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.

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.

Long-term Health Care Utilization and Associated Costs After Dialysis-Treated Acute Kidney Injury in Children.

RATIONALE & OBJECTIVE: Acute kidney injury (AKI) is common among hospitalized children and is associated with increased hospital length of stay and costs. However, there are limited data on postdischarge health care utilization after AKI hospitalization. Our objectives were to evaluate health care utilization and physician follow-up patterns after dialysis-treated AKI in a pediatric population. STUDY DESIGN: Retrospective cohort study, using provincial health administrative databases. SETTING & PARTICIPANTS: All children (0-18 years) hospitalized between 1996 and 2017 in Ontario, Canada. Excluded individuals comprised non-Ontario residents; those with metabolic disorders or poisoning; and those who received dialysis or kidney transplant before admission, a kidney transplant by 104 days after discharge, or were receiving dialysis 76-104 days from dialysis start date. EXPOSURE: Episodes of dialysis-treated AKI, identified using validated health administrative codes. AKI survivors were matched to 4 hospitalized controls without dialysis-treated AKI by age, sex, and admission year. OUTCOME: Our primary outcome was postdischarge hospitalizations, emergency department visits, and outpatient physician visits. Secondary outcomes included outpatient visits by physician type and composite health care costs. ANALYTICAL APPROACH: Proportions with≥1 event and rates (per 1,000 person-years). Total and median composite health care costs. Adjusted rate ratios using negative binomial regression models. RESULTS: We included 1,688 pediatric dialysis-treated AKI survivors and 6,752 matched controls. Dialysis-treated AKI survivors had higher rehospitalization and emergency department visit rates during the analyzed follow-up periods (0-1, 0-5, and 0-10 years postdischarge, and throughout follow-up), and higher outpatient visit rates in the 0-1-year follow-up period. The overall adjusted rate ratio for rehospitalization was 1.46 (95% CI, 1.25-1.69; P<0.0001) and for outpatient visits was 1.16 (95% CI, 1.09-1.23; P=0.01). Dialysis-treated AKI survivors also had higher health care costs. Nephrologist follow-up was infrequent among dialysis-treated AKI survivors (18.6% by 1 year postdischarge). LIMITATIONS: Potential miscoding of study exposures or outcomes. Residual uncontrolled confounding. Data for health care costs and emergency department visits was unavailable before 2006 and 2001, respectively. CONCLUSIONS: Dialysis-treated AKI survivors had greater postdischarge health care utilization and costs versus hospitalized controls. Strategies are needed to improve follow-up care for children after dialysis-treated AKI to prevent long-term complications.

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.

Racial and Ethnic Disparities in Acute Care Utilization Among Patients With Glomerular Disease.

RATIONALE & OBJECTIVE: The effects of race, ethnicity, socioeconomic status (SES), and disease severity on acute care utilization in patients with glomerular disease are unknown. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 1,456 adults and 768 children with biopsy-proven glomerular disease enrolled in the Cure Glomerulonephropathy (CureGN) cohort. EXPOSURE: Race and ethnicity as a participant-reported social factor. OUTCOME: Acute care utilization defined as hospitalizations or emergency department visits. ANALYTICAL APPROACH: Multivariable recurrent event proportional rate models were used to estimate associations between race and ethnicity and acute care utilization. RESULTS: Black or Hispanic participants had lower SES and more severe glomerular disease than White or Asian participants. Acute care utilization rates were 45.6, 29.5, 25.8, and 19.2 per 100 person-years in Black, Hispanic, White, and Asian adults, respectively, and 55.8, 42.5, 40.8, and 13.0, respectively, for children. Compared with the White race (reference group), Black race was significantly associated with acute care utilization in adults (rate ratio [RR], 1.76 [95% CI, 1.37-2.27]), although this finding was attenuated after multivariable adjustment (RR, 1.31 [95% CI, 1.03-1.68]). Black race was not significantly associated with acute care utilization in children; Asian race was significantly associated with lower acute care utilization in children (RR, 0.32 [95% CI 0.14-0.70]); no significant associations between Hispanic ethnicity and acute care utilization were identified. LIMITATIONS: We used proxies for SES and lacked direct information on income, household unemployment, or disability. CONCLUSIONS: Significant differences in acute care utilization rates were observed across racial and ethnic groups in persons with prevalent glomerular disease, although many of these difference were explained by differences in SES and disease severity. Measures to combat socioeconomic disadvantage in Black patients and to more effectively prevent and treat glomerular disease are needed to reduce disparities in acute care utilization, improve patient wellbeing, and reduce health care costs.

Therapeutic trials in difficult to treat steroid sensitive nephrotic syndrome: challenges and future directions.

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.

Family functioning and quality of life among children with nephrotic syndrome during the first pandemic wave.

BACKGROUND: During the SARS-CoV-2 global pandemic, one of the longest lockdowns worldwide occurred in Ontario, Canada, during the first wave. For parents and children managing care at home and at risk for COVID-19, the impact on their psychosocial functioning is unknown. METHODS: A total of 122 families of children aged 2-18 years were enrolled as part of the prospective cohort of childhood nephrotic syndrome and completed a survey during the first wave of the pandemic (August 21-December 10), 2020. In a subset, 107 families had data available pre-pandemic to assess change. Validated measures included the McMaster Family Assessment Device (FAD) for parents and children ≥ 12 years for family functioning, the Patient Health Questionnaire for Depression and Anxiety (PHQ-4) for both parent and child, and Pediatric Quality of Life Inventory (PEDSQL™-V4) for children only. Scores were compared using Student's t-test or the Mann-Whitney U test, as appropriate. RESULTS: Among the 107 children, 71% were male with a mean age of 9 years old at the time of questionnaire completion, and the mean age of parents was 41 years old. Parents and children reported that family functioning improved during COVID (parent: p < 0.01; child: p = 0.05). Children's overall HRQOL declined (p = 0.04), specifically increased sleep disruption (p = 0.01). Increasing child age was associated with a greater sleep disruption (ß = - 1.6 [IQR: - 2.6, - 0.67]) and a related decrease in QOL (ß = - 1.0 [IQR: - 1.7, - 0.2]), adjusted for sex. CONCLUSIONS: Despite the positive effects of family dynamics during the first wave, there were negative effects of sleep disruptions and reduced quality of life in children, especially among older children. A higher resolution version of the Graphical abstract is available as Supplementary information.

Incidence of cardiovascular disease and mortality in childhood solid organ transplant recipients: a population-based study.

BACKGROUND: With improved survival among children after transplantation, our understanding of the risk for developing other comorbidities is improving, yet little is known about the long-term risk of cardiovascular events and mortality after solid organ transplantation. METHODS: In a cohort study using health administrative data, we compared cardiovascular events in children (n = 615) with liver, lung, kidney, small bowel, or multi-organ transplant at the Hospital for Sick Children, Toronto, Canada, with asthmatic children (n = 481,697) between 1996 and 2014. Outcomes included non-fatal cardiovascular events, cardiovascular death, all-cause mortality, and a composite of non-fatal and fatal cardiovascular events. Time-stratified Cox proportional hazards models were used. RESULTS: Among 615 children, 317 (52%) were recipients of kidneys, 253 (41%) of livers, and the remaining 45 (7%) had lung, small bowel, or multi-organ transplants. Median follow-up was 12.1 [7.2, 16.7] years. Non-fatal incident cardiovascular events were 34 times higher among solid organ transplant recipients than non-transplanted children (incidence rate ratio (IRR) 34.4, 95% CI: 25.5, 46.4). Among transplant recipients, the cumulative incidence of non-fatal and fatal cardiovascular events was 2.3% and 13.0%, 5 and 15 years after transplantation, respectively. CONCLUSIONS: Increased rate of cardiovascular events in children after transplantation highlights the need for surveillance during transition into adulthood and beyond. A higher resolution version of the Graphical abstract is available as Supplementary information.

Shared genetic risk across different presentations of gene test-negative idiopathic nephrotic syndrome.

BACKGROUND: Idiop athic nephrotic syndrome (INS) is classified in children according to response to initial corticosteroid therapy into steroid-sensitive (SSNS) and steroid-resistant nephrotic syndrome (SRNS), and in adults according to histology into minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). However, there is well-recognised phenotypic overlap between these entities. Genome-wide association studies (GWAS) have shown a strong association between SSNS and variation at HLA, suggesting an underlying immunological basis. We sought to determine whether a risk score generated from genetic variants associated with SSNS could be used to gain insight into the pathophysiology of INS presenting in other ways. METHODS: We developed an SSNS genetic risk score (SSNS-GRS) from the five variants independently associated with childhood SSNS in a previous European GWAS. We quantified SSNS-GRS in independent cohorts of European individuals with childhood SSNS, non-monogenic SRNS, MCD, and FSGS, and contrasted them with SSNS-GRS quantified in individuals with monogenic SRNS, membranous nephropathy (a different immune-mediated disease-causing nephrotic syndrome), and healthy controls. RESULTS: The SSNS-GRS was significantly elevated in cohorts with SSNS, non-monogenic SRNS, MCD, and FSGS compared to healthy participants and those with membranous nephropathy. The SSNS-GRS in all cohorts with non-monogenic INS were also significantly elevated compared to those with monogenic SRNS. CONCLUSIONS: The shared genetic risk factors among patients with different presentations of INS strongly suggests a shared autoimmune pathogenesis when monogenic causes are excluded. Use of the SSNS-GRS, in addition to testing for monogenic causes, may help to classify patients presenting with INS. A higher resolution version of the Graphical abstract is available as Supplementary information.

Long-Term Efficacy and Safety of Repeated Rituximab to Maintain Remission in Idiopathic Childhood Nephrotic Syndrome: An International Study.

BACKGROUND: Long-term outcomes after multiple courses of rituximab among children with frequently relapsing, steroid-dependent nephrotic syndrome (FRSDNS) are unknown. METHODS: A retrospective cohort study at 16 pediatric nephrology centers from ten countries in Asia, Europe, and North America included children with FRSDNS who received two or more courses of rituximab. Primary outcomes were relapse-free survival and adverse events. RESULTS: A total of 346 children (age, 9.8 years; IQR, 6.6-13.5 years; 73% boys) received 1149 courses of rituximab. A total of 145, 83, 50, 28, 22, and 18 children received two, three, four, five, six, and seven or more courses, respectively. Median (IQR) follow-up was 5.9 (4.3-7.7) years. Relapse-free survival differed by treatment courses (clustered log-rank test P<0.001). Compared with the first course (10.0 months; 95% CI, 9.0 to 10.7 months), relapse-free period and relapse risk progressively improved after subsequent courses (12.0-16.0 months; HRadj, 0.03-0.13; 95% CI, 0.01 to 0.18; P<0.001). The duration of B-cell depletion remained similar with repeated treatments (6.1 months; 95% CI, 6.0 to 6.3 months). Adverse events were mostly mild; the most common adverse events were hypogammaglobulinemia (50.9%), infection (4.5%), and neutropenia (3.7%). Side effects did not increase with more treatment courses nor a higher cumulative dose. Only 78 of the 353 episodes of hypogammaglobulinemia were clinically significant. Younger age at presentation (2.8 versus 3.3 years; P=0.05), age at first rituximab treatment (8.0 versus 10.0 years; P=0.01), and history of steroid resistance (28% versus 18%; P=0.01) were associated with significant hypogammaglobulinemia. All 53 infective episodes resolved, except for one patient with hepatitis B infection and another with EBV infection. There were 42 episodes of neutropenia, associated with history of steroid resistance (30% versus 20%; P=0.04). Upon last follow-up, 332 children (96%) had normal kidney function. CONCLUSIONS: Children receiving repeated courses of rituximab for FRSDNS experience an improving clinical response. Side effects appear acceptable, but significant complications can occur. These findings support repeated rituximab use in FRSDNS.

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.

Outcomes of skin cancers in pediatric solid organ transplant patients: A systematic review.

BACKGROUND: The most frequently reported malignancies after solid organ transplant are cutaneous, but data on the risk in pediatric populations varies across studies. OBJECTIVES: To perform a systematic review including reported features and outcomes of skin cancers in pediatric solid organ transplant recipients. METHODS: EMBASE and MEDLINE were systematically searched (Prospero CRD42020201659). RESULTS: The review summarizes data from 20 studies on 337 patients, with a median age ranging from 15.0 to 19.5 years as reported in 4 studies, who developed skin malignancies after pediatric solid organ transplantation. Median ages at transplant and skin cancer diagnosis ranged from 1.5 to 17.0 years and 15.3 to 33.5 years, respectively. Squamous cell carcinoma (SCC) was most commonly reported (218 cases), followed by basal cell carcinoma (BCC) (91 cases), melanoma (18 cases), and unspecified keratinocyte carcinomas (2 cases). The median latency period between transplantation and cancer diagnosis ranged from 2.2 to 21.0 years. Overall, 4 studies reported 17 cases of metastasis in total, and recurrence was reported in one case. Six deaths were reported in one study related to SCC and melanoma metastases. The incidence rate of skin cancer after pediatric transplantation per 100 person-years of follow-up was 2.1 based on 5 studies. CONCLUSION: The most frequent post-transplant malignancy in pediatric organ transplant recipients was SCC.

Association of abnormal electrocardiograph metrics with prolonged recovery time in incident hemodialysis patients.

BACKGROUND: Patients receiving intermittent hemodialysis have variable times of recovery to feeling better after dialysis. QT prolongation, a precursor to clinical and subclinical cardiovascular events, may contribute to delayed recovery time. We hypothesized that abnormal electrocardiographic parameters indicating perturbations in ventricular action are associated with longer recovery times thus impacting a patient-centered quality of life. METHODS: Among 242 incident in-center hemodialysis participants from the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease (PACE) study, corrected QT interval (QTc), QRST angle and heart rate variance were measured on non-dialysis days using a standard 5-min electrocardiograph recording. Left ventricular hypertrophy (LVH) was defined using the Cornell voltage product. Recovery time was ascertained during a phone interview with a standardized validated questionnaire. Associations between QTc, QRST angle, heart rate variance, and LVH and natural log-transformed recovery time were examined using linear regression adjusted for participant characteristics and electrolytes. RESULTS: Mean age was 55 (standard deviation 13) years, 55% were male, 72% were African American. Longer QTc interval was associated with increased recovery time (per 10 ms increase in QTc, recovery time increased by 6.2%; 95% confidence interval: 0.0-10.5). QRST angle, heart rate, heart rate variability and LVH were not significantly associated with recovery time. CONCLUSION: Longer QTc intervals are associated with longer recovery time independent of serum electrolytes. This supports a relationship between a patient's underlying arrhythmic status and time to recovery after hemodialysis. Future studies will determine if maneuvers to reduce QTc improves recovery time and quality of life of patients on hemodialysis.

Long-Term Kidney Outcomes Following Dialysis-Treated Childhood Acute Kidney Injury: A Population-Based Cohort Study.

BACKGROUND: AKI is common during pediatric hospitalizations and associated with adverse short-term outcomes. However, long-term outcomes among survivors of pediatric AKI who received dialysis remain uncertain. METHODS: To determine the long-term risk of kidney failure (defined as receipt of chronic dialysis or kidney transplant) or death over a 22-year period for pediatric survivors of dialysis-treated AKI, we used province-wide health administrative databases to perform a retrospective cohort study of all neonates and children (aged 0-18 years) hospitalized in Ontario, Canada, from April 1, 1996, to March 31, 2017, who survived a dialysis-treated AKI episode. Each AKI survivor was matched to four hospitalized pediatric comparators without dialysis-treated AKI, on the basis of age, sex, and admission year. We reported the incidence of each outcome and performed Cox proportional hazards regression analyses, adjusting for relevant covariates. RESULTS: We identified 1688 pediatric dialysis-treated AKI survivors (median age 5 years) and 6752 matched comparators. Among AKI survivors, 53.7% underwent mechanical ventilation and 33.6% had cardiac surgery. During a median 9.6-year follow-up, AKI survivors were at significantly increased risk of a composite outcome of kidney failure or death versus comparators. Death occurred in 113 (6.7%) AKI survivors, 44 (2.6%) developed kidney failure, 174 (12.1%) developed hypertension, 213 (13.1%) developed CKD, and 237 (14.0%) had subsequent AKI. AKI survivors had significantly higher risks of developing CKD and hypertension versus comparators. Risks were greatest in the first year after discharge and gradually decreased over time. CONCLUSIONS: Survivors of pediatric dialysis-treated AKI are at higher long-term risks of kidney failure, death, CKD, and hypertension, compared with a matched hospitalized cohort.

Return to school and mask-wearing in class during the COVID-19 pandemic: Student perspectives from a school simulation study.

Objectives: This study examined children's perspectives about returning to in-person school following lockdown due to the pandemic and about mask-wearing in class, as well as the mental health of children and parents during the pandemic. Methods: This cross-sectional study was part of a 2-day school simulation exercise that randomized students to different masking recommendations. Parent-report of mental health and post-simulation child-report of COVID-19-related anxiety and mask-wearing were analyzed using descriptive and multiple regression analyses. Semi-structured focus groups were conducted with older students to supplement questionnaire data. Results: Of 190 students in this study, 31% were in grade 4 or lower 95% looked forward to returning to in-person school. Greater child anxiety about COVID-19 was predicted by increased parent/caregiver anxiety (ß=0.67; P<0.001), and lower parental educational attainment (ß=1.86; P<0.002). Older students were more likely than younger students to report that mask-wearing interfered with their abilities to interact with peers (χ2(1)=31.16; P<0.001) and understand the teacher (χ2(1)=13.97; P<0.001). Students in the group that did not require masks were more likely than students in the masking group to report worries about contracting COVID-19 at school (χ2(1)=10.07; P<0.05), and anticipated difficulty wearing a mask (χ2(1)=18.95; P<0.001). Conclusions: For children anxious about COVID-19, parental anxiety and education about COVID-19 may be targets for intervention. Future research should examine the impact of prolonged implementation of public health mitigation strategies in school on academic achievement and children's mental health.

Associations of Serum Calciprotein Particle Size and Transformation Time With Arterial Calcification, Arterial Stiffness, and Mortality in Incident Hemodialysis Patients.

RATIONALE & OBJECTIVE: Characteristics of the transformation of primary to secondary calciprotein particles (CPPs) in serum, including the size of secondary CPP (CPP2) aggregates and the time of transformation (T50), may be markers for arterial calcification in patients undergoing hemodialysis (HD). We examined the associations of CPP2 aggregate size and T50 with arterial calcification in incident HD patients. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Incident HD patients (n=402with available CPP2 measures and n=388with available T50 measures) from the Predictors of Arrhythmic and Cardiovascular Risk in End-Stage Renal Disease (PACE) Study PREDICTORS: Serum CPP2 size and T50 at baseline. OUTCOMES: Primary outcomes were baseline coronary artery and thoracic aorta calcifications. Exploratory outcomes included baseline arterial stiffness, measured by pulse wave velocity (PWV) and ankle brachial index, and longitudinally, repeat measures of PWV and all-cause mortality. ANALYTICAL APPROACH: Tobit regression, multiple linear regression, Poisson regression, linear mixed-effects regression, and Cox proportional hazards regression. RESULTS: Mean age was 55±13 years, 41% were women, 71% were Black, and 57% had diabetes mellitus. Baseline CPP2 size and T50 were correlated with baseline fetuin A level (r=-0.59 for CPP2 and 0.44 for T50; P<0.001 for both), but neither was associated with baseline measures of arterial calcification or arterial stiffness. Baseline CPP2 size and T50 were not associated with repeat measures of PWV. During a median follow-up of 3.5 (IQR, 1.7-6.2) years, larger CPP2 was associated with higher risk for mortality (HR, 1.17 [95% CI, 1.05-1.31] per 100nm larger CPP2 size) after adjusting for demographics and comorbid conditions, but there was no association between baseline T50 and risk for mortality. LIMITATIONS: Possible imprecision in assays, small sample size, limited generalizability to incident HD populations with different racial composition, and residual confounding. CONCLUSIONS: In incident HD patients, neither CPP2 size nor T50 was associated with prevalent arterial calcification and stiffness. Larger CPP2 was associated with risk for mortality, but this finding needs to be confirmed in future studies.

Impact of steroids and steroid-sparing agents on quality of life in children with nephrotic syndrome.

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.

Prevalence and Risk Factors for CKD in the General Population of Southwestern Nicaragua.

BACKGROUND: Studies have described Mesoamerican nephropathy among agricultural workers of El Salvador and northwestern Nicaragua. Data on prevalence and risk factors for CKD beyond agricultural workers and in other regions in Nicaragua are sparse. METHODS: We recruited participants from 32 randomly selected communities in the Department of Rivas's ten municipalities in two phases. In phase 1, we screened participants using a field-based capillary creatinine measuring system and collected self-reported information on lifestyle and occupational, exposure, and health histories. Two years later, in phase 2, we enrolled 222 new participants, performing serum creatinine testing in these participants and confirmatory serum creatinine testing in phase 1 participants. RESULTS: We enrolled 1242 of 1397 adults (89%) living in 533 households (median age 41 years; 43% male). We confirmed CKD (eGFR<60 ml/min per 1.73 m2) in 53 of 1227 (4.3%) evaluable participants. In multivariable testing, risk factors for prevalent CKD included age (odds ratio [OR], 1.92; 95% confidence interval [95% CI], 1.89 to 1.96) and self-reported history of hypertension (OR, 1.95; 95% CI, 1.04 to 3.64), diabetes (OR, 2.88; 95% CI, 1.40 to 5.93), or current or past work in the sugarcane industry (OR 2.92; 95% CI, 1.36 to 6.27). CONCLUSIONS: Adjusted CKD prevalence was about 5% with repeat confirmatory testing in southwest Nicaragua, lower than in the northwest region. Risk factors included diabetes, hypertension, and current or prior work in the sugarcane industry but not in other forms of agricultural work. Formal CKD surveillance programs in Nicaragua are needed to assess the overall burden of CKD nationally, with a focus on agricultural workers.

Frailty Prevalence in Younger End-Stage Kidney Disease Patients Undergoing Dialysis and Transplantation.

BACKGROUND: Frailty, originally characterized in community-dwelling older adults, is increasingly being studied and implemented for adult patients with end-stage kidney disease (ESKD) of all ages (>18 years). Frailty prevalence and manifestation are unclear in younger adults (18-64 years) with ESKD; differences likely exist based on whether the patients are treated with hemodialysis (HD) or kidney transplantation (KT). METHODS: We leveraged 3 cohorts: 378 adults initiating HD (2008-2012), 4,304 adult KT candidates (2009-2019), and 1,396 KT recipients (2008-2019). The frailty phenotype was measured within 6 months of dialysis initiation, at KT evaluation, and KT admission. Prevalence of frailty and its components was estimated by age (≥65 vs. <65 years). A Wald test for interactions was used to test whether risk factors for frailty differed by age. RESULTS: In all 3 cohorts, frailty prevalence was higher among older than younger adults (HD: 71.4 vs. 47.3%; candidates: 25.4 vs. 18.8%; recipients: 20.8 vs. 14.3%). In all cohorts, older patients were more likely to have slowness and weakness but less likely to report exhaustion. Among candidates, older age (odds ratio [OR] = 1.79, 95% CI: 1.47-2.17), non-Hispanic black race (OR = 1.30, 95% CI: 1.08-1.57), and dialysis type (HD vs. no dialysis: OR = 2.06, 95% CI: 1.61-2.64; peritoneal dialysis vs. no dialysis: OR = 1.78, 95% CI: 1.28-2.48) were associated with frailty prevalence, but sex and Hispanic ethnicity were not. These associations did not differ by age (pinteractions > 0.1). Similar results were observed for recipients and HD patients. CONCLUSIONS: Although frailty prevalence increases with age, younger patients have a high burden. Clinicians caring for this vulnerable population should recognize that younger patients may experience frailty and screen all age groups.

Genome-wide association study identifies novel loci for type 2 diabetes-attributed end-stage kidney disease in African Americans.

BACKGROUND: End-stage kidney disease (ESKD) is a significant public health concern disproportionately affecting African Americans (AAs). Type 2 diabetes (T2D) is the leading cause of ESKD in the USA, and efforts to uncover genetic susceptibility to diabetic kidney disease (DKD) have had limited success. A prior genome-wide association study (GWAS) in AAs with T2D-ESKD was expanded with additional AA cases and controls and genotypes imputed to the higher density 1000 Genomes reference panel. The discovery analysis included 3432 T2D-ESKD cases and 6977 non-diabetic non-nephropathy controls (N = 10,409), followed by a discrimination analysis in 2756 T2D non-nephropathy controls to exclude T2D-associated variants. RESULTS: Six independent variants located in or near RND3/RBM43, SLITRK3, ENPP7, GNG7, and APOL1 achieved genome-wide significant association (P < 5 × 10-8) with T2D-ESKD. Following extension analyses in 1910 non-diabetic ESKD cases and 908 non-diabetic non-nephropathy controls, a meta-analysis of 5342 AA all-cause ESKD cases and 6977 AA non-diabetic non-nephropathy controls revealed an additional novel all-cause ESKD locus at EFNB2 (rs77113398; P = 9.84 × 10-9; OR = 1.94). Exclusion of APOL1 renal-risk genotype carriers identified two additional genome-wide significant T2D-ESKD-associated loci at GRAMD3 and MGAT4C. A second variant at GNG7 (rs373971520; P = 2.17 × 10-8, OR = 1.46) remained associated with all-cause ESKD in the APOL1-negative analysis. CONCLUSIONS: Findings provide further evidence for genetic factors associated with advanced kidney disease in AAs with T2D.