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Background: Tubulointerstitial lesions and glomerular inflammation severity have been shown to correlate with proteinuria in children with IgA nephropathy (cIgAN). However, there is a lack of data regarding severity of histopathologic findings in cIgAN in patients with minimal to absent proteinuria since kidney biopsy indications are not well defined in these cases., Methods: Twenty-eight cIgAN patients with kidney biopsy from 4 different centers in Paris (France) and Montreal (Canada) with a urine protein/creatinine ratio (UPCr) ≤ 0.03 g/mmol and a normal estimated glomerular filtration rate (eGFR > 90 ml/min/1.73 m 2 ) on the day of kidney biopsy prior to treatment were included., Results: Median age was 11.82 (9.32-13.45) years, and median follow-up was 4 years (2.87-6.53). At time of biopsy, median eGFR was 116 (102.3-139.7) ml/min/1.73 m 2 , and median UPCr was 0.02 (0.011-0.03) g/mmol. Microscopic or macroscopic hematuria was present in 35.7% and 64.3% of cases, respectively. Kidney biopsy microscopy analysis showed mesangial (M1), endocapillary (E1), or extracapillary (C1) hypercellularity in 53.5%, 32.1%, and 7.1% of patients, respectively. Chronic histological lesions were also present: glomerulosclerosis (S1) in 42.8% and tubular atrophy/interstitial fibrosis in 7.1%. Podocytopathic features were detected in 21.4%. An ACE inhibitor or immunosuppressive therapy (IS) was prescribed in 42.8% and 21.4% of these patients respectively. One-third (35.7%) received no treatment. At last follow-up, median eGFR was 111.9 (90.47-136.1) ml/min/1.73 m 2 , and median UPCr was 0.028 (0.01-0.03) g/mmol., Conclusion: cIgAN with minimal proteinuria at time of biopsy might be linked with acute and chronic glomerular lesions., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Objectives: Complement factor I (CFI) deficiency is a rare autosomal recessive inborn error of immunity. In this report, we highlight that complete CFI deficiency may present with isolated and severe CNS inflammation without associated systemic features nor prior non-CNS episodes. This inflammation may respond to complement blockade therapy., Methods: This is a case description of a young girl with severe longitudinal transverse myelitis treated with aggressive immunotherapy that included eculizumab. Published cases of CFI-associated CNS inflammation were reviewed and discussed., Results: A primary immunodeficiency panel revealed 2 germline pathogenic variants in the CFI gene. Further complement testing of the index case and her family confirmed complete CFI deficiency., Discussion: We describe a unique case of severe spinal inflammation secondary to complete CFI deficiency. Although rare, isolated CNS inflammation may be the primary manifestation of complete CFI deficiency. To halt the uncontrolled complement-mediated inflammation associated with CFI deficiency, prompt targeted blockade of the complement pathway using eculizumab may be life changing in the acute phase. Long-lasting blockade of the complement pathway is also essential to prevent relapse in this subgroup of patients.

Introduction: Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are related podocytopathies with distinct kidney outcomes. Surprisingly, elevated urinary activation fragments have been found in FSGS despite little complement deposition on immunofluorescence (IF) staining. Whether complement activation distinguishes FSGS from MCD, participating in the development of segmental lesions, remains unknown., Methods: We performed an observational study in patients with MCD and FSGS, and proteinuria ≥1 g/g of creatinine. We included both primary and secondary or unknown causes. We compared urinary fragments of terminal pathway activation, sC5b9, and C5a expressed as creatinine ratios, between MCD and FSGS., Results: Patients with FSGS ( n  = 41) had a serum albumin of 31±10 g/l and proteinuria of 5.1 (2.6-9.1) g/g at sampling, whereas those with MCD ( n  = 15) had a lower serum albumin (22 ± 9 g/l; P  = 0.002), and a proteinuria of 3.8 (1.9-7.7) g/g ( P  = 0.40). Urinary sC5b9 and C5a were 8.7 (1.7-52.3) and 1.26 (0.45-1.84) μg/mmol of creatinine, respectively in patients with FSGS; compared to 0.8 (0.0-1.5) and 0.06 (0.01-0.15) μg/mmol of creatinine in MCD ( P  < 0.001), respectively. We found no association between urinary complement fragments and age, estimated glomerular filtration rate (eGFR), or chronic kidney lesions. When analyzing samples with proteinuria ≥ 3 g/g, the c-statistics for urinary sC5b9 and C5a were 0.96 and 1.00, respectively, in differentiating FSGS from MCD., Conclusion: We found no urinary complement activation fragments in MCD, in comparison to FSGS, despite similar levels of proteinuria. This suggests a role for complement activation in the pathogenesis of FSGS and provides an additional tool for distinguishing these 2 entities., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)

Background: This study aims to compare cardiopulmonary response to aerobic exercise between young adults born very preterm, including a subgroup with bronchopulmonary dysplasia (BPD), and term controls., Methods: 71 adults (aged 18-29 years) born <30 weeks gestational age (24 with BPD) and 73 term controls were recruited. Assessment included cardiopulmonary exercise testing with impedance cardiography. We compared group differences in peak oxygen uptake ( V ' O 2 ) and in ventilatory and cardiovascular responses to exercise using linear regression analyses., Results: Preterm participants had reduced peak V ' O 2 versus controls (mean difference (MD) -2.7 (95% CI -5.3- -0.1) mL per kg lean body mass per min). Those with BPD achieved lower peak work rate compared with term controls (MD -21 (95% CI -38- -5) W). There was no difference across groups in breathing reserve, ventilatory efficiency, peak heart rate and cardiac output. The V ' O 2 to work rate relationship (Δ V ' O 2 /ΔWR) was reduced in preterm versus term. Peak systolic blood pressure and circulatory power (systolic blood pressure× V ' O 2 ) were also lower in BPD versus term controls. In the preterm group, longer neonatal intensive care unit stay and lower peak cardiac output were associated with lower peak V ' O 2 ., Conclusions: Results suggest limitations with peripheral oxygen uptake in the muscles with reduced Δ V ' O 2 /ΔWR and peak circulatory power, but normal cardiac output. Investigations into skeletal muscle perfusion and oxygen use during exercise are warranted to better understand mechanisms of exercise limitation., Competing Interests: Conflict of interest: The authors declare no conflict of interest., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Thrombotic microangiopathies (TMA) are serious medical conditions requiring a prompt diagnosis to adapt treatment. The determination of ADAMTS-13 activity enables discriminating thrombotic thrombocytopenic purpura (TTP) from other forms of TMA. The purpose of this study was to provide an estimate of the incidence of TTP and TMA in the Canadian Quebec province using data collected from a laboratory centralizing ADAMTS-13 testing for the whole province., Results: From 2012 to 2019, 846 patients were evaluated for plasma ADAMTS-13 activity due to a suspicion of TMA. TTP was identified in 147 patients. Of these, 118 patients with a median age of 51.5 years and a male-female ratio of 1:1.4 had their first episode of TTP during the study period. The number of ADAMTS-13 tests performed and the number of patients with suspected TMA increased annually by 19% and 21% respectively. While the incidence of non-TTP TMA increased annually, that for TTP remained unchanged. This averaged 10.2 (95% CI 5.9-14.4) per million persons per year for suspected non-TTP TMA and 1.8 (95% CI 1.3-2.4) for confirmed TTP. The incidence rate of TMA other than TTP was higher in the age group 70-79 years (21.8; 95% CI 5.4-38.1) for females and in the age group 80-89 years (24.4; 95% CI 7.2-41.7) for males compared to other age groups. The incidence rate of TTP was higher in the age group 40-49 years (4.0; 95% CI 2.0-5.9) for women and in the age group 60-69 years (3.4; 95% CI 1.1-5.6) for men compared to other age groups., Conclusion: The analysis of centralized data measuring ADAMTS-13 activity allowed us to adequately establish the incidence rate and demographic characteristics of TMA, particularly TTP, in Quebec. TTP incidence remained stable while suspected non-TTP TMA steadily increased from 2012 to 2019., (© 2022. The Author(s).)

Introduction: Studies on complement activation have implicated a combination of the classical pathway (CP), lectin pathway (LP), and alternative pathway (AP) in triggering the terminal pathway (TP) for each common autoimmune glomerulonephritis (GN). Evaluating different pathways simultaneously may help identify whether one is preferentially activated and, consequently, which is best to target for each disease., Methods: We followed 112 patients with focal segmental glomerular sclerosis (FSGS), membranous nephropathy (MN), IgA nephropathy (IgAN), lupus nephritis (LN), and antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV) for a median duration of 22 (12-52) months. At the time of greatest clinical activity, we simultaneously evaluated urinary C3a (C3 convertase activity), C5a and sC5b-9 (TP), MASP-1 and MASP-2 (LP), C1q (CP), C4a (CP/LP), and Ba and Bb (AP). We evaluated the relation between activation fragments of the AP and CP/LP with the TP., Results: Urinary complement biomarkers for each pathway were associated with the severity of proteinuria. Fragments of the TP were higher among patients with FSGS and MN compared with patients with IgAN, LN, and AAV. For the AP, urinary Ba level was lower in those with IgAN and LN compared with those with FSGS. For the CP/LP, urinary C4a, MASP-1, and MASP-2 levels were similar between diseases whereas urinary C1q levels were lower in those with LN. For each GN, independent associations existed between the activation markers of the AP and CP/LP with the degree of TP activation, except for the AP in AAV, although perhaps underpowered., Conclusion: The AP and CP/LP contribute individually to the TP activation in autoimmune GN, and both seem to be valid potential therapeutic targets., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Background: Plasma copeptin, a surrogate marker for vasopressin levels, is increased in neonates born preterm, particularly in those with a more severe neonatal course, as reflected by bronchopulmonary dysplasia. Copeptin levels in adulthood are unknown., Methods: In this case-control study of 101 adults born very preterm (<30 weeks of gestation) and 105 control adults born full-term, a comprehensive clinical and biological assessment was performed, including blood pressure measurements, kidney ultrasound and determination of plasma copeptin, renin activity, angiotensin II, aldosterone, apelin, sodium and potassium, serum and morning urine osmolality., Results: The median age in the study was 23.1 years [interquartile range (IQR) 21.2-24.8] and 57% were females. In males, the median copeptin levels were 8.2 pmol/L (IQR 6.3-12.4) and 6.1 pmol/L (IQR 4.3-9.0) in the preterm and term groups, respectively (P = 0.022). In females, the median copeptin levels were 5.2 pmol/L (IQR 3.9-7.6) and 4.0 pmol/L (IQR 2.8-5.7) in the preterm and term groups, respectively (P = 0.005). Adults born preterm with a history of bronchopulmonary dysplasia had further increased copeptin levels. The kidney volume, adjusted for height, was smaller and albuminuria was higher in the preterm group, and both were associated with higher plasma copeptin levels., Conclusions: Plasma copeptin is higher in young adults born preterm and is related to a more severe neonatal course and smaller kidney volume., (© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA.)

Background: Variation in dose and duration of corticosteroids for childhood-onset steroid-sensitive nephrotic syndrome occurs worldwide, likely reflecting the evolving evidence on optimal dosing and variable severity of the disease observed between patients. We conducted a study to determine the associations between site, physician, and patient factors, and average daily corticosteroid dose and duration of therapy., Methods: Data were derived from the Canadian Childhood Nephrotic Syndrome (CHILDNEPH) Project, an observational longitudinal study from 2013 to 2019 of children with nephrotic syndrome involving pediatric nephrologists in 11 sites across Canada. The primary outcome was average daily corticosteroid dose prescribed per episode of proteinuria, reported as mg/m 2 prednisone equivalents. Secondary outcome was duration of treatment for each episode of proteinuria in days. Exposure variables were categorized into site-, physician-, and patient-level variables., Results: In total, 328 children, median age at enrollment of 4.3 years old (interquartile range [IQR], 3.6), participated and were followed for a median time of 2.62 years (IQR, 2.6). The observed variability in average daily corticosteroid dose and in duration of therapy was mostly attributed to the site where the patient was treated. Accounting for between patient, physician, and site differences, average daily corticosteroid dose decreased with increasing age (beta coefficient, -0.07; 95% confidence interval [95% CI], -0.09 to -0.05], P <0.001). African and Indigenous ethnicity was associated with longer treatment duration compared with White patients (beta coefficient: African, 42.29, 95% CI, 7.85 to 76.73, P =0.02; Indigenous, 29.65, 95% CI, 2.79 to 56.52, P =0.03)., Conclusions: We found practice variation with respect to corticosteroid prescriptions across 11 Canadian sites, and that variation is mostly explained at the site level. Age and ethnicity are important factors to be considered, because they are significantly associated with the average corticosteroid dose and duration of therapy., Competing Interests: A-L. Lapeyraque reports advisory board attendances for Alexion Inc. All remaining authors have nothing to disclose. The funding agencies had no role in the design of study, collection, analysis, or interpretation of data., (Copyright © 2021 by the American Society of Nephrology.)

Aims: Ganciclovir (GCV) and its prodrug valganciclovir (VGCV) are first-line agents to prevent and treat cytomegalovirus in transplant recipients. There is high pharmacokinetic (PK) interindividual variability and PK data are scarce, especially in paediatric stem cell transplant (SCT) recipients. We sought to determine the optimal GCV and VGCV dosing in transplanted children., Methods: We conducted a single-centre retrospective population PK (POPPK) study of IV GCV and enteral VGCV in paediatric solid organ transplant (SOT) and SCT recipients. We included children who were transplanted and had available plasma GCV concentrations, done per standard of care. POPPK analysis was performed using a nonlinear mixed effects modelling approach with NONMEM. Optimal dosing was determined based on the achievement of the surrogate efficacy target: GCV 24 h area under the concentration-time curve (AUC 0-24h ) of 40-60 mg.h.L -1 ., Results: Fifty children with a median [range] age of 7.5 years [0.5-17.4] contributed 580 PK samples. A two-compartment model with first-order absorption with a lag time and first-order elimination fit the data well. Creatinine clearance and body weight (WT) were significant covariates for GCV clearance (CL); and WT for the volumes of distribution. IV GCV 15-20 mg.kg -1 .day -1 divided every 12 hours achieved the highest probability of target achievement (PTA) (33.0-33.8%). Enteral VGCV 30 and 40 mg.kg -1 .day -1 divided every 12 hours in children 0-<6 years, and 6-18 years, respectively, achieved the highest PTA (29.1-33.0%)., Conclusion: This is the first POPPK model developed in children with either SOT or SCT. Concentration target achievement was low, suggesting a potential benefit for therapeutic drug monitoring to ensure optimal exposure., (© 2020 British Pharmacological Society.)

In the past 20 years, we have witnessed tremendous advances in our ability to diagnose and treat genetic diseases of the kidney caused by complement dysregulation. Staggering progress was realized toward a better understanding of the genetic underpinnings and pathophysiology of many forms of atypical hemolytic uremic syndrome (aHUS) and C3-dominant glomerulopathies that are driven by complement system abnormalities. Many of these seminal discoveries paved the way for the design and characterization of several innovative therapies, some of which have already radically improved patients' outcomes. This review offers a broad overview of the exciting developments that have occurred in the recent past, with a particular focus on single-gene (or Mendelian), complement-driven aHUS and C3-dominant glomerulopathies that should be of interest to both nephrologists and kidney researchers. The discussion is restricted to genes with robust associations with both aHUS and C3-dominant glomerulopathies (complement factor H, complement component 3, complement factor H-related proteins) or only aHUS (complement factor B, complement factor I, and membrane cofactor protein). Key questions and challenges are highlighted, along with potential avenues for future directions., (Copyright © 2021 by the American Society of Nephrology.)

Purpose of Review: Thrombotic microangiopathy (TMA) is suspected in patients presenting with thrombocytopenia and evidence of a microangiopathic hemolytic anemia. Patients with TMA can be critically ill, so rapid and accurate identification of the underlying etiology is essential. Due to better insights into pathophysiology and causes of TMA, we can now categorize TMAs as thrombotic thrombocytopenic purpura, postinfectious (mainly Shiga toxin-producing Escherichia coli -induced) hemolytic uremic syndrome (HUS), TMA associated with a coexisting condition, or atypical HUS (aHUS). We recognized an unmet need in the medical community to guide the timely and accurate identification of TMA, the selection of tests to clarify its etiology, and the sequence of steps to initiate treatment., Sources of Information: Key published studies relevant to the identification, classification, and treatment of TMAs in children or adults. These studies were obtained through literature searches conducted with PubMed or based on the prior knowledge of the authors., Methods: This review is the result of a consultation process that reflects the consensus of experts from Canada, the United States, and the United Arab Emirates. The members represent individuals who are clinicians, researchers, and teachers in pediatric and adult medicine from the fields of hematology, nephrology, and laboratory medicine. Authors, through an iterative review process identified and synthesized information from relevant published studies., Key Findings: Thrombotic thrombocytopenic purpura occurs in the setting of insufficient activity of the von Willebrand factor protease known as ADAMTS13. Shiga toxin-producing Escherichia coli -induced hemolytic uremic syndrome, also known as "typical" HUS, is caused by gastrointestinal infections with bacteria that produce Shiga toxin (initially called verocytotoxin). A variety of clinical conditions or drug exposures can trigger TMA. Finally, aHUS occurs in the setting of inherited or acquired abnormalities in the alternative complement pathway leading to dysregulated complement activation, often following a triggering event such as an infection. It is possible to break the process of etiological diagnosis of TMA into 2 distinct steps. The first covers the initial presentation and diagnostic workup, including the processes of identifying the presence of TMA, appropriate initial tests and referrals, and empiric treatments when appropriate. The second step involves confirming the etiological diagnosis and moving to definitive treatment. For many forms of TMA, the ultimate response to therapies and the outcome of the patient depends on the rapid and accurate identification of the presence of TMA and then a standardized approach to seeking the etiological diagnosis. We present a structured approach to identifying the presence of TMA and steps to identifying the etiology including standardized lab panels. We emphasize the importance of early consultation with appropriate specialists in hematology and nephrology, as well as identification of whether the patient requires plasma exchange. Clinicians should consider appropriate empiric therapies while following the steps we have recommended toward definitive etiologic diagnosis and management of the TMA., Limitations: The evidence base for our recommendations consists of small clinical studies, case reports, and case series. They are generally not controlled or randomized and do not lend themselves to a stricter guideline-based methodology or a Grading of Recommendations Assessment, Development and Evaluation (GRADE)-based approach., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The membership of the group of authors was identified following a series of meetings and conferences related to thrombotic microangiopathy (TMA). The final membership was struck following an industry-sponsored TMA meeting; however, the sponsor was not involved in the genesis or content of the project or the selection of physician members. There was no support either financial or otherwise provided to this group from any industry or other sponsors. P.A.M and J.G. received honoraria from Alexion and Sanofi Genzyme. M.B., A.-L.L., K.G., and D.B. from Alexion. C.B. from Alexion, Sanofi, Argenx, and Appelis. L.-P.G. from Alexion and Genzyme and clinical trials from Chemocentryx and Alexion. C.J.P. from Alexion, Octapharma, Apellis, Biocryst, and Sanofi; received research support from Alexion, Octapharma, and Sanofi; and clinical trial participation—Site PI—Alexion, Ra Pharma, Apellis, and Sanofi. K.P. from Alexion, Sanofi, and Takeda and clinical trials from Sanofi and Takeda. C.L. received honoraria and unrestricted grants from Alexion, Apellis, Aurin, and Novartis., (© The Author(s) 2021.)

We know that glutaric aciduria type II is an inborn metabolism. This case report highlights that polycystic kidneys with hepatomegaly in prenatal ultrasound are suggestive of glutaric aciduria type II and it identifies a new variant as pathogenic., Competing Interests: The authors declare that they have no conflict of interest., (© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Aim: Serum creatinine level is the most used test to evaluate renal function in patients with anorexia nervosa (AN). We investigated which formula of glomerular filtration rate (GFR) based on simple blood sample had the best correlation with the gold standard in malnourished adolescent patients with AN., Methods: A prospective study was conducted on 34 adolescents hospitalized for the restrictive type of AN between 2014 and 2017. The GFR was measured by isotopic technique and calculated using the Cockroft-Gault, Schwartz equations and 3 other formula., Results: For the 34 AN patients, mean BMI -2.7 zscore, the mean measured GFR was 107+/-26 mL/min/1.73 m 2 . Among them, 35% (12/34) had a GFR under 90 mL/min/1.73 m 2 . The calculated GFR with Cockroft-Gault formula had the best correlation with the measured GFR (R2 = 0.852), whatever the creatinine level. No correlation was found between creatinine level and measured GFR., Conclusion: Kidney dysfunction is common in malnourished AN adolescents, so clinicians should always evaluate AN patients for renal impairments. Creatinine level is a poor indicator of renal function in this population. The most accurate formula to test GFR with a simple blood test is the Cockroft-Gault formula., (Copyright © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: IgA nephropathy (IgAN) and Henoch-Schönlein purpura are common glomerular disorders in children sharing the same histopathologic pattern of IgA deposits within the mesangium, even if their physiopathology may be different. Repeated exposure to pathogens induces the production of abnormal IgA1. The immune complex deposition in the renal mesangium in IgAN or potentially in small vessels in Henoch-Schönlein purpura induces complement activation via the alternative and lectin pathways. Recent studies suggest that levels of membrane attack complex (MAC) in the urine might be a useful indicator of renal injury. Because of the emerging availability of therapies that selectively block complement activation, the aim of the present study is to investigate whether MAC immunostaining might be a useful marker of IgA-mediated renal injury., Methods: We conducted immunohistochemistry analysis of the MAC on renal biopsies from 67 pediatric patients with IgAN and Henoch-Schönlein purpura. We classified their renal biopsies according to the Oxford classification, retrieved symptoms, biological parameters, treatment, and follow-up., Results: We found MAC expression was significantly related to impaired renal function and patients whose clinical course required therapy. MAC deposits tend to be more abundant in patients with decreased glomerular filtration rate (p = 0.02), patients with proteinuria > 0.750 g/day/1.73 m 2 , and with nephrotic syndrome. No correlation with histological alterations was observed., Conclusions: We conclude that MAC deposition could be a useful additional indicator of renal injury in patients with IgAN and Henoch-Schönlein purpura, independent of other indicators.

Background: Atypical hemolytic uremic syndrome (aHUS) is an extremely rare, heterogeneous disease of uncontrolled activation of the alternative complement pathway that is difficult to diagnose. We have evaluated the Canadian patients enrolled in the Global aHUS Registry to provide a Canadian perspective regarding the diagnosis and management of aHUS and the specific challenges faced., Objective: To evaluate Canadian patients enrolled in the Global aHUS Registry to provide a Canadian perspective regarding the diagnosis and management of aHUS and the specific challenges faced., Methods: The Global aHUS Registry is an observational, noninterventional, multicenter study that has prospectively and retrospectively collected data from patients of all ages with an investigator-made clinical diagnosis of aHUS, irrespective of treatment. Patients of all ages with a clinical diagnosis of aHUS were eligible and invited for enrollment, and those with evidence of Shiga toxin-producing Escherichia coli infection, or with ADAMTS13 activity ≤10%, or a subsequent diagnosis of thrombotic thrombocytopenic purpura were excluded. Data were collected at enrollment and every 6 months thereafter and were analyzed descriptively for categorical and continuous variables. End-stage renal disease (ESRD)-free survival was evaluated using Kaplan-Meier estimates, and ESRD-associated risk factors of interest were assessed using Cox proportional hazards regression models. Patients were censored at start of eculizumab for any outcome measures., Results: A total of 37 Canadian patients were enrolled (15 pediatric and 22 adult patients) between February 2014 and May 2017; the median age at initial aHUS presentation was 25.9 (interquartile range = 6.7-51.7) years; 62.2% were female and 94.6% had no family history of aHUS. Over three-quarters of patients (78.4%) had no conclusive genetic or anti-complement factor H (CFH) antibody information available, and most patients (94%) had no reported precipitating factors prior to aHUS diagnosis. Nine patients (8 adults and 1 child) experienced ESRD prior to the study. After initial presentation, there appears to be a trend that children are less likely to experience ESRD than adults, with 5-year ESRD-free survival of 93 and 56% ( P = .05) in children and adults, respectively. Enrolling physicians reported renal manifestations in all patients at initial presentation, and 68.4% of patients during the chronic phase (study entry ≥6 months after initial presentation). Likewise, extrarenal manifestations also occurred in more patients during the initial presenting phase than the chronic phase, particularly for gastrointestinal (61.1% vs 15.8%) and central nervous system sites (38.9% vs 5.3%). Fewer children than adults experienced gastrointestinal manifestations (50.0% vs 70.0%), but more children than adults experienced pulmonary manifestations (37.5% vs 10.0%)., Conclusions: This evaluation provides insight into the diagnosis and management of aHUS in Canadian patients and the challenges faced. More genetic or anti-CFH antibody testing is needed to improve the diagnosis of aHUS, and the management of children and adults needs to consider several factors such as the risk of progression to ESRD is based on age (more likely in adults), and that the location of extrarenal manifestations differs in children and adults., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A-L.L. has received consultancy and speaker honoraria from Alexion Pharmaceuticals, Inc. and Alexion Pharma Canada. M.B. has received consultancy and speaker honoraria from Alexion Pharma Canada. I.A.-D. is an employee of Alexion Pharmaceuticals, Inc. M.F. is an employee of Alexion Pharma Canada. S.S.H. has received consultancy and speaker honoraria from Alexion Pharma Canada. R.K. is an employee of Alexion Pharma Canada. L.L. has received speaker honoraria from Alexion Pharma Canada. K.P. has received consultancy and speaker honoraria from Alexion Pharma Canada. C.R. has no disclosures to declare. A.T. has no disclosures to declare. C.L. has received consultancy and speaker honoraria from Alexion Pharmaceuticals and Alexion Pharma Canada. D.P. has received speaker honoraria from Alexion Pharma Canada., (© The Author(s) 2020.)

Purpose: Although primarily a mental health disorder, anorexia nervosa (AN) has many physical consequences. Among them, the consequences on kidney function are often underestimated. We evaluated renal function in adolescent AN inpatients and investigated the correlation between the GFR and intrinsic patient characteristics., Methods: A single-center retrospective study was conducted on 51 patients hospitalized for the restrictive type of AN in 2013. Data were divided into: (1) medical history of AN; (2) growth parameters and vital signs upon admission; and (3) blood tests. The glomerular filtration rate (GFR) was calculated using the Cockroft-Gault, MAYO Clinical Quadratic (MCQ), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), the Modification of Diet in Renal Disease (MDRD), and Schwartz equations., Results: The calculated percentages of patients with a GFR below 90 mL/min/1.73 m 2 according to the different equations were as follows: Cockroft-Gault, 45%; MDRD, 28%; CKD-EPI, 14%; MCQ, 12%, and Schwartz, 4%. There was a strong association between the body mass index (BMI) and the GFR according to all equations (p < 0.0001). The lowest heart rate was significantly associated with a reduced GFR according to the Cockroft-Gault equation (p = 0.03). The GFR values did not differ significantly after rehydration., Conclusion: Clinicians should evaluate AN patients for renal complications, especially when the BMI and heart rate are very low. Dehydration was not solely responsible for renal impairment., Level of Evidence: Level III, single-center retrospective cohort study.

Preterm birth incurs a higher risk for adult cardiovascular diseases, including hypertension. Because preterm birth may impact nephrogenesis, study objectives were to assess renal size and function of adults born preterm versus full term and to examine their relationship with blood pressure (BP; 24-hour ambulatory BP monitoring) and circulating renin-Ang (angiotensin) system peptides. The study included 92 young adults born (1987-1997) preterm (≤29 weeks of gestation) and term (n=92) matched for age, sex, and race. Young adults born preterm had smaller kidneys (80±17 versus 90±18 cm 3 /m 2 ; P<0.001), higher urine albumin-to-creatinine ratio (0.70; interquartile range, 0.47-1.14 versus 0.58, interquartile range 0.42 to 0.78 mg/mmol, P=0.007), higher 24-hour systolic (121±9 versus 116±8 mm Hg; P=0.001) and diastolic (69±5 versus 66±6 mm Hg; P=0.004) BP, but similar estimated glomerular filtration rate. BP was inversely correlated with kidney size in preterm participants. Plasma Ang I was higher in preterm versus term participants (36.3; interquartile range, 13.2-62.3 versus 19.4; interquartile range, 9.9-28.1 pg/mL; P<0.001). There was no group difference in renin, Ang II, Ang (1-7), and alamandine. In the preterm, but not in the term group, higher BP was significantly associated with higher renin and alamandine and lower birth weight and gestational age with smaller adult kidney size. Young adults born preterm have smaller kidneys, higher urine albumin-to-creatinine ratio, higher BP, and higher circulating Ang I levels compared with term controls. Preterm young adults with smaller kidneys have higher BP. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT03261609.

Background: Hemolytic uremic syndrome related to Shiga-toxin-secreting Escherichia coli infection (STEC-HUS) remains a common cause of acute kidney injury in young children. No specific treatment has been validated for this severe disease. Recently, experimental studies highlight the potential role of complement in STEC-HUS pathophysiology. Eculizumab (EC), a monoclonal antibody against terminal complement complex, has been used in severe STEC-HUS patients, mostly during the 2011 German outbreak, with conflicting results., Methods: On behalf of the French Society of Pediatric Nephrology, we retrospectively studied 33 children from 15 centers treated with EC for severe STEC-HUS. Indication for EC was neurologic involvement in 20 patients, cardiac and neurologic involvement in 8, cardiac involvement in 2, and digestive involvement in 3. Based on medical status at last follow-up, patients were divided into two groups: favorable (n = 15) and unfavorable outcomes (n = 18)., Results: Among patients with favorable outcome, 11/14 patients (79%) displayed persistent blockade of complement activity before each EC reinjection. Conversely, in patients with unfavorable outcome, only 9/15 (53%) had persistent blockade (p = n.s.). Among 28 patients presenting neurological symptoms, 19 had favorable neurological outcome including 17 with prompt recovery following first EC injection. Only two adverse effects potentially related to EC treatment were reported., Conclusions: Taken together, these results may support EC use in severe STEC-HUS patients, especially those presenting severe neurological symptoms. The study, however, is limited by absence of a control group and use of multiple therapeutic interventions in treatment groups. Thus, prospective, controlled trials should be undertaken.

Background: Cases reports and small series of patients with C3 glomerulopathy have reported variable efficacy of eculizumab., Study Design: Case series of C3 glomerulopathy., Setting & Participants: Pediatric and adult patients with C3 glomerulopathy treated with eculizumab between 2010 and 2016 were identified through the C3 glomerulopathy French registry database, and a questionnaire was sent to participating French pediatric and adult nephrology centers, as well as one pediatric referral center in Québec, Canada., Outcomes: Global or partial clinical renal response., Measurements: Evolution of serum creatinine and proteinuria values., Results: 26 patients (13 children/adolescents) were included. 22 (85%) patients had received steroids, plasma exchange, or immunosuppressive therapy before eculizumab, and 3 of them had rapid progression of their kidney disease despite treatment. At the initiation of eculizumab therapy, 11 (42%) patients had chronic kidney disease, 7 (27%) had rapidly progressive disease, and 3 (12%) required dialysis. After eculizumab treatment (median duration, 14 months), 6 (23%) patients had a global clinical response; 6 (23%), a partial clinical response; and 14 (54%), no response. Compared with those who had a partial clinical or no response, patients who had a global clinical response had lower estimated glomerular filtration rates, a more rapidly progressive course, and more extracapillary proliferation on kidney biopsy. Age, extent of renal fibrosis, frequency of nephrotic syndrome, low serum C3 and C3 nephritic factor and elevated soluble C5b-9 concentrations, or complement gene variants did not differ between responders and nonresponders., Limitations: Retrospective design without a control group, relatively small number of cases, inclusion of pediatric and adult cases., Conclusions: Eculizumab appears to be a potential treatment for patients with crescentic rapidly progressive C3 glomerulopathy. Its benefit in patients with non-rapidly progressing forms seems to be limited., (Copyright © 2017 National Kidney Foundation, Inc. All rights reserved.)

Atypical hemolytic uremic syndrome (aHUS) emerged during the last decade as a disease largely of complement dysregulation. This advance facilitated the development of novel, rational treatment options targeting terminal complement activation, e.g., using an anti-C5 antibody (eculizumab). We review treatment and patient management issues related to this therapeutic approach. We present consensus clinical practice recommendations generated by HUS International, an international expert group of clinicians and basic scientists with a focused interest in HUS. We aim to address the following questions of high relevance to daily clinical practice: Which complement investigations should be done and when? What is the importance of anti-factor H antibody detection? Who should be treated with eculizumab? Is plasma exchange therapy still needed? When should eculizumab therapy be initiated? How and when should complement blockade be monitored? Can the approved treatment schedule be modified? What approach should be taken to kidney and/or combined liver-kidney transplantation? How should we limit the risk of meningococcal infection under complement blockade therapy? A pressing question today regards the treatment duration. We discuss the need for prospective studies to establish evidence-based criteria for the continuation or cessation of anticomplement therapy in patients with and without identified complement mutations.

Background: C3 glomerulonephritis (C3GN) is a rare form of glomerulopathy that is characterized by predominant C3 deposits. Eculizumab, a humanized monoclonal C5 antibody, has recently emerged as a treatment option for C3GN. We report a C3GN patient successfully treated with eculizumab., Case Diagnosis/treatment: A 5-year-old boy who presented with proteinuria, hematuria, high ASO titers, and low C3 levels was initially diagnosed with post-streptococcal GN. His first kidney biopsy confirmed this diagnosis, but complement investigations identified three alternative pathway dysregulation factors: C3 nephritic factor, complement factor I heterozygous mutation (I398L), and anti-factor H autoantibodies (4,500 AU/ml). A second biopsy performed 11 months after initial presentation (nephrotic range proteinuria) showed a C3GN suggestive of isolated C3 deposits. Despite the use of intensive immunosuppressive therapy (rituximab, corticosteroids, mycophenolate), nephrotic-range proteinuria persisted and a third kidney biopsy showed the same C3GN pattern with more endocapillary proliferation. The serum C5b-9 level was elevated. Eculizumab was initiated and resulted in a significant decline of proteinuria (5.3 to 1.3 g/day) and an improvement in pathologic features. A transient interruption of eculizumab resulted in a rapid rise in proteinuria to 9.3 g/day, which decreased to 0.8 g/day after resumption of treatment., Conclusions: The administration of anti-C5 antibodies may represent a valuable therapeutic option in patients with C3GN.

Background: The optimal monitoring strategy for cyclosporine (CsA) in pediatric hematopoietic stem cell transplantation (HSCT) patients remains unclear. Although there is a growing interest in the use of the area under the concentration-time curve (AUC), measurement of AUC in clinical settings is often impractical. The objective of this study was to identify and validate limited sampling strategies (LSSs) for the prediction of CsA AUC after intravenous (IV) and oral (PO) administration in this population., Methods: Sixty-eight pediatric patients who underwent HSCT and received CsA were investigated. Twelve-hour pharmacokinetic profiles (n = 138) performed per standard of care were collected. Weighted multiple linear regression was used to investigate all possible LSSs consisting of 4 or less concentration-time points. Their predictive performance was evaluated by leave one out cross validation and external validation by measuring the root mean squared relative error (RMSE%) and the 95th percentile of the absolute relative error (AE%). Values less than 20% were considered clinically acceptable., Results: Nine LSSs (4 IV and 5 PO) convenient for clinical application proved to have clinically acceptable performance. Notably, LSS based on C0, C2, and C4 was found to be accurate for estimation of CsA exposure after both IV and PO administration with the 95th percentile of AE% of 19.7% and 17.5%, respectively., Conclusions: LSSs using 3 or 4 concentration-time points obtained within 4 hours postdose provide a convenient and reliable method to estimate CsA exposure in this population. These LSSs may facilitate future research aiming at better defining the relationship between AUC and clinical outcomes.

Purpose: Anorexia nervosa is a malady with possible long-lasting physiological consequences. Among these, little is known about the renal effects, which remain rarely investigated., Methods: A literature review was conducted using electronic databases and manual search of relevant articles, discussing the renal impacts of anorexia nervosa., Results: Renal failure has been described in malnourished patients, but the optimal non-invasive tool to assess the glomerular function rate in this population needs to be further evaluated. Significant disruptions in osmolar regulation, even in the absence of potomania, arise from multiple factors: hypothalamic dysfunction, intrinsic renal insufficiency, and use of psychotropic medications. Urinary urgency and nocturnal enuresis are frequent symptoms, rarely reported by patients. Among hydroelectrolytic disorders, hypokalemia is the most frequent, especially in settings of vomiting or medication misuse. Hyponatremia, hypomagnesemia, and hypophosphatemia may also be encountered. Urinary lithiases are relatively frequent as a consequence of dehydration, laxative use, or both., Conclusion: Investigation and follow-up of the renal function are essential in patients with an eating disorder, especially when the illness has been present for a long time.

Background: The choice of vascular access (VA) for hemodialysis (HD) in end-stage renal disease (ESRD) is arteriovenous fistula (AVF) or central venous catheter (CVC). Whereas clinical practice guidelines suggest AVF to preserve the vascular bed, pediatric nephrologists tend to favor CVC for shorter-term dialysis. Our objective was to determine whether pediatric priority allocation policies for deceased-donor kidneys affect VA planning., Methods: Pediatric priority for deceased-donor kidneys was instituted in Quebec in 2004. We retrospectively compared clinical practice on AVF, CVC, wait time on transplant list, HD duration in pre-policy (group A) and post-policy (group B) from 1997-2011., Results: We identified 78 patients with a median age of 14.7 years (range, 0.7-20.5 years) and weight of 46 kg (12.5-95 kg); AVF decreased from 76 % in group A to 41 % in group B (p = 0.002). Wait times on transplant list were significantly reduced: median 413.5 days (range, 2-1,910 days) in group A vs. 89 days (range, 18-692 days) in group B (p = 0.003). Time on HD for deceased-donor recipients was shorter: 705 (range, 51-1,965 days) group A vs. 349.5 days (range, 158-1,060 days) group B (p = 0.01)., Conclusions: This is the first study to document VA changes related to pediatric priority allocation policy. Our fistula-first center saw a shift toward CVC-first.

Background: The optimal marker for cyclosporine (CsA) monitoring in transplantation patients remains controversial. However, there is a growing interest in the use of the area under the concentration-time curve (AUC), particularly for cyclosporine dose adjustment in pediatric hematopoietic stem cell transplantation. In this paper, we develop Bayesian limited sampling strategies (B-LSS) for cyclosporine AUC estimation using population pharmacokinetic (Pop-PK) models and investigate related issues, with the aim to improve B-LSS prediction performance., Methods: Twenty five pediatric hematopoietic stem cell transplantation patients receiving intravenous and oral cyclosporine were investigated. Pop-PK analyses were carried out and the predictive performance of B-LSS was evaluated using the final Pop-PK model and several related ones. The performance of B-LSS when targeting different versions of AUC was also discussed., Results: A two-compartment structure model with a lag time and a combined additive and proportional error is retained. The final covariate model does not improve the B-LSS prediction performance. The best performing models for intravenous and oral cyclosporine are the structure ones with combined and additive error, respectively. Twelve B-LSS, consisting of 4 or less sampling points obtained within 4 hours post-dose, predict AUC with 95th percentile of the absolute values of relative prediction errors of 20% or less. Moreover, B-LSS perform better for the prediction of the 'underlying' AUC derived from the Pop-PK model estimated concentrations that exclude the residual errors, in comparison to their prediction of the observed AUC directly calculated using measured concentrations., Conclusions: B-LSS can adequately estimate cyclosporine AUC. However, B-LSS performance is not perfectly in line with the standard Pop-PK model selection criteria; hence the final model might not be ideal for AUC prediction purpose. Therefore, for B-LSS application, Pop-PK model diagnostic criteria should additionally account for AUC prediction errors.

Background: The objectives of this study were to investigate pharmacokinetic and pharmacogenetic parameters during the conversion on a 1:1 (mg:mg) basis from a twice-daily (Prograf) to once-daily (Advagraf) tacrolimus formulation in pediatric kidney transplant recipients., Methods: Twenty-four-hour pharmacokinetic profiles were analyzed before and after conversion in 19 stable renal transplant recipients (age 7-19 years). Tacrolimus pharmacokinetic parameters [area under the concentration-time curve (AUC0-24), minimum whole-blood concentration (Cmin), maximum whole-blood concentration (Cmax), and time to achieve maximum whole-blood concentration (tmax)] were compared between Tac formulations and between CYP3A5 and MDR1 genotypes after dose normalization., Results: Both AUC0-24 and Cmin decreased after conversion (223.3 to 197.5 ng.h/ml and 6.5 to 5.6 ng/ml; p = 0.03 and 0.01, respectively). However, the ratio of the least square means (LSM) for AUC0-24 was 90.8 %, with 90 % CI limits of 85.3 to 96.7 %, falling within bioequivalence limits. The CYP3A5 genotype influences the dose-normalized Cmin with the twice-daily formulation only., Conclusions: Both tacrolimus formulations are bioequivalent in pediatric renal recipients. However, we observed a decrease in AUC0-24 and Cmin after the conversion, requiring close pharmacokinetic monitoring during the conversion period.

Aims: The objectives of this study were to develop a population pharmacokinetic (PopPK) model for tacrolimus in paediatric liver transplant patients and determine optimal sampling strategies to estimate tacrolimus exposure accurately., Methods: Twelve hour intensive pharmacokinetic profiles from 30 patients (age 0.4-18.4 years) receiving tacrolimus orally were analysed. The PopPK model explored the following covariates: weight, age, sex, type of transplant, age of liver donor, liver function tests, albumin, haematocrit, drug interactions, drug formulation and time post-transplantation. Optimal sampling strategies were developed and validated with jackknife., Results: A two-compartment model with first-order absorption and elimination and lag time described the data. Weight was included on all pharmacokinetic parameters. Typical apparent clearance and central volume of distribution were 12.1 l h(-1) and 31.3 l, respectively. The PopPK approach led to the development of optimal sampling strategies, which allowed estimation of tacrolimus pharmacokinetics and area under the concentration–time curve (AUC) on the basis of practical sampling schedules (three or four sampling times within 4 h) with clinically acceptable prediction error limit. The mean bias and precision of the Bayesian vs. reference (trapezoidal) AUCs ranged from -2.8 to -1.9% and from 7.4 to 12.5%, respectively., Conclusions: The PopPK of tacrolimus and empirical Bayesian estimates represent an accurate and convenient method to predict tacrolimus AUC(0-12) in paediatric liver transplant recipients, despite high between-subject variability in pharmacokinetics and patient demographics. The developed optimal sampling strategies will allow the undertaking of prospective trials to define the tacrolimus AUC-based therapeutic window and dosing guidelines in this population.

We evaluated the pharmacokinetic profile of intravenous ganciclovir and oral valganciclovir in transplant children. Median AUC0-24 concentrations obtained after intravenous and oral formulations were 22.9 µg•h/mL (range, 17-65.2) and 34.55 µg•h/mL (range, 20.8-84.2), respectively. After normalization on a 20 mg/kg/d valganciclovir dosage, the median AUC0-24 concentration was 37.6 µg•h/mL (range, 23.6-68).

Mycophenolate mofetil (MMF) has emerged as a new therapeutic option in steroid-dependent nephrotic syndrome (SDNS). We conducted a phase II Bayesian trial of MMF in children with SDNS. Phase II trials, usually single-arm studies, investigate the effect of new treatments. Standard Fleming's procedure relies on observed results (relapse rate during the trial), whereas Bayesian approach combines observed results with prior information (expected relapse rate according to prior studies and clinical experience). All patients were required to have received prior alkylating-agent treatment. Sixty-seven percent of them had also received levamisole. Patients received MMF (1,200 mg/m(2)/day) and prednisone according to a defined schedule [reduction of alternate-day (e.o.d) dose to 50% of pre-MMF dose at 3 months, 25% at 6 months]. Twenty-four children (median age 6.0 years, 2.8-14.4) entered the study and 23 completed it. Bayesian analysis showed that adding four patients would not change significance of results, allowing stopping inclusions. Four patients relapsed during the first 6 months (estimated probability 17.6%, 95% credibility interval: 5.4-35.0%) and two at months 8 and 11.5. In the 19 patients free of relapse during the first 6 months, median (Q1-Q3) prednisone maintenance dose decreased from 25 (10-44) to 9 (7.5-11.2) mg/m(2) e.o.d (p < 0.001) and cumulative dose from 459 (382-689) to 264 (196-306) mg/m(2)/month (p < 0.001) before and on MMF respectively. Pre-MMF patient characteristics and MMF pharmacokinetics did not differ between patients with or without relapse. MMF reduces relapse rate and steroid dose in children with SDNS and should be proposed before cyclosporine and cyclophosphamide.

Aims. To assess trends in the incidence of pediatric diarrhea-associated hemolytic uremic syndrome (D(+) HUS) and document long-term renal sequelae. Methods. We conducted a retrospective cohort study of children with D(+) HUS admitted to a tertiary care pediatric hospital in Montreal, Canada, from 1976 to 2010. In 2010, we recontacted patients admitted before 2000. Results. Of 337 cases, median age at presentation was 3.01 years (range 0.4-14). Yearly incidence peaked in 1988 and 1994-95, returning to near-1977 levels since 2003. Twelve patients (3.6%) died and 19 (5.6%) experienced long-term renal failure. Almost half (47%) The patients required dialysis. Need for dialysis was the best predictor of renal sequelae, accounting for 100% of severe complications. Of children followed ≥1 year (n = 199, mean follow-up 8.20 ± 6.78 years), 19 had severe and 18 mild-to-moderate kidney injury, a total sequelae rate, of 18.6%. Ten years or more after-HUS (n = 85, mean follow-up 15.4 ± 5.32 years), 8 (9.4%) patients demonstrated serious complications and 22 (25.9%) mild-to-moderate, including 14 (16%) microalbuminuria: total sequelae, 35.3%. Conclusions. Patients with D(+) HUS should be monitored at least 5 years, including microalbuminuria testing, especially if dialysis was required. The cause of the declining incidence of D(+)HUS is elusive. However, conceivably, improved public health education may have played an important role in the prevention of food-borne disease.

Objective: To develop and validate limited sampling strategies (LSSs) for tacrolimus in pediatric liver transplant recipients., Methods: Thirty-six 12-hour pharmacokinetic profiles from 28 pediatric liver transplant recipients (0.4-18.5 years) were collected. Tacrolimus concentrations were measured by immunoassay and area under the curve (AUC0-12) was determined by trapezoidal rule. LSSs consisting of 1, 2, 3, or 4 concentration-time points were developed using multiple regression analysis. Eight promising models (2 per category) were selected based on the following criteria: r2 ≥ 0.90, inclusion of trough concentration (C0), and time points within 4 hours postdose. The predictive performance of these LSSs was evaluated in an independent set of data by measuring the mean prediction error and the root mean squared prediction error., Results: Five models including 2-4 time points predicted AUC0-12 with a ±15% error limit. Bias (mean prediction error) and precision (root mean squared prediction error) of LSS involving C0, C1, and C4 (AUCpredicted = 9.30 + 3.69 × C0 + 2.19 × C1 + 4.69 × C4) were -4.98% and 8.29%, respectively. Among single time point LSSs, the model using C0 had a poor correlation with AUC0-12 (r2 = 0.53), whereas the one with C4 had the highest correlation with tacrolimus exposure (r2 = 0.84)., Conclusions: Trough concentration is a poor predictor of tacrolimus AUC0-12 in pediatric liver transplant recipients. However, LSSs using 2-4 concentration-time points obtained within 4 hours postdose provide a reliable and convenient method to predict tacrolimus exposure in this population. The proposed LSSs represent an important step that will allow the undertaking of prospective trials aiming to better define tacrolimus target AUC in pediatric liver transplant recipients and to determine whether AUC-guided monitoring is superior to C0-based monitoring in terms of efficacy and safety.

Atypical hemolytic uremic syndrome (aHUS) is a rare, chronic, life-threatening disease due to complement dysregulation. The use of early-onset plasma therapy is recommended, but optimal long-term treatment regimen is not well defined. Eculizumab, a monoclonal humanized anti-C5 antibody, has shown success in patients with aHUS. We report a 7-year-old girl with aHUS associated with factor H mutations successfully treated with eculizumab. Weekly plasma infusion (PI) of 25-30 ml/kg with short-term intensified PI during aHUS exacerbations was effective for 4.3 years. Progressive mild renal failure (stage 2) was attributed to chronic glomerular lesions. Subsequently, she exhibited aHUS exacerbation unresponsive to intensified PI. Eculizumab was initiated at 600 mg, resulting in immediate and complete inhibition of terminal complement activation. During the week following treatment, we observed a complete reversal of aHUS activity. She has been receiving 600 mg eculizumab every 2 weeks for the last 12 months. She had no aHUS exacerbation, and serum creatinine level returned to normal. In this patient, eculizumab led to control of PI-resistant aHUS exacerbation and chronic microangiopathic hemolytic activity. Clinical trials are ongoing to assess the safety and efficacy of this drug in the management of aHUS.

The management and optimal care for the pediatric patient with chronic kidney disease requires attention not only to medical management, but also special focus on the psychosocial and developmental factors of children which is complicated by the presence of other disease-related complications. In recent years, specialized chronic kidney disease and predialysis clinics have been set up to facilitate and improve the quality of care of these patients with a multidisciplinary organisation and coordinated management approaches of a renal team. We present our experience in establishing such a renal management clinic named "Prévoir" for children with chronic kidney disease at Sainte-Justine Hospital.

Common variable immunodeficiency (CVID) is characterized by reduced serum immunoglobulin levels and recurrent bacterial infections. Granulomatous infiltrations are occasionally found in the lymphoid or solid organs of affected patients, but renal involvement is rare. We present a case of possible CVID with interstitial noncaseating granuloma and immunoglobulin (IgM)-complex glomerulonephritis with a membranoproliferative pattern and with a favorable response to corticosteroids, intravenously administered immunoglobulins (IVIGs) and rituximab. CVID must be included in the differential diagnosis of renal granuloma and should be differentiated from sarcoidosis to ensure appropriate therapy.

Data on the use of enteric-coated mycophenolic acid (EC-MPS) in pediatric transplantation cases are scarce. We undertook a 12-month, multicenter, open-label pilot study in which 16 de novo renal transplant patients aged 5-16 years received EC-MPS with cyclosporine A microemulsion (CsA-ME), steroids, and anti-interleukin-2 receptor antibody induction. The mean dose of EC-MPS was 916 +/- 93 mg/m(2) per day during weeks 1-2, 810 +/- 193 mg/m(2) per day during months 3-6, and 827 +/- 153 mg/m(2) per day during months 6-12. The mean CsA C(2) level exceeded target range up to month 6 post-transplant. Efficacy failure (biopsy-proven acute rejection, graft loss, death or loss to follow-up) occurred in two patients: one patient with primary non-function underwent nephrectomy, and one patient experienced biopsy-proven acute rejection (Grade 1B, day 344) following EC-MPS dose reduction. There were no deaths. Creatinine clearance (Schwartz) was 103 +/- 30 mL/min per 1.73 m(2) at month 6 and 100 +/- 16 mL/min per 1.73 m(2) at month 12. The majority of adverse events were mild or moderate (101/126, 80.2%). In this pilot study, EC-MPS 450 mg/m(2) administered twice daily with CsA, steroids, and interleukin-2 antibody induction resulted in a low rate of rejection with good renal function in a pediatric population. However, a larger, controlled trial is required to confirm these results.

Atypical hemolytic uremic syndrome (aHUS) frequently results in end-stage renal failure and can be lethal. Several studies have established an association between quantitative or qualitative abnormalities in complement factor H and aHUS. Although plasma infusion and exchange are often advocated, guidelines have yet to be established. Long-term outcome for patients under treatment is still unknown. We describe a patient who, at 7 months of age, presented with aHUS associated with combined de novo complement factor H mutations (S1191L and V1197A) on the same allele. Laboratory investigations showed normal levels of complements C4, C3 and factor H. Plasma exchanges and large-dose infusion therapy resulted in a resolution of hemolysis and recovery of renal function. Three recurrences were successfully treated by intensification of the plasma infusion treatment to intervals of 2 or 3 days. This patient showed good response to large doses of plasma infusions and her condition remained stable for 30 months with weekly plasma infusions (30 ml/kg). Long-term tolerance and efficacy of such intensive plasma therapy are still unknown. Reported secondary failure of plasma therapy in factor H deficiency warrants the search for alternative therapeutic approaches.

Type I pseudohypoaldosteronism (PHA1) is a rare form of mineralocorticoid resistance characterized by neonatal renal salt wasting and failure to thrive. Typical biochemical features include high levels of plasma aldosterone and renin, hyponatremia and hyperkalemia. Different mutations of the human mineralocorticoid receptor (hMR) gene have been identified in subjects affected by the autosomal dominant or sporadic form of the disease. Our laboratory has investigated a large number of subjects with familial and sporadic PHA1. Several different mutations have been detected, which are localized in different coding exons of the hMR gene. These mutations either create truncated proteins, either affect specific amino acids involved in receptor function. In this paper, we review hMR mutations described to date in PHA1 and their functional characterization. We discuss the absence of mutations in some kindreds and the role of precise phenotypic and biological examination of patients to allow for identification of other genes potentially involved in the disease.

The authors report the occurrence of sudden blindness in 5 children (mean age, 32 months; range, 11 to 60) during continuous peritoneal dialysis regimen. All children presented with loss of light perception, visual fixation and ocular pursuit, and bilateral mydriasis unreactive to bright light. Fundoscopic examination found signs of anterior ischemic optic neuropathy with disc swelling, edema, and hemorrhages. Whereas 1 patient was dehydrated, the 4 other patients appeared well and not dehydrated. Nevertheless, blood pressure was below the normal range in all of them. Therefore, hypovolemia is highly suspected to have been the cause of ischemic optic neuropathy in all cases. Treatment consisted of steroids (4 patients), anticoagulation or antiagregation drugs (3 patients), plasma or macromolecules infusions (2 patients), vasodilatators (2 patients), and transient dialysis interruption (1 patient). One child with hepatic cirrhosis died 4 days later of acute liver insufficiency owing to ischemic hepatic necrosis. The other children had only partial improvement of vision during the following months. Because the prognosis of ischemic optic neuropathy is very poor, diagnosis and treatment of chronic hypovolemia in children on continuous peritoneal dialysis is essential to prevent such a devastating complication.

Ganciclovir (GCV) is effective in preventing and treating cytomegalovirus (CMV) infection in solid organ transplant recipients. The aims of the present study were to determine the pharmacokinetics of GCV administered intravenously (IV) and orally (p.o.) as pre-emptive anti-CMV therapy in pediatric renal transplant recipients and to monitor trough levels and side-effects during pre-emptive therapy. Eleven pediatric renal transplant recipients (aged 11.0+/-3.9 years) were included. The diagnosis of CMV infection, based on two positive pp-65 CMV blood antigen tests at 1 week apart, was made at 39+/-12 days post renal transplantation. They received IV GCV at a dose of 5.0+/-0.3 mg/kg per 12 h for 15 days, followed by GCV p.o. at a dose of 46.7+/-8.2 mg/kg per 12 h for 3 months. Pharmacokinetics (PK) were studied at steady state and GCV plasma concentrations were measured by high-performance liquid chromatography. After IV GCV administration, PK parameters were: C(0)=0.84+/-0.66 microg/ml; C(max)=11.77+/-2.82 microg/ml; AUC(0-12 h)=42.29+/-17.57 microg/ml per hour; Cl=0.13+/-0.05 l/h per kg. After p.o. GCV administration, PK parameters were: C(0)=1.08+/-0.68 microg/ml; C(max)=2.70+/-1.07 microg/ml; AUC(0-12 h)=18.97+/-9.36 microg/ml per hour; Cl/F=2.97+/-1.42 l/h per kg. Bioavailability (F) was 4.9+/-1.2%. Pre-dose concentrations (C(0)) measured under p.o. GCV (n=51) were 1.29+/-0.80 microg/ml (8 C(0) values were below 0.5 microg/ml). Pp-65 CMV blood antigen tests became negative after 16+/-11 days of treatment. GCV was well tolerated. Because of the limited bioavailability, the recommended high doses of p.o. GCV (50 mg/kg per 12 h) were administered and were associated with trough levels over 0.5 microg/ml. In 1 patient who received an erroneously low dosage p.o., CMV resistance to GCV appeared, requiring foscarnet.

We have analyzed the human mineralocorticoid receptor (hMR) gene in 14 families with autosomal dominant or sporadic pseudohypoaldosteronism (PHA1), a rare form of mineralocorticoid resistance characterized by neonatal renal salt wasting and failure to thrive. Six heterozygous mutations were detected. Two frameshift mutations in exon 2 (insT1354, del8bp537) and one nonsense mutation in exon 4 (C2157A, Cys645stop) generate truncated proteins due to premature stop codons. Three missense mutations (G633R, Q776R, L979P) differently affect hMR function. The DNA binding domain mutant R633 exhibits reduced maximal transactivation, although its binding characteristics and ED(50) of transactivation are comparable with wild-type hMR. Ligand binding domain mutants R776 and P979 present reduced or absent aldosterone binding, respectively, which is associated with reduced or absent ligand-dependent transactivation capacity. Finally, P979 possesses a transdominant negative effect on wild-type hMR activity, whereas mutations G633R and Q776R probably result in haploinsufficiency in PHA1 patients. We conclude that hMR mutations are a common feature of autosomal dominant PHA1, being found in 70% of our familial cases. Their absence in some families underscores the importance of an extensive investigation of the hMR gene and the role of precise diagnostic procedures to allow for identification of other genes potentially involved in the disease.