Global aHUS Registry Analysis of Patients Switching to Ravulizumab From Eculizumab.

Introduction: Atypical hemolytic uremic syndrome (aHUS) is a progressive rare disease that, if untreated, can result in severe organ damage and death. Ravulizumab, a next-generation terminal complement inhibitor, provides immediate, complete, and sustained complement C5 inhibition. Real-world data in patients with aHUS who switched to ravulizumab from eculizumab are lacking. Methods: The Global aHUS Registry is a multicenter study (NCT01522183) collecting data on adult or pediatric patients with an aHUS diagnosis, regardless of treatment. Patient characteristics, genetic data, hematological and renal parameters, clinical events (e.g., dialysis and kidney transplantation), and adverse events (AEs) were extracted from patients who switched to ravulizumab from eculizumab up to July 3, 2023. Results: Overall, 60 patients switched to ravulizumab (adult: n = 43; pediatric: n = 17); 11 patients were excluded from effectiveness and genetic analyses (N = 49; adult: n = 40; pediatric: n = 9) because they received <3 months ravulizumab treatment and/or had >1 month between eculizumab discontinuation and ravulizumab initiation. Pathogenic complement variants were identified in 11 of 49 patients (22%); the most common was a complement factor H variant (n = 5/49 [10%]). During ravulizumab treatment, 20 AEs occurred in 13 patients, with no unexpected AEs and only 3 treatment-related AEs (infusion reaction, headaches, and fatigue). No meningococcal infections or deaths were reported. No new events of dialysis, kidney transplantation, or thrombotic microangiopathy were reported. Renal and hematological parameters remained stable after switching to ravulizumab. Conclusion: This is the first real-world cohort analysis of data from patients treated with ravulizumab and reinforces the real-world safety and effectiveness data of ravulizumab in patients with aHUS who switched from eculizumab.

Increased risk of kidney failure in patients with genetic kidney disorders.

BACKGROUNDIt is unknown whether the risk of kidney disease progression and failure differs between patients with and without genetic kidney disorders.METHODSThree cohorts were evaluated: the prospective Cure Glomerulonephropathy Network (CureGN) and 2 retrospective cohorts from Columbia University, including 5,727 adults and children with kidney disease from any etiology who underwent whole-genome or exome sequencing. The effects of monogenic kidney disorders and APOL1 kidney-risk genotypes on the risk of kidney failure, estimated glomerular filtration rate (eGFR) decline, and disease remission rates were evaluated along with diagnostic yields and the impact of American College of Medical Genetics secondary findings (ACMG SFs).RESULTSMonogenic kidney disorders were identified in 371 patients (6.5%), high-risk APOL1 genotypes in 318 (5.5%), and ACMG SFs in 100 (5.2%). Family history of kidney disease was the strongest predictor of monogenic disorders. After adjustment for traditional risk factors, monogenic kidney disorders were associated with an increased risk of kidney failure (hazard ratio [HR] = 1.72), higher rate of eGFR decline (-3.06 vs. 0.25 mL/min/1.73 m2/year), and lower risk of complete remission (odds ratioNot achieving CR = 5.25). High-risk APOL1 genotypes were associated with an increased risk of kidney failure (HR = 1.67) and faster eGFR decline (-2.28 vs. 0.25 mL/min/1.73 m2), replicating prior findings. ACMG SFs were not associated with personal or family history of associated diseases, but were predicted to impact care in 70% of cases.CONCLUSIONSMonogenic kidney disorders were associated with an increased risk of kidney failure, faster eGFR decline, and lower rates of complete remission, suggesting opportunities for early identification and intervention based on molecular diagnosis.TRIAL REGISTRATIONNA.FUNDINGNational Institute of Diabetes and Digestive and Kidney Diseases grants U24DK100845 (formerly UM1DK100845), U01DK100846 (formerly UM1DK100846), U01DK100876 (formerly UM1DK100876), U01DK100866 (formerly UM1DK100866), U01DK100867 (formerly UM1DK100867), U24DK100845, DK081943, RC2DK116690, 2U01DK100876, 1R01DK136765, 5R01DK082753, and RC2-DK122397; NephCure Kidney International; Department of Defense Research Awards PR201425, W81XWH-16-1-0451, and W81XWH-22-1-0966; National Center for Advancing Translational Sciences grant UL1TR001873; National Library of Medicine grant R01LM013061; National Human Genome Research Institute grant 2U01HG008680.

Ravulizumab in Atypical Hemolytic Uremic Syndrome: An Analysis of 2-Year Efficacy and Safety Outcomes in 2 Phase 3 Trials.

Rationale & Objective: Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) caused by complement dysregulation. Ravulizumab is a C5i approved for the treatment of aHUS. This analysis assessed long-term outcomes of ravulizumab in adults and pediatric patients with aHUS. Study Design: This analysis reports 2-year data from 2 phase 3, single-arm studies. Setting & Participants: One study included C5i-naïve adults (NCT02949128), and the other included 2 cohorts of pediatric patients (C5i-naïve and those who switched to ravulizumab from eculizumab [pediatric switch patients]; NCT03131219). Exposure: Patients received intravenous ravulizumab every 4-8 weeks, with the dose depending on body weight. Outcomes: The primary endpoint in the studies of C5i-naïve patients was complete TMA response, which consisted of platelet count normalization, lactate dehydrogenase normalization, and ≥25% improvement in serum creatinine concentrations from baseline, at 2 consecutive assessments ≥4 weeks apart. Analytical Approach: All analyses used descriptive statistics. No formal statistical comparisons were performed. Results: In total, 86 and 92 patients were included in efficacy and safety analyses, respectively. Complete TMA response rates over 2 years were 61% and 90% in C5i-naïve adults and pediatric patients, respectively. The median increase in estimated glomerular filtration rate from baseline was maintained over 2 years in C5i-naïve adults (35 mL/min/1.73 m2) and pediatric patients (82.5 mL/min/1.73 m2). Most adverse events and serious adverse events occurred during the first 26 weeks. No meningococcal infections were reported. Improvement in the Functional Assessment of Chronic Illness Therapy - Fatigue score achieved by 26 weeks was maintained over 2 years. Limitations: Limitations were the small sample of pediatric switch patients and limited availability of genetic data. Conclusions: Long-term treatment with ravulizumab is well tolerated and associated with improved hematologic and renal parameters and quality of life in adults and pediatric patients with aHUS.

This research tested a drug called ravulizumab for the treatment of atypical hemolytic uremic syndrome (aHUS). aHUS is a rare disease that causes clots in tiny blood vessels. This can damage the kidneys and other organs. We analyzed data from 2 clinical trials in which children and adults with aHUS received ravulizumab through a tube placed in a vein (intravenous line). They received ravulizumab every 4-8 weeks depending on their weight. We found that treating patients for 2 years with ravulizumab was associated with improved blood health, kidney function, and quality of life and was well tolerated. These results support ravulizumab as a long-term treatment for people with aHUS.

Nutritional management of the child with chronic kidney disease and on dialysis.

While it is widely accepted that the nutritional management of the infant with chronic kidney disease (CKD) is paramount to achieve normal growth and development, nutritional management is also of importance beyond 1 year of age, particularly in toddlers, to support the delayed infantile stage of growth that may extend to 2-3 years of age. Puberty is also a vulnerable period when nutritional needs are higher to support the expected growth spurt. Inadequate nutritional intake throughout childhood can result in failure to achieve full adult height potential, and there is an increased risk for abnormal neurodevelopment. Conversely, the rising prevalence of overweight and obesity among children with CKD underscores the necessity for effective nutritional strategies to mitigate the risk of metabolic syndrome that is not confined to the post-transplant population. Nutritional management is of primary importance in improving metabolic equilibrium and reducing CKD-related imbalances, particularly as the range of foods eaten by the child widens as they get older (including increased consumption of processed foods), and as CKD progresses. The aim of this review is to integrate the Pediatric Renal Nutrition Taskforce (PRNT) clinical practice recommendations (CPRs) for children (1-18 years) with CKD stages 2-5 and on dialysis (CKD2-5D). We provide a holistic approach to the overall nutritional management of the toddler, child, and young person. Collaboration between physicians and pediatric kidney dietitians is strongly advised to ensure comprehensive and tailored nutritional care for children with CKD, ultimately optimizing their growth and development.

Efficacy and Safety of Pharmacokinetically-Driven Dosing of Mycophenolate Mofetil for the Treatment of Pediatric Proliferative Lupus Nephritis-A Double-Blind Placebo Controlled Clinical Trial (The Pediatric Lupus Nephritis Mycophenolate Mofetil Study).

Background: The safety and efficacy of mycophenolate mofetil (MMF) for lupus nephritis (LN) treatment is established in adults and in some children. MMF is rapidly converted to the biologically active metabolite mycophenolic acid (MPA) whose pharmacokinetics (PK) is characterized by large inter- and intra-individual variability. Methods/Design: This randomized, double-blind, active comparator, controlled clinical trial of pediatric subjects with proliferative LN compares pharmacokinetically-guided precision-dosing of MMF (MMFPK, i.e. the dose is adjusted to the target area under the concentration-time curve (AUC0-12h) of MPA ≥ 60-70 mg*h/L) and MMF dosed per body surface area (MMFBSA, i.e. MMF dosed 600 mg/m2 body surface area), with MMF dosage taken about 12 hours apart. At baseline, subjects are randomized 1:1 to receive blinded treatment with MMFPK or MMFBSA for up to 53 weeks. The primary outcome is partial clinical remission of LN (partial renal response, PRR) at week 26, and the major secondary outcome is complete renal response (CRR) at week 26. Subjects in the MMFBSA arm with PRR at week 26 will receive MMFPK from week 26 onwards, while subjects with CRR will continue MMFBSA or MMFPK treatment until week 53. Subjects who achieve PRR at week 26 are discontinued from study intervention. Discussion: The Pediatric Lupus Nephritis Mycophenolate Mofetil (PLUMM) study will provide a thorough evaluation of the PK of MMF in pediatric LN patients, yielding a head-to-head comparison of MMFBSA and MMFPK for both safety and efficacy. This study has the potential to change current treatment recommendations for pediatric LN, thereby significantly impacting childhood-onset SLE (cSLE) disease prognosis and current clinical practice.

Piperacillin-Tazobactam versus Cefotaxime as Empiric Treatment for Febrile Urinary Tract Infection in Hospitalized Children.

BACKGROUND: According to international pediatric urinary tract infection (UTI) guidelines, selecting ampicillin/sulbactam or amoxicillin/clavulanate is recommended as the first-line treatment for pediatric UTI. In Korea, elevated resistance to ampicillin and ampicillin/sulbactam has resulted in the widespread use of third-generation cephalosporins for treating pediatric UTIs. This study aims to compare the efficacy of piperacillin-tazobactam (TZP) and cefotaxime (CTX) as first-line treatments in hospitalized children with UTIs. MATERIALS AND METHODS: The study, conducted at Jeju National University Hospital, retrospectively analyzed medical records of children hospitalized for febrile UTIs between 2014 and 2017. UTI diagnosis included unexplained fever, abnormal urinalysis, and the presence of significant uropathogens. Treatment responses, recurrence, and antimicrobial susceptibility were assessed. RESULTS: Out of 323 patients, 220 met the inclusion criteria. Demographics and clinical characteristics were similar between TZP and CTX groups. For children aged ≥3 months, no significant differences were found in treatment responses and recurrence. Extended-spectrum beta-lactamase (ESBL)-positive strains were associated with recurrence in those <3 months. CONCLUSION: In Korea, escalating resistance to empirical antibiotics has led to the adoption of broad-spectrum empirical treatment. TZP emerged as a viable alternative to CTX for hospitalized children aged ≥3 months with UTIs. Consideration of ESBL-positive strains and individualized approaches for those <3 months are crucial.

The Management of Dietary Fiber Intake in Children With Chronic Kidney Disease - Clinical Practice Recommendations From the Pediatric Renal Nutrition Taskforce.

The benefits of dietary fiber are widely accepted. Nevertheless, a substantial proportion of children fail to meet the recommended intake of dietary fiber. Achieving adequate fiber intake is especially challenging in children with chronic kidney disease (CKD). An international team of pediatric renal dietitians and pediatric nephrologists from the Pediatric Renal Nutrition Taskforce (PRNT) has developed clinical practice recommendations (CPRs) for the dietary intake of fiber in children and adolescents with CKD. In this CPR paper, we propose a definition of fiber, provide advice on the requirements and assessment of fiber intake, and offer practical guidance on optimizing dietary fiber intake in children with CKD. In addition, given the paucity of available evidence and to achieve consensus from international experts, a Delphi survey was performed in which all the clinical practice recommendations were reviewed.

Characterization of patients with aHUS and associated triggers or clinical conditions: A Global aHUS Registry analysis.

INTRODUCTION: Atypical haemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) associated with complement dysregulation; aHUS may be associated with other 'triggers' or 'clinical conditions'. This study aimed to characterize this patient population using data from the Global aHUS Registry, the largest collection of real-world data on patients with aHUS. METHODS: Patients enrolled in the Global aHUS Registry between April 2012 and June 2021 and with recorded aHUS-associated triggers or clinical conditions prior/up to aHUS onset were analysed. aHUS was diagnosed by the treating physician. Data were classified by age at onset of aHUS (< or ≥18 years) and additionally by the presence/absence of identified pathogenic complement genetic variant(s) and/or anti-complement factor H (CFH) antibodies. Genetically/immunologically untested patients were excluded. RESULTS: 1947 patients were enrolled in the Global aHUS Registry by June 2021, and 349 (17.9%) met inclusion criteria. 307/349 patients (88.0%) had a single associated trigger or clinical condition and were included in the primary analysis. Malignancy was most common (58/307, 18.9%), followed by pregnancy and acute infections (both 53/307, 17.3%). Patients with an associated trigger or clinical condition were generally more likely to be adults at aHUS onset. CONCLUSION: Our analysis suggests that aHUS-associated triggers or clinical conditions may be organized into clinically relevant categories, and their presence does not exclude the concurrent presence of pathogenic complement genetic variants and/or anti-CFH antibodies. Considering a diagnosis of aHUS with associated triggers or clinical conditions in patients presenting with TMA may allow faster and more appropriate treatment.

Assessment and management of vitamin status in children with CKD stages 2-5, on dialysis and post-transplantation: clinical practice points from the Pediatric Renal Nutrition Taskforce.

Children with chronic kidney disease (CKD) are at risk for vitamin deficiency or excess. Vitamin status can be affected by diet, supplements, kidney function, medications, and dialysis. Little is known about vitamin requirements in CKD, leading to practice variation.The Pediatric Renal Nutrition Taskforce (PRNT), an international team of pediatric kidney dietitians and pediatric nephrologists, was established to develop evidence-based clinical practice points (CPPs) to address challenges and to serve as a resource for nutritional care. Questions were formulated using PICO (Patient, Intervention, Comparator, Outcomes), and literature searches undertaken to explore clinical practice from assessment to management of vitamin status in children with CKD stages 2-5, on dialysis and post-transplantation (CKD2-5D&T). The CPPs were developed and finalized using a Delphi consensus approach. We present six CPPs for vitamin management for children with CKD2-5D&T. We address assessment, intervention, and monitoring. We recommend avoiding supplementation of vitamin A and suggest water-soluble vitamin supplementation for those on dialysis. In the absence of evidence, a consistent structured approach to vitamin management that considers assessment and monitoring from dietary, physical, and biochemical viewpoints is needed. Careful consideration of the impact of accumulation, losses, comorbidities, and medications needs to be explored for the individual child and vitamin before supplementation can be considered. When supplementing, care needs to be taken not to over-prescribe. Research recommendations are suggested.

Growth in children with nephrotic syndrome: a post hoc analysis of the NEPTUNE study.

BACKGROUND: Steroids, the mainstay of treatment for nephrotic syndrome in children, have multiple adverse effects including growth suppression. METHODS: Anthropometric measurements in children < 18 years enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) were collected. The longitudinal association of medication exposure and nephrotic syndrome characteristics with height z-score and growth velocity was determined using adjusted Generalized Estimating Equation regression and linear regression. RESULTS: A total of 318 children (57.2% males) with a baseline age of 7.64 ± 5.04 years were analyzed. The cumulative steroid dose was 216.4 (IQR 61.5, 652.7) mg/kg (N = 233). Overall, height z-scores were not significantly different at the last follow-up compared to baseline (- 0.13 ± 1.21 vs. - 0.23 ± 1.71, p = 0.21). In models adjusted for age, sex, and eGFR, greater cumulative steroid exposure (ß - 7.5 × 10-6, CI - 1.2 × 10-5, - 3 × 10-6, p = 0.001) and incident cases of NS (vs. prevalent) (ß - 1.1, CI - 2.22, - 0.11, p = 0.03) were significantly associated with lower height z-scores over time. Rituximab exposure was associated with higher height z-scores (ß 0.16, CI 0.04, 0.29, p = 0.01) over time. CONCLUSION: Steroid dose was associated with lower height z-score, while rituximab use was associated with higher height z-score.

Longitudinal analysis of blood pressure and lipids in childhood nephrotic syndrome.

BACKGROUND: In the current study, longitudinal BP and lipid measurements were examined in a NEPTUNE cohort of children with newly diagnosed nephrotic syndrome (cNEPTUNE). We hypothesized that hypertensive BP and dyslipidemia would persist in children with nephrotic syndrome, regardless of steroid treatment response. METHODS: A multi-center longitudinal observational analysis of data obtained from children < 19 years of age with new onset nephrotic syndrome enrolled in the Nephrotic Syndrome Study Network (cNEPTUNE) was conducted. BP and lipid data were examined over time stratified by disease activity and steroid exposure. Generalized estimating equation regressions were used to find determinants of hypertensive BP and dyslipidemia. RESULTS: Among 122 children, the prevalence of hypertensive BP at any visit ranged from 17.4% to 57.4%, while dyslipidemia prevalence ranged from 40.0% to 96.2% over a median of 30 months of follow-up. Hypertensive BP was found in 46.2% (116/251) of study visits during active disease compared with 31.0% (84/271) of visits while in remission. Dyslipidemia was present in 88.2% (120/136) of study visits during active disease and in 66.0% (101/153) while in remission. Neither dyslipidemia nor hypertensive BP were significantly different with/without medication exposure (steroids and/or CNI). In regression analysis, male sex and urine protein:creatinine ratio (UPC) were significant determinants of hypertensive BP over time, while eGFR was found to be a determinant of dyslipidemia over time. CONCLUSIONS: Results demonstrate persistent hypertensive BPs and unfavorable lipid profiles in the cNEPTUNE cohort regardless of remission status or concurrent steroid or calcineurin inhibitor treatment.

Association of COVID-19 Versus COVID-19 Vaccination With Kidney Function and Disease Activity in Primary Glomerular Disease: A Report of the Cure Glomerulonephropathy Study.

RATIONALE & OBJECTIVE: Patients with glomerular disease (GN) may be at increased risk of severe COVID-19, yet concerns over vaccines causing disease relapse may lead to vaccine hesitancy. We examined the associations of COVID-19 with longitudinal kidney function and proteinuria and compared these with similar associations with COVID-19 vaccination. STUDY DESIGN: Observational cohort study from July 1, 2021, to January 1, 2023. SETTING & PARTICIPANTS: A prospective observational study network of 71 centers from North America and Europe (CureGN) with children and adults with primary minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy. EXPOSURE: COVID-19 and COVID-19 vaccination. OUTCOME: Repeated measure of estimated glomerular filtration rate (eGFR); recurrent time-to-event outcome of GN disease worsening as defined by doubling of the urinary protein-creatinine ratio (UPCR) to at least 1.5g/g or increase in dipstick urine protein by 2 ordinal levels to 3+(300mg/dL) or above. ANALYTICAL APPROACH: Interrupted time series analysis for eGFR. Prognostic matched sequential stratification recurrent event analysis for GN disease worsening. RESULTS: Among 2,055 participants, 722 (35%) reported COVID-19 infection; of these, 92 (13%) were hospitalized, and 3 died (<1%). The eGFR slope before COVID-19 infection was-1.40mL/min/1.73m2 (± 0.29 SD); within 6 months after COVID-19 infection, the eGFR slope was-4.26mL/min/1.73m2 (± 3.02 SD), which was not significantly different (P=0.34). COVID-19 was associated with increased risk of worsening GN disease activity (HR, 1.35 [95% CI, 1.01-1.80]). Vaccination was not associated with a change in eGFR (-1.34mL/min/1.73m2±0.15 SD vs-2.16mL/min/1.73m2±1.74 SD; P=0.6) or subsequent GN disease worsening (HR 1.02 [95% CI, 0.79-1.33]) in this cohort. LIMITATIONS: Infrequent or short follow-up. CONCLUSIONS: Among patients with primary GN, COVID-19 infection was severe for 1 in 8 cases and was associated with subsequent worsening of GN disease activity, as defined by proteinuria. By contrast, vaccination against COVID-19 was not associated with change in disease activity or kidney function decline. These results support COVID-19 vaccination for patients with GN. PLAIN-LANGUAGE SUMMARY: In this cohort study of 2,055 patients with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy, COVID-19 resulted in hospitalization or death for 1 in 8 cases and was associated with a 35% increase in risk for worsening proteinuria. By contrast, vaccination did not appear to adversely affect kidney function or proteinuria. Our data support vaccination for COVID-19 in patients with glomerular disease.

Clinical Safety and Efficacy of Pegcetacoplan in a Phase 2 Study of Patients with C3 Glomerulopathy and Other Complement-Mediated Glomerular Diseases.

Introduction: Dysregulated complement activation is likely the primary driver of disease in C3 glomerulopathy (C3G) and contributes to other complement-mediated diseases, including immunoglobulin A nephropathy (IgAN), lupus nephritis (LN), and primary membranous nephropathy (PMN). No complement inhibitors are proven to halt disease progression in these diseases. Pegcetacoplan, a targeted C3 and C3b inhibitor, may mitigate complement-mediated kidney damage in C3G and other glomerular diseases in which complement may have a pathogenic role. Methods: This open-label, phase 2, 48-week study evaluated the preliminary efficacy and safety of subcutaneous pegcetacoplan for patients with complement-mediated glomerular diseases. The primary end point was proteinuria reduction, measured as 24-hour urine protein-to-creatinine ratio. Secondary end points included remission status, changes in estimated glomerular filtration rate (eGFR), and pharmacodynamic biomarkers. Treatment-emergent adverse events (TEAEs) were monitored. Results: Efficacy results for the C3G cohort are reported herein, along with safety results for the study population. In the C3G cohort, mean proteinuria reduction from baseline to week 48 was 50.9% in the intent-to-treat (ITT) population (n = 7) and 65.4% in the per-protocol (PP) population (n = 4). Mean serum albumin normalized and mean eGFR was stable over 48 weeks. Mean serum C3 levels increased 6-fold and mean soluble C5b-9 levels decreased by 57.3% at week 48. The most common adverse events (AEs) were upper respiratory tract infection, injection site erythema, nausea, and headache. No meningitis or sepsis cases were reported, and no serious treatment-related AEs were observed. Conclusion: Pegcetacoplan may provide therapeutic benefit for C3G and has a favorable safety profile across the 4 glomerular diseases studied.

Cure Glomerulonephropathy Pathology Classification and Core Scoring Criteria, Reproducibility, and Clinicopathologic Correlations.

Introduction: Cure Glomerulonephropathy (CureGN) is an observational cohort study of patients with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), or IgA nephropathy. We developed a conventional, consensus-based scoring system to document pathologic features for application across multiple pathologists and herein describe the protocol, reproducibility, and correlation with clinical parameters at biopsy. Methods: Definitions were established for glomerular, tubular, interstitial, and vascular lesions evaluated semiquantitatively using digitized light microscopy slides and electron micrographs, and reported immunofluorescence. Cases with curated pathology materials as of April 2019 were scored by a randomly assigned pathologist, with at least 10% of cases scored by a second pathologist. Scoring reproducibility was assessed using Gwet's agreement coefficient (AC)1 statistic and correlations with clinical variables were performed. Results: Of 800 scored biopsies (134 MCD, 194 FSGS, 206 MN, 266 IgA), 94 were scored twice (11.8%). Of 60 pathology features, 46 (76.7%) demonstrated excellent (AC1>0.8), and 12 (20.0%) had good (AC1 0.6-0.8) reproducibility. Mesangial hypercellularity scored as absent, focal, or diffuse had moderate reproducibility (AC1 = 0.58), but good reproducibility (AC1 = 0.71) when scored as absent or focal versus diffuse. The percent glomeruli scored as no lesions had fair reproducibility (AC1 = 0.34). Strongest correlations between pathologic features and clinical characteristics at biopsy included interstitial inflammation, interstitial fibrosis, and tubular atrophy with estimated glomerular filtration rate, foot process effacement with urine protein/creatinine ratio, and active crescents with hematuria. Conclusions: Most scored pathology features showed excellent reproducibility, demonstrating consistency for these features across multiple pathologists. Correlations between certain pathologic features and expected clinical characteristics show the value of this approach for future studies on clinicopathologic correlations and biomarker discovery.

Design and Rationale of the APPELHUS Phase 3 Open-Label Study of Factor B Inhibitor Iptacopan for Atypical Hemolytic Uremic Syndrome.

Introduction: Atypical hemolytic uremic syndrome (aHUS) is a rare, progressive, and life-threatening form of thrombotic microangiopathy (TMA) which is caused by dysregulation of the alternative complement pathway (AP). Complement inhibition is an effective therapeutic strategy in aHUS, though current therapies require intravenous administration and increase the risk of infection by encapsulated organisms, including meningococcal infection. Further studies are required to define the optimal duration of existing therapies, and to identify new agents that are convenient for long-term administration. Iptacopan (LNP023) is an oral, first-in-class, highly potent, proximal AP inhibitor that specifically binds factor B (FB). In phase 2 studies of IgA nephropathy, paroxysmal nocturnal hemoglobinuria, and C3 glomerulopathy, iptacopan inhibited the AP, showed clinically relevant benefits, and was well tolerated. Iptacopan thus has the potential to become an effective and safe treatment for aHUS, with the convenience of oral administration. Methods: Alternative Pathway Phase III to Evaluate LNP023 in aHUS (APPELHUS; NCT04889430) is a multicenter, single-arm, open-label, phase 3 study to evaluate the efficacy and safety of iptacopan in patients (N = 50) with primary complement-mediated aHUS naïve to complement inhibitor therapy (including anti-C5). Eligible patients must have evidence of TMA (platelet count <150 × 109/l, lactate dehydrogenase ≥1.5 × upper limit of normal, hemoglobin ≤ lower limit of normal, serum creatinine ≥ upper limit of normal) and will receive iptacopan 200 mg twice daily. The primary objective is to assess the proportion of patients achieving complete TMA response without the use of plasma exchange or infusion or anti-C5 antibody during 26 weeks of iptacopan treatment. Conclusion: APPELHUS will determine if iptacopan is safe and efficacious in patients with aHUS.

Application of GFR estimating equations to children with normal, near-normal, or discordant GFR.

BACKGROUND: The objective was to determine the extent that eGFR formulas correspond to measured plasma iohexol clearance (iGFR) in children with normal or near normal kidney function, particularly how different eGFR formulas yield discordant results. METHODS: iGFR from 2 (iGFR-2pt) and 4 (iGFR-4pt) time points along with creatinine and/or cystatin C-based eGFR were measured in children with mild CKD, stages 1-2. eGFR was calculated using 6 equations: 3 under 25 (U25) formulas from the Chronic Kidney Disease in Children (CKiD) study, the full age-combined cystatin C (cysC) and creatinine spectrum (FAS-combined), the European Kidney Function Consortium (EKFC-creatinine) equation, and the Chronic Kidney Disease Epidemiology Collaboration (CKD-epi) cysC-based equation. RESULTS: Twenty-nine children were included, of which 22 had discordant creatinine vs. cystatin C-based eGFR by ≥ 15mL/min/1.73 m2. Overall, the FAS-combined had the least bias, while the U25 most accurately identified children with an eGFR < 90 mL/min/1.73 m2. When Cr-eGFR was ≥ 15 mL/min higher than CysC-eGFR, the U25 creatinine eGFR was closest to iGFR-4pt. When CysC eGFR was higher, the U25-combined was closest to iGFR-4pt. CONCLUSION: The formulas that most closely approximated the measured GFR varied depending on the pattern of discordant eGFR results. Based on the results, we recommend using the CKiD U25-combined formula to screen for children with a low GFR. Either the CKiD U25-combined or FAS-combined would be recommended for changes in eGFR longitudinally. However, because all formulas were discordant from the iGFR-4pt in over a third of participants, further refinement of pediatric eGFR formulas is needed at the normal/near-normal range. A higher resolution version of the Graphical abstract is available as Supplementary information.

Patient-Reported Outcomes Over 24 Months in Pediatric CKD: Findings From the MyKidneyHealth Cohort Study.

RATIONALE & OBJECTIVE: The lived experience of children with chronic kidney disease (CKD) is poorly characterized. We examined the associations between patient-reported outcome (PRO) scores measuring their fatigue, sleep health, psychological distress, family relationships, and global health with clinical outcomes over time in children, adolescents, and younger adults with CKD and investigated how the PRO scores of this group compare with those of other children, adolescents, and younger adults. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 212 children, adolescentss, and adults aged 8 to 21 years with CKD and their parents recruited from 16 nephrology programs across North America. PREDICTORS: CKD stage, disease etiology, and sociodemographic and clinical variables. OUTCOME: PRO scores over 2 years. ANALYTICAL APPROACH: We compared PRO scores in the CKD sample with a nationally representative general pediatric population (ages 8 to 17 years). Change of PROs over time and association of sociodemographic and clinical variables with PROs were assessed using multivariable regression models. RESULTS: For all time points, 84% of the parents and 77% of the children, adolescents, and younger adults completed PRO surveys . The baseline PRO scores for the participants with CKD revealed a higher burden of fatigue, sleep-related impairment, psychological distress, impaired global health, and poorer family relationships compared with the general pediatric population, with median score differences≥1 SD for fatigue and global health. The baseline PRO scores did not differ by CKD stage or glomerular versus nonglomerular etiology. Over 2 years, PROs were stable with a<1-point annual change on average on each measure and intraclass correlation coefficients ranging from 0.53 to 0.79, indicating high stability. Hospitalization and parent-reported sleep problems were associated with worse fatigue, psychological health, and global health scores (all P<0.04). LIMITATIONS: We were unable to assess responsiveness to change with dialysis or transplant. CONCLUSIONS: Children with CKD experience a high yet stable burden of impairment across numerous PRO measures, especially fatigue and global health, independent of disease severity. These findings underscore the importance of assessing PROs, including fatigue and sleep measures, in this vulnerable population. PLAIN-LANGUAGE SUMMARY: Children with chronic kidney disease (CKD) have many treatment demands and experience many systemic effects. How CKD impacts the daily life of a child is poorly understood. We surveyed 212 children, adolescents, and younger adults with CKD and their parents over 24 months to assess the participants' well-being over time. Among children, adolescents, and younger adults with CKD we found a very high and persistent burden of psychological distress that did not differ by degree of CKD or type of kidney disease. The participants with CKD endorsed greater impairment in fatigue and global health compared with healthy children, adolescents, and younger adults, and parent-reported sleep problems were associated with poorer patient-reported outcome (PRO) scores across all domains. These findings emphasize the importance of including PRO measures, including fatigue and sleep measures, into routine clinical care to optimize the lived experience of children with CKD.

Nutritional management of children with acute kidney injury-clinical practice recommendations from the Pediatric Renal Nutrition Taskforce.

The nutritional management of children with acute kidney injury (AKI) is complex. The dynamic nature of AKI necessitates frequent nutritional assessments and adjustments in management. Dietitians providing medical nutrition therapies to this patient population must consider the interaction of medical treatments and AKI status to effectively support both the nutrition status of patients with AKI as well as limit adverse metabolic derangements associated with inappropriately prescribed nutrition support. The Pediatric Renal Nutrition Taskforce (PRNT), an international team of pediatric renal dietitians and pediatric nephrologists, has developed clinical practice recommendations (CPR) for the nutritional management of children with AKI. We address the need for intensive collaboration between dietitians and physicians so that nutritional management is optimized in line with AKI medical treatments. We focus on key challenges faced by dietitians regarding nutrition assessment. Furthermore, we address how nutrition support should be provided to children with AKI while taking into account the effect of various medical treatment modalities of AKI on nutritional needs. Given the poor quality of evidence available, a Delphi survey was conducted to seek consensus from international experts. Statements with a low grade or those that are opinion-based must be carefully considered and adapted to individual patient needs, based on the clinical judgment of the treating physician and dietitian. Research recommendations are provided. CPRs will be regularly audited and updated by the PRNT.