Impact of childhood nephrotic syndrome on obesity and growth: a prospective cohort study.

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.

Hypertension in diabetes.

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.

Safety and immunogenicity of the live-attenuated varicella vaccine in pediatric solid organ transplant recipients: A systematic review and meta-analysis.

This study aimed to synthesize the available evidence on the immunogenicity, safety, and effectiveness of live-attenuated varicella vaccine in solid organ transplant recipients. Medline and EMBASE were searched using predefined search terms to identify relevant studies. The included articles reported varicella vaccine administration in the posttransplant period in children and adults. A pooled proportion of transplant recipients who seroconverted and who developed vaccine-strain varicella and varicella disease was generated. Eighteen articles (14 observational studies and 4 case reports) were included, reporting on 711 transplant recipients who received the varicella vaccine. The pooled proportion was 88.2% (95% confidence interval 78.0%-96.0%, 13 studies) for vaccinees who seroconverted, 0% (0%-1.2%, 13 studies) for vaccine-strain varicella, and 0.8% (0%-4.9%, 9 studies) for varicella disease. Most studies followed clinical guidelines for administering live-attenuated vaccines, with criteria that could include being at least 1 year posttransplant, 2 months postrejection episode, and on low-dose immunosuppressive medications. Varicella vaccination in transplant recipients was overall safe in the included studies, with few cases of vaccine-strain-induced varicella or vaccine failure, and although it was immunogenic, the proportion of recipients who seroconverted was lower than that seen in the general population. Our data support varicella vaccination in select pediatric solid organ transplant recipients.

The loss of glycocalyx integrity impairs complement factor H binding and contributes to cyclosporine-induced endothelial cell injury.

Background: Calcineurin inhibitors (CNIs) are associated with nephrotoxicity, endothelial cell dysfunction, and thrombotic microangiopathy (TMA). Evolving evidence suggests an important role for complement dysregulation in the pathogenesis of CNI-induced TMA. However, the exact mechanism(s) of CNI-induced TMA remain(s) unknown. Methods: Using blood outgrowth endothelial cells (BOECs) from healthy donors, we evaluated the effects of cyclosporine on endothelial cell integrity. Specifically, we determined complement activation (C3c and C9) and regulation (CD46, CD55, CD59, and complement factor H [CFH] deposition) as these occurred on the endothelial cell surface membrane and glycocalyx. Results: We found that exposing the endothelium to cyclosporine resulted in a dose- and time-dependent enhancement of complement deposition and cytotoxicity. We, therefore, employed flow cytometry, Western blotting/CFH cofactor assays, and immunofluorescence imaging to determine the expression of complement regulators and the functional activity and localization of CFH. Notably, while cyclosporine led to the upregulation of complement regulators CD46, CD55, and CD59 on the endothelial cell surface, it also diminished the endothelial cell glycocalyx through the shedding of heparan sulfate side chains. The weakened endothelial cell glycocalyx resulted in decreased CFH surface binding and surface cofactor activity. Conclusion: Our findings confirm a role for complement in cyclosporine-induced endothelial injury and suggest that decreased glycocalyx density, induced by cyclosporine, is a mechanism that leads to complement alternative pathway dysregulation via decreased CFH surface binding and cofactor activity. This mechanism may apply to other secondary TMAs-in which a role for complement has so far not been recognized-and provide a potential therapeutic target and an important marker for patients on calcineurin inhibitors.

Utilizing therapeutic drug monitoring to optimize therapy with eculizumab and mycophenolate mofetil in a child with C3 glomerulonephritis.

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.

Immunogenicity of a quadrivalent human papillomavirus vaccine in pediatric kidney and liver transplant recipients.

BACKGROUND: Solid-organ transplant recipients are at increased risk of developing human papillomavirus-related diseases. METHODS: To evaluate the immunogenicity of a quadrivalent vaccine, a prospective observational study included females aged 12-19 years who had received kidney or liver transplants, or were otherwise healthy volunteers. With the three-dose vaccination, serum antibodies were measured. RESULTS: The study included 17 transplant recipients (seven kidney and 10 liver) and 16 healthy participants. Six of seven kidney transplant recipients were on three immunosuppressive medications, whereas 9 of the 10 liver transplant recipients were on one. For the serology within 6 months from the last vaccine dose, the geometric mean titers of human papillomavirus types 6, 11, 16, and 18 were 26.7, 8.6, 35.7, and 42.4 (kidney transplant); 579.2, 569.3, 3097.3, and 835.7 (liver transplant); and 860.5, 638.8, 4391.6, and 902.6 milli-Merck Units/ml (healthy). The seropositivity rates of kidney transplant recipients for the four serotypes ranged from 50% to 75%, while all liver transplant recipients and healthy participants had 100% seropositivity rates for all four types. While there were no statistical differences of titers between liver transplant recipients and healthy participants, the titers of kidney transplant recipients were lower than those of healthy participants for type 6 (p = .034), type 11 (p = .032), and type 16 (p = .032). CONCLUSIONS: The results support the recommendation of human papillomavirus vaccination in pediatric transplant recipients given the significant risk of human papillomavirus-related diseases in this population, though immunogenicity was lower in kidney transplant recipients on multiple immunosuppressive medications.

Variation in paediatric 24-h ambulatory blood pressure monitoring interpretation by Canadian and UK physicians.

Twenty-four-hour ambulatory blood pressure monitoring (ABPM) is widely accepted as a more accurate method for measurement of blood pressure (BP) compared to a single office-based measurement of BP. However, it is unclear how physicians interpret ABPM and make management decisions. This study's goal is to investigate variation in ABPM interpretation among paediatric nephrologists (Canada and UK) and paediatric cardiologists (Canada only) via an online survey. The survey content included baseline demographics, questions on the use and indications for ABPM, interpretation of results, and subsequent management decisions in various clinical scenarios. The survey was sent to 196 Canadian physicians, with 69 (35.2%) total responses. Thirty-five UK clinicians also completed the survey. Most respondents were >44 years old, were in practice for at least 11 years, and were university-based. There were substantial differences among clinicians in ABPM interpretation for isolated systolic, diastolic, and night-time hypertension. For example, only 53.1% of physicians would initiate or modify treatment in those with diastolic HTN in CKD. Further, even for the same abnormal ABPM parameter, the decision to start or alter treatment was influenced by the underlying medical condition. There is significant variation in clinical practice among physicians for interpretation and management of hypertension when using ABPM. Differences in guidelines among various jurisdictions, as well as knowledge gaps in the research on which guidelines are based, create ambiguity regarding ABPM interpretation and management decisions. A more protocolized approach and further insight into the reasoning behind the variation in physicians' interpretation may help to standardise practice.

A Guide for Adult Nephrologists and Hematologists to Managing Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy in Teens Transitioning to Young Adults.

Atypical hemolytic uremic syndrome and C3 glomerulopathy/immune complex membranoproliferative glomerulonephritis are ultra-rare chronic, complement-mediated diseases with childhood manifestation in a majority of cases. Transition of clinical care of patients from pediatric to adult nephrologists-typically with controlled disease in native or transplant kidneys in case of atypical hemolytic uremic syndrome and often with chronic progressive disease despite treatment efforts in case of C3 glomerulopathy/immune complex membranoproliferative glomerulonephritis-identifies a challenging juncture in the journey of these patients. Raising awareness for the vulnerability of this patient cohort; providing education on disease pathophysiology and management including the use of new, high-precision complement antagonists; and establishing an ongoing dialog of patients, families, and all members of the health care team involved on either side of the age divide will be inevitable to ensure optimal patient outcomes and a safe transition of these patients to adulthood.

Histopathological Changes of Long-Term Peritoneal Dialysis Using Physiological Solutions: A Case Report and Review of the Literature.

BACKGROUND: Long-term peritoneal dialysis (PD), especially with nonphysiological solutions, is afflicted with the severe complication of encapsulating peritoneal sclerosis (EPS). Physiologic PD solutions have been introduced to reduce pH trauma. Data on peritoneal biopsies in pediatrics with long-term PD using physiological solutions are scant. CASE REPORT: We report an adolescent who had been on 10-h continuous hourly cycles using mostly 2.27% Physioneal™ for 5 years. There were two episodes of peritonitis in October 2017 (Klebsiella oxytoca) and May 2018 (Klebsiella pneumoniae), which were treated promptly. This adolescent, who lost two kidney transplants from recurrent focal and segmental glomerulosclerosis, underwent a peritoneal membrane biopsy at the time of a third PD catheter placement, 16 months after the second renal transplant. Laparoscopically, the peritoneum appeared grossly normal, but fibrosis and abundant hemosiderin deposition were noted on histology. The thickness of the peritoneum was 200-900 (mean 680) µm; normal for age of 14 years is 297 [IQR 229, 384] µm. The peritoneum biopsy did not show specific EPS findings, as the mesothelial cells were intact, and there was a lack of fibrin exudation, neo-membrane, fibroblast proliferation, infiltration, or calcification. CONCLUSIONS: While the biopsy was reassuring with respect to the absence of EPS, significant histopathological changes suggest that avoiding pH trauma may not ameliorate the effects of glucose exposure in long-term PD.

Hospitalization following pediatric kidney transplantation: An international comparison among a Canadian pediatric transplant center, North American Pediatric Renal Trials and Collaborative Studies, and Cooperative European Pediatric Renal Transplant Initiative registry data.

BACKGROUND: There are several databases across the world that collect pediatric KT data. We compare the hospitalization outcomes for pediatric KT recipients from a large Canadian transplant center (SickKids database; The Hospital for Sick Children Kidney Transplantation Institutional Database), United States (NAPRTCS), and Europe (CERTAIN registry). METHODS: An institutional retrospective review of KT was performed between 2000 and 2015. Baseline characteristics, duration of initial hospitalization/readmission at 1-5 and 6- to 11-month posttransplant, and 1-year graft survival data were collected. Corresponding data from the NAPRTCS 2014 Annual Transplant Report and CERTAIN registry were compared. RESULTS: Posttransplant, patients from NAPRTCS had the shortest duration of hospitalization within the first month (10.4 days, SE 0.2), followed by SickKids (20.3 days, SE 0.7) and CERTAIN (25.5 days, SE 0.7). For both living and deceased donor populations, patients from SickKids were most likely to be hospitalized at 1- to 5-month posttransplant (82.4% [89/108]; 72.1% [98/136]), followed by Europe (52.1% [198/380]; 61.6% [501/813]) and United States (45.4% [2379/5241]; 51.4% [2517/4896]). Patients from Europe were most likely to be hospitalized at 6- to 12-month posttransplant (42.1% [160/380]; 51.7% [420/813]), followed by SickKids (35.2% [38/108]; 37.5% [51/136]) and United States (28.3% [1387/4901]; 31.6% [1411/4465]). Across all databases, the most commonly addressed issues during readmissions were infectious complications. CONCLUSION: The differences observed in this investigation may reflect the local reimbursement models, resources for outpatient management, and practice variations across a large Canadian transplant center, United States, and European countries.

Sex differences in cardiovascular disease burden in children with chronic kidney disease.

Cardiovascular disease is the leading cause of death in children and adults with chronic kidney disease. In this issue, Sugianto et al. demonstrated signs of increased cardiovascular damage (vascular stiffness) in children with chronic kidney disease and highlighted an increased susceptibility of girls, especially in the context of declining kidney function and longer transplant wait times. Understanding the determinants leading to these differences are essential to address the disparity in outcomes in children with chronic kidney disease.

Posterior Urethral Valves Outcomes Prediction (PUVOP): a machine learning tool to predict clinically relevant outcomes in boys with posterior urethral valves.

BACKGROUND: Early kidney and anatomic features may be predictive of future progression and need for additional procedures in patients with posterior urethral valve (PUV). The objective of this study was to use machine learning (ML) to predict clinically relevant outcomes in these patients. METHODS: Patients diagnosed with PUV with kidney function measurements at our institution between 2000 and 2020 were included. Pertinent clinical measures were abstracted, including estimated glomerular filtration rate (eGFR) at each visit, initial vesicoureteral reflux grade, and renal dysplasia at presentation. ML models were developed to predict clinically relevant outcomes: progression in CKD stage, initiation of kidney replacement therapy (KRT), and need for clean-intermittent catheterization (CIC). Model performance was assessed by concordance index (c-index) and the model was externally validated. RESULTS: A total of 103 patients were included with a median follow-up of 5.7 years. Of these patients, 26 (25%) had CKD progression, 18 (17%) required KRT, and 32 (31%) were prescribed CIC. Additionally, 22 patients were included for external validation. The ML model predicted CKD progression (c-index = 0.77; external C-index = 0.78), KRT (c-index = 0.95; external C-index = 0.89) and indicated CIC (c-index = 0.70; external C-index = 0.64), and all performed better than Cox proportional-hazards regression. The models have been packaged into a simple easy-to-use tool, available at https://share.streamlit.io/jcckwong/puvop/main/app.py CONCLUSION: ML-based approaches for predicting clinically relevant outcomes in PUV are feasible. Further validation is warranted, but this implementable model can act as a decision-making aid. A higher resolution version of the Graphical abstract is available as Supplementary information.

Implementing a fluid volume management program to decrease intra-dialytic hypotensive events in a paediatric in-centre haemodialysis unit: a quality improvement project.

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.

Canadian Association of Paediatric Nephrologists COVID-19 Rapid Response: Home and In-Center Dialysis Guidance.

PURPOSE OF THE PROGRAM: This article provides guidance on optimizing the management of pediatric patients with end-stage kidney disease (ESKD) who will be or are being treated with any form of home or in-center dialysis during the COVID-19 pandemic. The goals are to provide the best possible care for pediatric patients with ESKD during the pandemic and ensure the health care team's safety. SOURCES OF INFORMATION: The core of these rapid guidelines is derived from the Canadian Society of Nephrology (CSN) consensus recommendations for adult patients recently published in the Canadian Journal of Kidney Health and Disease (CJKHD). We also consulted specific documents from other national and international agencies focused on pediatric kidney health. Additional information was obtained by formal review of the published academic literature relevant to pediatric home or in-center hemodialysis. METHODS: The Leadership of the Canadian Association of Paediatric Nephrologists (CAPN), which is affiliated with the CSN, solicited a team of clinicians and researchers with expertise in pediatric home and in-center dialysis. The goal was to adapt the guidelines recently adopted for Canadian adult dialysis patients for pediatric-specific settings. These included specific COVID-19-related themes that apply to dialysis in a Canadian environment, as determined by a group of senior renal leaders. Expert clinicians and nurses with deep expertise in pediatric home and in-center dialysis reviewed the revised pediatric guidelines. KEY FINDINGS: We identified 7 broad areas of home dialysis practice management that may be affected by the COVID-19 pandemic: (1) peritoneal dialysis catheter placement, (2) home dialysis training, (3) home dialysis management, (4) personal protective equipment, (5) product delivery, (6) minimizing direct health care providers and patient contact, and (7) caregivers support in the community. In addition, we identified 8 broad areas of in-center dialysis practice management that may be affected by the COVID-19 pandemic: (1) identification of patients with COVID-19, (2) hemodialysis of patients with confirmed COVID-19, (3) hemodialysis of patients not yet known to have COVID-19, (4) management of visitors to the dialysis unit, (5) handling COVID-19 testing of patients and staff, (6) safe practices during resuscitation procedures in a pandemic, (7) routine hemodialysis care, and (8) hemodialysis care under fixed dialysis resources. We make specific suggestions and recommendations for each of these areas. LIMITATIONS: At the time when we started this work, we knew that evidence on the topic of pediatric dialysis and COVID-19 would be severely limited, and our resources were also limited. We did not, therefore, do formal systematic review or meta-analysis. We did not evaluate our specific suggestions in the clinical environment. Thus, this article's advice and recommendations are primarily expert opinions and subject to the biases associated with this level of evidence. To expedite the publication of this work, we created a parallel review process that may not be as robust as standard arms' length peer-review processes. IMPLICATIONS: We intend these recommendations to help provide the best care possible for pediatric patients prescribed in-center or home dialysis during the COVID-19 pandemic, a time of altered priorities and reduced resources.

Kidney disease in children with heart or liver transplant.

Over the past few decades, there has been increasing recognition of kidney disease in children with non-kidney solid organ transplantation. The risk of kidney disease in children undergoing heart or liver transplantation is higher than the general population as the underlying disease and its associated management may directly impair kidney function. Both heart and liver failures contribute to hypoperfusion and kidney ischemia before patients reach the point of transplant. The transplant surgery itself can often be complicated by acute kidney injury (AKI), which may be further exacerbated by a complicated postoperative course. In the short- and long-term post-transplant period, these children are at risk of acute illness, exposed to nephrotoxic medications, and susceptible to rare but severe infections and immunologic insults that may contribute to AKI and chronic kidney disease (CKD). In some, CKD can progress to kidney failure with replacement therapy (KFRT). CKD and KFRT are associated with increased morbidity and mortality in this patient population. Therefore, it is critical to monitor for and recognize the risk factors for kidney injury in this population and mitigate these risks. In this paper, the authors provide an overview of kidney disease pertaining to heart and liver transplantation in children with guidance on monitoring, diagnosis, prevention, and management.

Solid organ transplant-specific antibiogram in a tertiary pediatric hospital in Canada.

SOT recipients are more vulnerable to infections with antimicrobial-resistant organisms, and therefore, it may be useful for transplant centers to create transplant-specific antibiograms to direct empirical antimicrobial regimens and monitor trends in antimicrobial resistance. SOT-specific antibiograms were created using antimicrobial susceptibility data on isolates from 2012 to 2018 at The Hospital for Sick Children, Toronto, Ontario, Canada. The CLSI guidelines were followed to generate the antibiograms except that results from 2 years of data were pooled on a rolling basis to achieve larger sample sizes. The 3 most frequent organisms in one analysis period of the SOT antibiogram were Escherichia coli (average sample size ±standard deviation; n = 28.7 ± 3.8), Staphylococcus aureus (n = 27.8 ± 5.0), and Pseudomonas aeruginosa (non-CF) (n = 19.8 ± 8.8). For E.coli, susceptibilities in the SOT antibiogram were significantly lower than those in the hospital-wide antibiogram in 2017-2018 for ampicillin (27% vs 47%; p = .014), piperacillin/tazobactam (55% vs 88%; p < .001), cefotaxime (59% vs 89%; p < .001), ciprofloxacin (71% vs 88%; p = .007), and trimethoprim-sulfamethoxazole (41% vs 69%; p = .001), but not significantly different for aminoglycosides and meropenem. In the SOT antibiogram of E. coli, decreased susceptibility trend was confirmed in some antibiotics, including piperacillin/tazobactam (83% in 2012-2013 vs 55% in 2017-2018). At our center, the solid organ transplant-specific antibiogram revealed important differences in E. coli susceptibilities and trends in antimicrobial resistance. Developing a SOT antibiogram will assist in revising and improving empiric treatment guidelines as well as monitoring antimicrobial resistance in this population.