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Pediatric patients with nephrotic syndrome take medications long-term with significant toxicity and complex regimens, yet data on medication adherence are limited.In a multicenter observational study of patients with nephrotic syndrome, NEPTUNE (NCT01209000), we surveyed caregivers of patients19 years old and adolescent patients on medication adherence during longitudinal follow-up beginning in June 2015. Data extraction was in October 2020. We described the proportion of nonadherent patients at first survey. Participant social and economic factors, condition-related factors, therapy-related factors, and patient-related factors were examined for relationships with nonadherence by generalized linear mixed models using the longitudinal data. In exploratory fashion, we assessed the relationship between adherence and subsequent steroid response classification by binary logistic regression and adherence with healthcare utilization by Poisson regression.A total of 225 participants completed a median of 3 surveys during follow-up (IQR, 2-5), with a total of 743 surveys. Overall, 80 (36%) reported nonadherence with medications. In adjusted analysis, older age (per 1 year; OR 1.08; 95% CI, 1.03 1.12), lower maternal educational level (≥ high school vs.high school; OR 0.47; 95% CI 0.25 to 0.89), and increased parent and self-identification of medications barriers (per 1 point; OR 1.57; 95% CI, 1.15-2.15) were significantly associated with nonadherence. No relationship between nonadherence and subsequent frequency of healthcare utilization was observed. A trend toward increased subsequent steroid resistance classification was seen with nonadherence, though not statistically significant.Medication nonadherence is common in pediatric nephrotic syndrome. Investigations into the use of surveys in the clinic setting to identify at-risk patients and ways to support families over time are needed. A higher resolution version of the Graphical abstract is available as Supplementary information.

Kidney international 100(4), 753-779 (2021). doi:10.1016/j.kint.2021.05.015, Published by Elsevier, New York, NY

Introduction: Disparities in health-related quality of life (HRQOL) have been inadequately studied in patients with glomerular disease. The aim of this study was to identify relationships among race/ethnicity, socioeconomic status, disease severity, and HRQOL in an ethnically and racially diverse cohort of patients with glomerular disease. Methods: Cure Glomerulonephropathy (CureGN) is a multinational cohort study of patients with biopsy-proven glomerular disease. Associations between race/ethnicity and HRQOL were determined by the following: (1) missed school or work due to kidney disease and (2) responses to Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaires. We adjusted for demographics, socioeconomic status, and disease characteristics using multivariable logistic and linear regression. Results: Black and Hispanic participants had worse socioeconomic status and more severe glomerular disease than white or Asian participants. Black adults missed work or school most frequently due to kidney disease (30 vs. 16–23% in the other 3 groups, p = 0.04), and had the worst self-reported global physical health (median score 44.1 vs. 48.0–48.2, p < 0.001) and fatigue (53.8 vs. 48.5–51.1, p = 0.002), compared to other racial/ethnic groups. However, these findings were not statistically significant with adjustment for socioeconomic status and disease severity, both of which were strongly associated with HRQOL in adults. Among children, disease severity but not race/ethnicity or socioeconomic status was associated with HRQOL. Conclusions: Among patients with glomerular disease enrolled in CureGN, the worse HRQOL reported by black adults was attributable to lower socioeconomic status and more severe glomerular disease. No racial/ethnic differences in HRQOL were observed in children.

Introduction Lupus nephritis (LN) is an independent risk factor for venous thromboembolism (VTE). The risk of VTE has not been analyzed by International Society of Nephrology/Renal Pathology Society or World Health Organization LN class. Study goals were to measure VTE incidence in an LN patient cohort, to evaluate associations between VTE and LN class, and to investigate factors modifying associations between VTE and LN class. Methods A retrospective analysis was performed using Glomerular Disease Collaborative Network data. Image-confirmed VTE was compared between patients with any LN class V lesion and patients with only LN class III or IV. Logistic regression was used to calculate odds ratios and 95% confidence intervals. Effect modification was assessed between main effect and covariates. Results Our cohort consisted of 534 LN patients, 310 (58%) with class III/IV and 224 (42%) with class V with or without class III/IV, including 106 with class V alone. The VTE incidence was 62 of 534 (11.6%). The odds of VTE were not significantly different between patients with class III/IV and class V in adjusted analyses (odds ratio [OR] = 0.82, 95% confidence interval [CI] = 0.45−1.48). An age interaction was observed (P = 0.009), with increased odds of VTE with class III/IV diagnosed at a younger age (2.75, 0.90−8.41 estimated at age 16 years) and decreased odds with class III/IV diagnosed at an older age (0.23, 0.07−0.72 estimated at age 46 years), compared to class V. Conclusions The VTE incidence was similar among patients with LN classes III/IV and V, suggesting that VTE risk is not limited to class V−related nephrotic syndrome and that age may modulate LN class-specific VTE risk., Graphical abstract

Background Voclosporin, a novel calcineurin inhibitor approved for the treatment of adults with lupus nephritis, improved complete renal response rates in patients with lupus nephritis in a phase 2 trial. This study aimed to evaluate the efficacy and safety of voclosporin for the treatment of lupus nephritis.Methods This multicentre, double-blind, randomised phase 3 trial was done in 142 hospitals and clinics across 27 countries. Patients with a diagnosis of systemic lupus erythematosus with lupus nephritis according to the American College of Rheumatology criteria, and a kidney biopsy within 2 years that showed class III, IV, or V (alone or in combination with class III or IV) were eligible. Patients were randomly assigned (1: 1) to oral voclosporin (23.7 mg twice daily) or placebo, on a background of mycophenolate mofetil (1 g twice daily) and rapidly tapered low-dose oral steroids, by use of an interactive web response system. The primary endpoint was complete renal response at 52 weeks defined as a composite of urine protein creatinine ratio of 0.5 mg/mg or less, stable renal function (defined as estimated glomerular filtration rate [eGFR] >= 60 mL/min/1.73 m(2) or no confirmed decrease from baseline in eGFR of >20%), no administration of rescue medication, and no more than 10 mg prednisone equivalent per day for 3 or more consecutive days or for 7 or more days during weeks 44 through 52, just before the primary endpoint assessment. Safety was also assessed. Efficacy analysis was by intention-to-treat and safety analysis by randomised patients receiving at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, NCT03021499.Findings Between April 13, 2017, and Oct 10, 2019, 179 patients were assigned to the voclosporin group and 178 to the placebo group. The primary endpoint of complete renal response at week 52 was achieved in significantly more patients in the voclosporin group than in the placebo group (73 [41%] of 179 patients vs 40 [23%] of 178 patients; odds ratio 2.65; 95% CI 1.64-4.27; p

Background: The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1’s natural absence in laboratory animals makes studying its pathobiology challenging. Methods: In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light- or electron-microscopy traits measuring structural and cellular kidney changes. Results: Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR

In November 2017, the Kidney Disease: Improving Global Outcomes (KDIGO) initiative brought a diverse panel of experts in glomerular diseases together to discuss the 2012 KDIGO glomerulonephritis guideline in the context of new developments and insights that had occurred over the years since its publication. During this KDIGO Controversies Conference on Glomerular Diseases, the group examined data on disease pathogenesis, biomarkers, and treatments to identify areas of consensus and areas of controversy. This report summarizes the discussions on primary podocytopathies, lupus nephritis, anti-neutrophil cytoplasmic antibody-associated nephritis, complement mediated kidney diseases, and monoclonal gammopathies of renal significance.

Introduction Glucocorticoids (GCs) are the primary treatment for nephrotic syndrome (NS), although ∼10% to 20% of children develop steroid-resistant NS (SRNS). Unfortunately, there are no validated biomarkers able to predict SRNS at initial disease presentation. We hypothesized that a plasma cytokine panel could predict SRNS at disease presentation, and identify potential pathways regulating SRNS pathogenesis. Methods Paired plasma samples were collected from 26 children with steroid-sensitive NS (SSNS) and 14 with SRNS at NS presentation and after ∼7 weeks of GC therapy, when SSNS versus SRNS was clinically determined. Plasma cytokine profiling was performed with a panel of 27 cytokines. Results We identified 13 cytokines significantly different in Pretreatment SSNS versus SRNS samples. Statistical modeling identified a cytokine panel (interleukin [IL]-7, IL-9, monocyte chemoattractant protein–1 [MCP-1]) able to discriminate between SSNS and SRNS at disease presentation (receiver operating characteristic [ROC] value = 0.846; sensitivity = 0.643; specificity = 0.846). Furthermore, GC treatment resulted in significant decreases in plasma interferon-γ (IFN-γ), tumor necrosis factor–α (TNF-α), IL-7, IL-13, and IL-5 in both SSNS and SRNS patients. Conclusions These studies suggest that initial GC treatment of NS reduces the plasma cytokines secreted by both CD4+ TH1 cells and TH2 cells, as well as CD8+ T cells. Importantly, a panel of 3 cytokines (IL-7, IL-9, and MCP-1) was able to predict SRNS prior to GC treatment at disease presentation. Although these findings will benefit from validation in a larger cohort, the ability to identify SRNS at disease presentation could greatly benefit patients by enabling both avoidance of unnecessary GC-induced toxicity and earlier transition to more effective alternative treatments., Graphical abstract

The application of deep learning for automated segmentation (delineation of boundaries) of histologic primitives (structures) from whole slide images can facilitate the establishment of novel protocols for kidney biopsy assessment. Here, we developed and validated deep learning networks for the segmentation of histologic structures on kidney biopsies and nephrectomies. For development, we examined 125 biopsies for Minimal Change Disease collected across 29 NEPTUNE enrolling centers along with 459 whole slide images stained with Hematoxylin & Eosin (125), Periodic Acid Schiff (125), Silver (102), and Trichrome (107) divided into training, validation and testing sets (ratio 6:1:3). Histologic structures were manually segmented (30048 total annotations) by five nephropathologists. Twenty deep learning models were trained with optimal digital magnification across the structures and stains. Periodic Acid Schiff-stained whole slide images yielded the best concordance between pathologists and deep learning segmentation across all structures (F-scores: 0.93 for glomerular tufts, 0.94 for glomerular tuft plus Bowman's capsule, 0.91 for proximal tubules, 0.93 for distal tubular segments, 0.81 for peritubular capillaries, and 0.85 for arteries and afferent arterioles). Optimal digital magnifications were 5X for glomerular tuft/tuft plus Bowman's capsule, 10X for proximal/distal tubule, arteries and afferent arterioles, and 40X for peritubular capillaries. Silver stained whole slide images yielded the worst deep learning performance. Thus, this largest study to date adapted deep learning for the segmentation of kidney histologic structures across multiple stains and pathology laboratories. All data used for training and testing and a detailed online tutorial will be publicly available.

Rationale & Objective Surrogate outcomes for end-stage kidney disease often assume linear changes, which may not reflect true estimated glomerular filtration rate (eGFR) trajectories. This study’s objective was to characterize nonlinear eGFR trajectories in nephrotic syndrome. Study Design Observational cohort study. Setting & Participants Nephrotic Syndrome Study Network (NEPTUNE) is a multicenter study of adult and pediatric patients with proteinuria enrolled at clinically indicated kidney biopsy or initial presentation of disease (pediatric only). Predictors Patient demographic, clinical, and pathology variables at study enrollment and follow-up time. Outcome eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (patients ≥ 18 years old) or modified Chronic Kidney Disease in Children Study–Schwartz (patients < 18 years) formulas. The probability of nonlinearity (PNL) was calculated for individual eGFR trajectories. Analytical Approach Associations between predictors and PNL were assessed using multivariable linear regression. Results 453 patients with ≥3 eGFR measurements and 1 or more year of follow-up were included (median follow-up, 3.6 years). Median PNL was 0.052; 56% and 16% had PNL < 10% and >50%, respectively. In both adults and pediatric patients, higher baseline eGFR was associated with higher PNL, whereas longer follow-up time was associated with lower PNL. Higher urine protein-creatinine ratio and steroid use were also associated with higher PNL in adults. Higher percentages of tubular atrophy and foot-process effacement were associated with lower and higher PNLs, respectively, in adults. Limitations Relatively short follow-up time, inability to assess acute kidney injury events, and variable eGFR measurement frequency across patients. Conclusions Although increasing follow-up time resulted in more linear trajectories, nonlinear eGFR trajectories were common in this cohort. Future studies in nephrotic syndrome should consider novel outcomes that do not rely on linearity assumptions., Graphical abstract

Introduction Glomerular diseases are characterized by variable disease activity over many years. We aimed to analyze the relationship between clinical disease activity and duration of glomerular disease. Methods Disease activity in adults with chronic minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy (IgAN; first diagnostic biopsy >5 years before enrollment; Of Longstanding Disease [OLD] cohort, n = 256) followed at Columbia University Medical Center (CUMC), was compared with disease activity of an internal and external cohort of patients with first diagnostic biopsy, Graphical abstract

BackgroundAcute kidney injury (AKI) is highly associated with mortality risk in children worldwide. Trauma can lead to AKI and is a leading cause of pediatric death in Africa. However, there is no information regarding the epidemiology of pediatric, trauma-associated AKI in Africa.MethodsProspective cohort study of pediatric trauma patients admitted to a tertiary referral hospital in Malawi. Participants enrolled at admission were followed prospectively throughout their hospitalization. AKI was defined by creatinine-only Kidney Disease Improving Global Outcomes criteria. We calculated descriptive statistics and univariate relative risks (RR) for hypothesis-generation of potential risk factors associated with AKI.ResultsWe analyzed data from 114 participants. Depending on baseline creatinine definition, AKI incidence ranged from 4 to 10%. The new Schwartz equation estimated baseline creatinine values best and yielded an AKI incidence of 9.7%. Almost one in ten children died during hospitalization, but those with AKI (n = 4) were at significantly higher risk of death compared to those without AKI (40.0% vs 6.2%; RR 6.5, 95% CI 2.2–19.1). Burn injuries were most commonly associated with AKI (63.6%). Other potential AKI risk factors included multiple injuries, trunk or facial injuries, and recent consumption of herbal remedies.ConclusionsAKI occurs in up to 10% of admitted pediatric trauma patients in Malawi and increases the risk of death 7-fold compared to those without AKI. This large unrecognized burden in trauma requires further investment by researchers, clinicians and policymakers to develop evidenced-based triage, recognition, and management approaches to prevent the associated sequelae and potential mortality from AKI.

Alport syndrome is an inherited disease characterized by progressive loss of kidney function. We aimed to evaluate the safety and efficacy of bardoxolone methyl in patients with Alport syndrome.We randomly assigned patients with Alport syndrome, ages 12-70 years and eGFR 30-90 ml/min per 1.73 mPatients randomized to bardoxolone methyl experienced preservation in eGFR relative to placebo at 48 and 100 weeks (between-group differences: 9.2 [97.5% confidence interval, 5.1 to 13.4;In adolescent and adult patients with Alport syndrome receiving standard of care, treatment with bardoxolone methyl resulted in preservation in eGFR relative to placebo after a 2-year study period; off-treatment results using all available data were not significantly different.A Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Alport Syndrome - CARDINAL (CARDINAL), NCT03019185.

The diagnosis of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies, but not specific to underlying pathobiology. Consequently, there are variable rates of progression and response to therapy within diagnoses. Here, an unbiased transcriptomic-driven approach was used to identify molecular pathways which are shared by subgroups of patients with either minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). Kidney tissue transcriptomic profile-based clustering identified three patient subgroups with shared molecular signatures across independent, North American, European, and African cohorts. One subgroup had significantly greater disease progression (Hazard Ratio 5.2) which persisted after adjusting for diagnosis and clinical measures (Hazard Ratio 3.8). Inclusion in this subgroup was retained even when clustering was limited to those with less than 25% interstitial fibrosis. The molecular profile of this subgroup was largely consistent with tumor necrosis factor (TNF) pathway activation. Two TNF pathway urine markers were identified, tissue inhibitor of metalloproteinases-1 (TIMP-1) and monocyte chemoattractant protein-1 (MCP-1), that could be used to predict an individual's TNF pathway activation score. Kidney organoids and single nucleus RNA-sequencing of participant kidney biopsies, validated TNF-dependent increases in pathway activation score, transcript and protein levels of TIMP-1 and MCP-1, in resident kidney cells. Thus, molecular profiling identified a subgroup of patients with either MCD or FSGS who shared kidney TNF pathway activation and poor outcomes. A clinical trial testing targeted therapies in patients selected using urinary markers of TNF pathway activation is ongoing.

Contains fulltext : 283145.pdf (Publisher’s version ) (Open Access)

Introduction Childhood-onset nephrotic syndrome has a variable clinical course. Improved predictive markers of long-term outcomes in children with nephrotic syndrome are needed. This study tests the association between baseline urinary epidermal growth factor (uEGF) excretion and longitudinal kidney function in children with nephrotic syndrome. Methods The study evaluated 191 participants younger than 18 years enrolled in the Nephrotic Syndrome Study Network, including 118 with their first clinically indicated kidney biopsy (68 minimal change disease; 50 focal segmental glomerulosclerosis) and 73 with incident nephrotic syndrome without a biopsy. uEGF was measured at baseline for all participants and normalized by the urine creatinine (Cr) concentration. Renal epidermal growth factor (EGF) mRNA was measured in the tubular compartment microdissected from kidney biopsy cores from a subset of patients. Linear mixed models were used to test if baseline uEGF/Cr and EGF mRNA expression were associated with change in estimated glomerular filtration rate (eGFR) over time. Results Higher uEGF/Cr at baseline was associated with slower eGFR decline during follow-up (median follow-up = 30 months). Halving of uEGF/Cr was associated with a decrease in eGFR slope of 2.0 ml/min per 1.73 m2 per year (P < 0.001) adjusted for age, race, diagnosis, baseline eGFR and proteinuria, and APOL1 genotype. In the biopsied subgroup, uEGF/Cr was correlated with EGF mRNA expression (r = 0.74; P < 0.001), but uEGF/Cr was retained over mRNA expression as the stronger predictor of eGFR slope after multivariable adjustment (decrease in eGFR slope of 1.7 ml/min per 1.73 m2 per year per log2 decrease in uEGF/Cr; P < 0.001). Conclusion uEGF/Cr may be a useful noninvasive biomarker that can assist in predicting the long-term course of kidney function in children with incident nephrotic syndrome., Graphical abstract

Introduction The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for Glomerulonephritis recommend that patients with membranous nephropathy (MN) at risk for progression receive immunosuppressive therapy (IST), usually after 6 months of observation. A cyclophosphamide (CYC) or calcineurin inhibitor (CNI)–based regimen is recommended as first-line IST. However, the extent to which KDIGO recommendations are adopted in practice remains largely unknown. Methods We evaluated prescribing practice among patients with primary MN (diagnosed 2010–2018) enrolled in the Cure Glomerulonephropathy Network (CureGN) cohort study. We also evaluated the availability of testing for phospholipase A2 receptor (PLA2R) in the contemporary era. Results Among 361 patients (324 adults and 37 children) with MN who were IST-naïve at biopsy and had at least 6 months of follow-up, 55% of adults and 58% of children initiated IST, Graphical abstract

Kidney international 100(4, Supplement) S1-S276 (2021). doi:10.1016/j.kint.2021.05.021 special issue: "KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases", Published by Elsevier, New York, NY

Background Trauma is a common cause of acute kidney injury (AKI). Yet little data exist regarding trauma-related-AKI in low-resourced settings, where the majority of deaths from AKI and trauma occur. We prospectively evaluated epidemiology of AKI in hospitalized Malawian trauma patients. Methods AKI was defined by creatinine-only Kidney Disease Improving Global Outcomes (KDIGO) criteria. Those with AKI were followed up 3–6 months later to determine persistent kidney abnormalities. We calculated univariate statistics with Wilcoxon rank sum tests, Fisher’s exact, and chi-square tests to compare those with and without AKI. Multivariate log-risk regression modelling was used to determine risk ratios (RR) and 95% confidence intervals (CI) for AKI development. Results Of 223 participants, 14.4% (n = 32) developed AKI. Most patients were young (median age 32) males (n = 193, 86.5%) involved in road traffic injuries (n = 120, 53.8%). After adjusting for confounders, those with severe anemia during their admission were 1.4 times (RR 1.4, 95% CI 1.1–1.8) more likely to develop AKI than those without. Overall mortality was 7.6% (n = 17), and those who developed AKI were more likely to die than those who did not (18.8% vs 5.6%, p-value = 0.02). Almost half of those with AKI (n = 32) either died (n = 6) or had persistent kidney dysfunction at follow-up (n = 8). Conclusion In one of the few African studies on trauma-related AKI, we found a high incidence of AKI (14.4%) in Malawian trauma patients with associated poor outcomes. Given AKI’s association with increased mortality and potential ramifications on long-term morbidity, urgent attention is needed to improve AKI-related outcomes.

BackgroundClassification of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies. This approach does not reflect underlying disease biology, limiting the ability to predict progression or treatment response.MethodsSystems biology approaches were used to categorize patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) based on kidney biopsy tissue transcriptomics across three cohorts and assessed association with clinical outcomes. Patient-level tissue pathway activation scores were generated using differential gene expression. Then, functional enrichment and non-invasive urine biomarker candidates were identified. Biomarkers were validated in kidney organoid models and single nucleus RNA-seq (snRNAseq) from kidney biopsies.ResultsTranscriptome-based categorization identified three subgroups of patients with shared molecular signatures across independent North American, European and African cohorts. One subgroup demonstrated worse longterm outcomes (HR 5.2, p = 0.001) which persisted after adjusting for diagnosis and clinical measures (HR 3.8, p = 0.035) at time of biopsy. This subgroup’s molecular profile was largely (48%) driven by tissue necrosis factor (TNF) activation and could be predicted based on levels of TNF pathway urinary biomarkers TIMP-1 and MCP-1 and clinical features (correlation 0.63, p ConclusionsMolecular profiling identified a patient subgroup within nephrotic syndrome with poor outcome and kidney TNF pathway activation. Clinical trials using non-invasive biomarkers of pathway activation to target therapies are currently being evaluated.Significance StatementMechanistic, targeted therapies are urgently needed for patients with nephrotic syndrome. The inability to target an individual’s specific disease mechanism using currently used diagnostic parameters leads to potential treatment failure and toxicity risk. Patients with focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) were grouped by kidney tissue transcriptional profiles and a subgroup associated with poor outcomes defined. The segregation of the poor outcome group was driven by tumor necrosis factor (TNF) pathway activation and could be identified by urine biomarkers, MCP1 and TIMP1. Based on these findings, clinical trials utilizing non-invasive biomarkers of pathway activation to target therapies, improve response rates and facilitate personalized treatment in nephrotic syndrome have been initiated.

Introduction: Nephrotic syndrome (NS) is a characterized by massive proteinuria, edema, hypoalbuminemia, and dyslipidemia. Glucocorticoids (GCs), the primary therapy for >60 years, are ineffective in approximately 50% of adults and approximately 20% of children. Unfortunately, there are no validated biomarkers able to predict steroid-resistant NS (SRNS) or to define the pathways regulating SRNS. Methods: We performed proteomic analyses on paired pediatric NS patient plasma samples obtained both at disease presentation before glucocorticoid initiation and after approximately 7 weeks of GC therapy to identify candidate biomarkers able to either predict steroid resistance before treatment or define critical molecular pathways/targets regulating steroid resistance. Results: Proteomic analyses of 15 paired NS patient samples identified 215 prevalent proteins, including 13 candidate biomarkers that predicted SRNS before GC treatment, and 66 candidate biomarkers that mechanistically differentiated steroid-sensitive NS (SSNS) from SRNS. Ingenuity Pathway Analyses and protein networking pathways approaches further identified proteins and pathways associated with SRNS. Validation using 37 NS patient samples (24 SSNS/13 SRNS) confirmed vitamin D binding protein (VDB) and APOL1 as strong predictive candidate biomarkers for SRNS, and VDB, hemopexin (HPX), adiponectin (ADIPOQ), sex hormone–binding globulin (SHBG), and APOL1 as strong candidate biomarkers to mechanistically distinguish SRNS from SSNS. Logistic regression analysis identified a candidate biomarker panel (VDB, ADIPOQ, and matrix metalloproteinase 2 [MMP-2]) with significant ability to predict SRNS at disease presentation (P = 0.003; area under the receiver operating characteristic curve = 0.78). Conclusion: Plasma proteomic analyses and immunoblotting of serial samples in childhood NS identified a candidate biomarker panel able to predict SRNS at disease presentation, as well as candidate molecular targets/pathways associated with clinical steroid resistance. Keywords: biomarkers, nephrotic syndrome, proteomics, steroid resistance

Introduction There is limited information on effective disease monitoring for prompt interventions in childhood nephrotic syndrome. We examined the feasibility and effectiveness of a novel text messaging system (SMS) for disease monitoring in a multicenter, prospective study. Methods A total of 127 patients, Graphical abstract

Contains fulltext : 203024.pdf (Publisher’s version ) (Open Access) In November 2017, the Kidney Disease: Improving Global Outcomes (KDIGO) initiative brought a diverse panel of experts in glomerular diseases together to discuss the 2012 KDIGO glomerulonephritis guideline in the context of new developments and insights that had occurred over the years since its publication. During this KDIGO Controversies Conference on Glomerular Diseases, the group examined data on disease pathogenesis, biomarkers, and treatments to identify areas of consensus and areas of controversy. This report summarizes the discussions on primary podocytopathies, lupus nephritis, anti-neutrophil cytoplasmic antibody-associated nephritis, complement-mediated kidney diseases, and monoclonal gammopathies of renal significance.

Background and Aims Alport syndrome is a genetic disease accounting for an estimated 3% of children with end-stage kidney disease (ESKD) in the US (USRDS, 2014). Current management recommendations include the use of renin-angiotensin-aldosterone system inhibitors (RAASi) in patients with proteinuria, but no specific therapies have been approved for this disease. A Phase 3 study (CARDINAL; NCT03019185) assessed the safety and efficacy of bardoxolone methyl (Bard) in adult and adolescent patients with Alport syndrome. Method CARDINAL was an international, multicenter, double-blind, placebo-controlled, randomized trial. Eligible participants were 12 to 70 years old, had confirmed diagnosis of Alport syndrome, baseline eGFR 30-90 mL/min/1.73 m2 and urinary albumin to creatinine ratio (UACR) ≤ 3500 mg/g. For pediatric patients (12 to < 18 years of age), eGFR was calculated using the Bedside Schwartz equation. Patients were randomized 1:1 to Bard or placebo and were to be followed for up to 104 weeks (2 treatment periods of 48 weeks and 4 weeks off treatment between Weeks 48 and 52). The primary efficacy endpoints were changes from baseline in eGFR in patients randomized to Bard compared to placebo at Week 48 and Week 100. The key secondary endpoints were the off-treatment changes from baseline in eGFR in patients randomized to Bard compared to placebo at Week 52 and Week 104, 4 weeks after withdrawal. Results A total of 23 (15%) pediatric patients were randomized to Bard (n=11) or placebo (n=12). The average age was 15.3 years, mean (± SD) baseline eGFR was 69.9 ± 15.4 mL/min/1.73 m2 and geometric mean (± SE) baseline UACR was 230.9 ± 95.8 mg/g. A total of 19 of 23 (83%) pediatric patients were male, and 14 (61%) patients had X-linked Alport syndrome, while 6 (26%) patients had autosomal disease. Mean (± SD) baseline body weight was 65.5 ± 10.2 kg and 57.8 ± 16.0 kg and baseline height was 171.7 ± 5.9 cm and 166.3 ± 14.9 cm for Bard and placebo patients, respectively. Seventeen (74%) pediatric patients were on RAASi treatment. Treatment of pediatric patients with Bard resulted in a significantly higher mean change from baseline in on-treatment eGFR relative to placebo at Week 100 (13.8 mL/min/1.73 m2; p = 0.017) and higher mean off-treatment eGFR relative to placebo at Week 104 (14.6 mL/min/1.73 m2; p = 0.0035). In pediatric patients treated with Bard, UACR remained generally unchanged relative to baseline at Week 100 (geometric mean ± SE to baseline ratio: 0.7 ± 0.3), while placebo patients had an increase in UACR (geometric mean ± SE to baseline ratio: 2.1 ± 0.9). Pediatric patients generally continued along their baseline growth curves for height and weight in both treatment groups. At Week 100, mean ± SD changes from baseline in body weight were 0.5 ± 3.9 kg and 3.2 ± 3.5 kg and those for height were 1.6 ± 1.4 cm and 4.3 ± 5.1 cm for Bard and placebo patients, respectively. Changes in blood pressure (BP) were similar across treatment groups. As seen in the adult population, treatment with Bard resulted in transient increases in mean aminotransferase levels in pediatric patients that remained below 3 x ULN for a majority (8/11 [73%]) of patients and returned to baseline at Week 104, 4 weeks after drug withdrawal (mean ± SD change from baseline in ALT: 0.4 ± 3.7 U/L; AST: -0.9 ± 5.6 U/L). Increases in ALT did not coincide with increases in total bilirubin and no Hy’s law cases were reported. No serious adverse events (AEs) were reported in pediatric patients treated with Bard and reported AEs were consistent with those observed in previous studies. One placebo-treated pediatric patient and no Bard patients developed ESKD during the trial. Conclusion In CARDINAL, the addition of Bard to RAASi in pediatric patients with chronic kidney disease due to Alport syndrome appeared to preserve kidney function and very importantly from a safety standpoint, was safe and well-tolerated.

Introductions: Kidney injury molecule-1 (KIM-1) and periostin (POSTN) are proximal and distal tubule injury biomarkers. We tested whether baseline urine KIM-1/Cr (uKIM-1/Cr) and/or uPOSTN/Cr correlated with disease severity or improved a remission prediction model. Methods: Baseline uKIM-1/Cr and uPOSTN/Cr were measured on spot urine samples from immunosuppression-free patients enrolled in Nephrotic Syndrome Study Network until December 15, 2014. Urine protein/Cr (UPCR) and albumin/Cr (UACR) were measured at baseline, 4 months, and until last follow-up. Glomerular and tubulointerstitial (TI) expression arrays were analyzed from a baseline research renal biopsy core collected during a clinically indicated biopsy. Renal diagnoses were centrally confirmed, sections scanned, and measured morphometrically. Correlations between baseline uKIM-1/Cr and uPOSTN/Cr and UPCR, UACR, histopathologic features, glomerular and TI KIM-1 and POSTN expression levels, and renal outcomes were assessed. Results: Baseline uKIM-1/cr correlated with UPCR and UACR and were associated with complete remission (CR) after adjustment for proteinuria, histopathologic diagnosis, and treatment. Baseline uKIM-1/Cr also correlated with degree of foot process effacement and acute tubular injury. Glomerular and TI KIM-1 expression levels correlated with UPCR and UACR. Higher TI KIM-1 expression levels correlated with interstitial fibrosis, tubular atrophy, and global glomerulosclerosis, while glomerular KIM-1 expression correlated with time to remission. Findings for POSTN were of lesser statistical strength. Discussion/Conclusion: Lower baseline uKIM-1/Cr values were associated with more rapid time to CR after adjusting for proteinuria, histopathologic diagnosis, and treatment. Increased TI KIM-1 expression levels in proteinuric states were associated with chronic morphological injury; lower glomerular expression levels were associated with a greater potential for proteinuria reversibility.

Introduction: Alport syndrome is a rare genetic disorder that affects as many as 60,000 persons in the USA and a total of 103,000 persons (200 pg/mL at baseline or with significant cardiovascular histories were excluded. Patients were randomized 1:1 to bardoxolone methyl or placebo, with stratification by baseline UACR. Results: A total of 371 patients were screened, and 157 patients were randomly assigned to receive bardoxolone methyl ( n = 77) or placebo ( n = 80). The average age at screening was 39.2 years, and 23 (15%) were

The flow cytometric crossmatch is currently the gold standard for evaluating donor and recipient histocompatibility. The assay however does have limitations and is sensitive to false positive reactions resulting from the presence of non-HLA antibodies or therapy related immune biologics. Such false positive reactions can lead to the inappropriate decline of an acceptable donor organ or unnecessary therapeutic intervention. Here we describe the successful validation of anti-idiotype blocking antibodies in prevention of false positive flow crossmatch results caused by biologic therapy. Blocking antibodies specific for the Fab portion of Rituximab and/or Alemtuzumab were incubated with biologic containing patient serum prior to use in flow cytometric crossmatching. Biologic blocking successfully negated false positive crossmatch results with Rituximab (B cell ave. % change = -97%) or Alemtuzumab (T cell ave. % change = -99%, B cell ave. % change = -95%) infused sera respectively. Simultaneous blocking of these biologics was also successful. A complex case is presented to demonstrate the application of this procedure.

Background/Aims: Obesity is a known risk factor for cardiovascular disease and contributes to the development and progression of kidney disease. However, the specific influence of obesity on outcomes in primary glomerular disease has not been well characterized. Methods: In this prospective cohort study, data were from 541 participants enrolled in the Nephrotic Syndrome Study Network (NEPTUNE), between 2010 and 2019, at 23 sites across North America. Blood pressure, lipids, and kidney disease outcomes including complete proteinuria remission, kidney failure, and chronic kidney disease progression were evaluated. Data were analyzed using linear and logistic regression with generalized estimating equations and time-varying Cox regression with Kaplan-Meier plots. Results: The prevalence of obesity at baseline was 43.3% (N = 156) in adults and 37.6% (N = 68) in children. In adults, obesity was longitudinally associated with higher systolic BP (β = 6.49, 95% CI: 2.41, 10.56, p = 0.002), dyslipidemia (OR = 1.74, 95% CI: 1.30, 2.32, p < 0.001), triglycerides (β = 41.92, 95% CI: 17.12, 66.71, p = 0.001), and lower HDL (β = −6.92, 95% CI: −9.32, −4.51, p < 0.001). In children, obesity over time was associated with higher systolic BP index (β = 0.04, 95% CI: 0.02, 0.06, p < 0.001) and hypertension (OR = 1.43, 95% CI: 1.04, 1.98, p = 0.03). In both adults and children, obesity was associated with a significantly lower hazard of achieving complete remission of proteinuria (adult HR = 0.80, 95% CI: 0.69, 0.88, p < 0.001; pediatric HR = 0.72, 95% CI: 0.61, 0.84, p < 0.001). Conclusion: Obesity was associated with higher cardiovascular risk and less proteinuria remission from nephrotic syndrome in adults and children with proteinuric glomerulopathies. Weight-loss strategies may forestall cardiovascular disease and progressive kidney function decline in this high-risk patient group.

Background Thrombosis is a potentially life‐threatening nephrotic syndrome (NS) complication. We have previously demonstrated that hypercoagulopathy is proportional to NS severity in rat models and that pioglitazone (Pio) reduces proteinuria both independently and in combination with methylprednisolone (MP), a glucocorticoid (GC). However, the effect of these treatments on NS‐associated hypercoagulopathy remains unknown. We thus sought to determine the ability of Pio and GC to alleviate NS‐associated hypercoagulopathy. Methods Puromycin aminonucleoside‐induced rat NS was treated with sham, Low‐ or High‐dose MP, Pio, or combination (Pio + Low‐MP) and plasma was collected at day 11. Plasma samples were collected from children with steroid‐sensitive NS (SSNS) and steroid‐resistant NS (SRNS) upon presentation and after 7 weeks of GC therapy. Plasma endogenous thrombin potential (ETP), antithrombin (AT) activity, and albumin (Alb) were measured using thrombin generation, amidolytic, and colorimetric assays, respectively. Results In a rat model of NS, both High‐MP and Pio improved proteinuria and corrected hypoalbuminemia, ETP and AT activity (p, Acquired hypercoagulopathy contributes to thrombotic‐risk in patients with nephrotic syndrome. Here we show that treatments directed at reversing the glomerular filtration defect effectively reduce hypercoagulopathy in both animal models and childhood nephrosis. These data imply that effective treatment for nephrotic syndrome may simultaneously reduce thrombotic risk.

Background and Aims Knowledge about genetic causes of chronic kidney disease (CKD) is one of the key gaps in global kidney research and recent International Society of Nephrology recommendations encourage the adoption of genetic testing to enable a goal of providing precision medicine based on individual risk (1). A recent whole-exome sequencing study showed that genetic inheritance may be responsible for up to 10% of CKD diagnoses, many of which may be previously undiagnosed or mis-diagnosed (2). Continued advances in DNA sequencing technology have made genetic testing, even whole-exome sequencing, applicable to routine clinical diagnoses. In order to test the hypothesis that genetic testing can provide valuable information to increase the accuracy and precision of diagnosis in CKD, we designed a gene panel to prospectively provide genetic testing in a subset of patients with CKD defined by a specific set of inclusion criteria. Method Reata Pharmaceuticals is partnering with Invitae on a program called KidneyCode, which provides no-charge genetic testing to enable diagnosis of three specific rare monogenic causes of CKD: Alport syndrome (AS), autosomal dominant polycystic kidney disease (ADPKD) due to PKD2 mutations, and focal segmental glomerulosclerosis (FSGS), as well as detection of variants in one of the autosomal recessive polycystic kidney disease gene, PKHD1. Invitae’s renal disease panel includes 17 genes (ACTN4, ANLN, CD2AP, COL4A3, COL4A4, COL4A5, CRB2, HNF1A, INF2, LMX1B, MYO1E, NPHS1, NPHS2, PAX2, PKD2, PKHD1, and TRPC6), and its assay includes both full-gene sequencing and intragenic deletion/duplication analysis using next-generation sequencing (NGS). The assay targets the coding exons and flanking 10bp of intronic sequences. Invitae’s method of variant classification uses a systematic process for assessing evidence based on guidelines published by the American College of Medical Genetics (3). Patients in the US at risk for hereditary CKD (eGFR ≤ 90 mL/min/1.73m2 plus hematuria or a family history of CKD) or with a known diagnosis of AS or FSGS are eligible. Family members of those with suspected or known AS or FSGS are also eligible. All participants in the KidneyCode program have access to genetic counseling follow-up at no additional charge. Results In the first five months of the KidneyCode program, 152 genetic tests have been completed. A genetic variant was reported in 87 patients. Of those 87 patients, 67 patients had 75 variants in COL4A3, 4, or 5 genes (34 Pathogenic/Likely Pathogenic (P/LP), 41 Variants of Uncertain Significance (VUS)), 20 patients had 24 variants in genes associated with FSGS (3 P/LP, 21 VUS), 15 patients had 20 variants in PKHD1 (1 P/LP, 19 VUS), and 2 patients had variants in PKD2 (1 P/LP, 1 VUS). Of the 34 patients with Pathogenic or Likely Pathogenic COL4A variants, 19 reported a previous diagnosis of Alport syndrome. Other diagnoses in patients with COL4A mutations included FSGS, thin basement membrane disease, and familial hematuria. Extra-renal manifestations such as hearing loss and eye disease were reported in 7 of the 34 patients with COL4A variants. Conclusion Initial results with the KidneyCode panel demonstrate the utility of NGS and support the hypothesis that combining genetic testing with clinical presentation and medical history can significantly improve accuracy and precision of diagnosis in patients with hereditary CKD.

BACKGROUND AND OBJECTIVES: Infections contribute to patient morbidity and mortality in glomerular disease. We sought to describe the incidence of, and identify risk factors for, infection-related acute care events among Cure Glomerulonephropathy Network (CureGN) study participants. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: CureGN is a prospective, multicenter, cohort study of children and adults with biopsy sample–proven minimal change disease, FSGS, membranous nephropathy, or IgA nephropathy/vasculitis. Risk factors for time to first infection-related acute care events (hospitalization or emergency department visit) were identified using multivariable Cox proportional hazards regression. RESULTS: Of 1741 participants (43% female, 41% 3.5 mg/mg), compared with serum albumin >2.5 g/dl and urinary protein-creatinine ratio ≤3.5 mg/mg, was associated with higher risk of time to first infection (adjusted hazard ratio, 2.49; 95% CI, 1.51 to 4.12). CONCLUSIONS: Among CureGN participants, infection-related acute care events were common and associated with younger age, corticosteroid exposure, and hypoalbuminemia with proteinuria.

Introduction Acute kidney injury (AKI) is a major cause of mortality worldwide, particularly in low-resource settings with limited diagnostic testing. Neutrophil gelatinase-associated lipocalin (NGAL) has shown promise in predicting AKI. Nested within a larger, prospective cohort study evaluating AKI incidence in admitted trauma patients, our objective was to evaluate a novel dipstick, NGALds, for the prediction of AKI in Malawi, Africa. Methods Participants were >6 months of age. Spearman rank correlation coefficients (R) assessed NGAL categories (negative [≤50 ng/ml], low risk [51−149 ng/ml], moderate risk [150−299 ng/ml], and high risk [≥300 ng/ml]) for the urine NGALds dipstick and laboratory-based NGAL Test. Results We enrolled 285 participants (one-third children). Thirteen percent developed AKI. The dipstick captured 45 of 52 participants (86.5%) with moderate- or high-risk NGAL values on laboratory-based testing (R = 0.74). The dipstick had sensitivity of 44.4%, specificity of 73.5%, positive predictive value of 19.5%, and negative predictive value of 90.2% for predicting AKI. Acute kidney injury was associated with an increased risk of mortality (relative risk [RR] = 3.9, 95% confidence interval [CI] = 1.9−8.2), but mortality risk greatly increased among children who first had a positive (≥150 ng/ml) NGALds result (RR = 12.0, 95% CI = 1.8−78.4). Conclusions The NGALds dipstick performed similarly to the NGAL Test in this low-resource setting and may be a useful tool to rule out AKI. It may be even more important in predicting high mortality risk among children.

Background Understanding the relationship between clinical and patient-reported outcomes (PROs) will help support clinical care and future clinical trial design of novel therapies for focal segmental glomerulosclerosis (FSGS). Methods FSGS patients ≥8 years of age enrolled in the Nephrotic Syndrome Study Network completed Patient-Reported Outcomes Measurement Information System PRO measures of health-related quality of life (HRQoL) (children: global health, mobility, fatigue, pain interference, depression, anxiety, stress and peer relationships; adults: physical functioning, fatigue, pain interference, sleep impairment, mental health, depression, anxiety and social satisfaction) at baseline and during longitudinal follow-up for a maximum of 5 years. Linear mixed-effects models were used to determine which demographic, clinical and laboratory features were associated with PROs for each of the eight children and eight adults studied. Results There were 45 children and 114 adult FSGS patients enrolled that had at least one PRO assessment and 519 patient visits. Multivariable analyses among children found that edema was associated with global health (−7.6 points, P = 0.02) and mobility (−4.2, P = 0.02), the number of reported symptoms was associated with worse depression (−2.7 per symptom, P = 0.009) and anxiety (−2.3, P = 0.02) and the number of emergency room (ER) visits in the prior 6 months was associated with worse mobility (−2.8 per visit, P Conclusions PROs provide important information about HRQoL for persons with FSGS that is not captured solely by the examination of laboratory-based markers of disease. However, it is critical that instruments capture the patient experience and FSGS clinical trials may benefit from a disease-specific instrument more sensitive to within-patient changes.

BACKGROUND AND OBJECTIVES: Steroid resistant nephrotic syndrome (SRNS) due to focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) is a leading cause of end stage kidney disease in children. Recurrence of primary disease following transplantation is a major cause of allograft loss. The clinical determinants of disease recurrence are not completely known. Our objectives were to determine risk factors for recurrence of FSGS/MCD following kidney transplantation, and factors that predict response to immunosuppression following recurrence. STUDY DESIGN: Multicenter study of pediatric patients with kidney transplants performed for ESKD due to SRNS between 1/2006–12/2015. Demographics, clinical course, and biopsy data were collected. Patients with primary-SRNS (PSRNS) were defined as those initially resistant to corticosteroid therapy at diagnosis, and patients with late-SRNS (LSRNS) as those initially responsive to steroids who subsequently developed steroid resistance. We performed logistic regression to determine risk factors associated with nephrotic syndrome (NS) recurrence. RESULTS: We analyzed 158 patients; 64 (41%) had recurrence of NS in their renal allograft. Disease recurrence occurred in 78% of patients with LSRNS compared to 39% of those with PSRNS. Patients with MCD on initial native kidney biopsy had a 76% recurrence rate compared with a 40% recurrence rate in those with FSGS. Multivariable analysis showed that MCD histology (OR; 95% CI: 5.6; 1.3–23.7) compared to FSGS predicted disease recurrence. CONCLUSIONS: Pediatric patients with MCD and LSRNS are at higher risk of disease recurrence following kidney transplantation. These findings may be useful for designing studies to test strategies for preventing recurrence.

Hypertension and blood pressure variability (BPV; SD and average real variability) in primary proteinuric glomerulopathies are not well described. Data were from 433 participants in the NEPTUNE (Nephrotic Syndrome Study Network). Hypertensive BP status was defined as previous history of hypertension or BP ≥140/90 mm Hg for adults/≥95th percentile for children at baseline. BPV was measured in participants with ≥3 visits in the first year. Two-hundred ninety-six adults (43 years [interquartile range, 32–57.8 years], 61.5% male) and 147 children (11 years [interquartile range, 5–14 years], 57.8% male) were evaluated. At baseline, 64.8% of adults and 46.9% of children were hypertensive. Histological diagnosis was associated with hypertensive status in adults ( P =0.036). In adults, hypertensive status was associated with lower hazard of complete remission (hazard ratio, 0.36; 95% confidence interval, 0.19–0.68) and greater hazard of achieving the composite end point (end-stage renal disease or estimated glomerular filtration rate decline >40%; hazard ratio, 4.1; 95% confidence interval, 1.4–12). Greater systolic and diastolic SD and average real variability were also associated with greater hazard of reaching the composite end point in adults (all P P

BACKGROUND: Acute kidney injury (AKI) significantly increases morbidity and mortality for hospitalized children, yet sociodemographic risk factors for pediatric AKI are poorly described. We examined sociodemographic differences in pediatric AKI amongst a national cohort of hospitalized children. METHODS: Secondary analysis of the most recent (2012) Kids’ Inpatient Database (KID) from the Agency for Healthcare Research and Quality. Study sample weights were used to obtain national estimates of AKI (defined by administrative data). KID is a nationally representative sample of pediatric discharges throughout the USA. Linear risk regression models were used to assess the relationship between our primary exposures (race/ethnicity, health insurance, household urbanization, gender, and age) and the diagnosis of AKI, adjusting for comorbidities. RESULTS: A total of 1,699,841 hospitalizations met our study criteria. In 2012, AKI occurred in approximately 12.3/1000 pediatric hospitalizations, which translates to almost 30,000 children nationally. Asian/Pacific Islander, African-American, and Hispanic children were at slightly increased risk for AKI compared to Caucasian children (adjusted risk difference (RD) 4.5 per 1000 hospitalizations, 95% confidence interval (CI) 2.9–6.0; 2.5/1000 hospitalizations, 95% CI 1.7–3.3; and 1.7/1000 hospitalizations, 95% CI 0.9–2.5, respectively). Uninsured children were more likely to suffer AKI compared to children with any health insurance (e.g., no insurance versus Medicaid: adjusted RD 14.4/1000 hospitalizations, 95% CI 12.7–16.2). Based on these national estimates, one episode of AKI might be prevented if 70 (95% CI 62–79) hospitalized children without insurance were provided with Medicaid. CONCLUSIONS: Pediatric AKI occurs more fequently in racial minority and uninsured children, factors linked to lower socioeconomic status.

Contains fulltext : 202673.pdf (Publisher’s version ) (Open Access) The Kidney Disease: Improving Global Outcomes (KDIGO) initiative organized a Controversies Conference on glomerular diseases in November 2017. The conference focused on the 2012 KDIGO guideline with the aim of identifying new insights into nomenclature, pathogenesis, diagnostic work-up, and, in particular, therapy of glomerular diseases since the guideline's publication. It was the consensus of the group that most guideline recommendations, in particular those dealing with therapy, will need to be revisited by the guideline-updating Work Group. This report covers general management of glomerular disease, IgA nephropathy, and membranous nephropathy.

Background The aim of this study was to describe the experience of pediatric and young adult hemodialysis (HD) patients from a global cohort. Methods The Pediatric Investigation and Close Collaborative Consortium for Ongoing Life Outcomes for MONitoring Dialysis Outcomes (PICCOLO MONDO) study provided de-identified electronic information of 3244 patients, ages 0–30 years from 2000 to 2012 in four regions: Asia, Europe, North America and South America. The study sample was categorized into pediatric (≤18 years old) and young adult (19–30 years old) groups based on the age at dialysis initiation. Results For those with known end-stage renal disease etiology, glomerular disease was the most common diagnosis in children and young adults. Using Europe as a reference group, North America [odds ratio (OR) 2.69; CI 1.29, 5.63] and South America (OR 4.21; CI 2.32, 7.63) had the greatest mortality among young adults. North America also had higher rates of overweight, obesity, hypertension, cardiovascular disease, hospitalizations and secondary diabetes compared with all other regions. Initial catheter use was greater for North American (86.4% in pediatric patients and 75.2% in young adults) and South America (80.6% in pediatric patients and 75.9% in young adults). Catheter use at 1-year follow-up was most common in North American children (77.3%) and young adults (62.9%). Asia had the lowest rate of catheter use. For both age groups, dialysis adequacy (equilibrated Kt/V) ranged between 1.4 and 1.5. In Asia, patients in both age groups had significantly longer treatment times than in any other region. Conclusions The PICCOLO MONDO study has provided unique baseline and 1-year follow-up information on children and young adults receiving HD around the globe. This cohort has brought to light aspects of care in these age groups that warrant further investigation.

Background and objectives This analysis from the Nephrotic Syndrome Study Network (NEPTUNE) assessed the phenotypic and pathology characteristics of proteinuric patients undergoing kidney biopsy and defined the frequency and factors associated with complete proteinuria remission (CRever). Design, setting, participants, & measurements We enrolled adults and children with proteinuria ≥0.5 g/d at the time of first clinically indicated renal biopsy at 21 sites in North America from April 2010 to June 2014 into a prospective cohort study. NEPTUNE central pathologists assigned participants to minimal-change disease (MCD), FSGS, membranous nephropathy, or other glomerulopathy cohorts. Outcome measures for this analysis were (1) CRever with urine protein-to-creatinine ratio (UPC)