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Background C3 glomerulonephritis (C3GN) can be a devastating disease with poor response to immunosuppressive therapy. Complement inhibition with eculizumab has had equivocal results in patients with C3GN. Case-Diagnosis/Treatment We report a case of a 6-year-old boy with C3GN presenting with nephrotic syndrome, severe hypertension and impaired kidney function. He did not respond to initial treatment with prednisone and mycophenolate (mofetil and sodium), and subsequent treatment with standard dosing of eculizumab. Pharmacokinetic studies identified a lack of eculizumab exposure and subsequent intensification of treatment with weekly dosing of eculizumab led to significant clinical improvement: his kidney function normalized, hypertension (weaned off 3 antihypertensive drugs), edema and proteinuria improved. Additionally, exposure to mycophenolic acid (MPA), active metabolite of mycophenolate, determined by area under the concentration-time curve of MPA was low throughout, despite significant dosing escalation. Conclusions This case report demonstrates that individualized therapy guided by therapeutic drug monitoring might be needed in patients with nephrotic range proteinuria treated with eculizumab and mycophenolate (mofetil and sodium), an important finding that needs to be considered for further treatment trials., Author(s): Magdalena Riedl Khursigara [sup.1] , Erin Chung [sup.2] [sup.3] , James Tjon [sup.2] [sup.3] , Damien Noone [sup.1] [sup.4] , Rose Chami [sup.5] [sup.6] , Christoph Licht [sup.1] [sup.4] [...]

Steroid sensitive nephrotic syndrome is a common condition in pediatric nephrology, and most children have excellent outcomes. Yet, 50% of children will require steroid-sparing agents due to frequently relapsing disease and may suffer consequences from steroid dependence or use of steroid-sparing agents. Several steroid-sparing therapeutic agents are available with few high quality randomized controlled trials to compare efficacy leading to reliance on observational data for clinical guidance. Reported trials focus on short-term outcomes such as time to first relapse, relapse rates up to 1-2 years of follow-up, and few have studied long-term remission. Trial designs often do not consider inter-individual variability, and differing response to treatments may occur due to heterogeneity in pathogenic mechanisms, and genetic and environmental influences. Strategies are proposed to improve the quantity and quality of trials in steroid sensitive nephrotic syndrome with integration of biomarkers, novel trial designs, and standardized outcomes, especially for long-term remission. Collaborative efforts among international trial networks will help move us toward a shared goal of finding a cure for children with nephrotic syndrome., Author(s): Ashlene M. McKay [sup.1] , Rulan S. Parekh [sup.1] [sup.2] [sup.3] [sup.4] [sup.5] , Damien Noone [sup.1] [sup.2] Author Affiliations: (1) grid.42327.30, 0000 0004 0473 9646, Division of Nephrology, [...]

Objective Von Willebrand factor (VWF) antigen plays a role in vascular inflammation and thrombosis, both of which are important in the pathogenesis of ANCA-associated vasculitis (AAV). Previous work found that VWF correlates with disease activity in childhood-onset primary CNS vasculitis. We sought to determine the relationship between VWF and disease activity over time in children with AAV. Methods AAV patients with more than one VWF level measured were included in this retrospective study, and the relationships between active vasculitis, VWF and other disease measures were analysed. Generalized estimating equations analysis was used to account for repeated VWF measurements within a patient. Repeated measures correlation was used to determine associations of paired laboratory observations. Diagnostic performance was evaluated using receiver operating curve analysis. Results A total of 732 total VWF measurements were collected in 33 AAV patients. VWF antigen levels were higher during active disease [median 2.03 IU/ml, interquartile range (IQR) 1.35, 2.55] compared with inactive disease (median 1.18 IU/ml, IQR 0.94, 1.53). VWF antigen was the only variable that was significantly associated with active disease (odds ratio 3.01, P  < 0.001, 95% CI 2.3, 3.93). The effect of VWF did not show a substantial difference between the disease subtypes. There was a moderate positive correlation between VWF antigen and disease activity, with an acceptable sensitivity and specificity rates. Conclusion Increased VWF antigen levels correlate with active vasculitis in this paediatric-onset AAV cohort and may be used as an additional biomarker in childhood AAV. [ABSTRACT FROM AUTHOR]

Background Steroids and/or steroid-sparing medications are commonly used for nephrotic syndrome treatment; however, the impact of these medications on health-related quality of life over time is not well described. Methods Longitudinal cohort is up to 5 years where children were assessed with baseline and annual Pediatric Quality of Life Inventory questionnaire. A mixed-effects linear regression determined differences in scores among children receiving steroids and/or steroid-sparing agents for at least 30 days compared with those not on medication at 1, 3, 6, and 12 months prior to assessment. Results Among 295 children, 64% were male, with a median age of 3.7 (interquartile range [IQR], 2.7, 5.9) years at diagnosis, and comprised 25% Europeans, 40% South Asians, and 8% East/Southeast Asians. Adjusted HRQOL scores were reduced among children taking steroids and steroid-sparing agents among 705 HRQOL measures (median 2 [IQR, 1, 3] per child). Compared to children without medication, steroid and steroid-sparing agent use up to 12 months prior to assessment were associated with an overall HRQOL drop of 3.17 (95% confidence interval [CI], - 5.25, - 1.08) and 3.18 (95% CI, - 5.24, - 1.12), respectively, after adjustment. Functioning domain scores were reduced by 4.41 points (95% CI, - 6.57, - 2.25) in children on steroids, whereas fatigue domain scores were reduced by 5.47 points (95% CI, - 9.28, - 1.67) in children on steroid-sparing agents after adjustment. Conclusions HRQOL is consistently decreased in children receiving steroids and steroid-sparing agents, with differential effects on functioning and fatigue. Counseling families on possible effects of prolonged treatment periods is important in the management of childhood nephrotic syndrome., Author(s): Shawn Khullar [sup.1] [sup.2] , Tonny Banh [sup.1] , Jovanka Vasilevska-Ristovska [sup.1] , Rahul Chanchlani [sup.3] [sup.4] , Josefina Brooke [sup.5] , Christoph P. B. Licht [sup.5] [sup.6] [sup.7] [...]

Background Low birth weight (LBW)/prematurity have been proposed as risk factors for the development of kidney disease in adulthood. Whether there is an association between LBW/prematurity and poor renal outcomes in childhood onset nephrotic syndrome remains unknown. Methods Children with nephrotic syndrome diagnosed between 1 and 18 years of age were followed prospectively from 1996 to 2016 at The Hospital for Sick Children (N = 377). LBW/prematurity was defined as birth weight < 2500 g or gestational age < 36 weeks. Normal birth weight (NBW) was defined as birth weight [greater than or equal to] 2500 g. Measures evaluating clinical course of nephrotic syndrome include initial steroid-resistant nephrotic syndrome (SRNS), time to first relapse, and frequently relapsing nephrotic syndrome. Kaplan-Meier survival analysis, logistic regression, and Cox proportional hazards regression were used to determine the association of LBW/prematurity with clinical outcomes. Results Median birth weights in LBW/premature (n = 46) and NBW (n = 331) children were 2098 g (interquartile range [IQR] 1700-2325 g) and 3317 g (IQR 2977-3685 g), respectively. Odds of having SRNS were 3.78 (95% confidence interval [CI] 1.28-11.21) times higher among LBW/premature children than NBW children. An 8% decrease in odds of developing SRNS was observed for every 100 g increase in birth weight (adjusted odds ratio [OR] 0.92; 95% CI 0.86-0.98). Median time to first relapse did not differ (hazard ratio [HR] 0.89; 95% CI 0.53-1.16). Conclusions LBW/premature children were more likely to develop SRNS but did not have a difference in time to first relapse with NBW children. Understanding the impact and mechanism of birth weight and steroid-resistant disease needs further study., Author(s): Natalia Konstantelos [sup.1] [sup.2] , Tonny Banh [sup.1] , Viral Patel [sup.2] , Jovanka Vasilevska-Ristovska [sup.1] , Karlota Borges [sup.1] , Neesha Hussain-Shamsy [sup.2] , Damien Noone [sup.2] [sup.3] [...]

Thrombotic microangiopathy (TMA) is caused by thrombus formation in the microvasculature. The disease spectrum of TMA includes, amongst others, thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uraemic syndrome (aHUS). TTP is caused by defective cleavage of von Willebrand factor (VWF), whereas aHUS is caused by overshooting complement activation and subsequent endothelial cell (EC) injury. Despite their distinct pathophysiology, the clinical manifestation of TTP and aHUS consisting of microangiopathic haemolytic anaemia and thrombocytopenia is often similar and difficult to distinguish. Recent evidence hints at both a genetic and functional link between TTP and aHUS, especially between VWF and the complement system. There is novel in vitro evidence that complement activation not only results in VWF release from ECs, but that VWF also functions as a negative complement regulator, thus protecting the EC surface from ongoing complement attack. Although contrary to previous experimental work suggesting that complement can be activated on VWF multimers, there may be an explanation in vivo that rationalizes these apparently contradictory findings, whereby a system primarily meant to regulate becomes overwhelmed or pathologic in the disease state. The importance of unravelling these recent findings for our understanding of TMA pathology becomes even more evident considering that glomerular ECs express VWF in a heterogeneous pattern with an overall decreased expression level, thus potentially leaving the glomerular ECs vulnerable to complement-mediated injury. Taken together, these findings support the concept that TTP and aHUS represent two extreme ends of a TMA disease spectrum rather than isolated disease entities., Author(s): Damien G. Noone [sup.1] [sup.2] , Magdalena Riedl [sup.3] , Christoph Licht [sup.1] [sup.2] [sup.3] [sup.4] [sup.5] Author Affiliations: (Aff1) 0000 0004 0473 9646, grid.42327.30, Division of Nephrology, The [...]

Background This is a report of an infant born near term with neonatal stroke and haematuria. The renal phenotype, pathogenic genotype and pathological findings on renal biopsy are discussed. Case-Diagnosis Prenatal magnetic resonance imaging revealed anomalies which persisted postnatally. Haematuria was detected during follow-up. The posttnatal renal ultrasound scan was normal, and there was no associated proteinuria. A likely pathogenic genetic mutation was detected. Conclusions This case highlights a relatively newly discovered cause of hereditary nephropathy in which the basement membrane is affected, with initial effects on the glomerular membranes and subsequent effects on the renal tubular basement membranes., Author(s): Sally Kellett [sup.1] [sup.2] , Mathieu Lemaire [sup.1] [sup.2] , Steven P. Miller [sup.2] [sup.3] , Christoph Licht [sup.1] [sup.2] , Grace Yoon [sup.2] [sup.4] , Nomazulu Dlamini [sup.2] [...]

Background: Bevacizumab is a vascular endothelial growth factor (VEGF) inhibitor that is used off-label for select cases of recurrent respiratory papillomatosis (RRP) that are severe, involve the distal airway or lung parenchyma, and refractory to other forms of adjuvant therapy. However, there is limited safety data for the use of bevacizumab in children and VEGF inhibitors are reported to have a range of adverse renal effects, including hypertension, proteinuria, and thrombotic microangiopathy (TMA). Case-Diagnosis/Treatment: This report describes a case of severe juvenile-onset RRP that had an exceptionally high operative burden that was refractory to several adjuvant treatment strategies (including intralesional cidofovir and subcutaneous pegylated interferon). Bevacizumab treatment resulted in a dramatic and sustained improvement in disease control over a 5-year period. However, after 3 years of treatment, the patient developed hypertension and proteinuria and was found to have evidence of a glomerular TMA on kidney biopsy. These complications were successfully managed with a reduction in bevacizumab frequency and angiotensin-converting enzyme inhibitor initiation. Conclusions: Clinicians caring for children treated with VEGF inhibitors should be aware of the potential renal complications and their management. [ABSTRACT FROM AUTHOR]

The antineutrophil cytoplasm autoantibody (ANCA)-associated vasculitides (AAV), although rare in childhood, can have devastating effects on affected organs, especially the kidney. In this review we present an update on the pathogenesis and treatment of ANCA vasculitis, with a particular emphasis on the role of the alternative pathway of complement. The rationale and evidence for the current treatment strategies are summarized. Targeting the activation of neutrophils by the anaphylatoxin C5a may serve as an additional therapeutic strategy, however the results of clinical studies are awaited., Author(s): Damien Noone [sup.1] [sup.2] , Diane Hebert [sup.1] [sup.2] , Christoph Licht [sup.1] [sup.2] [sup.3] [sup.4] [sup.5] Author Affiliations: (1) Division of Nephrology, The Hospital for Sick Children, 0000 [...]

The purpose of the review is to summarize the current pharmacological management of chronic kidney disease (CKD) in pediatric patients and critically present emerging evidence for the use of mineralocorticoid receptor antagonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors. Globally, CKD is the 19th leading cause of years of life lost and the current total number of children and adolescents affected with CKD Stages II-V is predicted to exceed 2 million in a global population of 2 billion children. The severity of kidney disease is strongly correlated with the extent of proteinuria. Agents that target the renin-angiotensin-aldosterone-system reduce proteinuria in mild to moderate CKD, slowing disease progression. Recent clinical trials evaluating mineralocorticoid receptor antagonists, such as finerenone and SGLT2 inhibitors, demonstrate similar results. However, additional pediatric clinical trials are necessary to determine their complete therapeutic potential. [ABSTRACT FROM AUTHOR]

Objectives Data on kidney transplant outcomes for pediatric patients with end-stage renal disease (ESRD) secondary to anti-neutrophil cytoplasmic antibody glomerulonephritis (ANCA GN), particularly granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), is limited. We describe our experience of kidney transplantation in pediatric ANCA GN patients. Methods We performed a retrospective review of patients with ANCA GN who developed ESRD and were transplanted at a single center between the years 2000 and 2014. Results Since 2000, there were seven pediatric patients with ANCA GN (four MPA) transplanted. Mean age at ANCA GN diagnosis was 11.8 ± 2.8 (range, 7.2-15.4) years. All seven were ANCA (three anti-PR3/four anti-MPO) positive. Estimated glomerular filtration rate (eGFR) at diagnosis was 11.7 ± 6.3 ml/min/1.73 m.sup.2. All received steroids and cyclophosphamide and three (23.3%) received plasma exchange. Six were dialysis dependent by 6 months post diagnosis. Time from diagnosis to transplant was 30 ± 12 (range, 17-48) months. Six of the seven received a deceased donor transplant. All patients received induction therapy and standard maintenance immunosuppression post transplant. Median duration of follow-up post transplantation was 27 months (range, 13-88 months). Median eGFR at last follow-up was 77 ml/min/1.73 m.sup.2 (range, 7.9-83.5). One patient lost her transplant to acute cellular rejection following non-adherence to immunosuppression after 21 months of stable transplant function. No patient had recurrence of vasculitis, either renal or extra-renal. Conclusions Short-term patient and allograft survival in pediatric patients with ESRD secondary to ANCA GN seems excellent, with no recurrence of vasculitis post transplant in this small cohort., Author(s): Damien Noone [sup.1] [sup.2], Rae S. M. Yeung [sup.2] [sup.3] [sup.4], Diane Hebert [sup.1] [sup.2] Author Affiliations: (1) 0000 0004 0473 9646, grid.42327.30, Division of Nephrology, The Hospital for [...]

Background Despite peritoneal dialysis being the preferred mode of renal replacement therapy in neonates and infants, long-term haemodialysis may be necessary in a minority of patients with its attendant risks. Case Diagnosis/Treatment This case identifies plastic bronchitis as a rare yet serious complication of long-term large bore vascular access when a vessel-sparing approach is not possible. Conclusions An appropriately sized catheter should be used for the dialytic therapy required and to optimize access survival., Author(s): Simon Carter [sup.1] , Dayna van de Hoef [sup.2] , Michael Temple [sup.3] , Elizabeth Harvey [sup.1] , Suhail Al-Saleh [sup.4] , Christoph Licht [sup.1] , Damien Noone [sup.1] [...]