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BACKGROUNDRare diseases collectively impose significant burden on healthcare systems, especially in underserved regions, like the Middle East, which lack access to genomic diagnostic services and the associated personalized management plans.METHODSWe established a clinical genomics and genetic counselling facility, within a multidisciplinary tertiary paediatric center, in the United Arab Emirates to locally diagnose and manage patients with rare diseases. Clinical genomic investigations included exome-based sequencing, chromosomal microarrays, and/or targeted testing. We assessed the diagnostic yield and implications for clinical management among this population.RESULTSWe present data on 529 patients with rare diseases (47% females; Average age, 4 years) representing 41 countries primarily from the Arabian Peninsula, the Levant, Africa, and Asia. The cumulative diagnostic yield was 35.7% (95% CI, 31.8% - 39.9%) and was higher for genomic sequencing-based testing than chromosomal microarrays (41.2% versus 16.9%, P=0.0001) across all indications, consistent with the higher burden of single gene disorders. Of the 124 Mendelian disorders identified in this cohort, the majority (N = 110) were encountered only once, and those with recessive inheritance accounted for ~60% of sequencing diagnoses. Of patients with positive genetic findings (N = 189), 71.9% were less than 5 years of age, and 65.6% were offered modified management and/or intervention plans. Interestingly, 18.5% of patients with positive genetic findings received delayed diagnoses (age range 7 – 37 years), most likely due to lack of access to genomic investigations in this region. One such genetic finding ended over a 10-year long diagnostic odyssey, leading to a life-threatening diagnosis in one patient, who was then successfully treated using an experimental allogenic bone marrow transplant. Finally, we present cases with candidate genes within regions of homozygosity, likely underlying novel recessive disorders.CONCLUSIONSEarly access to genomic diagnostics for patients with suspected rare disorders in the Middle East is likely to improve clinical outcomes while driving gene discovery in this historically underrepresented population.

Peritonitis is an important complication and cause of morbidity in patients undergoing peritoneal dialysis (PD). Corynebacterium species, often considered skin and mucosal contaminants, are a rare cause of PD-associated peritonitis and have been acknowledged in published guidelines for the diagnosis and treatment of PD peritonitis only over the last decade.We present two children with difficult-to-treat episodes of PD peritonitis due to Corynebacterium amycolatum. Episodes were associated with fever, abdominal pain and cloudy dialysate, high dialysate polymorphonuclear leukocyte counts, and elevated serum C-reactive protein and procalcitonin concentrations. Symptoms persisted beyond 5 days in 4 of 5 peritonitis episodes, and peritonitis relapsed despite in vitro sensitivity of the bacterial isolates to guideline-recommended antibiotics. C. amycolatum was cultured from the PD catheter tip despite 4 weeks of intraperitoneal glycopeptide therapy and clinical peritonitis resolution suggestive of efficient biofilm formation. Our systematic literature search identified three previous (adult) case descriptions of C. amycolatum peritonitis, all with repeat episodes by the same organism. The incidence of C. amycolatum as a cause of PD peritonitis has not yet been established but is likely underreported due to challenges in species differentiation.C. amycolatum is a rarely identified cause of refractory and/or relapsing PD peritonitis. Species differentiation of non-diphtheriae Corynebacterium isolates is critical, and prolonged antibiotic treatment, preferably with a glycopeptide antibiotic, is recommended, with a low threshold for PD catheter change or removal in case of repeat peritonitis.

Background: Peripheral nervous system (PNS) involvement, including Guillain Barré Syndrome (GBS), accounts for fewer than 10% of SLE cases with neuropsychiatric manifestations. GBS as the presenting, major manifestation of pediatric SLE is extremely rare, and the best treatment approach is unknown. Case presentation: A 14-year-old, previously healthy female Emirati teenager presented with a classic picture of GBS with ascending, progressive bilateral muscle weakness leading to respiratory insufficiency within five weeks of symptom onset, associated with typical protein-cell dissociation in cerebro-spinal fluid and nerve root enhancement demonstrated by spinal MRI. Subsequently, elevated anti-dsDNA and anti-Smith/RNP and anti-SS-A and -B antibody concentrations were detected in serum, suggestive of SLE. GBS treatment was initiated with IVIG and methylprednisolone pulses, with minimal improvement. The patient required endotracheal intubation and ventilation, followed by a second course of IVIG, rituximab, and eventually plasma exchange (PLEX) therapy. The diagnosis of lupus-associated GBS was corroborated by a kidney biopsy demonstrating lupus nephritis WHO class II with “full house” immunofluorescence pattern. After 14 PLEX sessions, her muscle strength and respiratory efforts had improved substantially. Treatment was completed with two more rituximab infusions, followed by mycophenolate mofetil, in addition to HCQ and tapering doses of oral prednisolone. Five weeks after the last PLEX treatment, she had regained her usual strength and achieved full, sustained recovery from GBS. While she continued to demonstrate moderate anti-dsDNA antibodies and high-level anti-Smith and Sjogren antibodies, C3, C4 and urine readings quickly normalized with no other manifestations of lupus or lupus nephritis 11 months after the initial assessment. At this time she was maintained with hydroxychloroquine, with ongoing depletion of circulating B cells. To our knowledge, this is only the third pediatric patient reported with SLE-GBS.Conclusions: We report severe GBS as the first, dominant manifestation of pediatric SLE. Our case and a review of the literature reveal that cconventional GBS therapy may not be adequate to treat this rare lupus presentation. SLE should be included in the differential diagnosis of GBS. Importantly, treatment experiences and outcomes of such cases need be reported to inform future treatment recommendations.

Renal tubular dysgenesis (RTD) is a developmental abnormality of the nephron characterized by fetal anuria, oligohydramnios, and severe postnatal hypotension. Genetic forms have an autosomal recessive inheritance and are caused by mutations in genes encoding key components of the renin-angiotensin pathway. We report three patients from two unrelated families with RTD due to pathogenic variants of the angiotensin-converting enzyme (ACE) gene, in whom RTD was associated with microcolon. We also detail key variations of the renin-angiotensin system in one of these infants. The severe intestinal developmental abnormality culminating in microcolon and early terminal ileum perforation/necrotizing enterocolitis is a novel finding not previously associated with RTD, which points to a role of the renin-angiotensin system in gut development.

ObjectiveTo compare the efficacy and safety of theophylline or aminophylline for prevention of acute kidney injury (AKI) in neonates and children.DesignSystematic review and meta-analysis with application of Grading of Recommendations, Assessment, Development and Evaluation system.Data sourcesPubMed/MEDLINE, Embase, Google Scholar and Cochrane renal group were searched from 1970 to May 2018.Eligibility criteriaRandomised clinical trials and quasi-randomised trials comparing the efficacy and safety of prophylactic theophylline or aminophylline for prevention of AKI in neonates and children were included. The primary outcomes were: incidence of AKI, serum creatinine levels and all-cause mortality.ResultsA total of nine trials were included in the qualitative synthesis. Six trials including 436 term neonates with birth asphyxia who received a single dose of theophylline were finally included in the meta-analysis. The pooled estimate showed 60% reduction in the incidence of AKI in neonates with severe birth asphyxia (RR: 0.40; 95% CI 0.3 to 0.54; heterogeneity: I2=0%) (moderate quality evidence), decrease in serum creatinine over days 2–5 (very low to low quality evidence) without significant difference in all-cause mortality (RR: 0.88; 95% CI 0.52 to 1.50; heterogeneity: I2=0%) (very low-quality evidence). A significant difference in the negative fluid balance, increase in GFR and decrease in urinary β2 microglobulin was seen in favour of theophylline.Conclusion and relevanceA single dose of prophylactic theophylline helps in prevention of AKI/severe renal dysfunction in term neonates with severe birth asphyxia (moderate quality evidence) without increasing the risk of complications and without affecting all-cause mortality (very low-quality evidence).Trial registration numberCRD 42017073600.

A hyperchloremic non-anion gap metabolic acidosis, in the absence of grastrointestinal bicarbonate loss, is due to either renal loss of bicarbonate or an inability of the kidney to excrete protons in the urine. This chapter outlines renal tubular mechanisms mediating bicarbonate reabsorption by the nephron and acid secretion by the kidney and the pathologies that disturb them. Bicarbonate reabsorption predominantly occurs in the proximal tubule while acid secretion takes place in the distal nephron. Consequently, specific pathologies, which prevent bicarbonate reclamation and lead to a metabolic acidosis are referred to as proximal renal tubular acidosis (pRTA). Conversely, a failure of the kidney to excrete acid is known as distal renal tubular acidosis (dRTA). These forms of renal tubular acidosis are typically accompanied by hypokalemia. In the distal nephron acid secretion is facilitated by the electrogenic reabsorption of sodium in response to aldosterone, a process that also permits potassium secretion. Consequently actual or functional absence of aldosterone leads to a hyperkalemic metabolic acidosis. After identifying the clinical presentation of these types of disorders, with particular emphasis on genetic causes of RTA, we highlight a diagnostic approach to and treatment for them.

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-producingKey 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.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.Thrombotic thrombocytopenic purpura occurs in the setting of insufficient activity of the von Willebrand factor protease known as ADAMTS13. Shiga toxin-producingThe 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.La microangiopathie thrombotique (MAT) est suspectée chez les patients présentant une thrombocytopénie et la preuve d’une anémie hémolytique microangiopathique (AHMA). Les patients atteints de MAT peuvent être gravement malades, il est donc essentiel de déterminer rapidement et précisément l’étiologie sous-jacente. Grâce à une meilleure connaissance de la physiopathologie et des causes de la MAT, nous pouvons désormais classer les MAT par catégorie: purpura thrombocytopénique thrombotique (PTT), syndrome hémolytique urémique post-infectieux (SHU) principalement induit par STEC (Des recherches documentaires sur PubMed et les connaissances antérieures des auteurs ont permis de colliger les principales études publiées portant sur la détection, la classification et le traitement de la MAT chez les enfants ou les adultes.Cet examen est le résultat d’un processus de consultation qui reflète le consensus des experts du Canada, des États-Unis et des Émirats arabes Unis. Les membres représentent des cliniciens, des chercheurs et des enseignants en médecine pédiatrique et adulte dans les domaines de l’hématologie, de la néphrologie et de la médecine de laboratoire. Les auteurs, par le biais d’un processus d’examen itératif, ont colligé et synthétisé l’information provenant des études publiées jugées pertinentes.Le PTT survient lors d’une activité insuffisante de la protéase du facteur Willebrand connue sous le nom d’ADAMTS13. Le SHU-STEC, aussi appelé SHU « typique », est causé par des infections gastro-intestinales dues à des bactéries produisant la toxine Shiga (initialement appelée vérocytotoxine). Plusieurs états pathologiques ou expositions à des médicaments peuvent déclencher la MAT. Quant au SHU atypique (SHUa), il survient en présence d’anomalies héréditaires ou acquises de la voie du complément alternatif qui mènent à un dérèglement de l’activation du complément, souvent à la suite d’un événement déclencheur comme une infection. On peut diviser le processus de diagnostic étiologique de la MAT en deux étapes distinctes. La première couvre la présentation initiale et le diagnostic, y compris les processus de détection de la MAT, les tests initiaux et aiguillages appropriés, ainsi que les traitements empiriques si nécessaire. La deuxième étape consiste à confirmer le diagnostic étiologique et à procéder au traitement définitif. Pour de nombreuses formes de MAT, la réponse ultime aux traitements et le résultat du patient dépendent de la détection rapide et précise de la MAT et ensuite, d’une approche standardisée pour la recherche du diagnostic étiologique. Nous présentons une approche structurée pour détecter la présence de MAT ainsi qu’une démarche pour rechercher l’étiologie, y compris des tableaux de laboratoire normalisés. Nous soulignons l’importance d’une consultation précoce avec les spécialistes appropriés en hématologie et en néphrologie, et de la détermination d’un éventuel besoin d’échange de plasma (PLEX) pour le patient. Les cliniciens devraient envisager les traitements empiriques appropriés tout en suivant la démarche que nous recommandons pour le diagnostic étiologique définitif et la gestion de la MAT.La base factuelle de nos recommandations est constituée de petites études cliniques, de rapports de cas et de séries de cas. Ces études ne sont généralement pas contrôlées ou randomisées et ne se prêtent pas à une méthodologie plus stricte basée sur des lignes directrices ni à une approche fondée sur le GRADE (

Objective: To assess the performance of a hemolytic uremic syndrome (HUS) severity score among children with Shiga toxin-producing Escherichia coli (STEC) infections and HUS by stratifying them according to their risk of adverse events. The score has not been previously evaluated in a North American acute care setting. Study design: We reviewed medical records of children 13 were designated as high-risk. We assessed score performance to predict severe adverse events (ie, dialysis, neurologic complication, respiratory failure, and death) using discrimination and net benefit (ie, threshold probability), with subgroup analyses by age and day-of-illness. Results: A total of 167 children had HUS, of whom 92.8% (155/167) had relevant data to calculate the score; 60.6% (94/155) experienced a severe adverse event. Discrimination was acceptable overall (area under the curve 0.71, 95% CI 0.63-0.79) and better among children 26%. Conclusions: The HUS severity score was able to discriminate between high- and low-risk children

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.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.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-producingA 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% (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.Le syndrome hémolytique et urémique atypique (SHUa) se caractérise par l’activation incontrôlée de la voie alternative du complément. Il s’agit d’une maladie rare, hétérogène et très difficile à diagnostiquer. Nous avons évalué les patients Canadiens inscrits au registre international du SHUa afin d’offrir une perspective canadienne sur le diagnostic et la prise en charge du SHUa, de même que sur les défis posés par la maladie.Évaluer les patients Canadiens inscrits au registre international du SHUa afin d’offrir une perspective canadienne sur le diagnostic et la prise en charge du SHUa, de même que sur les défis posés par la maladie.Le registre international du SHUa est une étude observationnelle, non interventionnelle et multicentrique ayant recueilli, de façon rétrospective et prospective, des données auprès de patients de tous âges ayant reçu un diagnostic clinique de SHUa, quel que soit le traitement. Tous ces patients étaient admissibles et ont été invités à participer à l’étude. Les patients présentant une infection diagnostiquée àAu total, 37 patients canadiens ont été inscrits (15 enfants et 22 adultes) entre février 2014 et mai 2017. L’âge médian lors de l’épisode initial était de 25,9 ans (intervalle interquartile: 6,7–51,7); 62,2 % des sujets étaient de sexe féminin et 94,6 % n’avaient pas d’antécédents familiaux de SHUa. Plus des trois quarts des patients (78,4 %) ne disposaient d’aucune information génétique ou relative aux anticorps anti-complément du facteur H concluante, et aucun facteur précipitant n’avait été rapporté avant le diagnostic pour la majorité des patients (94 %). Neuf patients (8 adultes et 1 enfant) avaient souffert d’IRT avant l’étude. Une tendance semble indiquer qu’après l’épisode initial, les enfants seraient moins susceptibles que les adultes de progresser vers l’IRT (survie sans IRT après 5 ans: 93 % et 56 % respectivement;Cette étude offre un éclairage sur le diagnostic et la prise en charge du SHUa chez les patients canadiens, de même que sur les défis posés par la maladie. Davantage de dépistage génétique et de dépistage des anticorps anti-CFH sont requis pour améliorer le diagnostic du SHUa. La prise en charge de la maladie doit tenir compte de plusieurs facteurs, notamment du risque de progression vers l’IRT qui varie selon l’âge (plus probable chez l’adulte) et du fait que le site des manifestations extrarénales diffère chez l’enfant et l’adulte.

Children with genetic causes of steroid-resistant nephrotic syndrome (SRNS) usually do well after renal transplantation, while some with idiopathic SRNS show recurrence due to a putative podocyte-toxic factor. Distinguishing different forms of SRNS based on clinical criteria has been difficult. The aim of our study was to test a novel approach that allows categorization of patients into clinically useful subgroups. Seventeen patients with clinically confirmed SRNS were analyzed by next-generation sequencing (NGS) of 37 known SRNS genes and a functional assay of cultured human podocytes, which indirectly tests for toxicity of patients’ sera by evidenced loss of podocyte focal adhesion complex (FAC) number. We identified a pathogenic mutation in seven patients (41%). Sera from patients with monogenic SRNS caused mild loss of FAC number down to 73% compared to untreated controls, while sera from seven of the remaining ten patients with idiopathic SRNS caused significant FAC number loss to 43% (non-overlapping difference 30%, 95% CI 26–36%, P

Background Thrombotic thrombocytopenic purpura (TTP) is caused by the abundance of uncleaved ultralarge von Willebrand factor multimers (ULvWF) due to acquired (autoantibody-mediated) or congenital vWF protease ADAMTS13 deficiency. Current treatment recommendations include plasma exchange therapy and immunosuppression for the acquired form and (fresh) frozen plasma for congenital TTP. Case-diagnosis/treatment A previously healthy, 3-year-old boy presented with acute microangiopathic hemolytic anemia, thrombocytopenia, erythrocyturia and mild proteinuria, but normal renal function, and elevated circulating sC5b-9 levels indicating complement activation. He was diagnosed with atypical hemolytic uremic syndrome and treated with a single dose of eculizumab, followed by prompt resolution of all hematological parameters. However, undetectably low plasma ADAMTS13 activity in the pre-treatment sample, associated with inhibitory ADAMTS13 antibodies, subsequently changed the diagnosis to acquired TTP. vWF protease activity normalized within 15 months without further treatment, and the patient remained in long-term clinical and laboratory remission. Extensive laboratory workup revealed a homozygous deletion of CFHR3/1 negative for anti-CFH antibodies, but no mutations of ADAMTS13, (other) alternative pathway of complement regulators or coagulation factors. Conclusions This case, together with a previous report of a boy with congenital TTP (Pecoraro et al. Am J Kidney Dis 66:1067, 2015), strengthens evolving in-vitro and ex-vivo evidence that ULvWF interferes with complement regulation and contributes to the TTP phenotype. Comprehensive, prospective complement studies in patients with TTP may lead to a better pathophysiological understanding and novel treatment approaches for acquired or congenital forms.

Thrombotic microangiopathy (TMA) refers to phenotypically similar disorders, including hemolytic uremic syndromes (HUS) and thrombotic thrombocytopenic purpura (TTP). This review explores the role of the influenza virus as trigger of HUS or TTP. We conducted a literature survey in PubMed and Google Scholar using HUS, TTP, TMA, and influenza as keywords, and extracted and analyzed reported epidemiological and clinical data. We identified 25 cases of influenza-associated TMA. Five additional cases were linked to influenza vaccination and analyzed separately. Influenza A was found in 83%, 10 out of 25 during the 2009 A(H1N1) pandemic. Two patients had bona fide TTP with ADAMTS13 activity

Background Shiga toxin–producing Escherichia coli (STEC) infections are leading causes of pediatric acute renal failure. Identifying hemolytic uremic syndrome (HUS) risk factors is needed to guide care. Methods We conducted a multicenter, historical cohort study to identify features associated with development of HUS (primary outcome) and need for renal replacement therapy (RRT) (secondary outcome) in STEC-infected children without HUS at initial presentation. Children aged Results Of 927 STEC-infected children, 41 (4.4%) had HUS at presentation; of the remaining 886, 126 (14.2%) developed HUS. Predictors (all shown as odds ratio [OR] with 95% confidence interval [CI]) of HUS included younger age (0.77 [.69–.85] per year), leukocyte count ≥13.0 × 103/μL (2.54 [1.42–4.54]), higher hematocrit (1.83 [1.21–2.77] per 5% increase) and serum creatinine (10.82 [1.49–78.69] per 1 mg/dL increase), platelet count Conclusions The complex nature of STEC infection renders predicting its course a challenge. Risk factors we identified highlight the importance of avoiding dehydration and performing close clinical and laboratory monitoring.

Hemolytic uremic syndrome is a rare complication of invasive pneumococcal infection (pnHUS). Its pathogenesis is poorly understood, and treatment remains controversial. The emerging role of complement in various forms of HUS warrants a new look at this “old” disease. We performed a retrospective analysis of clinical and laboratory features of three sequential cases of pnHUS since 2008 associated with pneumonia/pleural empyema, two due to Streptococcus pneumoniae serotype 19 A. Profound depletion of complement C3 (and less of C4) was observed in two patients. One patient was Coombs test positive. Her red blood cells (RBCs) strongly agglutinated with blood group compatible donor serum at 0 °C, but not at 37 °C. All three patients were treated with hemodialysis, concentrated RBCs, and platelets. Patient 2 received frozen plasma for hepatic failure with coagulation factor depletion. Intravenous immunoglobulin infusion, intended to neutralize pneumococcal neuraminidase in patient 3, was associated with rapid normalization of platelets and cessation of hemolysis. Two patients recovered without sequelae or disease recurrence. Patient 2 died within 2½ days of admission due to complicating Pseudomonas aeruginosa sepsis and multiorgan failure. Our observations suggest that pnHUS can be associated with dramatic, transient complement consumption early in the course of the disease, probably via the alternative pathway. A critical review of the literature and the reported cases argue against the postulated pathological role of preformed antibodies against the neuraminidase-exposed Thomsen-Friedenreich neoantigen (T antigen) in pnHUS. The improved understanding of complement regulation and bacterial strategies of complement evasion allows to propose a testable, new pathogenetic model of pnHUS. This model shifts emphasis from the action of natural anti-T antibodies toward impaired Complement Factor H (CFH) binding and function on desialylated membranes. Removal of neuraminic acid residues converts (protected) self to non-self surfaces that supports membrane attack complex (MAC) assembly. Complement activation is potentially exacerbated by decreased CFH availability following tight CFH binding to pneumococcal evasion proteins and/or by the presence of genetic variants of complement regulator proteins. Detailed clinical and experimental investigations are warranted to better understand the role of unregulated complement activation in pnHUS. Instead of avoidance of plasma, a new, integrated model is evolving, which may include short-term therapeutic complement blockade, particularly where genetic or functional APC dysregulation is suspected, in addition to bacterial elimination and, potentially, neuraminidase neutralization.

Pediatric nephrology has rapidly evolved over the last several decades, with major advances in the pathophysiology, genetics, diagnosis, and treatment of children with kidney diseases. In the post-vaccination era urinary tract infections have become an important cause of serious bacterial infection in childhood, and children with underlying congenital abnormalities of the kidney and urological tract (CAKUT), including those with vesicoureteral reflux, are known to be a high risk group. Recent controversies on the appropriate diagnostic workup of children with febrile UTIs and the decision to prescribe long-term antibiotic prophylaxis in the changing landscape of increased antimicrobial resistance have sparked a lively debate in the medical community on appropriate management strategies. Improved understanding of the molecular mechanisms and genetic risk factors underlying glomerulonephritis have resulted in more rational therapeutics with immunosuppressant medications and rapidly expanding treatment options. With refined therapeutics, increasing survival of chronic illnesses, and technological advances in hospital and critical care medicine also come the growing awareness of the increased risk of acute kidney injury in hospitalized children. The economic and social burden of chronic kidney disease remains substantial in children, although much progress has been made in identifying factors associated with CKD progression and better management of various co-morbid conditions. The epidemiology, diagnosis, and management of childhood hypertension has changed greatly in the last decade, in part fueled by the rising obesity epidemic. Some of the most exciting recent breakthroughs in pediatric nephrology have been in the genetics of kidney development and disease. Emerging tools of next generation sequencing and whole exome sequencing have revolutionized the understanding of the genotype-phenotype associations underlying many pediatric kidney disorders and already have started to transform routine clinical management. Despite these impressive advances much work remains to be done, with the hope for progress to tailor therapies to individual patients based on their underlying molecular genetics in the coming era of personalized medicine.

We report on the proceedings of a national workshop held in Canada with the aims to identify priorities for research in childhood nephrotic syndrome and to develop a national strategy to address these priorities.A diverse group of participants attended the meeting, including patients, family members, researchers, and health care providers. We used small group discussions to explore priorities as perceived by patients and families and by health care providers and researchers.Research evaluating glucocorticoid minimization or glucocorticoid-sparing regimens was a consistent theme in the patient and family discussion group. Families also indicated the need for precise prognostic information at diagnosis, more information to help them choose the best available therapy, and more resources for disease management. Health care providers emphasized the importance of better disease characterization including genotyping and phenotyping patients, better understanding the pathogenesis, and the need of providing targeted therapy and precise prognostic information.These priorities will inform the development and future directions of the Canadian Childhood Nephrotic Syndrome (CHILDNEPH) project, a national research initiative to improve care and outcomes of patients with childhood onset nephrotic syndrome.Nous rapportons les travaux d’un atelier national qui s’est tenu au Canada et qui avait pour objectif de définir les priorités dans la recherche sur le syndrome néphrotique de l’enfant et d’élaborer une stratégie nationale pour répondre à celles-ci.Un groupe diversifié de participants a assisté à la réunion, notamment des patients, des membres de leurs familles, des chercheurs et des fournisseurs de soins de santé. Nous avons utilisé de petits groupes de discussion pour explorer les priorités telles que perçues par les patients et leurs familles, de même que par les fournisseurs de soins et les chercheurs.La recherche évaluant la minimisation des glucocorticoïdes ou les traitements substituant les glucocorticoïdes a été un thème récurrent dans le groupe de discussion constitué des patients et de leurs familles. De plus, les familles ont souligné le besoin d’obtenir des informations précises sur le pronostic au moment du diagnostic. Ils ont notamment parlé d’obtenir plus d’informations pour aider à choisir le meilleur traitement disponible et davantage de ressources pour la gestion de la maladie. Les fournisseurs de soins de santé ont quant à eux insisté sur l’importance d’une meilleure caractérisation de la maladie, incluant le génotypage et le phénotypage des patients, une meilleure compréhension de la pathogenèse de la maladie et la nécessité de fournir des thérapies ciblées et des renseignements précis sur le pronostic.Ces priorités guideront le développement et les futures orientations du

The KDIGO (Kidney Disease: Improving Global Outcomes) clinical practice guideline for management of glomerulonephritis was recently released. The Canadian Society of Nephrology convened a working group to review the recommendations and comment on their relevancy and applicability to the Canadian context. A subgroup of adult nephrologists reviewed the guideline statements for management of glomerular disease in adults and agreed with most of the guideline statements developed by KDIGO. This commentary highlights areas for which there is lack of evidence and areas in need of translation of evidence into clinical practice. Areas of controversy or uncertainty, including the choice of second-line agents, are discussed in more detail. Existing practice variation also is addressed. The relevance of treatment recommendations to the Canadian practitioner is discussed.

Focal segmental glomerulosclerosis (FSGS) is frequently found in biopsies of patients with steroid resistant nephrotic syndrome (SRNS). The pathogenesis of SRNS/FSGS is often unknown and the disease will recur in up to 50% of patients post-transplant, indicating the presence of circulating podocyte-toxic factor(s). Several studies have reported clinical improvement after anti-TNFα therapy. However, prediction of the clinical outcome in SRNS/FSGS is difficult, and novel predictive biomarkers are needed. An image-based assay, which measures disassembly of focal adhesion complexes in cultured podocytes, was used to ascertain the presence of podocyte toxic activity in SRNS/FSGS sera. Expression of TNFα pathway genes was analysed in the Nephroseq FSGS cohort and in cultured podocytes treated with SRNS/FSGS sera. Podocyte toxic activity was detected in 48/96 SRNS/FSGS patients. It did not correlate with serum TNFα levels, age, sex, ethnicity or glomerular filtration rate. In ~25% of the toxic samples, the toxicity was strongly inhibited by blockade of TNFα signaling. Transcriptional profiling of human FSGS biopsies and podocytes treated with FSGS sera revealed significant increases in expression of TNFα pathway genes. We identified patients with serum podocyte toxic activity who may be at risk for FSGS recurrence, and those patients in whom serum podocyte toxicity may be reversed by TNFα blockade. Activation of TNFα pathway genes occurs in podocytes of FSGS patients suggesting a causative effect of this pathway in response to circulating factor(s). In vitro analyses of patient sera may stratify patients according to prognostic outcomes and potential responses to specific clinical interventions.

Background Practice variation is common for nephrotic syndrome (NS) treatment. Methods A cross-sectional, web-based survey on NS treatment was administered to 58 Canadian pediatric nephrologists with the aim to document existing practice variation and compare practice with the recommendations of the Kidney Disease Improving Global Outcomes Clinical Practice Guideline for NS. Results Of the 58 nephrologists asked to participate in the survey, 40 (69 %) responded. Among these, 62 % prescribed initial daily glucocorticoid (GC) therapy for 6 weeks, 26 % for 4w eeks by 26 %, and 10 %p rescribed‘other’ .A lternateday GC was continued for 6 weeks by 63 % of respondents and for >6 and

Item does not contain fulltext 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.

In the absence of mutant genes encoding components of the podocyte slit diaphragm, about 30–50 % of children with primary glucocorticoid-resistant focal segmental glomerulosclerosis (FSGS) develop recurrent proteinuria and slowly progressive FSGS lesions following renal transplantation. Recurrence of FSGS in the allograft strongly suggests a circulating factor that disturbs normal podocyte biology. To date, the nature of the circulating factor is unclear, and there is no cure for the recurrent form of FSGS (R-FSGS). Cultured differentiated human podocytes were exposed to the plasmapheresis effluent or blood plasma samples from pediatric patients with recurrent or primary FSGS; in some cases, podocytes were pre-incubated with specific antibodies to block the tumor necrosis factor-alpha (TNFα) signaling pathway. Integrity of focal adhesion complexes and actin cytoskeleton were investigated by immunofluorescent microscopy. Plasmapheresis effluent from an R-FSGS child or fresh plasma from two children with primary FSGS rapidly disturbed the cytoskeleton of normal human podocytes in vitro. Plasma from a child with R-FSGS also activated β3 integrin and dispersed focal adhesion complexes. The effects were reversed by pre-incubation with antibodies against TNFα or either of the two TNFα receptors. When our patient with R-FSGS became resistant to plasmapheresis, we initiated treatment with twice weekly etanercept injections and then infliximab. Within 3 weeks of regular anti-TNFα therapy, the patient achieved sustained partial remission of proteinuria, allowing us to wean her off plasmapheresis completely. We suggest that in some FSGS patients, disruption of the podocyte cytoskeleton and β3 integrin-mediated podocyte attachment are driven by the TNFα pathway.

Background Pre-transplant nephrectomy is performed to reduce risks to graft and recipient. The aims of this study were to evaluate (1) indications, surgical approach, and morbidity of native nephrectomy and (2) the effects of kidney removal on clinical and biological parameters. Methods This study was designed as a single-center retrospective cohort study in which 49 consecutive patients with uni- or bilateral native nephrectomies were identified from a total of 126 consecutive graft recipients in our pediatric kidney transplantation database between 1992 and 2011. Demographic, clinical, and laboratory details were extracted from charts and electronic records, including operation reports and pre- and post-operative clinic notes. Results Of the 49 nephrectomized patients, 47% had anomalies of the kidneys and urinary tract, 22% had cystinosis, 12% had focal segmental glomerulosclerosis, and 6% had congenital nephrotic syndrome. Nephrectomy decisions were based on clinical judgment, taking physiological and psychosocial aspects into consideration. Nephrectomy was performed in patients with polyuria (>2.5 ml/kg/h) and/or large proteinuria (>40 mg/m2/h), recurrent urinary tract infection or (rarely) hypertension. Urine output decreased from (median) 3.79 to 2.32 ml/kg/h (−34%), and proteinuria from 157 to 100 mg/m2/h (−40%) after unilateral nephrectomy (p = 0.005). After bilateral nephrectomy, serum albumin, protein and fibrinogen concentrations normalized in 93, 73, and 55% of nephrectomized patients, respectively. Clinically relevant procedure-related complications (peritoneal laceration, hematoma) occurred in five patients. Conclusion In summary, we demonstrate quantitatively that native nephrectomy prior to transplantation improved serum protein levels and anticipated post-transplant fluid intake needs in select children, reducing the risk of graft hypoperfusion and its postulated consequences for graft outcome.

The MYH9 gene encodes a non-muscle myosin IIA heavy chain (NMMHC-IIA) expressed in podocytes. Heterozygous MYH9 mutations cause a set of overlapping syndromes characterized by variable degrees of deafness, morphologic abnormalities of platelets and focal segmental glomerulosclerosis (FSGS) with progressive renal dysfunction. Similar glomerular lesions are seen in a variety of nephropathies, including an idiopathic form of FSGS in children which recurs in renal allografts, implying a circulating factor that affects glomerular podocyte biology. It is unknown whether NMMHC-IIA is perturbed in the idiopathic form of FSGS. We describe a pediatric patient with typical idiopathic FSGS, in whom proteinuria recurred within hours of deceased donor renal transplantation but who responded to plasmapheresis. We demonstrate in vitro that plasmapheresis effluent from our patient rapidly decreased cultured podocyte levels of the phosphorylated myosin light chain (MLC) that mediates NMMHC-IIA binding to actin and induced dispersion of NMMHC-IIA from its usual position along actin stress fibers. FSGS plasma also caused dispersion of slit diaphragm proteins (nephrin and podocin) and vinculin-positive focal adhesion complexes. Our observations suggest that the putative circulating factor in idiopathic FSGS disrupts normal NMMHC-IIA function in podocytes and might contribute to the pathogenesis of recurrent FSGS in other children.

Typical enteropathic HUS (eHUS) is triggered by Shiga toxin (Stx)-producing bacteria (STPB), predominantly Stx-producing ESCHERICHIA COLI O157. The cell biological aspects of Stx have been well defined, but host factors potentially predisposing to the development or severity of HUS remain elusive. Treatment of eHUS includes supportive measures and invasive extracorporeal therapies. Thirty to 60% of children with eHUS require dialysis. Peritoneal and hemodialysis appear equally effective. Patient age, center experience, and equipment availability determine the choice of the modality; circulatory instability may require continuous renal replacement therapies. At present, no evidence indicates that plasma infusion or exchange therapies improve outcome of Stx-induced HUS. However, the traditional separation between diarrhea-positive (D (+)) and negative (D (-)) HUS, implying two entirely different pathological pathways, requires a fresh look: Atypical HUS may follow nonspecific diarrhea, and, conversely, STPB and fecal Stx may not be detected anymore at the time of the diagnosis of HUS. Recently, Stx has been found to directly interfere with the alternative complement pathway regulator factor H in vitro, whereas some patients with Stx-HUS demonstrate evidence of complement activation. Among newer treatments for eHUS, development of Stx-neutralizing monoclonal antibodies is the most advanced. This review concludes with a discussion of the rationale, mode of action, and status of presently available therapeutic antibodies against Stx2 and Stx1.

Introduction Pulmonary toxicity of delayed onset is a rare complication of B-lymphocyte depleting antibody therapy and has been almost exclusively reported in older patients with B-cell malignancies. Aims To describe a pediatric patient with rituximab-associated lung injury (RALI), to systematically analyze previous reports of pulmonary complications, and to summarize common clinico-pathological features, treatment, and outcome. Results A teenage boy with focal segmental glomerulosclerosis (FSGS) presented with progressive dyspnea, fever, hypoxemia and fatigue 18 days after the completion of a second course of rituximab infusions for calcineurin inhibitor-dependent nephrotic syndrome. Respiratory symptoms started while he received high-dose prednisone for persistent proteinuria. Bilateral, diffuse ground-glass infiltrates corresponded to the presence of inflammatory cells in the bronchioalveolar lavage fluid. Empiric antibiotic treatment including clarithromycin was given, but the microbiological work-up remained negative. Serum IgE, C3, and C4 concentrations were normal. He recovered within 3 weeks after onset. We systematically reviewed 23 reports describing 30 additional cases of rituximab-associated lung disease. Twenty eight patients had received rituximab for B-cell malignancies, one for graft-versus-host disease and one for immune thrombocytopenia. Median age was 64 years (interquartile range [IQR] 58–69 years). Seventy one percent received concomitant chemotherapy. Time to onset from the last rituximab dose was 14 days (IQR 11–22 days). Eleven of 31 patients required mechanical ventilation, and 9 died (29%). Ventilation was a significant predictor of fatal outcome (odds ratio 46.7; confidence interval 9.5–229.9). High dose glucocorticoid therapy did not improve survival or prevent severe lung disease or death. Conclusions With the expanding use of rituximab for novel indications, additional cases of RALI affecting younger age groups are expected to emerge. Mechanical ventilation predicts poor outcome. Glucocorticoids may not be protective. Pediatr Pulmonol. 2009; 44:922–934. © 2009 Wiley-Liss, Inc.

A 13-year-old girl with obesity and hyperinsulinism developed steroid-resistant nephrotic syndrome due to collapsing glomerulopathy with dominant C1q-containing mesangial immune deposits (CG/C1qN). She became overtly diabetic while receiving alternate-day prednisone and tacrolimus, requiring insulin injections. Despite the addition of mycophenolate mofetil to the treatment regimen, renal function subsequently declined. Rituximab (four weekly doses of 375 mg/m2) was tried 6 months after initial presentation and 3 months after weaning all glucocorticoids. Glomerular filtration rate (GFR) and proteinuria improved. Unexpectedly, blood sugar control normalized 6 weeks after antibody infusion. Rituximab was readministered 20 months after the first course because of deteriorating renal function, but the effect on GFR and proteinuria was modest. A retrospective analysis revealed that tubulointerstitial infiltrates present in the biopsies prior to treatment with rituximab contained numerous CD20+ and CD3+ (CD4 > CD8) lymphocyte aggregates. Rebiopsy 10 weeks after repeat rituximab therapy demonstrated the elimination of B-cell infiltrates and the apparent decrease of interstitial T-cell infiltrates, yet persistent, advanced global glomerulosclerosis, interstitial fibrosis and tubular atrophy. In conclusion, CG/C1qN was associated with B- and T-cell-rich tubulointerstitial infiltrates. B-cell-directed therapy delayed clinical progression during early disease but failed to prevent or ameliorate chronic changes, despite effective tissue B-cell clearance. The incidental resolution of diabetes was noted after rituximab treatment.

Focal segmental glomerular sclerosis (FSGS) is an irreversible renal pathology characterized by podocyte detachment from the glomerular basement membrane, hyalinosis, and sclerosis. Clinically, it manifests with proteinuria and progressive loss of glomerular filtration. Primary idiopathic FSGS can occur in isolation and frequently progresses to end-stage renal disease, requiring dialysis or kidney transplantation. In 30–50% of these patients, proteinuria and FSGS recur in the renal allograft, suggesting the presence of a podocyte-toxic factor(s) in the recipient's serum. Currently, there is no reliable way to quantify the serum activity or predict the subset of FSGS patients at risk for recurrence after transplantation. We describe a novel in vitro method that measures the podocyte-toxic activity of sera from FSGS patients using cultured human podocytes; we compare this with the effect of compounds such as adriamycin. Using immunofluorescence microscopy followed by computerized image-processing analysis, we show that incubation of human podocytes with adriamycin leads to a dose-dependent disassembly of focal adhesion complexes (FACs). We then demonstrate that sera from patients with posttransplant recurrent or idiopathic FSGS cause a similar FAC disturbance. In contrast, sera from nonrecurrent FSGS patients do not affect FACs. In some FSGS patients, toxic effects of serum can be prevented by blockade of the tumor necrosis factor-α pathway. We propose that this method may be useful as a diagnostic tool to identify FSGS patients with serum podocyte-toxic activity that presumably places them at increased risk for recurrence in the renal allograft.

Escherichia coli O157 lipopolysaccharide (LPS)-specific antibodies were measured in sequential serum samples from 131 children with serologically defined E. coli O157-associated hemolytic-uremic syndrome (HUS), using an enzyme immunoassay. On the basis of evaluation of 66 children with culture-proven E. coli O157 infection and serum samples from 132 age-matched control subjects, the assay showed a sensitivity of 95%, 88%, and 74% and a specificity of 99%, 99%, and 98% for IgM, IgA, and IgG, respectively. Anti-O157 LPS antibodies decreased below the cut-off levels in >50% of the children at 11 (IgM), 5 (IgA), and 11 weeks (IgG) after onset of diarrhea and 10, 4, and 10 weeks, respectively, after the onset of HUS. Children with enteropathic HUS fail to develop a long-lasting humoral immune response to the O157 antigen. Incomplete immunity to E. coli O157 may signal a risk for recurrent infections and has implications for serodiagnostic studies.

Treatment with rituximab, a monoclonal antibody against the B-lymphocyte surface protein CD20, leads to the depletion of B cells. Recently, rituximab was reported to effectively prevent relapses of glucocorticoid-dependent or frequently relapsing minimal change disease (MCD). MCD is thought to be T-cell mediated; how rituximab controls MCD is not understood. In this review, we summarize key clinical studies demonstrating the efficacy of rituximab in idiopathic nephrotic syndrome, mainly MCD. We then discuss immunological features of this disease and potential mechanisms of action of rituximab in its treatment based on what is known about the therapeutic action of rituximab in other immune-mediated disorders. We believe that studies aimed at understanding the mechanisms of action of rituximab in MCD will provide a novel approach to resolve the elusive immune pathophysiology of MCD.

The KDIGO (Kidney Disease: Improving Global Outcomes) clinical practice guideline for management of glomerulonephritis was recently released. The Canadian Society of Nephrology convened a working group to review the recommendations and comment on their relevancy and applicability to the Canadian context. A subgroup of pediatric nephrologists reviewed the guideline statements for management of childhood nephrotic syndrome and agreed with most of the guideline statements developed by KDIGO. This commentary highlights areas in which there is lack of evidence and areas in need of translation of evidence into clinical practice. Areas of controversy or uncertainty, including the length of corticosteroid therapy for the initial presentation and relapses, definitions of steroid resistance, and choice of second-line agents, are discussed in more detail. Existing practice variation is also addressed.

Helicobacter pylori, the etiologic agent of chronic-active gastritis and duodenal ulcers in humans, and Helicobacter mustelae, a gastric pathogen in ferrets, bind to phosphatidylethanolamine (PE), a constituent of host gastric mucosal cells, and to gangliotetraosylceramide (Gg4) and gangliotriaosylceramide (Gg3). The effect of a bovine colostrum concentrate (BCC) on the interaction of H. pylori and H. mustelae to their lipid receptors was examined. BCC blocked attachment of both species to Gg4, Gg3, and PE. Partial inhibition of binding was observed with native bovine and human colostra. BCC lacked detectable antibodies (by immunoblotting) to H. pylori surface proteins (adhesins). However, colostral lipid extracts contained PE and lyso-PE that bound H. pylori in vitro. These results indicate that colostrum can block the binding of Helicobacter species to select lipids and that binding inhibition is conferred, in part, by colostral PE or PE derivatives. Colostral lipids may modulate the interaction of H. pylori and other adhesin-expressing pathogens with their target tissues.