Long-Term Kidney Outcomes after Pediatric Acute Kidney Injury.

BACKGROUND: Acute kidney injury (AKI) is common in hospitalized children. Pediatric AKI receiving acute kidney replacement therapy (KRT) is associated with long-term chronic kidney disease (CKD), hypertension, and death. We aim to determine the outcomes after AKI in children who did not receive acute KRT, since these remain uncertain. METHODS: Retrospective cohort study of all hospitalized children (0-18 years) surviving AKI without acute KRT between 1996-2020 in Ontario, Canada, identified by validated diagnostic codes in provincial administrative health databases. Children with prior KRT, CKD, or AKI were excluded. Cases were matched with up to four hospitalized comparators without AKI by age, neonatal status, sex, intensive care unit admission, cardiac surgery, malignancy, hypertension, hospitalization era, and a propensity score for AKI. Patients were followed until death, provincial emigration, or censoring in March 2021. The primary outcome was long-term major adverse kidney events (MAKE-LT; a composite of all-cause mortality, long-term KRT, or incident CKD). RESULTS: We matched 4,173 pediatric AKI survivors with 16,337 hospitalized comparators. Baseline covariates were well-balanced following propensity score matching. During median 9.7-year follow-up, 18% of AKI survivors developed MAKE-LT vs. 5% of hospitalized comparators (hazard ratio [HR] 4.0, 95% confidence interval [CI] 3.6-4.4). AKI survivors had higher rates of long-term KRT (2% vs. <1%; HR 11.7, 95%CI 7.5-18.4), incident CKD (16% vs. 2%; HR 7.9, 95%CI 6.9-9.1), incident hypertension (17% vs. 8%; HR 2.3, 95%CI 2.1-2.6), and AKI during subsequent hospitalization (6% vs. 2%; HR 3.7, 95%CI 3.1-4.5), but no difference in all-cause mortality (3% vs. 3%; HR 0.9, 95%CI 0.7-1.1). CONCLUSIONS: Children surviving AKI without acute KRT were at higher long-term risk of CKD, long-term KRT, hypertension, and subsequent AKI vs. hospitalized comparators.

"Weighing the Pros and Cons of Everything": A Qualitative Descriptive Study Exploring Perspectives About Living Donor Kidney Transplantation From Parents of Chinese Canadian Pediatric Patients With Chronic Kidney Disease.

Background: As of 2021, more than 6000 children and youth in Canada were living with end-stage kidney disease (ESKD), for which kidney transplantation is considered the preferred treatment by health professionals. Research shows that living donor kidney transplantation (LDKT) has superior allograft and recipient survival compared to deceased donor kidney transplantation (DDKT). However, in a pediatric setting, the choice of LDKT or DDKT is a summative consideration of factors weighed carefully by the patient's family, health care team, and patient. Decision-making surrounding transplantation may be more complex for racial and ethnic minorities as culturally specific values and beliefs are interwoven within dominant understandings and concepts of health and accepted models of health care. For example, Chinese Canadians have an increased risk of ESKD, yet reduced access to LDKT compared to White patients, despite being the largest visible minority population in Canada. Objective: The objective of this qualitative study is to deepen our understandings of the decision-making process surrounding DDKT versus LDKT among parents of Chinese Canadian pediatric patients with chronic kidney disease (CKD). Design: Qualitative descriptive study design. Setting: The Nephrology Program at The Hospital for Sick Children in Toronto, Canada. Participants: Caregivers of Chinese Canadian patients with CKD, 18 years of age or older, and who spoke English, Cantonese, or Mandarin. Methods: One-on-one, semistructured interviews were conducted virtually, by a member of the research team and were audio-recorded and transcribed verbatim. Thematic analysis was used to explore participants' shared experience. Results: Seven interviews were conducted with 6 mothers and 1 father of 6 Chinese Canadian pediatric patients with CKD: 4 patients had undergone a kidney transplant, and 2 were not yet listed for transplant. Analysis of data highlighted that cultural influences affected whether parents shared with others about their child's illness and experience. The cultural understanding that it is inappropriate to burden others contributed to the creation of an isolating experience for participants. Cultural influences also impacted whether parents asked others to be a living donor as participants articulated this would place a physical burden on the living donor (e.g., potential risk to their health) and an emotional burden on the participant as they would be indebted to a willing donor. Ultimately, parents' decision to choose DDKT or LDKT for their patient-child was a result of evaluating both options carefully and within an understanding that the ideal treatment choice reflected what was best for all family members. Limitations: Findings reflect experiences of a small sample from a single recruitment site which may limit transferability. Conclusions: Parents in this study felt that they had access to the necessary evidence-based information to make an informed decision about the choice of DDKT versus LDKT for their child. Participant narratives described feeling isolated within cultural communities of family and friends and participants' suggestion of benefiting from increased support may guide future research directions. Practitioners can offer direct and indirect support to families, with recognition of the importance of cultural values and family-centered care on decision-making within families. Opportunities are needed for accessible, virtual social support platforms to increase parental feelings of culturally mediated peer support from parents who share similar experiences.

Contexte: En 2021, plus de 6000 enfants et jeunes au Canada vivaient avec une insuffisance rénale terminale (IRT), une affection pour laquelle la transplantation rénale est considérée comme le traitement préférentiel par les professionnels de la santé. La recherche montre que la transplantation d'un rein de donneur vivant (TRDV) présente des taux de survie du greffon et du receveur supérieurs à ceux de la transplantation d'un rein de donneur décédé (TRDD). En contexte pédiatrique, le choix entre la TRDV et la TRDD fait l'objet d'une évaluation sommative de facteurs soigneusement pesés par le patient, sa famille et l'équipe de soins. La prise de décision entourant la transplantation peut s'avérer encore plus complexe pour les personnes issues des minorités raciales et ethniques, car des valeurs et croyances spécifiques à la culture sont imbriquées dans les conceptions et concepts dominants de la santé et les modèles de soins acceptés. Les Canadiens d'origine chinoise, par exemple, présentent un risque accru d'IRT, mais leur accès à la TRDV est réduit par rapport aux patients d'origine caucasienne, bien qu'ils constituent la plus importante minorité visible dans la population Canadienne. Objectif: L'objectif de cette étude qualitative est d'approfondir notre compréhension du processus décisionnel entourant le choix entre la TRDD et la TRDV chez les parents de patients pédiatriques d'origine chinoise atteints d'insuffisance rénale chronique (IRC). Conception: Étude qualitative et descriptive. Cadre: Le program de néphrologie de l'Hospital for Sick Children de Toronto (Canada). Sujets: Des adultes proches aidants de patients Canadiens d'origine chinoise atteints d'IRC et parlant anglais, cantonais ou mandarin. Méthodologie: Des entrevues individuelles semi-structurées ont été menées en mode virtuel par un membre de l'équipe de recherche; les entrevues ont été enregistrées (audio) et transcrites textuellement. L'analyze thématique a été utilisée pour explorer l'expérience commune des participants. Résultats: Sept entrevues ont été menées auprès des parents (6 mères et un père) de 6 patients pédiatriques Canadiens d'origine chinoise atteints d'IRC: quatre avaient subi une greffe rénale, les deux autres n'étaient pas encore inscrits sur la liste pour une transplantation. L'analyze des données a révélé que les influences culturelles affectaient la façon dont les parents parlent de la maladie et de l'expérience de leur enfant avec d'autres personnes. La conception d'origine culturelle selon laquelle il n'est pas approprié d'accabler les autres a contribué à créer de l'isolement chez les participants. Les influences culturelles ont également interféré dans le fait de demander ou non à d'autres personnes d'être donneurs vivants; les participants ont expliqué que le don vivant imposait un fardeau physique au donneur vivant (p. ex., un risque pour sa santé) et un fardeau émotionnel au participant, car ceux-ci seraient redevables au donneur consentant. La décision des parents de choisir la TRDD ou la TRDV pour leur enfant aura finalement été le résultat d'une évaluation minutieuse des deux options, avec la perspective que le choix de traitement idéal reflétait ce qui était le mieux pour tous les membres de la famille. Limites: Ces résultats reflètent les expériences d'un faible échantillon de sujets provenant d'un seul centre, ce qui peut limiter la transférabilité. Conclusion: Les parents interrogés pour cette étude estimaient avoir eu accès aux informations factuelles nécessaires pour prendre une décision éclairée dans leur choix entre la TRDD et la TRDV pour leur enfant. Les récits des participants ont décrit leur sentiment d'isolement au sein des communautés culturelles de la famille et des amis; la suggestion des participants de bénéficier d'un soutien accru pourrait guider les orientations futures de la recherche. Les praticiens peuvent offrir un soutien direct et indirect aux familles en reconnaissant l'importance des valeurs culturelles et des soins centrés sur la famille dans la prise de décisions par les familles. Il est nécessaire de créer des plateformes de soutien social virtuelles et accessibles, afin que les parents aient le sentiment de bénéficier davantage du soutien culturel d'autres parents qui partagent des expériences similaires.

Capacity for the management of kidney failure in the International Society of Nephrology North America and the Caribbean region: report from the 2023 ISN Global Kidney Health Atlas (ISN-GKHA).

The International Society of Nephrology Global Kidney Health Atlas charts the availability and capacity of kidney care globally. In the North America and the Caribbean region, the Atlas can identify opportunities for kidney care improvement, particularly in Caribbean countries where structures for systematic data collection are lacking. In this third iteration, respondents from 12 of 18 countries from the region reported a 2-fold higher than global median prevalence of dialysis and transplantation, and a 3-fold higher than global median prevalence of dialysis centers. The peritoneal dialysis prevalence was lower than the global median, and transplantation data were missing from 6 of the 10 Caribbean countries. Government-funded payments predominated for dialysis modalities, with greater heterogeneity in transplantation payor mix. Services for chronic kidney disease, such as monitoring of anemia and blood pressure, and diagnostic capability relying on serum creatinine and urinalyses were universally available. Notable exceptions in Caribbean countries included non-calcium-based phosphate binders and kidney biopsy services. Personnel shortages were reported across the region. Kidney failure was identified as a governmental priority more commonly than was chronic kidney disease or acute kidney injury. In this generally affluent region, patients have better access to kidney replacement therapy and chronic kidney disease-related services than in much of the world. Yet clear heterogeneity exists, especially among the Caribbean countries struggling with dialysis and personnel capacity. Important steps to improve kidney care in the region include increased emphasis on preventive care, a focus on home-based modalities and transplantation, and solutions to train and retain specialized allied health professionals.

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.

Circulating small extracellular vesicles mediate vascular hyperpermeability in diabetes.

AIMS/HYPOTHESIS: A hallmark chronic complication of type 2 diabetes mellitus is vascular hyperpermeability, which encompasses dysfunction of the cerebrovascular endothelium and the subsequent development of associated cognitive impairment. The present study tested the hypothesis that during type 2 diabetes circulating small extracellular vesicles (sEVs) exhibit phenotypic changes that facilitate pathogenic disruption of the vascular barrier. METHODS: sEVs isolated from the plasma of a mouse model of type 2 diabetes and from diabetic human individuals were characterised for their ability to disrupt the endothelial cell (EC) barrier. The contents of sEVs and their effect on recipient ECs were assessed by proteomics and identified pathways were functionally interrogated with small molecule inhibitors. RESULTS: Using intravital imaging, we found that diabetic mice (Leprdb/db) displayed hyperpermeability of the cerebrovasculature. Enhanced vascular leakiness was recapitulated following i.v. injection of sEVs from diabetic mice into non-diabetic recipient mice. Characterisation of circulating sEV populations from the plasma of diabetic mice and humans demonstrated increased quantity and size of sEVs compared with those isolated from non-diabetic counterparts. Functional experiments revealed that sEVs from diabetic mice or humans induced the rapid and sustained disruption of the EC barrier through enhanced paracellular and transcellular leak but did not induce inflammation. Subsequent sEV proteome and recipient EC phospho-proteome analysis suggested that extracellular vesicles (sEVs) from diabetic mice and humans modulate the MAPK/MAPK kinase (MEK) and Rho-associated protein kinase (ROCK) pathways, cell-cell junctions and actin dynamics. This was confirmed experimentally. Treatment of sEVs with proteinase K or pre-treatment of recipient cells with MEK or ROCK inhibitors reduced the hyperpermeability-inducing effects of circulating sEVs in the diabetic state. CONCLUSIONS/INTERPRETATION: Diabetes is associated with marked increases in the concentration and size of circulating sEVs. The modulation of sEV-associated proteins under diabetic conditions can induce vascular leak through activation of the MEK/ROCK pathway. These data identify a new paradigm by which diabetes can induce hyperpermeability and dysfunction of the cerebrovasculature and may implicate sEVs in the pathogenesis of cognitive decline during type 2 diabetes.

Phenome-wide analysis reveals epistatic associations between APOL1 variants and chronic kidney disease and multiple other disorders.

BACKGROUND: APOL1 variants G1 and G2 are common in populations with recent African ancestry. They are associated with protection from African sleeping sickness, however homozygosity or compound heterozygosity for these variants is associated with chronic kidney disease (CKD) and related conditions. What is not clear is the extent of associations with non-kidney-related disorders, and whether there are clusters of diseases associated with individual APOL1 genotypes. METHODS: Using a cohort of 7462 UK Biobank participants with recent African ancestry, we conducted a phenome-wide association study investigating associations between individual APOL1 genotypes and conditions identified by the International Classification of Disease phenotypes. FINDINGS: We identified 27 potential associations between individual APOL1 genotypes and a diverse range of conditions. G1/G2 compound heterozygotes were specifically associated with 26 of these conditions (all deleteriously), with an over-representation of infectious diseases (including hospitalisation and death resulting from COVID-19). The analysis also exposed complexities in the relationship between APOL1 and CKD that are not evident when risk variants are grouped together: G1 homozygosity, G2 homozygosity, and G1/G2 compound heterozygosity were each shown to be associated with distinct CKD phenotypes. The multi-locus nature of the G1/G2 genotype means that its associations would go undetected in a standard genome-wide association study. INTERPRETATION: Our findings have implications for understanding health risks and better-targeted detection, intervention, and therapeutic strategies, particularly in populations where APOL1 G1 and G2 are common such as in sub-Saharan Africa and its diaspora. FUNDING: This study was funded by the Wellcome Trust (209511/Z/17/Z) and H3Africa (H3A/18/004).

A Canadian Commentary on the NKF-ASN Task Force Recommendations on Reassessing the Inclusion of Race in Diagnosing Kidney Disease.

In 2021, a committee was commissioned by the Canadian Society of Nephrology to comment on the 2021 National Kidney Foundation-American Society of Nephrology Task Force recommendations on the use of race in glomerular filtration rate estimating equations. The committee met on numerous occasions and agreed on several recommendations. However, the committee did not achieve unanimity, with a minority group disagreeing with the scope of the commentary. As a result, this report presents the viewpoint of the majority members. We endorsed many of the recommendations from the National Kidney Foundation-American Society of Nephrology Task Force, most importantly that race should be removed from the estimated glomerular filtration rate creatinine-based equation. We recommend an immediate implementation of the new Chronic Kidney Disease Epidemiology Collaboration equation (2021), which does not discriminate among any group while maintaining precision. Additionally, we recommend that Canadian laboratories and provincial kidney organizations advocate for increased testing and access to cystatin C because the combination of cystatin C and creatinine in revised equations leads to more precise estimates. Finally, we recommend that future research studies evaluating the implementation of the new equations and changes to screening, diagnosis, and management across provincial health programs be prioritized in Canada.