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.

Immunosuppressive therapy for IgA nephropathy in children.

BACKGROUND: IgA nephropathy (IgAN) is the most common cause of primary glomerulonephritis. It is a heterogeneous disease with different presentations and high morbidity. Thirty per cent of adults and 20% of children (followed into adulthood) will have a 50% decline in kidney function or develop kidney failure after 10 years. OBJECTIVES: To determine the benefits and harms of immunosuppressive therapy for the treatment of IgAN in children. SEARCH METHODS: We contacted the Information Specialist and searched the Cochrane Kidney and Transplant Register of Studies up to 03 October 2023 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: We included randomised controlled trials (RCTs) and non-randomised studies of interventions (NRSIs) investigating the treatment of IgAN in children with immunosuppressive therapies compared to placebo, no treatment, supportive care, standard therapy (Japanese protocol), other immunosuppressive therapies or non-immunosuppressive therapies. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed the risk of bias. Random effects meta-analyses were used to summarise estimates of treatment effects. Treatment effects were expressed as risk ratios (RR) and 95% confidence intervals (CI) for dichotomous outcomes, and the mean difference (MD) and 95% CI for continuous outcomes. The risk of bias was assessed using the Cochrane risk of bias tool for RCTs and the ROBIN-I tool for NRSIs. The certainty of the evidence was assessed using Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). MAIN RESULTS: This review included 13 studies with 686 participants. Ten RCTs included 334 children and 191 adults, and three NRSIs included 151 participants, all children. Most participants had mild kidney disease. The risk of bias was unclear for most of the domains relating to allocation concealment, blinding of participants, personnel, and outcome assessment. In children with IgAN, it is uncertain if corticosteroid (steroid) therapy, compared to placebo reduces proteinuria (1 study, 64 children and young adults: RR 0.47, 95% CI 0.13 to 1.72; low certainty evidence) or the decline in estimated glomerular filtration rate (eGFR) (1 study, 64 children and young adults: RR 0.47, 95% CI 0.09 to 2.39; low certainty evidence). It is uncertain if steroids reduce proteinuria compared to supportive care (2 studies, 61 children: RR 0.04, 95% CI -0.83 to 0.72; low certainty evidence). Adverse events associated with steroid therapy were not assessed due to heterogeneity in steroid protocols, including dose and duration, and lack of systematic assessment for adverse events in the included studies. Azathioprine, mycophenolate mofetil, mizoribine, or cyclophosphamide alone or in combination with steroid therapy had uncertain effects on improving proteinuria or preventing eGFR decline in children with IgAN. Fish oil, vitamin E and tonsillectomy had uncertain effects on improving proteinuria or preventing eGFR decline. Effects of other immunosuppressive therapies, secondary outcomes and adverse events were not assessed due to insufficient data. AUTHORS' CONCLUSIONS: There is a lack of high-quality evidence to guide the management of IgAN in children. There is no evidence to indicate that steroids, other immunosuppressive therapies, or tonsillectomy, when added to optimal supportive care, prevent a decline in eGFR or proteinuria in children with IgAN. Available studies were few, with small numbers, low-quality evidence, high or uncertain risk of bias, did not systematically assess harms associated with treatment, or report net benefits or harms. Severe cases and atypical presentations of IgAN were not included in the reviewed studies, and our findings cannot be generalised to these situations.

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.

The Canadian childhood nephrotic syndrome (CHILDNEPH) study: report on mid-study feasibility, recruitment and main measures.

BACKGROUND: To assess reasons for continuing practice variation in the management of childhood nephrotic syndrome despite expert reviews and guidelines, we are conducting a longitudinal cohort study in children with glucocorticoid sensitive nephrotic syndrome. Objectives of this mid-study report are to describe patient and physician recruitment characteristics, glucocorticoid prescriptions, use of second line agents, biopsy practices, and adherence to study protocol. METHODS: Children with new onset nephrotic syndrome and providers are being recruited from all 12 pediatric nephrology centres across Canada with > 2½ years follow-up. Data collection points of observation are over a minimum 36 months. Details of prescribed glucocorticoids and of all second line agents used during treatment are being collected. All relapses are being recorded with time to urinary remission of proteinuria. RESULTS: To date, 243 patients (57.1% male) from 12 centres were included. Median number of patients per centre was 29 (range 2-45), and median age of cohort was 7.3 (IQR 4.2) at enrollment. Forty-eight physicians were recruited, median 5 (range 2-8) per site. Median number of relapses per patient year of follow-up was 2.1 (IQR 4). Cumulative dose variability of glucocorticoids prescribed per episode of proteinuria and length of treatment was observed between participating centres. CONCLUSION: The Canadian pediatric nephrology community established a longitudinal childhood nephrotic syndrome cohort study that confirms ongoing practice variability. The study will help to evaluate its impact on patient outcomes, and facilitate clinical trial implementation in nephrotic syndrome.

Blood pressure in children with attention deficit/hyperactivity disorder.

OBJECTIVES: Children with attention deficit/hyperactivity disorder (ADHD) are frequently treated with psycho-stimulant agents causing a modest but significant increase in blood pressure and heart rate. The objective of this study was to define blood pressure characteristics in children with ADHD treated with a variety of medications in a community setup. METHODS: Children registered at a large paediatric clinic in Calgary, AB with documented histories of ADHD were randomly contacted. Consenting participants had standardized office BP measurements, ambulatory blood pressure monitoring (ABPM) studies and were asked to complete the sleep disturbance scale for children (SDSC) questionnaire. Findings were compared with data from the Canadian Health Measures Survey (CMHS). RESULTS: Fifty-five children (47 males) aged 7 to 17 years (average 11.6 ± 2.5 years) with an average BMI z-score of -0.37 ± 1.22 completed the study. All children were medicated, the majority (82%), with various types of stimulant agents. Elevated office BP values were more prevalent than in the CMHS; >90th percentile in 5 (9.1%) and >95th percentile in 3 (5.5%). ABPM confirmed 'white coat hypertension' in 3 (5.5%), masked hypertension in 2 (3.6%) and nondipping in 28 (51%). The SDSC score suggested that 43 (78%) children had disturbed sleep. Logistic regression modelling indicated that nondipping correlated with disturbed sleep. CONCLUSION: The 'white coat' phenomenon may be responsible for increased prevalence of elevated rest/office BP values in children with ADHD. Prevalent sleep 'non-dipping' in this population is associated with sleep disturbances but clinical significance of this finding requires further investigation.

Variation in estimated glomerular filtration rate at dialysis initiation in children.

BACKGROUND: Data guiding the timing of dialysis initiation in children are limited. We sought to determine current practice and secular trends in Canada with respect to the timing of dialysis initiation in children based on estimated glomerular filtration rate (eGFR). METHODS: This observational study included incident chronic dialysis patients aged ≤21 years identified from the Canadian Organ Replacement Register who started dialysis in Canada between January 2001 and December 2010 at any of the nine participating Canadian centers (n = 583). Youth were categorized utilizing CKiD Schwartz eGFR into ≥10.5 (higher) or <10.5 ml/min/1.73 m2 (lower) eGFR groups. Differences at dialysis initiation by facility and region were examined, and secular trends were determined. RESULTS: Median eGFR at dialysis initiation was 8.1 (interquartile range 5.4-11.0) ml/min/1.73 m2. Overall, 29 % of the patients started dialysis with an eGFR of ≥10.5 ml/min/1.73 m2. The proportion of children starting with higher eGFR increased from 27.3 % in 2001 to 35.4 % in 2010 (p = 0.04) and differed by treatment facility (12-70 %; p = 0.0001). Factors associated with higher eGFR at dialysis initiation in the adjusted regression model were female sex [odds ratio (OR) 1.48; 95 % confidence interval (CI) 1.02-2.14], genetic cause of end-stage kidney disease (OR 2.77; 95 % CI 1.37-5.58) and living ≥50 km from treatment facility (OR 1.47; 95 % CI 1.01-2.14). CONCLUSIONS: One-third of the children were found to have initiated dialysis with an eGFR ≥10.5 ml/min/1.73 m2, however significant practice variation exists with respect to timing of dialysis initiation by treatment facility. More data is required to evaluate the clinical implications of this practice variation.

Association between First Nations ethnicity and progression to kidney failure by presence and severity of albuminuria.

BACKGROUND: Despite a low prevalence of chronic kidney disease (estimated glomerular filtration rate [GFR]<60 mL/min per 1.73 m2), First Nations people have high rates of kidney failure requiring chronic dialysis or kidney transplantation. We sought to examine whether the presence and severity of albuminuria contributes to the progression of chronic kidney disease to kidney failure among First Nations people. METHODS: We identified all adult residents of Alberta (age≥18 yr) for whom an outpatient serum creatinine measurement was available from May 1, 2002, to Mar. 31, 2008. We determined albuminuria using urine dipsticks and categorized results as normal (i.e., no albuminuria), mild, heavy or unmeasured. Our primary outcome was progression to kidney failure (defined as the need for chronic dialysis or kidney transplantation, or a sustained doubling of serum creatinine levels). We calculated rates of progression to kidney failure by First Nations status, by estimated GFR and by albuminuria category. We determined the relative hazard of progression to kidney failure for First Nations compared with non-First Nations participants by level of albuminuria and estimated GFR. RESULTS: Of the 1 816 824 participants we identified, 48 669 (2.7%) were First Nations. First Nations people were less likely to have normal albuminuria compared with non-First Nations people (38.7% v. 56.4%). Rates of progression to kidney failure were consistently 2- to 3-fold higher among First Nations people than among non-First Nations people, across all levels of albuminuria and estimated GFRs. Compared with non-First Nations people, First Nations people with an estimated GFR of 15.0-29.9 mL/min per 1.73 m2 had the highest risk of progression to kidney failure, with similar hazard ratios for those with normal and heavy albuminuria. INTERPRETATION: Albuminuria confers a similar risk of progression to kidney failure for First Nations and non-First Nations people.

The extrafollicular B cell response is a hallmark of childhood idiopathic nephrotic syndrome.

The efficacy of the B cell-targeting drug rituximab (RTX) in childhood idiopathic nephrotic syndrome (INS) suggests that B cells may be implicated in disease pathogenesis. However, B cell characterization in children with INS remains limited. Here, using single-cell RNA sequencing, we demonstrate that a B cell transcriptional program poised for effector functions represents the major immune perturbation in blood samples from children with active INS. This transcriptional profile was associated with an extrafollicular B cell response marked by the expansion of atypical B cells (atBCs), marginal zone-like B cells, and antibody-secreting cells (ASCs). Flow cytometry of blood from 13 children with active INS and 24 healthy donors confirmed the presence of an extrafollicular B cell response denoted by the expansion of proliferating RTX-sensitive extrafollicular (CXCR5-) CD21low T-bet+ CD11c+ atBCs and short-lived T-bet+ ASCs in INS. Together, our study provides evidence for an extrafollicular origin for humoral immunity in active INS.

Incidence and causes of end-stage renal disease among Aboriginal children and young adults.

BACKGROUND: Although Aboriginal adults have a higher risk of end-stage renal disease than non-Aboriginal adults, the incidence and causes of end-stage renal disease among Aboriginal children and young adults are not well described. METHODS: We calculated age- and sex-specific incidences of end-stage renal disease among Aboriginal people less than 22 years of age using data from a national organ failure registry. Incidence rate ratios were used to compare rates between Aboriginal and white Canadians. To contrast causes of end-stage renal disease by ethnicity and age, we calculated the odds of congenital diseases, glomerulonephritis and diabetes for Aboriginal people and compared them with those for white people in the following age strata: 0 to less than 22 years, 22 to less than 40 years, 40 to less than 60 years and older than 60 years. RESULTS: Incidence rate ratios of end-stage renal disease for Aboriginal children and young adults (age < 22 yr, v. white people) were 1.82 (95% confidence interval [CI] 1.40-2.38) for boys and 3.24 (95% CI 2.60-4.05) for girls. Compared with white people, congenital diseases were less common among Aboriginal people aged less than 22 years (odds ratio [OR] 0.56, 95% CI 0.36-0.86), and glomerulonephritis was more common (OR 2.18, 95% CI 1.55-3.07). An excess of glomerulonephritis, but not diabetes, was seen among Aboriginal people aged 22 to less than 40 years. The converse was true (higher risk of diabetes, lower risk of glomerulonephritis) among Aboriginal people aged 40 years and older. INTERPRETATION: The incidence of end-stage renal disease is higher among Aboriginal children and young adults than among white children and young adults. This higher incidence may be driven by an increased risk of glomerulonephritis in this population.

Association between residence location and likelihood of transplantation among pediatric dialysis patients.

Many children with ESRD reside far from a kidney transplant center. It is unknown whether this geographical barrier affects likelihood of transplantation. We used data from a national ESRD database. Patients ≤ 18 yr old who started renal replacement in nine Canadian provinces during 1992-2007 were followed until death or last contact. Primary outcome was kidney transplantation (living or deceased donor). Distance between nearest pediatric transplant center and each patient's residence was categorized as: <50, 50 to <150, 150 to <300, and ≥ 300 km. Using survival analysis, we compared likelihood of transplantation between whites and non-whites living in various distance categories. Among 728 patients, 52.2% were males and 62.5% were whites. Compared to white children living < 50 km from a transplant center, white (HR, 0.73; 95% CI, 0.56-0.95) and non-white (HR, 0.66; 95% CI, 0.48-0.92) children living ≥ 300 km away were less likely to receive a transplant. Non-white children living < 50 km away (HR, 0.59; 95% CI 0, 45-0.78) were also less likely to receive a transplant compared to otherwise similar whites living < 50 km away. Although equitable access to transplantation by residence location is observed among remote-dwelling adults with ESRD, white and non-white children with ESRD living ≥ 300 km from a transplant center were less likely to receive transplants.

Survival and transplantation outcomes of children less than 2 years of age with end-stage renal disease.

BACKGROUND: Young children with end-stage renal disease (ESRD) requiring renal replacement therapy (RRT) have traditionally experienced high rates of morbidity and mortality; however, detailed long-term follow-up data is limited. METHODS: Using a population-based retrospective cohort with data from a national organ failure registry and administrative data from Canada's universal health care system, we analysed the outcomes of 87 children starting RRT (before age 2 years) and followed them until death or date of last contact [median follow-up 4.7 years, interquartile range (IQR) 1.4-9.8). We assessed secular trends in survival and the influence of: (1) age at start of RRT and (2) etiology of ESRD with survival and time to transplantation. RESULTS: Patients were mostly male (69.0 %) with ESRD predominantly due to renal malformations (54.0 %). Peritoneal dialysis was the most common initial RRT (83.9 %). Fifty-seven (65.5 %) children received a renal transplant (median age at first transplant: 2.7 years, IQR 2.0-3.3). During 490 patient-years of follow-up, there were 23 (26.4 %) deaths, of which 22 occurred in patients who had not received a transplant. Mortality was greater for patients commencing dialysis between 1992 and 1999 and among the youngest children starting RRT (0-3 months). Children with ESRD secondary to renal malformations had better survival than those with ESRD due to other causes. Among the transplanted patients, all but one survived to the end of the observation period. CONCLUSION: Children who start RRT before 3 months of age have a high risk of mortality. Among our paediatric patient cohort, mortality rates were much lower among children who had received a renal transplant.

Dialysis and transplantation among Aboriginal children with kidney failure.

BACKGROUND: Relatively little is known about the management and outcomes of Aboriginal children with renal failure in Canada. We evaluated differences in dialysis modality, time spent on dialysis, rates of kidney transplantation, and patient and allograft survival between Aboriginal children and non-Aboriginal children. METHODS: For this population-based cohort study, we used data from a national pediatric end-stage renal disease database. Patients less than 18 years old who started renal replacement treatment (dialysis or kidney transplantation) in nine Canadian provinces (Quebec data were not available) and all three territories between 1992 and 2007 were followed until death, loss to follow-up or end of the study period. We compared initial modality of dialysis and time to first kidney transplant between Aboriginal children, white children and children of other ethnicity. We examined the association between ethnicity and likelihood of kidney transplantation using adjusted Cox proportional hazard models for Aboriginal and white children (data for the children of other ethnicity did not meet the assumptions of proportional hazards). RESULTS: Among 843 pediatric patients included in the study, 104 (12.3%) were Aboriginal, 521 (61.8%) were white, and 218 (25.9%) were from other ethnic minorities. Hemodialysis was the initial modality of dialysis for 48.0% of the Aboriginal patients, 42.7% of the white patients and 62.6% of those of other ethnicity (p < 0.001). The time from start of dialysis to first kidney transplant was longer among the Aboriginal children (median 1.75 years, interquartile range 0.69-2.81) than among the children in the other two groups (p < 0.001). After adjustment for confounders, Aboriginal children were less likely than white children to receive a transplant from a living donor (hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.21-0.61) or a transplant from any donor (HR 0.54, 95% CI 0.40-0.74) during the study period. INTERPRETATION: The time from start of dialysis to first kidney transplant was longer among Aboriginal children than among white children. Further evaluation is needed to determine barriers to transplantation among Aboriginal children.

Overview of the Canadian pediatric end-stage renal disease database.

BACKGROUND: Performing clinical research among pediatric end-stage renal disease patients is challenging. Barriers to successful initiation and completion of clinical research projects include small sample sizes and resultant limited statistical power and lack of longitudinal follow-up for hard clinical end-points in most single center studies. DESCRIPTION: Existing longitudinal organ failure disease registry and administrative health datasets available within a universal access health care system can be used to study outcomes of end-stage renal disease among pediatric patients in Canada. To construct the Canadian Pediatric End-Stage Renal Disease database, registry data were linked to administrative health data through deterministic linkage techniques creating a research database which consists of socio-demographic variables, clinical variables, all-cause hospitalizations, and relevant outcomes (death and renal allograft loss) for this patient population. The research database also allows study of major cardiovascular events using previously validated administrative data definitions. CONCLUSION: Organ failure registry linked to health administrative data can be a powerful tool to perform longitudinal studies in pediatric end-stage renal disease patients. The rich clinical and demographic information found in this database will facilitate study of important medical and non-medical risk factors for death, graft loss and cardiovascular disease among pediatric end-stage renal disease patients.

Acute kidney injury among paediatric emergency room admissions in a tertiary hospital in South West Nigeria: a cohort study.

BACKGROUND: Epidemiological data on paediatric acute kidney injury (AKI) in sub-Saharan Africa are limited and largely retrospective. We performed a prospective study of AKI among patients admitted through the emergency room. METHODS: Children admitted to the post-neonatal emergency room of the University College Hospital, Ibadan, Nigeria between February 2016 and January 2017 were studied. AKI was defined by Kidney Disease: Improving Global Outcomes serum creatinine criteria. AKI ascertainment relied on serum creatinine measurements carried out in routine care by post-admission Day 1. We compared in-hospital mortality by post-admission Day 7 for patients with and without AKI (no-AKI). RESULTS: Of the 1344 children admitted to the emergency room, 331 were included in the study. AKI occurred in 112 patients (33.8%) with a median age of 3.1 years [interquartile range (IQR) 0.9-9.4] and was Stage 3 in 50.5% of the cases. The no-AKI group had a median age of 1.8 (IQR 0.7-5.8) years. The underlying diagnoses in patients with AKI were sepsis (33.0%), malaria (12.5%) and primary renal disorders (13.4%). Twenty-four of the patients with AKI underwent dialysis: haemodialysis in 20 and peritoneal dialysis in 4. By Day 7 of admission, 7 of 98 (7.1%) patients in the AKI group had died compared with 5 of 175 (2.9%) patients in the no-AKI group [odds ratio 2.6 (95% confidence interval 0.8-8.5)]. Outcome data were not available for 58 (17.5%) patients. CONCLUSIONS: AKI is common among paediatric emergency room admissions in a tertiary care hospital in sub-Saharan Africa. It is associated with high mortality risk that may be worse in settings without dialysis.

Kidney disease in hepatitis B surface antigen-positive children: experience from a centre in south-west Nigeria and a review of the Nigerian literature.

BACKGROUND: Kidney disease is an important extra-hepatic manifestation of hepatitis B virus (HBV) infection. However, there is paucity of recent literature on kidney disease in children and adolescents with HBV infection from several parts of sub-Saharan Africa including Nigeria. OBJECTIVE: To review the pattern of kidney disease in hepatitis B surface antigen (HBsAg)-positive children and adolescents seen at a tertiary hospital in south-west Nigeria. METHODS: A retrospective study was undertaken of HBsAg-seropositive children with kidney disease managed at University College Hospital, Ibadan, from January 2004 to December 2015. Patients were identified from the paediatric nephrology unit admissions and the renal histology registers. RESULTS: 24 children and adolescents were studied, 17 of whom were male (70.8%), and the median age was 10.0 years (range 3-15). Ten (41.7%) had nephrotic syndrome, five (20.8%) had non-nephrotic glomerulonephritis, five (20.8%) were in end-stage renal disease (ESRD), including a patient with posterior urethral valves, and four had acute kidney injury secondary to acute tubular necrosis. Renal histology was available for 10 patients: nine had nephrotic syndrome associated with minimal change disease in six, focal segmental glomerulosclerosis in two and one had membanoproliferative glomerulonephritis. The patient with non-nephrotic glomerulonephritis had diffuse global sclerosis. CONCLUSION: The pattern of kidney disease in HBV-positive children demonstrated a predominance of nephrotic syndrome, followed by non-nephrotic glomerulonephritis, ESRD and acute kidney injury. Better diagnostic facilities and treatment are required. Prevention of HBV infection by universal childhood immunisation is the ultimate goal.

Setting New Directions for Research in Childhood Nephrotic Syndrome: Results From a National Workshop.

BACKGROUND: We report on the proceedings of a national workshop held in Canada with the aims to identify priorities for research in childhood nephrotic syndrome and to develop a national strategy to address these priorities. METHODS: A diverse group of participants attended the meeting, including patients, family members, researchers, and health care providers. We used small group discussions to explore priorities as perceived by patients and families and by health care providers and researchers. RESULTS: Research evaluating glucocorticoid minimization or glucocorticoid-sparing regimens was a consistent theme in the patient and family discussion group. Families also indicated the need for precise prognostic information at diagnosis, more information to help them choose the best available therapy, and more resources for disease management. Health care providers emphasized the importance of better disease characterization including genotyping and phenotyping patients, better understanding the pathogenesis, and the need of providing targeted therapy and precise prognostic information. CONCLUSIONS: These priorities will inform the development and future directions of the Canadian Childhood Nephrotic Syndrome (CHILDNEPH) project, a national research initiative to improve care and outcomes of patients with childhood onset nephrotic syndrome.

CONTEXTE: Nous rapportons les travaux d'un atelier national qui s'est tenu au Canada et qui avait pour objectif de définir les priorités dans la recherche sur le syndrome néphrotique de l'enfant et d'élaborer une stratégie nationale pour répondre à celles-ci. MÉTHODOLOGIE: Un groupe diversifié de participants a assisté à la réunion, notamment des patients, des membres de leurs familles, des chercheurs et des fournisseurs de soins de santé. Nous avons utilisé de petits groupes de discussion pour explorer les priorités telles que perçues par les patients et leurs familles, de même que par les fournisseurs de soins et les chercheurs. RÉSULTATS: La recherche évaluant la minimisation des glucocorticoïdes ou les traitements substituant les glucocorticoïdes a été un thème récurrent dans le groupe de discussion constitué des patients et de leurs familles. De plus, les familles ont souligné le besoin d'obtenir des informations précises sur le pronostic au moment du diagnostic. Ils ont notamment parlé d'obtenir plus d'informations pour aider à choisir le meilleur traitement disponible et davantage de ressources pour la gestion de la maladie. Les fournisseurs de soins de santé ont quant à eux insisté sur l'importance d'une meilleure caractérisation de la maladie, incluant le génotypage et le phénotypage des patients, une meilleure compréhension de la pathogenèse de la maladie et la nécessité de fournir des thérapies ciblées et des renseignements précis sur le pronostic. CONCLUSIONS: Ces priorités guideront le développement et les futures orientations du Canadian Childhood Nephrotic Syndrome project (CHILDNEPH), une initiative de recherche nationale visant à améliorer les soins et les résultats des patients atteints du syndrome néphrotique apparu durant l'enfance.

Factors influencing practice variation in the management of nephrotic syndrome: a qualitative study of pediatric nephrology care providers.

BACKGROUND: Treatment protocols for childhood nephrotic syndrome are highly variable between providers and care centres. We conducted a qualitative study to understand the complex multilevel processes that lead to practice variation and influence provider management of nephrotic syndrome. METHODS: Focus groups with multidisciplinary pediatric nephrology care providers (n = 67) from 10 Canadian pediatric nephrology centres that had more than 1 pediatric nephrologist were conducted between September 2013 and April 2015. Focus group discussions were guided by the Ottawa Model for Research Use. We used a semistructured interview guide to elicit participants' perspectives regarding 1) the work setting and context of the clinical environment, 2) reasons for variation at the provider level and 3) clinical practice guidelines for nephrotic syndrome. Focus group discussions were transcribed and analyzed concurrently with the use of qualitative content analysis. RESULTS: Emerging themes were grouped into 2 categories: centre-level factors and provider-level factors. At the centre level, the type of care model used, clinic structures and resources, and lack of communication and collaboration within and between Canadian centres influenced care variation. At the provider level, use of experiential knowledge versus empirical knowledge and interpretation of patient characteristics influenced provider management of nephrotic syndrome. INTERPRETATION: Centre- and provider-level factors play an important role in shaping practice differences in the management of childhood nephrotic syndrome. Further research is needed to determine whether variation in care is associated with disparities in outcomes.

The See Kidney Disease Targeted Screening Program for CKD.

BACKGROUND AND OBJECTIVES: The effectiveness of targeted screening for identification of CKD is largely unknown. The See Kidney Disease (SeeKD) targeted screening project aimed to determine the prevalence of unrecognized CKD in Canada. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The SeeKD project was conducted across Canada using a convenience sample approach and events to identify adults with risk factors for CKD (i.e., diabetes, hypertension, vascular disease, family history of kidney problems, etc.). Participants with at least one risk factor received a point-of-care creatinine measurement to identify unrecognized CKD (CKD-Epidemiology Collaboration eGFR <60 ml/min per 1.73 m(2)). Baseline information included clinical characteristics, sociodemographics, and health knowledge. Semistructured telephone interviews were conducted with each Kidney Foundation of Canada branch (regionalized locations) after the screening events to characterize local screening strategies, which were subsequently categorized as individual-targeted (specifically targeting individuals at risk of CKD) and community-targeted (event in a community location in proximity to a high-risk population). We calculated the prevalence of unrecognized CKD overall, and by screening strategy. RESULTS: Between January 2011 and February 2014, 6329 Canadians participated in SeeKD screening events. Participants were predominantly female (65.3%), middle-aged (mean, 58.5 years), and the majority (88.9%) self-reported at least one risk factor for CKD. Of participants with at least one risk factor, 92.3% (n=5194) were screened, of whom 18.8% (95% confidence interval [95% CI], 17.8 to 19.9) had unrecognized CKD; the majority (13.8%) had stage 3a CKD (eGFR=45-60 ml/min per 1.73 m(2)). The prevalence of unrecognized CKD was higher for branches with individual versus community-targeted events (21.9% [95% CI, 20.5 to 23.4] versus 14.7% [95% CI, 13.2 to 16.2]). CONCLUSIONS: Targeted screening identified a high proportion of individuals with risk factors for CKD and a high prevalence of unrecognized CKD. Future research will evaluate the ability of targeted screening to promote self-management behaviors addressing priorities for people with CKD.

Perceptions of pediatric nephrologists regarding timing of dialysis initiation in children in Canada.

BACKGROUND: Significant practice variation exists in Canada with respect to timing of dialysis initiation in children. In the absence of evidence to guide practice, physicians' perceptions may significantly influence decision-making. OBJECTIVE: The objectives of this study are to (1) evaluate Canadian pediatric nephrologists' perceptions regarding dialysis initiation in children with chronic kidney disease (CKD) and (2) determine the factors guiding practice that may contribute to practice variation across Canada. DESIGN: This study was a cross-sectional online survey. SETTING: This study was done in academic pediatric nephrology centers in Canada. PARTICIPANTS: The participants of this study are pediatric nephrologists. MEASUREMENTS AND METHODS: An anonymous web-based survey was administered to pediatric nephrologists in Canada to evaluate perspectives and practice patterns regarding timing of dialysis initiation. We also explored the importance of estimated glomerular filtration rate (eGFR) vs. symptoms and the role of patient and provider factors influencing decisions. RESULTS: Thirty-five nephrologists (59 %) completed the survey. Most respondents care for advanced CKD patients in a multidisciplinary clinic (86 %) and no centers have a formal policy on timing of dialysis initiation. Seventy-five percent of centers follow <20 stage 4-5 CKD patients, and 9 % follow >30 patients. Discussions about dialysis initiation are generally informal (75 %) and the decision to start is made by the nephrologist (37 %) or a team (57 %). Fifty percent agreed GFR was important when deciding when to initiate dialysis, 41 % were neutral, and 9 % disagreed. Variability exists in the threshold that nephrologists considered early (vs. late) dialysis initiation: >20 (21 %), >15 (38 %), >12 (26 %), and >10 ml/min/1.73 m(2) (12 %). Practitioners however typically start dialysis in asymptomatic patients at eGFRs of 7-9 (9 %), 10-11 (41 %), 12-14 (38 %), and 15-19 (6 %) ml/min/1.73 m(2). Patient factors important in the decision to start dialysis for >90 % of nephrologists were fatigue, >10 % weight loss, nausea, increasing missed school, and awaiting a pre-emptive transplant. Age was only a factor for 56 %. LIMITATIONS: This study has a 59 % response rate. CONCLUSIONS: Variability exists in Canada regarding the importance and threshold of eGFR guiding the decision as to when to start dialysis in children, whereas patient symptoms are almost universally important to pediatric nephrologists' decision-making. Additional studies evaluating outcomes of children starting dialysis earlier vs. later are needed to standardize decision-making and care for children with kidney failure.

MISE EN CONTEXTE: Des différences significatives existent dans la pratique au Canada quant au moment où des traitements de dialyse devraient être entrepris chez les enfants souffrant d'insuffisance rénale. En absence de données probantes pour guider leur pratique, les différentes approches des néphrologues exerçant auprès de cette population jouent probablement un rôle majeur dans leur prise de décision. OBJECTIFS DE L'ÉTUDE: Dans un premier temps, l'étude visait à évaluer la perception des néphrologues canadiens en regard de l'amorce de traitements de dialyse chez les enfants atteints d'insuffisance rénale chronique (IRC). Ensuite, on a voulu déterminer les facteurs qui guident la pratique et qui font en sorte que des variations subsistent à cet égard dans la pratique en néphrologie pédiatrique à travers le Canada. CADRE ET TYPE D'ÉTUDE: Il s'agit d'un sondage transversal mené en ligne auprès des néphrologues pratiquant dans les unités pédiatriques des centres hospitaliers universitaires dans tout le Canada. MÉTHODOLOGIE: Un sondage accessible par le web, auquel les participants répondaient de façon anonyme, a été distribué aux spécialistes canadiens pratiquant en néphrologie pédiatrique. Ce sondage avait pour objectif d'évaluer les perceptions et les schémas de pratique relativement au moment le plus propice pour amorcer la dialyse. Le sondage explorait aussi l'importance du débit de filtration glomérulaire estimé (DFGe) par rapport aux symptômes ressentis par le patient dans la prise de décision. Finalement, nous avons tenté d'identifier les facteurs pouvant influencer le patient et son médecin traitant au moment de décider d'entreprendre des traitements de dialyse. RÉSULTATS: Tous les pédiatres-néphrologues pratiquant au Canada ont reçu le questionnaire. Toutefois, seulement 35 d'entre eux, soit un peu plus de la moitié (59 %), l'ont complété et renvoyé. La grande majorité des répondants (86 %) exerçaient au sein de cliniques multidisciplinaires, auprès de cas sévères d'IRC. Aucun des centres de soins où ces spécialistes pratiquent ne possédait de politique formelle quant au moment d'entreprendre des traitements de dialyse chez les patients suivis en néphrologie pédiatrique. Les trois quarts des centres de soins cités (75 %) suivaient moins de 20 cas d'IRC de stade 4 ou 5, alors que 9 % en suivaient plus de 30. Les répondants ont indiqué dans une proportion de 75 % que la discussion concernant l'amorce de la dialyse se déroulait de façon informelle. De plus, le sondage révèle que la décision d'amorcer la dialyse est prise par le néphrologue soignant seulement (37 % des cas) ou par une équipe (57 % des cas). La moitié des répondants (50 %) s'accordait pour dire que le DFGe était important dans leur prise de décision d'amorcer des traitements de dialyse chez leurs patients, 41 % avaient une opinion neutre à ce sujet alors que 9 % ne jugeaient pas cet élément important. Les pédiatres-néphrologues répondants sont partagés quant à la valeur seuil de DFGe qu'ils considèrent comme une amorce « hâtive ¼ de dialyse. Pour 21 % des répondants, cette valeur se situe à 20 ml/min/1,73 m2; pour 38 % elle se situe plutôt à 15 ml/min/1,73 m2; 26 % l'établissent à 12 ml/min/1,73 m2; alors que 12 % des répondants jugent l'amorce d'une dialyse dite « hâtive ¼ à un DFGe de 10 ml/min/1,73 m2. De façon générale, chez les patients asymptomatiques, la dialyse est amorcée lorsque le DFGe se situe entre 7 et 9 ml/min/1,73 m2 (9 % des cas), entre 10 et 11 ml/min/1,73 m2 (41 % des cas), entre 12 et 14 ml/min/1,73 m2 (38 % des cas) ou entre 15 et 19 ml/min/1,73 m2 (6 % des cas). Enfin, parmi les facteurs motivant les patients à entreprendre des traitements de dialyse, tels que rapportés par les répondants dans une proportion de plus de 90 %, on trouve : une sensation de fatigue, une perte de poids de plus de 10 %, des nausées, les absences répétées à l'école et l'attente d'une greffe rénale préventive. L'âge n'a été mentionné comme facteur que dans 56 % des cas. LIMITES DE L'ÉTUDE: Le taux de réponse au sondage relativement faible (59 %) limite la portée des résultats. CONCLUSIONS: En néphrologie pédiatrique, alors que les symptômes ressentis par les patients sont considérés de façon universelle dans la décision d'entreprendre une dialyse, les pédiatres-néphrologues canadiens ont des perceptions très différentes quant à la valeur seuil de DFGe qui devrait guider cette décision et à l'importance du rôle que ce paramètre devrait y jouer. Des études supplémentaires comparant les résultats chez les patients qui amorcent une dialyse dite hâtive par rapport à ceux de patients l'amorçant plus tard s'avèrent nécessaires pour établir des pratiques standardisées en matière de soins pour les enfants atteints d'insuffisance rénale.

Establishing a Canadian national clinical trials network for kidney disease: proceedings of a planning workshop.

Knowledge generation through randomized controlled trials (RCTs) is critical to advance the medical evidence base, inform decision-making, and improve care and outcomes. Unfortunately, nephrology has typically lagged behind other medical specialties in this regard. The establishment of formal clinical trial networks can facilitate the successful conduct of RCTs and has significantly increased the number of RCTs performed worldwide in other medical specialties. No such formal network of nephrology trialists exists in Canada. On April 24, 2014, the Canadian Kidney Knowledge Translation and Generation Network (CANN-NET) Clinical Trials Committee held a stakeholder engagement meeting to address this gap and improve the nephrology clinical trial landscape in Canada. The meeting was held in Vancouver in association with the 2014 Canadian Society of Nephrology Annual General Meeting and was co-sponsored by the Kidney Foundation of Canada and CANN-NET. Attendees included nephrologists from university- and non-university-affiliated nephrology practices, administrators, and representatives from the Kidney Foundation of Canada. Through structured presentations and facilitated group discussions, the group explored the extent to which nephrology trials are currently happening in Canada, barriers to leading or participating in larger investigator-initiated trials, and strategies to improve clinical trial output in nephrology in Canada. The themes and action items arising from this meeting are discussed.

La création d'un bagage de connaissances commun par la conduite d'essais cliniques est essentielle pour assurer l'avancement des notions de base en médecine, étayer la prise de décisions, améliorer les soins aux patients et assurer de meilleurs résultats cliniques. L'établissement d'un réseau officiel et reconnu de partage des connaissances issues d'essais cliniques peut en faciliter la conduite et assurer leur bon déroulement. La preuve en est faite par l'augmentation du nombre d'essais cliniques probants ayant été menés à travers le monde, dans d'autres disciplines médicales. Malheureusement, la néphrologie tire de l'arrière à cet égard par rapport aux autres spécialités, un tel réseau de partage n'existe pas dans le domaine au Canada. C'est dans ce contexte que le 24 avril 2014, le comité des essais cliniques de la « Canadian Kidney Knowledge Translation and Generation Network ¼ (CANN-NET) a tenu une assemblée générale afin de mobiliser les parties intéressées. On a voulu leur exposer cette lacune, tenter d'apporter des solutions et ultimement, faire progresser le bilan de la néphrologie en cette matière. La conférence, en collaboration avec l'assemblée générale annuelle de la Société canadienne de néphrologie, s'est tenue à Vancouver et était subventionnée conjointement par la Fondation canadienne du Rein et le CANN-NET. Parmi les participants, on comptait des néphrologues pratiquants associés ou non à un établissement universitaire ainsi que des administrateurs et des représentants de la Fondation canadienne du Rein. À l'aide de présentations structurées et de discussions de groupe, les participants ont pu observer l'état actuel des essais cliniques au pays, identifier les barrières entravant la participation à plus grande échelle à des essais entrepris sous l'initiative d'un chercheur, et discuter de stratégies pour améliorer les résultats d'essais cliniques en néphrologie au Canada. Le présent article fait état des thèmes abordés lors de cette assemblée et des mesures à prendre pour atteindre les objectifs fixés.