"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.

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.

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.

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.

Post-transplant recurrence of focal segmental glomerular sclerosis: consensus statements.

Focal segmental glomerular sclerosis (FSGS) is 1 of the primary causes of nephrotic syndrome in both pediatric and adult patients, which can lead to end-stage kidney disease. Recurrence of FSGS after kidney transplantation significantly increases allograft loss, leading to morbidity and mortality. Currently, there are no consensus guidelines for identifying those patients who are at risk for recurrence or for the management of recurrent FSGS. Our work group performed a literature search on PubMed/Medline, Embase, and Cochrane, and recommendations were proposed and graded for strength of evidence. Of the 614 initially identified studies, 221 were found suitable to formulate consensus guidelines for recurrent FSGS. These guidelines focus on the definition, epidemiology, risk factors, pathogenesis, and management of recurrent FSGS. We conclude that additional studies are required to strengthen the recommendations proposed in this review.

Ensuring access to innovative therapies for children, adolescents, and young adults across Canada: The single patient study experience.

Innovative therapeutic approaches are needed to alleviate the burden of life-limiting, rare, and chronic conditions affecting children, adolescents, and young adults (CAYA). This includes a need for improved access to both clinical research and to non-approved or off-label therapies, together with, ultimately, more therapies achieving regulatory approval in Canada. The single patient study (SPS), also known as an open label individual patient (OLIP) study, was introduced by Health Canada to open access to non-marketed drugs where a clinical trial is not readily available, but the drug is considered too investigational to be managed on a standard Special Access Program. SPS is designed for patients who have a serious or life-threatening condition and have exhausted available treatment options. Our report summarizes this relatively new development in the Canadian regulatory environment and highlights the opportunities and challenges as identified by regulators, pharmaceutical representatives, academic researchers, and patient/parent advocates.

Prevalence of Pediatric Masked Hypertension and Risk of Subclinical Cardiovascular Outcomes: A Systematic Review and Meta-Analysis.

Masked hypertension (MH) occurs when office blood pressure is normal, but hypertension is confirmed using out-of-office blood pressure measures. Hypertension is a risk factor for subclinical cardiovascular outcomes, including left ventricular hypertrophy, increased left ventricular mass index, carotid intima media thickness, and pulse wave velocity. However, the risk factors for ambulatory blood pressure monitoring defined MH and its association with subclinical cardiovascular outcomes are unclear. A systematic literature search on 9 databases included English publications from 1974 to 2023. Pediatric MH prevalence was stratified by disease comorbidities and compared with the general pediatric population. We also compared the prevalence of left ventricular hypertrophy, and mean differences in left ventricular mass index, carotid intima media thickness, and pulse wave velocity between MH versus normotensive pediatric patients. Of 2199 screened studies, 136 studies (n=28 612; ages 4-25 years) were included. The prevalence of MH in the general pediatric population was 10.4% (95% CI, 8.00-12.80). Compared with the general pediatric population, the risk ratio (RR) of MH was significantly greater in children with coarctation of the aorta (RR, 1.91), solid-organ or stem-cell transplant (RR, 2.34), chronic kidney disease (RR, 2.44), and sickle cell disease (RR, 1.33). MH patients had increased risk of subclinical cardiovascular outcomes compared with normotensive patients, including higher left ventricular mass index (mean difference, 3.86 g/m2.7 [95% CI, 2.51-5.22]), left ventricular hypertrophy (odds ratio, 2.44 [95% CI, 1.50-3.96]), and higher pulse wave velocity (mean difference, 0.30 m/s [95% CI, 0.14-0.45]). The prevalence of MH is significantly elevated among children with various comorbidities. Children with MH have evidence of subclinical cardiovascular outcomes, which increases their risk of long-term cardiovascular disease.

The Significance of Hematuria in Podocytopathies.

BACKGROUND: Hematuria is frequently present in podocytopathies, but its significance and prognostic value is not well described in these proteinuric kidney diseases. This study describes the prevalence and association between hematuria and kidney-related outcomes in these disorders. METHODS: Hematuria was assessed at the initial urinalysis in participants with the following podocytopathies, membranous nephropathy, minimal change disease, and focal segmental glomerulosclerosis, in the Nephrotic Syndrome Study Network (NEPTUNE) and Cure Glomerulonephropathy (CureGN) cohorts with >24 months of follow-up. Multivariable Cox proportional hazards models were fit for time to composite outcome (end-stage kidney disease or 40% decline in estimated glomerular filtration rate (eGFR) and eGFR <60 ml/min/1.73 m2) and proteinuria remission (UPCR <0.3 mg/mg). RESULTS: Among the 1,516 adults and children in the study, 528 (35%) participants had focal segmental glomerulosclerosis, 499 (33%) had minimal change disease, and 489 (32%) had membranous nephropathy. Median (IQR) time from biopsy until the initial study urinalysis was 260 days (49, 750), and 498 (33%) participants were positive for hematuria. Participants with hematuria compared to those without, were older (37 [16, 55] vs 33 years [12, 55]), more likely to have an underlying diagnosis of membranous nephropathy (44% vs 27%), had shorter time since biopsy (139 [27, 477] vs 325 [89, 878] days) and higher UPCR (3.8 [1.4, 8.0] vs 0.9 [0.1, 3.1]g/g). After adjusting for diagnosis, age, sex, UPCR, eGFR, time since biopsy, and study cohort, hematuria was associated with a higher riskof reaching the composite outcome (HR 1.31 [1.04, 1.65], p-value 0.02) and lower rate of reaching proteinuria remission (HR 0.80 [0.65-0.98], p-value 0.03). CONCLUSIONS: Hematuria is prevalent among participants with the three podocytopathies and is significantly and independently associated with worse kidney-related outcomes, including both progressive loss of kidney function remission of proteinuria.

Common Risk Variants in AHI1 Are Associated With Childhood Steroid Sensitive Nephrotic Syndrome.

Introduction: Steroid-sensitive nephrotic syndrome (SSNS) is the most common form of kidney disease in children worldwide. Genome-wide association studies (GWAS) have demonstrated the association of SSNS with genetic variation at HLA-DQ/DR and have identified several non-HLA loci that aid in further understanding of disease pathophysiology. We sought to identify additional genetic loci associated with SSNS in children of Sri Lankan and European ancestry. Methods: We conducted a GWAS in a cohort of Sri Lankan individuals comprising 420 pediatric patients with SSNS and 2339 genetic ancestry matched controls obtained from the UK Biobank. We then performed a transethnic meta-analysis with a previously reported European cohort of 422 pediatric patients and 5642 controls. Results: Our GWAS confirmed the previously reported association of SSNS with HLA-DR/DQ (rs9271602, P = 1.12 × 10-27, odds ratio [OR] = 2.75). Transethnic meta-analysis replicated these findings and identified a novel association at AHI1 (rs2746432, P = 2.79 × 10-8, OR = 1.37), which was also replicated in an independent South Asian cohort. AHI1 is implicated in ciliary protein transport and immune dysregulation, with rare variation in this gene contributing to Joubert syndrome type 3. Conclusions: Common variation in AHI1 confers risk of the development of SSNS in both Sri Lankan and European populations. The association with common variation in AHI1 further supports the role of immune dysregulation in the pathogenesis of SSNS and demonstrates that variation across the allele frequency spectrum in a gene can contribute to disparate monogenic and polygenic diseases.

Rationale and Design of the Diet, CKD, and Apolipoprotein L1 Study in Low-Income and Middle-Income Countries.

Introduction: Diet, chronic kidney disease (CKD), and Apolipoprotein L1 (APOL1) (DCA) Study is examining the role of dietary factors in CKD progression and APOL1 nephropathy. We describe enrollment and retention efforts and highlight facilitators and barriers to enrollment and operational challenges, as well as accommodations made in the study protocol. Methods: The DCA study is enrolling participants in 7 centers in West Africa. Participants who consented were invited to complete dietary recalls and 24-hour urine collections in year 1. We conducted focus groups and semistructured interviews among study personnel to identify facilitators and barriers to enrollment as well as retention and operational challenges in the execution of the study protocol. We analyzed emerging themes using content analyses. Results: A total of 712 participants were enrolled in 18 months with 1256 24-hour urine and 1260 dietary recalls. Barriers to enrollment were the following: (i) a lack of understanding of research, (ii) the burden of research visits, and (iii) incorporating cultural and traditional nuances when designing research protocols. Factors facilitating enrollment were the following: (i) designing convenient research visits, (ii) building rapport and increased communication between the research team and participants, and (iii) cultural sensitivity - adapting research protocols for the populations involved. Offering home visits, providing free dietary counseling, reducing the volume of study blood collection, and reducing the frequency of visits were some changes made in the study protocol that increased participant satisfaction. Conclusion: Adopting a participant-centered approach with accommodations in the protocol for cultural adaptability and incorporating participant feedback is vital for carrying out research in low-income and middle-income regions.

Cardiovascular Risk Factor Burden and Association With CKD in Ghana and Nigeria.

Introduction: Cardiovascular disease is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD); however, the burden of cardiovascular risk factors in patients with CKD in Africa is not well characterized. We determined the prevalence of selected cardiovascular risk factors, and association with CKD in the Human Heredity for Health in Africa Kidney Disease Research Network study. Methods: We recruited patients with and without CKD in Ghana and Nigeria. CKD was defined as estimated glomerular filtration rate of <60 ml/min per 1.73 m2 and/or albuminuria as albumin-to-creatinine ratio <3.0 mg/mmol (<30 mg/g) for ≥3 months. We assessed self-reported (physician-diagnosis and/or use of medication) hypertension, diabetes, and elevated cholesterol; and self-reported smoking as cardiovascular risk factors. Association between the risk factors and CKD was determined by multivariate logistic regression. Results: We enrolled 8396 participants (cases with CKD, 3956), with 56% females. The mean age (45.5 ± 15.1 years) did not differ between patients and control group. The prevalence of hypertension (59%), diabetes (20%), and elevated cholesterol (9.9%), was higher in CKD patients than in the control participants (P < 0.001). Prevalence of risk factors was higher in Ghana than in Nigeria. Hypertension (adjusted odds ratio [aOR] = 1.69 [1.43-2.01, P < 0.001]), elevated cholesterol (aOR = 2.0 [1.39-2.86, P < 0.001]), age >50 years, and body mass index (BMI) <18.5 kg/m2 were independently associated with CKD. The association of diabetes and smoking with CKD was modified by other risk factors. Conclusion: Cardiovascular risk factors are prevalent in middle-aged adult patients with CKD in Ghana and Nigeria, with higher proportions in Ghana than in Nigeria. Hypertension, elevated cholesterol, and underweight were independently associated with CKD.

Rapid Progression of Focal Segmental Glomerulosclerosis in Patients with High-Risk APOL1 Genotypes.

BACKGROUND: FSGS is a heterogeneous diagnosis with a guarded prognosis. Polymorphisms in the apolipoprotein L1 ( APOL1 ) gene are associated with developing FSGS and faster progression to kidney failure in affected patients. Better understanding the natural history of patients with FSGS and APOL1 risk alleles is essential to improve patient care and support the design and interpretation of interventional studies. The objective of this study was to evaluate the quantitative association between APOL1 and kidney disease progression and the interaction with other clinical and laboratory factors. METHODS: CureGN cohort study participants with biopsy diagnosis of FSGS, regardless of self-identified race, were included. The exposure of interest was two APOL1 risk alleles (high risk) versus zero to one risk alleles (low risk). The primary outcome was eGFR slope categorized as rapid progressor (eGFR slope ≤-5 ml/min per year), intermediate progressor (slope between 0 and -5), or nonprogressor (slope ≥0). Multivariable ordinal logistic and linear regressions were used for adjusted analyses. Missing data were addressed using multiple imputation. RESULTS: Of 650 participants, 476 (73%) had genetic testing, among whom 87 (18%) were high risk. High-risk participants were more likely to have lower median eGFR (62 [interquartile range, 36-81] versus low-risk participants 76 ml/min per 1.73 m 2 [interquartile range, 44-106]; P <0.01). In adjusted analysis, the odds of more rapid progression of eGFR was 2.75 times higher (95% confidence interval, 1.67 to 4.53; P <0.001) in the high-risk versus low-risk groups. CONCLUSIONS: In patients with FSGS, high-risk APOL1 genotype is the predominant factor associated with more rapid loss of kidney function.

Utility of SARS-CoV-2 Genomic Sequencing for Understanding Transmission and School Outbreaks.

OBJECTIVE: An understanding of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) transmission in schools is important. It is often difficult, using epidemiological information alone, to determine whether cases associated with schools represent multiple introductions from the community or transmission within the school. We describe the use of whole genome sequencing (WGS) in multiple schools to investigate outbreaks of SARS-CoV-2 in the pre-Omicron period. STUDY DESIGN: School outbreaks were identified for sequencing by local public health units based on multiple cases without known epidemiological links. Cases of SARS-CoV-2 from students and staff from 4 school outbreaks in Ontario underwent WGS and phylogenetic analysis. The epidemiological clinical cohort data and genomic cluster data are described to help further characterize these outbreaks. RESULTS: A total of 132 positive SARS-CoV-2 cases among students and staff from 4 school outbreaks were identified with 65 (49%) of cases able to be sequenced with high-quality genomic data. The 4 school outbreaks consisted of 53, 37, 21 and 21 positive cases; within each outbreak there were between 8 and 28 different clinical cohorts identified. Among the sequenced cases, between 3 and 7 genetic clusters, defined as different strains, were identified in each outbreak. We found genetically different viruses within several clinical cohorts. CONCLUSIONS: WGS, together with public health investigation, is a useful tool to investigate SARS-CoV-2 transmission within schools. Its early use has the potential to better understand when transmission may have occurred, can aid in evaluating how well mitigation interventions are working and has the potential to reduce unnecessary school closures when multiple genetic clusters are identified.

Risk of Target Organ Damage in Children With Primary Ambulatory Hypertension: A Systematic Review and Meta-Analysis.

BACKGROUND: Target organ damage (TOD) such as left ventricular hypertrophy (LVH), abnormal pulse wave velocity, and elevated carotid intima-media thickness are common among adults with hypertension and are associated with overt cardiovascular events. The risk of TOD among children and adolescents with hypertension confirmed by ambulatory blood pressure monitoring is poorly understood. In this systematic review, we compare the risks of TOD among children and adolescents with ambulatory hypertension to normotensive individuals. METHODS: A literature search was conducted to include all relevant English-language publications from January 1974 to March 2021. Studies were included if patients underwent 24-hour ambulatory blood pressure monitoring and ≥1 TOD was reported. Ambulatory hypertension was defined by society guidelines. Primary outcome was the risk of TOD, including LVH, left ventricular mass index, pulse wave velocity, and carotid intima-media thickness among children with ambulatory hypertension compared with those with ambulatory normotension. Meta-regression calculated the effect of body mass index on TOD. RESULTS: Of 12 252 studies, 38 (n=3609 individuals) were included for analysis. Children with ambulatory hypertension had an increased risk of LVH (odds ratio, 4.69 [95% CI, 2.69-8.19]), elevated left ventricular mass index (pooled difference, 5.13 g/m2.7; [95% CI, 3.78-6.49]), elevated pulse wave velocity (pooled difference, 0.39 m/s [95% CI, 0.20-0.58]), and elevated carotid intima-media thickness (pooled difference, 0.04 mm [95% CI, 0.02-0.05]), compared with normotensive children. Meta-regression showed a significant positive effect of body mass index on left ventricular mass index and carotid intima-media thickness. CONCLUSIONS: Children with ambulatory hypertension have adverse TOD profiles, which may increase their risk for future cardiovascular disease. This review highlights the importance of optimizing blood pressure control and screening for TOD in children with ambulatory hypertension. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42020189359.

Age of Onset and Disease Course in Biopsy-Proven Minimal Change Disease: An Analysis From the Cure Glomerulonephropathy Network.

RATIONALE & OBJECTIVE: Adolescent- and adult-onset minimal change disease (MCD) may have a clinical course distinct from childhood-onset disease. We characterized the course of children and adults with MCD in the Cure Glomerulonephropathy Network (CureGN) and assessed predictors of rituximab response. STUDY DESIGN: Prospective, multicenter, observational study. STUDY PARTICIPANTS: CureGN participants with proven MCD on biopsy. EXPOSURE: Age at disease onset, initiation of renin-angiotensin-aldosterone system (RAAS) blockade, and immunosuppression including rituximab during the study period. OUTCOME: Relapse and remission, change in estimated glomerular filtration rate (eGFR), and kidney failure. ANALYTICAL APPROACH: Remission and relapse probabilities were estimated using Kaplan-Meier curves and gap time recurrent event models. Linear regression models were used for the outcome of change in eGFR. Cox proportional hazards models were used to estimate the association between rituximab administration and remission. RESULTS: The study included 304 childhood- (≤12 years old), 49 adolescent- (13-17 years old), and 201 adult- (≥18 years) onset participants with 2.7-3.2 years of follow-up after enrollment. Children had a longer time to biopsy (238 vs 23 and 36 days in adolescent- and adult-onset participants, respectively; P<0.001) and were more likely to have received therapy before biopsy. Children were more likely to be treated with immunosuppression but not RAAS blockade. The rate of relapse was higher in childhood- versus adult-onset participants (HR, 1.69 [95% CI, 1.29-2.21]). The probability of remission was also higher in childhood-onset disease (HR, 1.33 [95%CI, 1.02-1.72]). In all groups eGFR loss was minimal. Children were more likely to remit after rituximab than those with adolescent- or adult-onset disease (adjusted HR, 2.1; P=0.003). Across all groups, glucocorticoid sensitivity was associated with a greater likelihood of achieving complete remission after rituximab (adjusted HR, 2.62; P=0.002). LIMITATIONS: CureGN was limited to biopsy-proven disease. Comparisons of childhood to nonchildhood cases of MCD may be subject to selection bias, given that childhood cases who undergo a biopsy may be limited to patients who are least responsive to initial therapy. CONCLUSIONS: Among patients with MCD who underwent kidney biopsy, there were differences in the course (relapse and remission) of childhood-onset compared with adolescent- and adult-onset disease, as well as rituximab response. PLAIN-LANGUAGE SUMMARY: Minimal change disease is a biopsy diagnosis for nephrotic syndrome. It is diagnosed in childhood, adolescence, or adulthood. Patients and clinicians often have questions about what to expect in the disease course and how to plan therapies. We analyzed a group of patients followed longitudinally as part of the Cure Glomerulonephropathy Network (CureGN) and describe the differences in disease (relapse and remission) based on the age of onset. We also analyzed rituximab response. We found that those with childhood-onset disease had a higher rate of relapse but also have a higher probability of reaching remission when compared with adolescent- or adult-onset disease. Children and all steroid-responsive patients are more likely to achieve remission after rituximab.