Longitudinal analysis of blood pressure and lipids in childhood nephrotic syndrome.

BACKGROUND: In the current study, longitudinal BP and lipid measurements were examined in a NEPTUNE cohort of children with newly diagnosed nephrotic syndrome (cNEPTUNE). We hypothesized that hypertensive BP and dyslipidemia would persist in children with nephrotic syndrome, regardless of steroid treatment response. METHODS: A multi-center longitudinal observational analysis of data obtained from children < 19 years of age with new onset nephrotic syndrome enrolled in the Nephrotic Syndrome Study Network (cNEPTUNE) was conducted. BP and lipid data were examined over time stratified by disease activity and steroid exposure. Generalized estimating equation regressions were used to find determinants of hypertensive BP and dyslipidemia. RESULTS: Among 122 children, the prevalence of hypertensive BP at any visit ranged from 17.4% to 57.4%, while dyslipidemia prevalence ranged from 40.0% to 96.2% over a median of 30 months of follow-up. Hypertensive BP was found in 46.2% (116/251) of study visits during active disease compared with 31.0% (84/271) of visits while in remission. Dyslipidemia was present in 88.2% (120/136) of study visits during active disease and in 66.0% (101/153) while in remission. Neither dyslipidemia nor hypertensive BP were significantly different with/without medication exposure (steroids and/or CNI). In regression analysis, male sex and urine protein:creatinine ratio (UPC) were significant determinants of hypertensive BP over time, while eGFR was found to be a determinant of dyslipidemia over time. CONCLUSIONS: Results demonstrate persistent hypertensive BPs and unfavorable lipid profiles in the cNEPTUNE cohort regardless of remission status or concurrent steroid or calcineurin inhibitor treatment.

Precision nephrology identified tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis.

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.

COL4A gene variants are common in children with hematuria and a family history of kidney disease.

BACKGROUND: Inherited kidney diseases are a common cause of chronic kidney disease (CKD) in children. Identification of a monogenic cause of CKD is more common in children than in adults. This study evaluated the diagnostic yield and phenotypic spectrum of children who received genetic testing through the KIDNEYCODE sponsored genetic testing program. METHODS: Unrelated children < 18 years of age who received panel testing through the KIDNEYCODE sponsored genetic testing program from September 2019 through August 2021 were included (N = 832). Eligible children met at least one of the following clinician-reported criteria: estimated GFR ≤ 90 ml/min/1.73 m2, hematuria, a family history of kidney disease, or suspected or biopsy confirmed Alport syndrome or focal segmental glomerulosclerosis (FSGS) in the tested individual or family member. RESULTS: A positive genetic diagnosis was observed in 234 children (28.1%, 95% CI [25.2-31.4%]) in genes associated with Alport syndrome (N = 213), FSGS (N = 9), or other disorders (N = 12). Among children with a family history of kidney disease, 30.8% had a positive genetic diagnosis. Among those with hematuria and a family history of CKD, the genetic diagnostic rate increased to 40.4%. CONCLUSIONS: Children with hematuria and a family history of CKD have a high likelihood of being diagnosed with a monogenic cause of kidney disease, identified through KIDNEYCODE panel testing, particularly COL4A variants. Early genetic diagnosis can be valuable in targeting appropriate therapy and identification of other at-risk family members. A higher resolution version of the Graphical abstract is available as Supplementary information.

The association of low birthweight and prematurity on outcomes in children and adults with nephrotic syndrome-a NEPTUNE cohort study.

BACKGROUND: In single-center studies, both preterm birth and low birth weight (LBW) are associated with worse outcomes in childhood nephrotic syndrome. Using the Nephrotic Syndrome Study Network (NEPTUNE) observational cohort, we tested the hypothesis that in patients with nephrotic syndrome, hypertension, proteinuria status, and disease progression would be more prevalent and more severe in subjects with LBW and prematurity singly or in combination (LBW/prematurity). METHODS: Three hundred fifty-nine adults and children with focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD) and available birth history were included. Estimated glomerular filtration rate (eGFR) decline and remission status were primary outcomes, and secondary outcomes were kidney histopathology, kidney gene expression, and urinary biomarkers. Logistic regression was used to identify associations with LBW/prematurity and these outcomes. RESULTS: We did not find an association between LBW/prematurity and remission of proteinuria. However, LBW/prematurity was associated with greater decline in eGFR. This decline in eGFR was partially explained by the association of LBW/prematurity with APOL1 high-risk alleles, but the association remained after adjustment. There were no differences in kidney histopathology or gene expression in the LBW/prematurity group compared to normal birth weight/term birth. CONCLUSION: LBW and premature babies who develop nephrotic syndrome have a more rapid decline in kidney function. We did not identify clinical or laboratory features that distinguished the groups. Additional studies in larger groups are needed to fully ascertain the effects of (LBW) and prematurity alone or in combination on kidney function in the setting of nephrotic syndrome.

Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular Diseases.

The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Glomerular Diseases is an update to the KDIGO 2012 guideline. The aim is to assist clinicians caring for individuals with glomerulonephritis (GN), both adults and children. The scope includes various glomerular diseases, including IgA nephropathy and IgA vasculitis, membranous nephropathy, nephrotic syndrome, minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), infection-related GN, antineutrophil cytoplasmic antibody (ANCA) vasculitis, lupus nephritis, and anti-glomerular basement membrane antibody GN. In addition, this guideline will be the first to address the subtype of complement-mediated diseases. Each chapter follows the same format providing guidance related to diagnosis, prognosis, treatment, and special situations. The goal of the guideline is to generate a useful resource for clinicians and patients by providing actionable recommendations based on evidence syntheses, with useful infographics incorporating views from experts in the field. Another aim is to propose research recommendations for areas where there are gaps in knowledge. The guideline targets a broad global audience of clinicians treating GN while being mindful of implications for policy and cost. Development of this guideline update followed an explicit process whereby treatment approaches and guideline recommendations are based on systematic reviews of relevant studies, and appraisal of the quality of the evidence and the strength of recommendations followed the "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) approach. Limitations of the evidence are discussed, with areas of future research also presented.

Study Design and Baseline Characteristics of the CARDINAL Trial: A Phase 3 Study of Bardoxolone Methyl in Patients with Alport Syndrome.

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 (<5 per 10,000) in the European Union [1, 2]. It is the second most common inherited cause of kidney failure and is characterized by progressive loss of kidney function that often leads to end-stage kidney disease. Currently, there are no approved disease-specific agents for therapeutic use. We designed a phase 3 study (CARDINAL; NCT03019185) to evaluate the safety, tolerability, and efficacy of bardoxolone methyl in patients with Alport syndrome. METHODS: The CARDINAL phase 3 study is an international, multicenter, double-blind, placebo-controlled, randomized registrational trial. Eligible patients were of ages 12-70 years with confirmed genetic or histologic diagnosis of Alport syndrome, eGFR 30-90 mL/min/1.73 m2, and urinary albumin to creatinine ratio (UACR) ≤3,500 mg/g. Patients with B-type natriuretic peptide values >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 <18 years of age. Of the randomized population, 146 (93%) had confirmed genetic diagnosis of Alport syndrome, and 62% of patients had X-linked mode of inheritance. Mean baseline eGFR was 62.7 mL/min/1.73 m2, and the geometric mean UACR was 141.0 mg/g. The average annual rate of eGFR decline prior to enrollment in the study was -4.9 mL/min/1.73 m2 despite 78% of the patient population receiving ACE inhibitor (ACEi) or ARB therapy. DISCUSSION/CONCLUSION: CARDINAL is one of the largest interventional, randomized controlled trials in Alport syndrome conducted to date. Despite the use of ACEi or ARB, patients were experiencing significant loss of kidney function prior to study entry.

APOL1 genotype-associated morphologic changes among patients with focal segmental glomerulosclerosis.

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 <0.1) with decreased global mesangial hypercellularity, decreased condensation of cytoskeleton, and increased tubular microcysts. No significant correlations were detected in MCD cohort. Independent of risk alleles, glomerular APOL1 expression in FSGS patients was not correlated with morphologic features. CONCLUSIONS: While APOL1-associated FSGS is associated with two risk alleles, both one and two risk alleles are associated with cellular/tissue changes in this study of FSGS patients. Our lack of discovery of a large group of tissue differences in FSGS and no significant difference in MCD may be due to the lack of power but also supports investigating whether machine learning methods may more sensitively detect APOL1-associated changes.

Management and treatment of glomerular diseases (part 2): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

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.

APOL1-associated glomerular disease among African-American children: a collaboration of the Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE) cohorts.

BACKGROUND: Individuals of African ancestry harboring two variant alleles within apolipoprotein L1 ( APOL1 ) are classified with a high-risk (HR) genotype. Adults with an HR genotype have increased risk of focal segmental glomerulosclerosis and chronic kidney disease compared with those with a low-risk (LR) genotype (0 or 1 variants). The role of APOL1 risk genotypes in children with glomerular disease is less well known. METHODS: This study characterized 104 African-American children with a glomerular disease by APOL1 genotype in two cohorts: the Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE). RESULTS: Among these subjects, 46% had an HR genotype with a similar age at cohort enrollment. For APOL1 HR children, the median age of disease onset was older (CKiD: 4.5 versus 11.5 years for LR versus HR; NEPTUNE: 11 versus 14 years for LR versus HR, respectively) and preterm birth was more common [CKiD: 27 versus 4%; NEPTUNE: 26 versus 12%; combined odds ratio 4.6 (95% confidence interval: 1.4, 15.5)]. Within studies, HR children had lower initial estimated glomerular filtration rate (eGFR) (CKiD: 53 versus 69 mL/min/1.73 m 2 ; NEPTUNE: 74 versus 94 mL/min/1.73 m 2 ). Longitudinal eGFR decline was faster among HR children versus LR (CKiD: -18 versus -8% per year; NEPTUNE: -13 versus -3% per year). CONCLUSIONS: Children with an HR genotype in CKiD and NEPTUNE seem to have a more aggressive form of glomerular disease, in part due to a higher prevalence of focal segmental glomerulosclerosis. These consistent findings across independent cohorts suggest a common natural history for children with APOL1 -associated glomerular disease. Further study is needed to determine the generalizability of these findings.

Back to the future: therapies for idiopathic nephrotic syndrome.

BACKGROUND: Roughly 20-40% of individuals with idiopathic nephrotic syndrome will fail to respond to standard therapies and have a high risk of progression to end stage kidney disease (ESKD). In the last 50 years, no new therapies have been approved specifically for the treatment of these individuals with recalcitrant disease. SUMMARY: Recent in vitro, translational, and clinical studies have identified novel targets and pathways that not only expand our understanding of the complex pathophysiology of proteinuric disease but also provide an opportunity to challenge the tradition of relying on histologic classification of nephrotic diseases to make treatment decisions. KEY MESSAGES: The traditional methods of directing the care of individuals with nephrotic syndrome by histological classification or deciding second line therapies on the basis of steroid-responsiveness may soon yield customizing therapies based on our expanding understanding of molecular targets. Important non-immunologic mechanisms of widely used immunosuppressive therapies may be just as important in palliating proteinuric disease as proposed immunologic functions.

Minimal Change Disease.

Minimal change disease represents a common cause of nephrotic syndrome in both pediatric and adult patients. Although much remains to be discovered, there have been significant recent advancements in our understanding of the pathophysiology of minimal change disease, including the discovery of antinephrin antibodies as a marker for diagnosis of disease. Here we will review what is known about the pathophysiology, treatment, and prognosis of minimal change disease and the differences between pediatric and adult patients. Recent advances in our understanding of the mechanisms of disease will be noted. We will discuss how this may change the treatment of minimal change disease going forward and what remains to be studied.

Lupus nephritis kidney biopsy characteristics and preterm birth.

Individuals with lupus nephritis (LN) are at high risk of adverse maternal and fetal outcomes in pregnancy. Outside of pregnancy, proliferative lesions on kidney biopsies are associated with disease progression, but these have not been consistently associated with increased risk in pregnancy. This retrospective, single-center study examines how histologic findings, the timing from kidney biopsy to pregnancy, and the clinical features in the first trimester are associated with preterm birth among individuals with LN. Among 35 deliveries in 31 women, the mean gestational age at delivery was 33.8 weeks. The presence of a urine protein-to-creatinine ratio >0.5 g/g in the first trimester was associated with preterm delivery (81% vs. 36%, p = 0.04). Preterm birth was more common in individuals with glomerular crescents on biopsy (89% in those with >20% crescents vs. 50% in those with <20%, p = 0.06). A pregnancy occurring within 2 years after a kidney biopsy was more likely to result in preterm birth than if the biopsy was performed more than 2 years prior to conception (82% vs. 23%, p = 0.01). The time from diagnostic biopsy may be a surrogate for disease activity, and a 2-year delay from biopsy might allow sufficient time to achieve disease remission. Overall, these data could aid family planning discussions and promote preconception disease optimization for patients and their providers.

Design of the Nephrotic Syndrome Study Network (NEPTUNE) to evaluate primary glomerular nephropathy by a multidisciplinary approach.

The Nephrotic Syndrome Study Network (NEPTUNE) is a North American multicenter collaborative consortium established to develop a translational research infrastructure for nephrotic syndrome. This includes a longitudinal observational cohort study, a pilot and ancillary study program, a training program, and a patient contact registry. NEPTUNE will enroll 450 adults and children with minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy for detailed clinical, histopathological, and molecular phenotyping at the time of clinically indicated renal biopsy. Initial visits will include an extensive clinical history, physical examination, collection of urine, blood and renal tissue samples, and assessments of quality of life and patient-reported outcomes. Follow-up history, physical measures, urine and blood samples, and questionnaires will be obtained every 4 months in the first year and biannually, thereafter. Molecular profiles and gene expression data will be linked to phenotypic, genetic, and digitalized histological data for comprehensive analyses using systems biology approaches. Analytical strategies were designed to transform descriptive information to mechanistic disease classification for nephrotic syndrome and to identify clinical, histological, and genomic disease predictors. Thus, understanding the complexity of the disease pathogenesis will guide further investigation for targeted therapeutic strategies.

Reimagining Nephrology Fellowship Education to Meet the Future Needs of Nephrology: A Report of the American Society of Nephrology Task Force on the Future of Nephrology.

The American Society of Nephrology (ASN) Task Force on the Future of Nephrology was established in April 2022 in response to requests from the American Board of Internal Medicine and the Accreditation Council for Graduate Medical Education regarding training requirements in nephrology. Given recent changes in kidney care, ASN also charged the task force with reconsidering all aspects of the specialty's future to ensure that nephrologists are prepared to provide high-quality care for people with kidney diseases. The task force engaged multiple stakeholders to develop 10 recommendations focused on strategies needed to promote: ( 1 ) just, equitable, and high-quality care for people living with kidney diseases; ( 2 ) the value of nephrology as a specialty to nephrologists, the future nephrology workforce, the health care system, the public, and government; and ( 3 ) innovation and personalization of nephrology education across the scope of medical training. This report reviews the process, rationale, and details (the "why" and the "what") of these recommendations. In the future, ASN will summarize the "how" of implementing the final report and its 10 recommendations.

Disease activity, proteinuria, and vitamin D status in children with systemic lupus erythematosus and juvenile dermatomyositis.

OBJECTIVE: To evaluate relationships among vitamin D, proteinuria, and disease activity in pediatric systemic lupus erythematosus (SLE) and juvenile dermatomyositis (JDM). STUDY DESIGN: Multiple linear regression was used to associate subject-reported race, sunscreen use, and vitamin D intake with physician-assessed disease activity and serum 25-hydroxyvitamin D (25[OH]D) in 58 subjects with pediatric SLE (n=37) or JDM (n=21). Serum 25(OH)D was correlated with urinary vitamin D binding protein/creatinine ratio (DBP/C) and other indicators of proteinuria. RESULTS: Serum 25(OH)D levels in subjects with SLE were inversely associated with the natural log of urinary DBP/C (r=-0.63, P<.001) and urine protein to creatinine ratio (r=-0.60, P<.001), with an adjusted mean 10.9-ng/mL (95% CI, 5.1-16.8) decrease in 25(OH)D for those with proteinuria. Excluding subjects with proteinuria, serum 25(OH)D levels were inversely associated with disease activity in JDM, but not in SLE. Overall, 66% of all subjects were taking concurrent corticosteroids, but this was not associated with 25(OH)D levels. CONCLUSIONS: Low serum 25(OH)D in patients with SLE is associated with proteinuria and urinary DBP. Vitamin D deficiency is associated with disease activity in patients with JDM and SLE; this relationship in SLE may be confounded by proteinuria.

Effects of Bardoxolone Methyl in Alport Syndrome.

BACKGROUND AND OBJECTIVES: 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. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We randomly assigned patients with Alport syndrome, ages 12-70 years and eGFR 30-90 ml/min per 1.73 m2, to bardoxolone methyl (n=77) or placebo (n=80). Primary efficacy end points were change from baseline in eGFR at weeks 48 and 100. Key secondary efficacy end points were change from baseline in eGFR at weeks 52 and 104, after an intended 4 weeks off treatment. Safety was assessed by monitoring for adverse events and change from baseline in vital signs, 12-lead electrocardiograms, laboratory measurements (including, but not limited to, aminotransferases, urinary albumin-creatinine ratio, magnesium, and B-type natriuretic peptide), and body weight. RESULTS: Patients 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; P<0.001] and 7.4 [95% confidence interval, 3.1 to 11.7; P=0.0008] ml/min per 1.73 m2, respectively). After a 4-week off-treatment period, corresponding mean differences in eGFR were 5.4 (97.5% confidence interval, 1.8 to 9.1; P<0.001) and 4.4 (95% confidence interval, 0.7 to 8.1; P=0.02) ml/min per 1.73 m2 at 52 and 104 weeks, respectively. In a post hoc analysis with no imputation of missing eGFR data, the difference at week 104 was not statistically significant (1.5 [95% confidence interval, -1.9 to 4.9] ml/min per 1.73 m2). Discontinuations from treatment were more frequent among patients randomized to bardoxolone methyl; most discontinuations were due to protocol-specified criteria being met for increases in serum transaminases. Serious adverse events were more frequent among patients randomized to placebo. Three patients in each group developed kidney failure. CONCLUSIONS: 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. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: A Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Alport Syndrome - CARDINAL (CARDINAL), NCT03019185.

Kidney Injury Molecule-1 and Periostin Urinary Excretion and Tissue Expression Levels and Association with Glomerular Disease Outcomes.

INTRODUCTIONS: Kidney injury molecule-1 (KIM-1) and periostin (POSTN) are proximal and distal tubule injury biomarkers. We tested whether baseline urine KIM-1/creatinine (uKIM-1/cr) and/or uPOSTN/cr correlated with disease severity or improved a remission prediction model. METHODS: Baseline uKIM1/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/creatinine (UPCR) and albumin/creatinine (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 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 complete remission 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.

Association of Lupus Nephritis Histopathologic Classification With Venous Thromboembolism-Modification by Age at Biopsy.

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.

Association of Obesity with Cardiovascular Risk Factors and Kidney Disease Outcomes in Primary Proteinuric Glomerulopathies.

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 (ß = 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 (ß = 41.92, 95% CI: 17.12, 66.71, p = 0.001), and lower HDL (ß = -6.92, 95% CI: -9.32, -4.51, p < 0.001). In children, obesity over time was associated with higher systolic BP index (ß = 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.