual endothelin-angiotensin receptor antagonists (sparsentan), are being assessed for efficacy and safety. This is an update of a review first published in 2004 and updated in 2006, 2010, 2016 and 2019. Objective: 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. Methods: The Cochrane Kidney and Transplant (CKT) Information Specialist searched the CKT Register of Studies to 28 January 2025 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. Methods: We included randomised controlled trials (RCTs) and quasi-RCTs that compared different immunosuppressive or non-immunosuppressive agents with placebo, prednisone or another agent given orally or parenterally in children aged three months to 18 years with steroid-resistant nephrotic syndrome (SRNS). We included studies that enrolled children and adults, in which paediatric data could not be separated from adult data. Methods: Two review authors independently screened the search results, determined study eligibility, assessed risk of bias and extracted study data. We expressed dichotomous outcomes as risk ratios (RRs) with 95% confidence intervals (CIs), and continuous outcomes as mean differences (MDs) with 95% CIs. We used a random-effects model to pool data, and GRADE to assess the certainty of the evidence. The main outcomes of interest were treatment response (complete, partial, or complete or partial remission), kidney failure and adverse events. Results: We included 29 studies (1248 evaluated children). Sixteen studies were at low risk of bias for sequence generation and allocation concealment. Seven and 21 studies were at low risk of performance and detection bias, respectively. Sixteen, 15 and 15 studies were at low risk of attrition bias, reporting bias and other bias, respectively. Compared with placebo, corticosteroid or no treatment, cyclosporin may increase the number who achieve complete remission (RR 3.50, 95% CI 1.09 to 11.20; 4 studies, 74 children) or complete or partial remission (RR 3.15, 95% CI 1.04 to 9.57; 4 studies, 74 children) by two to six months (low-certainty evidence). It is uncertain whether cyclosporin reduces the likelihood of kidney failure or increases the likelihood of worsening hypertension or infection (very low-certainty evidence). Compared with intravenous cyclophosphamide, calcineurin inhibitors may increase the number with complete remission (RR 3.43, 95% CI 1.84 to 6.41; 2 studies, 156 children) and complete or partial remission (RR 1.98, 95% CI 1.25 to 3.13; 2 studies, 156 children) at three to six months (low-certainty evidence), and probably reduces the number with treatment failure (no response, serious infection, persistently elevated creatinine) and medications ceased due to adverse events (moderate-certainty evidence), with little or no increase in serious infections (moderate-certainty evidence). Kidney failure was not reported. Tacrolimus may make little or no difference to the number who achieve complete, or complete or partial remission at six and 12 months compared with cyclosporin, but may reduce the number who relapse during treatment (RR 0.22, 95% CI 0.06 to 0.90; 1 study, 34 children) or the number with worsening hypertension (low-certainty evidence). Hypertrichosis and gingival hyperplasia probably increased with cyclosporin. Kidney failure was not reported. Compared with mycophenolate mofetil (MMF) and dexamethasone, cyclosporin probably makes little or no difference to complete, partial, or complete or partial remission (moderate-certainty evidence), and may make little or no difference to kidney failure, serious infection requiring hospitalisation or hypertension (low-certainty evidence). Among children who have achieved complete remission, tacrolimus compared with MMF may increase the number who maintain complete, partial, or complete or partial response for 12 months, but may make little or no difference to serious adverse events and serious infection (low-certainty evidence). Oral cyclophosphamide plus prednisone compared with prednisone alone may make little or no difference to the number who achieve complete remission (low-certainty evidence) and has uncertain effects on adverse events. Kidney failure was not reported. Compared with oral cyclophosphamide plus intravenous dexamethasone, intravenous cyclophosphamide may make little or no difference to complete, partial, or complete or partial remission at six months. There may be little or no difference in bacterial infections; however, hypertension may decrease (all low-certainty evidence). Kidney failure was not reported. It is uncertain whether rituximab/cyclosporin/prednisolone compared with cyclosporin/prednisolone increases the likelihood of remission or reduces adverse events because the certainty of the evidence is very low. Kidney failure was not reported. Conclusions: Calcineurin inhibitors may increase the likelihood of complete or partial remission compared with placebo/no treatment or cyclophosphamide. For other regimens, it remains unclear 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 people with SRNS.

Health research results are primarily disseminated through scientific peer-reviewed journals and are not readily accessible to patients and caregivers, which can impede informed decision-making and limit the impact of research on patient outcomes. The aim of the workshop was to identify strategies to disseminate research in chronic kidney disease (CKD) to patients and caregivers. The workshop involved patients, caregivers (n = 27), and health professionals (n = 54) from Australia (10 breakout groups). The transcripts were thematically analyzed. Three themes (strategies) were identified. Generating interest encompassed emphasizing the benefits and impacts of research, using engaging modes of delivery, increasing visibility in clinical settings, and harnessing popular culture. Eliminating barriers to access included ensuring free access to journal articles, translating into different languages, providing plain-language summaries, considering convenience in the context of CKD-related burdens, and maximizing exposure. Demonstrating trustworthiness and repute entailed filtering for high-quality information and propagating through familiar networks and community-based channels. Ensuring ease of access to research, drawing attention, and prompting motivation to engage in research, and instilling confidence in patients about the quality of research may support effective dissemination. Adopting patient-prioritized models to increase translation of research may support shared decision-making in practice and improve care and patient outcomes.

Objective: Current generic childhood health-related quality-of-life instruments lack comprehensive psychometric evidence across all ages. The Pediatric Quality-of-Life Inventory v4.0 Generic Core Scales (PedsQL GCS) covers ages 2 to 18 years old, but evidence on its psychometric properties is limited to restricted age groups. This study aimed to evaluate the proxy-reported PedsQL GCS across the entire childhood lifespan. Methods: The study used data from the Longitudinal Study of Australian Children for children aged 2 to 17 years with 1 of 6 health conditions: high weight status, eczema, attention deficit hyperactivity disorder, vision problems, hearing problems, and learning difficulty. Psychometric properties of the proxy-reported PedsQL GCS were assessed in early childhood, middle childhood, and adolescence against established criteria. Results: In analyses of 9317 children with 50 934 total observations, the PedsQL GCS demonstrated good acceptability across the childhood lifespan, except for high rates of missing data in 2 to 9 year olds (range = 12%-30%). Strong internal consistency was evident across health conditions and age (α range = 0.72-0.93; item-total correlations range = 0.28-0.80). Known group validity was strong with differentiation between children with/without the condition across all ages, except for eczema. Responsiveness was variable with inconsistencies mainly in early childhood. Conclusions: This study adds to the PedsQL psychometric evidence base, finding that the proxy-reported PedsQL GCS demonstrated robust reliability and known group validity, good acceptability, and mixed responsiveness in Australian children with health conditions across age. We propose the PedsQL GCS as a robust instrument to take forward for valuation to directly generate utility values for use in economic evaluations.

Background: Sex, as a biological construct, and gender, defined as the cultural attitudes and behaviours attributed by society, may be associated with allograft loss, death, cancer, and rejection. Other factors, such as recipient age and donor sex, may modify the association between sex/gender and post-transplant outcomes. Objectives: We sought to evaluate the prognostic effects of recipient sex and, separately, gender as independent predictors of graft loss, death, cancer, and allograft rejection following kidney or simultaneous pancreas-kidney (SPK) transplantation. We aimed to evaluate this prognostic effect by defining the relationship between recipient sex or gender and post-transplantation outcomes identifying reasons for variations between sexes and genders, and then quantifying the magnitude of this relationship. Search Methods: We searched MEDLINE and EMBASE databases from inception up to 12 April 2023, through contact with the Cochrane Kidney and Transplant Information Specialist, using search terms relevant to this review and no language restrictions. Selection criteria: Cohort, case-control, or cross-sectional studies were included if sex or gender were the primary exposure and clearly defined. Studies needed to focus on our defined outcomes post-transplantation. Sex was defined as the chromosomal, gonadal, and anatomical characteristics associated with the biological sex, and we used the terms "males" and "females". Gender was defined as the attitudes and behaviours that a given culture associates with a person's biological sex, and we used the terms "men" and "women". Data collection and analysis: Two authors independently assessed the references for eligibility, extracted the data and assessed the risk of bias using the Quality in Prognosis Studies (QUIPS) tool. Whenever appropriate, we performed random-effects meta-analyses to estimate the mean difference in outcomes. The outcomes of interest included the Standardised Outcomes in Nephrology-Kidney Transplant (SONG-Tx) core outcomes, allograft loss, death, cancer (overall incidence and site-specific) and acute or chronic graft rejection. Main Results: Fifty-three studies (2,144,613 patients; range 59 to 407,963) conducted between 1990 and 2023 were included. Sixteen studies were conducted in the Americas, 12 in Europe, 11 in the Western Pacific, four in the Eastern Mediterranean, three in Africa, two in Southeast Asia, and five across multiple regions. All but one study focused on sex rather than gender as the primary exposure of interest. The number identified as male was 54%; 49 studies included kidney transplant recipients, and four studies included SPK transplant recipients. Twenty-four studies included adults and children, 25 studies included only adults, and four studies included only children. Data from 33 studies were included in the meta-analyses. Among these, six studies presented unadjusted hazard ratios (HRs) that assessed the effect of recipient sex on kidney allograft loss. The other studies reported risk ratios (RRs) for the pre-defined outcomes. Notably, the decision to restrict the meta-analyses to unadjusted estimates arose from the variation in covariate adjustment methods across studies, lacking a common set of adjusted variables. Only three studies considered the modifying effect of recipient age on graft loss or death, which is likely crucial to evaluating sex differences in post-transplant outcomes. No studies considered the modifying effect of recipient age on cancer incidence or allograft rejection risk. In low certainty evidence, compared with male recipients, being female may make little or no difference in kidney allograft loss post-transplantation (7 studies, 5843 patients: RR 0.91, 95% CI 0.73 to 1.12; I2 = 73%). This was also observed in studies that included time-to-event analyses (6 studies, 238,937 patients; HR 1.07, 95% CI, 0.95 to 1.20; I2 = 44%). Two recent large registry-based cohort studies that considered the modifying effects of donor sex and recipient age showed that female recipients under 45 years of age had significantly higher graft loss rates than age-matched male recipients in the setting of a male donor. In contrast, female recipients 60 years and older had lower graft loss rates than age-matched male recipients, regardless of donor sex. Compared with male recipients, being female may make little or no difference in death up to 30 years post-transplantation; however, the evidence is very uncertain (13 studies, 60,818 patients: RR 0.94, 95% CI 0.81 to 1.09; I2 = 92%). Studies that considered the modifying effect of recipient age and donor sex showed that female recipients had a higher excess death risk than males under 45 years of age in the setting of a male donor. Compared with male recipients, being female may make little or no difference in cancer incidence up to 20 years post-transplantation; however, the evidence is very uncertain (7 studies, 25,076 patients; RR 0.84, 95% CI 0.70 to 1.01; I2 = 60%). Compared with male recipients, being female may make little or no difference in the incidence of acute and chronic kidney allograft rejection up to 15 years post-transplantation (9 studies, 6158 patients: RR 0.89, 95% CI 0.75 to 1.05; I2 =54%; low certainty evidence). One study assessed gender and reported that when compared with men, women experienced better five-year survival in high (HR 0.71, 95% CI 0.59 to 0.87) and middle-income areas (HR 0.82, 95% CI 0.74 to 0.92), with no difference in low-income areas (HR 0.85, 95% CI 0.72 to 1.01). There was considerable uncertainty regarding any association between sex or gender and post-transplant patient-relevant outcomes. This was primarily due to clinical and methodological heterogeneity. The observed clinical heterogeneity between studies could be attributed to diverse patient characteristics within sample populations. As a result of limited sex-stratified demographic data being provided, further investigation of this heterogeneity was constrained. However, factors contributing to this finding may include recipient age, donor age, types, and sex. Methodological heterogeneity was noted with the interchangeable use of sex and gender, outcome misclassification, the use of different measures of effects, inconsistent covariate profiles, and disregard for important effect modification. Authors' Conclusions: There is very low to low certainty evidence to suggest there are no differences in kidney and pancreas allograft survival, patient survival, cancer, and acute and chronic allograft rejection between male and female kidney and SPK transplant recipients.