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Background: Steroid-sparing immunosuppression is used in 50% of children with nephrotic syndrome, to prevent relapses and steroid-related toxicity. However, rates and predictors of prolonged remission after cyclophosphamide and tacrolimus are uncertain., Methods: Retrospective analysis of children (1-18 years) enrolled in a longitudinal cohort. We included children diagnosed with steroid-sensitive nephrotic syndrome between 1996-2019 from Toronto, Canada. The exposure was cyclophosphamide or tacrolimus initiation. The primary outcome was prolonged remission (no further relapse or steroid-sparing immunosuppression). We evaluated predictors of prolonged remission and calcineurin inhibitor nephrotoxicity by logistic regression., Results: Of 578 children with steroid-sensitive nephrotic syndrome, 252 received cyclophosphamide and 120 received tacrolimus. Over median 5.4-year (IQR 2.4-9.1) follow-up, prolonged remission occurred in 72 (28.6%) after cyclophosphamide and 17 (14.2%) after tacrolimus. Relapse frequency decreased after initiation of either medication. Lower prior relapse rate, more recent treatment era, and female sex were predictive of prolonged remission after cyclophosphamide treatment. Use of tacrolimus as the first steroid-sparing medication was the only factor predictive of calcineurin inhibitor nephrotoxicity., Conclusions: Less than one-third of children achieve prolonged remission after initiating cyclophosphamide or tacrolimus, although both reduce short-term relapse rates. Few factors predict prolonged remission after cyclophosphamide or tacrolimus use, or calcineurin inhibitor nephrotoxicity., Competing Interests: Declarations. Research ethics and consent: Research ethics approval for INSIGHT was obtained from The Hospital for Sick Children (Toronto, Canada). Informed consent for the study was obtained from all participants. Disclosures: All authors declare no real or perceived conflicts of interest that could affect the study design, collection, analysis and interpretation of data, writing of the report, or the decision to submit for publication., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: The circumstances surrounding chronic kidney disease and its impact on families can be complex and difficult to navigate, leading to these cases being labeled "challenging.", Case Presentation: We present the case of an adolescent with kidney failure due to unremitting systemic illness and multiple complications ultimately resulting in the family's request to forgo dialysis. Medical team members wrestled with meeting the family's needs among internal and external constraints., Conclusion: Past experiences, systemic inequities, differing perspectives, and consequential decision-making within individual belief systems can lead to friction between and among medical team members and families. As pediatric nephrologists, we must shift our focus from the "challenging" patient or family to addressing what is challenging their ability to flourishing., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

We describe the unexpected challenges pediatricians may experience when children conceived with assisted reproduction are diagnosed with a rare genetic condition. A local case series triggered a dialogue between many stakeholders with varied expertise. Indeed, diagnosing a genetic disease in a child conceived by embryo, egg, or sperm donation is becoming more common now that genetic testing and in vitro fertilization (IVF) are readily accessible. However, how and whether to share that information with other stakeholders in the gamete donation process has not been fully explored, and the clinical responsibilities of the treating clinician remain ill-defined. This work centers on a patient with a confirmed diagnosis of X-linked nephrogenic diabetes insipidus. Ultimately, we found the same AVPR2 mutation in two children from two families conceived by egg donation. It led to multigenerational cascade diagnoses in the family of the shared, anonymous egg donor. First, we review current genetic testing practices in gamete donation and third-party reproduction. Then, we provide an overview of relevant genomic, ethical, legal, and psychosocial considerations for sharing relevant genomic information. Finally, and to maximize the best interests of genetic relatives, we discuss how a pediatrician can play a role in the early disclosure of relevant clinical information to all stakeholders in the gamete donation process, starting with the fertility clinic. While these clinical cases are cast in a Canadian context, we submit that its important lessons generally apply to medical systems of nearly all developed countries, broadly defined., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Children with nephrotic syndrome are at risk of obesity and growth impairment from repeated steroid treatment. However, incidence and risk factors for obesity and short stature remain uncertain, which is a barrier to preventative care. Our aim was to determine risk, timing, and predictors of obesity and short stature among children with nephrotic syndrome., Methods: We evaluated obesity and longitudinal growth among children (1-18 years) enrolled in Insight into Nephrotic Syndrome: Investigating Genes, Health, and Therapeutics. We included children with nephrotic syndrome diagnosed between 1996-2019 from the Greater Toronto Area, Canada, excluding congenital or secondary nephrotic syndrome. Primary outcomes were obesity (body mass index Z-score ≥  + 2) and short stature (height Z-score ≤ -2). We evaluated prevalence of obesity and short stature at enrolment (< 1-year from diagnosis) and incidence during follow-up. Cox proportional hazards models determined the association between nephrotic syndrome classification and new-onset obesity and short stature., Results: We included 531 children with nephrotic syndrome (30% frequently relapsing by 1-year). At enrolment, obesity prevalence was 23.5%, 51.8% were overweight, and 4.9% had short stature. Cumulative incidence of new-onset obesity and short stature over median 4.1-year follow-up was 17.7% and 3.3% respectively. Children with frequently relapsing or steroid dependent nephrotic syndrome within 1-year of diagnosis were at increased risk of new-onset short stature (unadjusted hazard ratio 3.99, 95%CI 1.26-12.62) but not obesity (adjusted hazard ratio 1.56, 95%CI 0.95-2.56). Children with ≥ 7 and ≥ 15 total relapses were more likely to develop obesity and short stature, respectively., Conclusions: Obesity is common among children with nephrotic syndrome early after diagnosis. Although short stature was uncommon overall, children with frequently relapsing or steroid dependent disease are at increased risk of developing short stature. Effective relapse prevention may reduce steroid toxicity and the risk of developing obesity or short stature., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Diabetes mellitus, a disease that affects hundreds of millions of people worldwide, is increasing in prevalence in all age groups, including children and adolescents. Much of the morbidity and mortality associated with diabetes is closely related to hypertension, often coincident with diabetes. Comorbid hypertension and diabetes often worsen the outcomes of each other, likely rooted in some overlapping pathogenic mechanisms. In this educational review, we will discuss the shared pathophysiology of diabetes and hypertension, particularly in regard to inflammation and oxidative stress, the sympathetic nervous system, vascular remodeling, and the renin-angiotensin-aldosterone system (RAAS). We will also review current hypertension diagnosis and management guidelines from many international jurisdictions for both adult and paediatric populations in the setting of diabetes. Many of these guidelines highlight the use and utility of RAAS blockers in this clinical scenario; however, on review of the evidence for their use, several meta-analyses and systematic reviews fail to demonstrate superiority of RAAS blockers over other anti-hypertensive medications. Finally, we discuss several new anti-hypertensive medications, review their mechanisms of action, and highlight some of the evidence for their use in the setting of hypertension and diabetes., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

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., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

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., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Intra-dialytic hypotension (IDH) is the most common serious adverse event in paediatric haemodialysis (HD). Repeated IDH results in chronic multi-organ damage and increased mortality. At the Hospital for Sick Children, Toronto, retrospective data from all in-centre HD sessions revealed frequently occurring IDH events (16.5 ± 5.6% of HD sessions per week). Based on literature review and clinical expertise, fluid volume management was selected as a potential modifiable risk factor to decrease IDH. Root causes identified as contributing to IDH were incorporated into a Paediatric haemodialysis fluid volume management (PedHDfluid) program using the Model for Improvement methodology including rapid cycles of change., Methods: Multiple measures were evaluated including (i) Outcome: IDH events per number of HD sessions per week; (ii) Process: number of changes to estimated dry weight per number of HD sessions per week; (iii) Balancing: time spent on dry weight meeting per week. Data was analysed using statistical process control charts. We aimed to decrease IDH in our dialysis unit to < 10% of HD sessions per week over a 6-month period by implementing a PedHDfluid program, including a multifaceted dry weight assessment protocol, multidisciplinary meetings and electronic health records "Dry Weight Evaluation flow sheet/synopsis"., Results: The project resulted in a decline in IDH events from 16.5 ± 5.6% to 8.8 ± 3.3% of HD sessions per week. More frequent dry weight changes and increased awareness of fluid removal goals were noted., Conclusions: A multidisciplinary approach including regular assessment, guidelines and systematic discussion, with an embedded electronic health record assessment and data gathering tool may sustainably reduce IDH events. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2021. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

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.

Improving quality of care delivery is an important focus for all practicing physicians. Frontline clinicians are in a great position to identify clinical problems and find innovative solutions. The current review describes the method used for quality improvement based on the Model for Improvement, a structural framework to guide improvement work. At its basis are three fundamental questions: What are we trying to accomplish? How will I know that a change will lead to improvement? And what changes could we make that will result in improvement? This preparation phase aims to identify and understand the problem, choose an intervention, and determine reliable measures to gauge improvement. The intervention is then tested using PLAN-DO-STUDY-ACT (PDSA) cycles, an iterative approach to systematically improve processes and outcomes. PLAN focuses on defining the goal of the cycle and describing in details what will be done. DO concentrates on the concrete application of the plan. STUDY focuses on data analyses as ACT identifies lessons learned from the cycle and orientate the goals of the following PDSA cycle. Learning from each cycle, developing an interdisciplinary team and repeated interventions are core principles involved in implementing a sustainable quality improvement program. The Model for Improvement will be illustrated by a common quality problem in pediatric nephrology.

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 ≥ 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.

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.

Background: Sarcoidosis is a multisystem granulomatous disease of unknown etiology that rarely presents in childhood. Here, we report a case of pediatric sarcoidosis, presenting with renal failure and hypercalcemia., Case Diagnosis/treatment: A previously well 14-year-old Caucasian boy was admitted to the Hospital for Sick Children, Canada, for hypertension and renal failure following work-up by his family physician for initial concerns of growth failure. On admission, his weight was 35 kg (<3rd percentile), his height was 148 cm (<<3rd percentile), and his blood pressure was 154/116 mmHg (>99th percentile for height). Laboratory findings showed elevated creatinine (218 umol/L), hypercalcemia (3.21 mmol/L), and normocytic anemia (hemoglobin 105 g/L). His further assessment showed a urinary concentrating defect with hypercalciuria (calcium/creatinine 1.76 mmol/mmol) and nephrocalcinosis on ultrasound. His eye examination showed uveitis with conjunctival biopsy remarkable for granulomas, which led to pursuit of a diagnosis of possible sarcoidosis. Angiotensin Angiotensin-converting enzyme was found to be high at 96 U/L, and he had a renal biopsy that was consistent with interstitial nephritis with granulomas. Treatment was started with prednisone leading to resolution of his hypercalcemia but persistence of his mild chronic kidney disease., Conclusions: This case represents an atypical presentation of a rare pediatric disease and highlights the spectrum of renal manifestations and treatment options in sarcoidosis.

Background: Sarcoidosis is a multisystem granulomatous disease of unknown etiology that rarely presents in childhood. Here, we report a case of pediatric sarcoidosis presenting with renal failure and hypercalcemia., Case Diagnosis/treatment: A previously well 14-year-old Caucasian boy was admitted to the Hospital for Sick Children, Canada, for hypertension and renal failure following work-up by his family physician for initial concerns of growth failure. On admission, his weight was 35 kg (<3rd percentile), his height was 148 cm (≪3rd percentile), and his blood pressure was 154/116 mmHg (>99th percentile for height). Laboratory findings showed elevated creatinine (218 μmol/L), hypercalcemia (3.21 mmol/L), and normocytic anemia (hemoglobin 105 g/L). His further assessment showed a urinary concentrating defect with hypercalciuria (calcium/creatinine 1.76 mmol/mmol) and nephrocalcinosis on ultrasound. His eye examination showed uveitis with conjunctival biopsy remarkable for granulomas, which led to pursuit of a diagnosis of possible sarcoidosis. Angiotensin-converting enzyme was found to be high at 96 U/L, and he had a renal biopsy that was consistent with interstitial nephritis with granulomas. Treatment was started with prednisone leading to resolution of his hypercalcemia but persistence of his mild chronic kidney disease., Conclusions: This case represents an atypical presentation of a rare pediatric disease and highlights the spectrum of renal manifestations and treatment options in sarcoidosis.

This is a report of an infant born near term with neonatal stroke and haematuria. Changes were noted on foetal magnetic resonance images, and these persisted postnatally. A routine renal ultrasound scan during follow-up detected haematuria with no associated proteinuria. A likely pathogenic genetic mutation was identified. This case highlights a relatively newly discovered cause for hereditary nephropathy affecting the basement membrane, initially affecting the glomerular but later the renal tubular basement membranes. The renal phenotype, pathogenic genotype and pathological findings on renal biopsy are discussed.

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.

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.

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 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 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.

Background: We aimed to evaluate the role of post-procedural hemoglobin (hb), without pre-discharge ultrasound (US), after US-guided renal biopsy in children., Methods: A retrospective review was conducted of consecutive outpatient native kidney biopsies over an 8-year period. Procedures were performed under real-time US guidance. Data collected included number of passes, presence and size of perinephric hematoma, age, body mass index (BMI), blood pressure (BP), fasting status, hb and platelets. Continuous variables were expressed as mean ± standard deviation, group differences were tested with Student's unpaired t test and analysis of variance and correlations were assessed using Pearson's r. Significance was defined as p < 0.05. Hb changes (g/L), percentage hb (%hb) change, hematoma size and positive and negative predictive values (PPV, NPV, respectively) were analyzed., Results: A total of 330 procedures in 300 children (141 females, mean age 11.2 ± 4.30 years) were analyzed. Post-procedural hematoma occurred in 63%. There was a significant (p = 0.0001) post-procedural hb decrease of 6.3 ± 5.5 g/L and %hb decrease of 4.56 ± 4.01%. Fasting during pre-procedural hb estimation and procedural hematoma was associated with a greater hb drop. A ≥10% hb drop had 73% PPV for repeat blood work and US and a 17% PPV for admission, whereas a <10% hb drop had a NPV of 84% and 98%, respectively. Hb change showed a weak correlation with age, and hematoma size showed a weak inverse correlation with platelet count, but no correlation with BMI, number of passes or BP., Conclusions: Bleeding complications from US-guided native kidney biopsies in pediatric outpatients can be safely followed by a complete blood count at 6 h post procedure. A 10% hb decrease is strongly associated with requirement for further testing and/or admission.

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.

The concept of renoprotection has evolved significantly, driven by improved understanding of the pathophysiology of chronic kidney disease (CKD) and the advent of novel treatment options. Glomerular hyperfiltration, hypertension and proteinuria represent key mediators of CKD progression. It is increasingly recognized that proteinuria may actually be pathological and etiological in CKD progression and not just symptomatic. It initiates a sequence of events involving activation of proinflammatory and profibrotic signaling pathways in proximal tubular epithelial cells with transmission of the disease to the tubulointerstitium and progression to end-stage kidney disease (ESKD). Although the etiology and epidemiology of pediatric CKD differs to that in adults, studies in the various animal models of kidney disease, from obstructive uropathy to glomerulonephritis, have revealed that many common proinflammatory and profibrotic pathways are induced in progressive proteinuric CKD, irrespective of the primary disease. This pathomechanistic overlap therefore translates into the potential for common treatment targets for a wide spectrum of kidney diseases. In this review we therefore discuss the experimental and clinical evidence for an array of prospective future drug treatments of CKD progression. While conceptually promising, clear definitive evidence beyond preclinical data does not exist for many of these treatments, and others are limited by serious adverse effects. More studies are needed before general recommendations can be given.

Background: Deficiency of complement factor H-related (CFHR) proteins and CFH autoantibody-positive hemolytic uremic syndrome (DEAP-HUS) represents a unique subgroup of complement-mediated atypical HUS (aHUS). Autoantibodies to the C-terminus of CFH block CFH surface recognition and mimic mutations found in the genetic form of (CFH-mediated) aHUS. CFH autoantibodies are found in 10-15 % of aHUS patients and occur--so far unexplained--almost exclusively in the background of CFHR1 or CFHR3/CFHR1 deletions., Methods: As a well-defined role for eculizumab in the treatment of complement-mediated aHUS is becoming established, its role in DEAP-HUS is less conspicuous, where a B-cell-depleting and immunosuppressive treatment strategy is being proposed in the literature., Results: We here show eculizumab to be safe and effective in maintaining a disease-free state, without recurrence, in a previously plasma-therapy-dependent DEAP-HUS patient, and in another patient in whom, although showing a good clinical response to plasma therapy, the therapy was hampered by allergic reactions to fresh frozen plasma and contend there is a rationale for the use of eculizumab in concert with an immunosuppressive strategy in the treatment of DEAP-HUS. Considering the high rate of early relapse, the possible coexistence and contribution of both known and unknown complement-gene mutations, the probable pathogenic role of CFHR1 as a complement alternative pathway (CAP) regulator, the experimental nature of measuring and using anti-CFH autoantibodies to guide management, and until the positive reports of immunosuppression in addition to plasma therapy are confirmed in prospective studies, we feel that a complement-directed therapy should not be neglected in DEAP-HUS. Serial CFH autoantibody titer testing may become a valuable tool to monitor treatment response, and weaning patients off eculizumab may become an option once CFH autoantibody levels are depleted., Conclusions: A prospective study of eculizumab treatment in a larger cohort of DEAP-HUS patients is required to validate the applicability of our positive experience.

Alport Syndrome (AS) is an inherited progressive disease that is caused by mutations of the genes encoding the key collagen chains, α3, α4, and α5, which are necessary for the composition of collagen type IV to form a robust glomerular basement membrane (GBM), capable of withstanding the significant biomechanical strain to which the glomerulus is subjected. Progressive loss of the filtration barrier allows excessive proteinuria, which ultimately leads to end-stage kidney disease (ESKD). The evidence for a beneficial renoprotective effect of renin-angiotensin-aldosterone system (RAAS) blockade by angiotensin-converting enzyme (ACE) inhibition and/or angiotensin receptor blockers (ARBs) is well established in AS and recent evidence has shown that it can significantly delay the time to onset of renal replacement therapy and ESKD. Future potential treatments of AS disease progression are evaluated in this review.

Purpose: This study's aim was to assess the use of intravesical injection of botulinum neurotoxin type A (BoNT-A) as a treatment of overactive bladder (OAB) in children., Methods: A 6-year retrospective study of children who received BoNT-A for OAB was performed. Treatment outcome was classified as complete success (CS), partial success (PS) or treatment failure (TF)., Results: Of the 57 patients who received BoNT-A treatment for OAB, 35 were males. CS occurred in 74.2% of males and 54.5% of females. PS was achieved in 20% of males and 18.2% of females. TF occurred in 2.9% of males and 22.7% of females. Anticholinergics had previously been used and had been effective in 58.6% and 83.3% of males and females. Significant side effects to medications were experienced in 12 (41.4%) males and 4 (22.2%) females. Of these, BoNT-A achieved CS in seven (53.3%) males and two (50%) females and PS in three (25%) males and one (25%) female. BoNT-A was successful in seven (58.3%) males and two (66.7%) females where anticholinergics were ineffective., Conclusions: BoNT-A has a role in a carefully selected subgroup of children with overactive bladder symptoms including those with medication side effects and treatment compliance issues. It may have a role in patients who do not respond to conventional therapy.