International cohort of 382 children with lupus nephritis - presentation, treatment and outcome at 24 months.

BACKGROUND: Children with lupus have a higher chance of nephritis and worse kidney outcome than adult patients. METHODS: We retrospectively analyzed clinical presentation, treatment and 24-month kidney outcome in a cohort of 382 patients (≤ 18 years old) with lupus nephritis (LN) class ≥ III diagnosed and treated in the last 10 years in 23 international centers. RESULTS: The mean age at onset was 11 years 9 months and 72.8% were females. Fifty-seven percent and 34% achieved complete and partial remission at 24-month follow-up, respectively. Patients with LN class III achieved complete remission more often than those with classes IV or V (mixed and pure). Only 89 of 351 patients maintained stable complete kidney remission from the 6th to 24th months of follow-up. eGFR ≥ 90 ml/min/1.73 m2 at diagnosis and biopsy class III were predictive of stable kidney remission. The youngest and the oldest age quartiles (2y-9y, 5m) (14y, 2m-18y,2m) showed lower rates of stable remission (17% and 20.7%, respectively) compared to the two other age groups (29.9% and 33.7%), while there was no difference in gender. No difference in achieving stable remission was found between children who received mycophenolate or cyclophosphamide as induction treatment. CONCLUSION: Our data show that the rate of complete remission in patients with LN is still not high enough. Severe kidney involvement at diagnosis was the most important risk factor for not achieving stable remission while different induction treatments did not impact outcome. Randomized treatment trials involving children and adolescents with LN are needed to improve outcome for these children. A higher resolution version of the Graphical abstract is available as Supplementary information.

Long-Term Efficacy and Safety of Repeated Rituximab to Maintain Remission in Idiopathic Childhood Nephrotic Syndrome: An International Study.

BACKGROUND: Long-term outcomes after multiple courses of rituximab among children with frequently relapsing, steroid-dependent nephrotic syndrome (FRSDNS) are unknown. METHODS: A retrospective cohort study at 16 pediatric nephrology centers from ten countries in Asia, Europe, and North America included children with FRSDNS who received two or more courses of rituximab. Primary outcomes were relapse-free survival and adverse events. RESULTS: A total of 346 children (age, 9.8 years; IQR, 6.6-13.5 years; 73% boys) received 1149 courses of rituximab. A total of 145, 83, 50, 28, 22, and 18 children received two, three, four, five, six, and seven or more courses, respectively. Median (IQR) follow-up was 5.9 (4.3-7.7) years. Relapse-free survival differed by treatment courses (clustered log-rank test P<0.001). Compared with the first course (10.0 months; 95% CI, 9.0 to 10.7 months), relapse-free period and relapse risk progressively improved after subsequent courses (12.0-16.0 months; HRadj, 0.03-0.13; 95% CI, 0.01 to 0.18; P<0.001). The duration of B-cell depletion remained similar with repeated treatments (6.1 months; 95% CI, 6.0 to 6.3 months). Adverse events were mostly mild; the most common adverse events were hypogammaglobulinemia (50.9%), infection (4.5%), and neutropenia (3.7%). Side effects did not increase with more treatment courses nor a higher cumulative dose. Only 78 of the 353 episodes of hypogammaglobulinemia were clinically significant. Younger age at presentation (2.8 versus 3.3 years; P=0.05), age at first rituximab treatment (8.0 versus 10.0 years; P=0.01), and history of steroid resistance (28% versus 18%; P=0.01) were associated with significant hypogammaglobulinemia. All 53 infective episodes resolved, except for one patient with hepatitis B infection and another with EBV infection. There were 42 episodes of neutropenia, associated with history of steroid resistance (30% versus 20%; P=0.04). Upon last follow-up, 332 children (96%) had normal kidney function. CONCLUSIONS: Children receiving repeated courses of rituximab for FRSDNS experience an improving clinical response. Side effects appear acceptable, but significant complications can occur. These findings support repeated rituximab use in FRSDNS.

Structured re-training to reduce peritonitis in a pediatric peritoneal dialysis program: a quality improvement intervention.

BACKGROUND: Decline in skills and knowledge among patients and/or caregivers contributes to peritoneal-dialysis (PD)-related peritonitis. Re-training is important, but no guidelines exist. We describe the implementation of a structured re-training program to decrease peritonitis rates. METHODS: This is a prospective quality improvement study involving pediatric patients on long-term home automated PD at National University Hospital, Singapore, between 2012 and 2018. With increasing peritonitis rates, systematic root cause analysis was performed, and based on the contributory factors identified, a structured re-training program was implemented from 2015. This was conducted in 5 cycles, each consisting of 4 modules (hand hygiene, exit site care, peritonitis, and PD troubleshooting). RESULTS: Peritonitis rates were analyzed in 2 phases: Phase 1 (2012-2014) when no re-training was performed and Phase 2 (2016-2018) after re-training was instituted. Fifty-nine patients were included. Of these, 45 patients were in Phase 1, 32 in Phase 2, and 18 in both phases. Peritonitis rates decreased from 0.37 ± 0.67 episodes per patient-year in Phase 1 to 0.13 ± 0.32 episodes per patient-year in Phase 2. After adjusting for age at kidney failure onset, PD vintage, years of nursing experience, and the average patient-to-nurse ratio over the study period for each patient, the adjusted peritonitis rates decreased by 0.38 episodes per patient-year (95% CI, 0.09 to 0.67, p = 0.011) from Phase 1 to Phase 2. CONCLUSION: Despite an improvement in staffing ratio, peritonitis rates only improved significantly after intensive structured re-training was instituted.

Developing Consensus-Based Outcome Domains for Trials in Children and Adolescents With CKD: An International Delphi Survey.

RATIONALE & OBJECTIVE: The inconsistency in outcomes reported and lack of patient-reported outcomes across trials in children with chronic kidney disease (CKD) limits shared decision making. As part of the Standardized Outcomes in Nephrology (SONG)-Kids initiative, we aimed to generate a consensus-based prioritized list of critically important outcomes to be reported in all trials in children with CKD. STUDY DESIGN: An online 2-round Delphi survey in English, French, and Hindi languages. SETTINGS & PARTICIPANTS: Patients (aged 8-21 years), caregivers/family, and health care professionals (HCPs) rated the importance of outcomes using a 9-point Likert scale (7-9 indicating critical importance) and completed a Best-Worst Scale. ANALYTICAL APPROACH: We assessed the absolute and relative importance of outcomes. Comments were analyzed thematically. RESULTS: 557 participants (72 [13%] patients, 132 [24%] caregivers, and 353 [63%] HCPs) from 48 countries completed round 1 and 312 (56%) participants (28 [40%] patients, 64 [46%] caregivers, and 220 [56%] HCPs) completed round 2. Five outcomes were common in the top 10 for each group: mortality, kidney function, life participation, blood pressure, and infection. Caregivers and HCPs rated cardiovascular disease higher than patients. Patients gave lower ratings to all outcomes compared with caregivers/HCPs except they rated life participation (round 2 mean difference, 0.1), academic performance (0.1), mobility (0.4), and ability to travel (0.4) higher than caregivers and rated ability to travel (0.4) higher than HCPs. We identified 3 themes: alleviating disease and treatment burden, focusing on the whole child, and resolving fluctuating and conflicting goals. LIMITATIONS: Most participants completed the survey in English. CONCLUSIONS: Mortality, life participation, kidney function, and blood pressure were consistently highly prioritized by patients, caregivers, and HCPs. Patients gave higher priority to some lifestyle-related outcomes compared with caregivers/HCPs. Establishing critically important outcomes for all trials in children with CKD may improve consistent reporting of survival, kidney health, and clinical and life impact outcomes that are meaningful for decision making.

Metabolite diagnosis of primary hyperoxaluria type 3.

BACKGROUND: Primary hyperoxaluria type 3 (PH3) is a recently described cause of childhood renal calculi. It results from mutations in the HOGA1 gene and most cases have been diagnosed after clinical ascertainment, exclusion of other genetic hyperoxalurias and mutation testing. Metabolite testing has not been widely applied but holds promise for the rapid screening and diagnosis of patients who are not specifically suspected to have PH3. CASE-DIAGNOSIS/TREATMENT: Two cases presented with renal calculi. Urine metabolite testing by tandem mass spectrometry was performed as part of the routine diagnostic work-up for this condition. Both had significantly increased levels of the PH3 urine marker 4-hydroxyglutamate and related metabolites. The diagnosis of PH3 was confirmed by the finding of bi-allelic damaging HOGA1 mutations. CONCLUSIONS: Urine screening by tandem mass spectrometry is a rapid, high-throughput test that can detect PH3 cases that may otherwise not be diagnosed.

SARS-CoV-2 Humoral Immunity Persists Following Rituximab Therapy.

Long-term humoral immunity is mediated by short-lived plasma cells (replenished by memory B cells) and long-lived plasma cells. Their relative contributions are uncertain for immunity to SARS-CoV-2, especially given the widespread use of novel mRNA vaccines. Yet, this has far-reaching implications in terms of the need for regular booster doses in the general population and perhaps even revaccination in patients receiving B cell-depleting therapy. We aimed to characterise anti-SARS-CoV-2 antibody titres in patients receiving Rituximab following previous SARS-CoV-2 vaccination. We recruited 10 fully vaccinated patients (age: 16.9 ± 2.52 years) with childhood-onset nephrotic syndrome, not in relapse, receiving Rituximab for their steroid/calcineurin-inhibitor sparing effect. Antibodies to SARS-CoV-2 spike (S) and nucleocapsid (N) proteins were measured immediately prior to Rituximab and again ~6 months later, using the Roche Elecys® Anti-SARS-CoV-2 (S) assay. All ten patients were positive for anti-S antibodies prior to Rituximab, with six patients (60%) having titres above the upper limit of detection (>12,500 U/mL). Following Rituximab therapy, there was a reduction in anti-S titres (p = 0.043), but all patients remained positive for anti-S antibodies, with five patients (50%) continuing to have titres >12,500 U/mL. Six patients (60%) were positive for anti-N antibodies prior to Rituximab. Following Rituximab therapy, only three of these six patients remained positive for anti-N antibodies (p = 0.036 compared to anti-S seroreversion). Humoral immunity to SARS-CoV-2 is likely to be mediated in part by long-lived plasma cells.

Blood filters in children with COVID-19 and acute kidney injury: A review.

COVID-19 has challenged the global healthcare system through rapid proliferation and lack of existing treatment resulting in over 180 million cases and 3.8 million deaths since December 2019. Although pediatric patients only comprise 1%-2% of diagnosed cases, their incidence of acute kidney injury ranges from 8.2% to 18.2% compared to 49% in adults. Severe infection, initiated by dysregulated host response, can lead to multiorgan failure. In this review, we focus on the use of various blood filters approved for use in pediatric kidney replacement therapy to mitigate adverse effects of severe illness. Therapeutic effects of these blood filters range from cytokine removal (CytoSorb, HA330, HCO/MCO), endotoxin removal (Toraymyxin, CPFA), both cytokine and endotoxin removal (oXiris), and nonspecific removal of proteins (PMMA) that have already been established and can be used to mitigate the various effects of the cytokine storm syndrome in COVID-19.

Corrigendum: PCRRT Expert Committee ICONIC position paper on prescribing kidney replacement therapy in critically sick children with acute liver failure.

[This corrects the article DOI: 10.3389/fped.2021.833205.].

Low regulatory T-cells: A distinct immunological subgroup in minimal change nephrotic syndrome with early relapse following rituximab therapy.

Rituximab is an important second line therapy in difficult nephrotic syndrome (NS), especially given toxicity of long-term glucocorticoid or calcineurin inhibitor (CNI) use. However, clinical response to rituximab is heterogenous. We hypothesized that this was underpinned by immunological differences amongst patients with NS. We recruited a cohort of 18 subjects with glucocorticoid-dependent or glucocorticoid-resistant childhood-onset minimal change NS who received rituximab either due to CNI nephrotoxicity, or due to persistent glucocorticoid toxicity with inadequate response to cyclophosphamide or CNIs. Immunological subsets, T-cell activation assays and plasma cytokines were measured at baseline and 6-months post-rituximab. Time to relapse was bifurcated: 56% relapsed within one year ("early relapse"), while the other 44% entered remission mainly lasting ≥3 years ("sustained remission"). At baseline, early relapse compared to sustained remission group had lower regulatory T-cells (Tregs) [2.94 (2.25, 3.33)% vs 6.48 (5.08, 7.24)%, P<0.001], PMA-stimulated IL-2 [0.03 (0, 1.85)% vs 4.78 (0.90, 9.18)%, P=0.014] and IFNγ [2.22 (0.18, 6.89)% vs 9.47 (2.72, 17.0)%, P=0.035] levels. Lower baseline Treg strongly predicted early relapse (ROC-AUC 0.99, 95% CI 0.97-1.00, P<0.001). There were no differences in baseline plasma cytokine levels. Following rituximab, there was significant downregulation of Th2 cytokines in sustained remission group (P=0.038). In particular, IL-13 showed a significant decrease in sustained remission group [-0.56 (-0.64, -0.35)pg/ml, P=0.007)], but not in the early relapse group. In conclusion, early relapse following rituximab is associated with baseline reductions in Treg and T-cell hyporesponsiveness, which suggest chronic T-cell activation and may be useful predictive biomarkers. Sustained remission, on the other hand, is associated with downregulation of Th2 cytokines following rituximab.

PCRRT Expert Committee ICONIC Position Paper on Prescribing Kidney Replacement Therapy in Critically Sick Children With Acute Liver Failure.

Management of acute liver failure (ALF) and acute on chronic liver failure (ACLF) in the pediatric population can be challenging. Kidney manifestations of liver failure, such as hepatorenal syndrome (HRS) and acute kidney injury (AKI), are increasingly prevalent and may portend a poor prognosis. The overall incidence of AKI in children with ALF has not been well-established, partially due to the difficulty of precisely estimating kidney function in these patients. The true incidence of AKI in pediatric patients may still be underestimated due to decreased creatinine production in patients with advanced liver dysfunction and those with critical conditions including shock and cardiovascular compromise with poor kidney perfusion. Current treatment for kidney dysfunction secondary to liver failure include conservative management, intravenous fluids, and kidney replacement therapy (KRT). Despite the paucity of evidence-based recommendations concerning the application of KRT in children with kidney dysfunction in the setting of ALF, expert clinical opinions have been evaluated regarding the optimal modalities and timing of KRT, dialysis/replacement solutions, blood and dialysate flow rates and dialysis dose, and anticoagulation methods.

Improving clean-catch contamination rates: A prospective interventional cohort study.

OBJECTIVES: The clean-catch method of urine collection carries a high contamination rate. This study aims to evaluate the effects on contamination rate of providing a parent handout and pre-made urine collection pack for clean-catch urine collection. METHODS: We conducted a single-centre prospective cohort interventional study in a tertiary paediatric ED. All children younger than 24 months who presented from April 2013 to June 2014 requiring a urine sample to be obtained were included. The intervention was provision of a pre-made urine collection pack including a standardised information handout. The primary outcome measure was the difference in proportion of urine contamination in samples obtained via a clean-catch pre- and post-intervention. RESULTS: The total number of urine specimens included was 288 in the pre-intervention group and 333 in the post-intervention group. Contamination rates were 14.9% in the pre-intervention group and 11.4% in the post-intervention group. There was no statistically significant reduction in contamination (P = 0.19). The contamination rates appeared to be associated with gender, with (pooled) female contamination rates being 16.4% (44/269) and male contamination rates being 10.5% (37/352). Most specimens of urine were collected via the clean-catch method (81.2%), followed by catheter urine specimen (13.7%) and suprapubic aspirate (5.1%). The contamination rate in our study for clean-catch urine collectively was 13%, catheter urine specimen 3.8% and suprapubic aspirate 0%. CONCLUSION: The contamination rate of clean-catch urine did not improve with the implementation of a pre-made urine collection pack including standardised written instructions.

Evaluation of a post-operative thrombin inhibitor replacement protocol to reduce haemorrhagic and thrombotic complications after paediatric liver transplantation.

INTRODUCTION: Bleeding and thrombotic complications contribute to morbidity and mortality following paediatric orthotopic liver transplantation (OLT). However, the pathophysiology of haemostasis during paediatric OLT is not well understood. This report consists of two complimentary studies examining the frequency of haemostatic complications before and after the introduction of a post-operative thrombin inhibitor replacement therapy protocol at a single institution. MATERIALS AND METHODS: A retrospective study of 40 patients who underwent 43 liver transplants between July 1992 and July 2002, identified bleeding to be the most frequent complication associated with OLT (30%), however thrombotic complications were also common (12.5%). In 2003, following a detailed analysis of haemostatic profiles of children undergoing OLT, a thrombin inhibitor replacement protocol was introduced. A prospective clinical outcome audit was undertaken from April 2003 to September 2008 to determine the effect of the new protocol on haemostasis. RESULTS: Commencement of the thrombin inhibitor replacement protocol significantly reduced the incidence of thrombosis (from 5 to 1, p<0.05), graft loss (from 4 to none, p<0.05), mortality due to thrombosis or bleeding (from 3 to none, p<0.05) and was associated with a 50% reduction in frequency of major bleeding. CONCLUSION: In conclusion, the introduction of a post-operative thrombin inhibitor replacement therapy protocol following paediatric OLT significantly improved haemostasis-related morbidity and mortality outcomes in children.