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Background: Steroids, the mainstay of treatment for nephrotic syndrome in children, have multiple adverse effects including growth suppression., Methods: Anthropometric measurements in children < 18 years enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) were collected. The longitudinal association of medication exposure and nephrotic syndrome characteristics with height z-score and growth velocity was determined using adjusted Generalized Estimating Equation regression and linear regression., Results: A total of 318 children (57.2% males) with a baseline age of 7.64 ± 5.04 years were analyzed. The cumulative steroid dose was 216.4 (IQR 61.5, 652.7) mg/kg (N = 233). Overall, height z-scores were not significantly different at the last follow-up compared to baseline (- 0.13 ± 1.21 vs. - 0.23 ± 1.71, p = 0.21). In models adjusted for age, sex, and eGFR, greater cumulative steroid exposure (β - 7.5 × 10 -6 , CI - 1.2 × 10 -5 , - 3 × 10 -6 , p = 0.001) and incident cases of NS (vs. prevalent) (β - 1.1, CI - 2.22, - 0.11, p = 0.03) were significantly associated with lower height z-scores over time. Rituximab exposure was associated with higher height z-scores (β 0.16, CI 0.04, 0.29, p = 0.01) over time., Conclusion: Steroid dose was associated with lower height z-score, while rituximab use was associated with higher height z-score., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

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., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Objectives: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) commonly presents with diffuse alveolar haemorrhage (DAH) and/or glomerulonephritis. Patients who present with DAH but without kidney involvement have been understudied., Methods: Patients with DAH diagnosed by bronchoscopy and attributed to AAV over 8.5 years were retrospectively identified through electronic medical records and bronchoscopy reporting software. Patients with end-stage kidney disease (ESKD) or prior kidney transplant were excluded. Characteristics, treatments, and outcomes were abstracted., Results: 30 patients were identified with DAH secondary to AAV. Five with ESKD or prior kidney transplant, and one with concomitant anti-glomerular basement membrane disease, were excluded, leaving 24 patients for analysis. At the time of qualifying bronchoscopy, six patients had no apparent kidney involvement by AAV, while eight of 18 with kidney involvement required dialysis. Of the eight patients dialysed during the initial hospitalisation, four were declared to have ESKD and three died in the subsequent year (one of whom did both). None of the 16 patients without initial dialysis requirement developed kidney involvement requiring dialysis in the subsequent year, though three of the six without initial evidence of kidney involvement by AAV ultimately developed it. No patient without initial kidney involvement died during follow-up., Conclusions: In our cohort, patients with DAH due to AAV without initial kidney involvement did not develop kidney involvement requiring dialysis or die during the follow-up period, though half of patients without initial evidence of kidney involvement subsequently developed it. Larger studies are warranted to better characterise this population and guide medical management.

Background: Deposition of wild-type or mutant transthyretin (TTR) amyloid fibrils in the myocardium causes TTR amyloid cardiomyopathy (ATTR-CM). Targeted therapeutics for ATTR-CM include TTR stabilizers (tafamidis and diflunisal) and oligonucleotide drugs (revusiran, patisiran, and inotersen). TTR stabilizers prevent dissociation of transthyretin tetramers. Transthyretin monomers can misfold and form amyloid fibrils. TTR stabilizers thereby limit amyloid fibrils development and deposition. Oligonucleotide drugs inhibit hepatic synthesis of transthyretin, which decreases transthyretin protein levels and thus the amyloid fibril substrate., Areas of Uncertainty: To study the safety and efficacy of targeted therapeutics in patients with ATTR-CM, we performed a pooled analysis. A random-effects model with the Mantel-Haenszel method was used to pool the data., Data Sources: A literature search was performed using PubMed, Cochrane CENTRAL, and Embase databases using the search terms "cardiac amyloidosis" AND "tafamidis" OR "patisiran" OR "inotersen" OR "revusiran" OR "diflunisal.", Therapeutic Advances: We identified 6 studies that compared targeted therapeutics with placebo. One study was stopped prematurely because of increased mortality in the targeted therapeutics arm. Pooled analysis included 1238 patients, of which 738 patients received targeted therapeutics and 500 patients received placebo. When compared with placebo, targeted therapeutics significantly reduced all-cause mortality [OR 0.39, 95% confidence interval (CI): 0.16-0.97, P = 0.04]. Only 2 studies reported the effect on cardiovascular-related hospitalizations. There was a trend toward an improvement in global longitudinal strain (mean difference -0.69, 95% CI: -1.44 to 0.05, P = 0.07). When compared with placebo, there was no increase in serious adverse events with targeted therapeutics (OR 1.06, 95% CI: 0.78-1.44, P = 0.72)., Conclusion: Evidence from the pooled analysis revealed targeted therapeutics improve survival and are well-tolerated. These findings suggest a potential role for targeted therapeutics in the treatment of patients with ATTR-CM., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Although the alternative complement pathway has been implicated in the pathogenesis of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV), the specific nature of its involvement is unclear. This study measured levels of urine and plasma complement fragment Ba at multiple time points in a group of patients with AAV., Methods: The complement fragment Ba was measured by enzyme-linked immunosorbent assay in serial urine and plasma samples from 21 patients with AAV who developed a renal flare, 19 who developed a nonrenal flare, and 20 in long-term remission. Urine Ba levels were corrected for urine creatinine concentration. Changes in Ba levels were modeled using mixed linear-effect models. A logistic regression model was fit to predict a renal flare using Ba levels at the time of flare versus the nonrenal flare and long-term remission groups., Results: Data from 60 patients with AAV were used for this analysis; 53% were male, 93% were White, and 74% had antiproteinase3-ANCA. Urine Ba levels increased at renal flare ( P  < 0.001) but remained stable during a nonrenal flare or long-term remission. Plasma Ba levels were stable over time in all groups. Urine Ba levels predicted a renal flare with an area under the curve of 0.76 ( P  < 0.001), with a cutoff of 12.53 ng/mg urine creatinine yielding a sensitivity of 76.2% and a specificity of 68.4%., Conclusion: Urine Ba levels, but not plasma Ba levels, are increased at the time of a renal flare in AAV, suggesting intrarenal complement activation and highlighting the potential use of this biomarker for surveillance of active renal vasculitis.

Glomerular diseases (GDs) represent the third leading cause of end-stage kidney disease (ESKD) in the US Diabetes was excluded from the CureGN Study, an NIH/NIDDK-sponsored observational cohort study of four leading primary GDs: IgA nephropathy (IgAN), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), and minimal change disease (MCD). CureGN-Diabetes, an ancillary study to CureGN, seeks to understand how diabetes influences the diagnosis, treatment, and outcomes of GD. It is a multicenter, prospective cohort study, targeting an enrollment of 300 adults with prevalent type 1 or type 2 diabetes and MCD, FSGS, MN, or IgAN, with first kidney biopsy obtained within 5 years of enrollment in 80% (20% allowed if biopsy after 2010). CureGN and Transformative Research in DiabEtic NephropaThy (TRIDENT) provide comparator cohorts. Retrospective and prospective clinical data and patient-reported outcomes are obtained. Blood and urine specimens are collected at study visits annually. Kidney biopsy reports and digital images are obtained, and standardized pathologic evaluations performed. Light microscopy images are uploaded to the NIH pathology repository. Outcomes include relapse and remission rates, changes in proteinuria and estimated glomerular filtration rate, infections, cardiovascular events, malignancy, ESKD, and death. Multiple analytical approaches will be used leveraging the baseline and longitudinal data to compare disease presentation and progression across subgroups of interest. With 300 patients and an average of 3 years of follow-up, the study has 80% power to detect a HR of 1.4-1.8 for time to complete remission of proteinuria, a rate ratio for hospitalizations of 1.18-1.56 and difference in eGFR slope of 6.0-8.6 mL/min/year between two groups of 300 participants each. CureGN-Diabetes will enhance our understanding of diabetes as a modifying factor of the pathology and outcomes of GDs and support studies to identify disease mechanisms and improve patient outcomes in this understudied patient population., Competing Interests: None of the authors have a COI related to this study. A.K.M. has received research support from Alexion, Bayer, Boehringer-Ingelheim, Calliditas, Duke Clinical Research Institute, and Pfizer; consulting fees from Bayer; and royalties from UpToDate. L.H.M. receives research support from Boehringer-Ingelheim and Travere Therapeutics; consulting fees from Reata Pharmaceuticals, Chinook Therapeutics, Travere Therapeutics, and Calliditas Therapeutics., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

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., (Copyright © 2022 National Kidney Foundation, Inc. All rights reserved.)

Introduction: Preeclampsia increases the risk for future chronic kidney disease (CKD). Among those diagnosed with CKD, it is unclear whether a prior history of preeclampsia, or other complications in pregnancy, negatively impact kidney disease progression. In this longitudinal analysis, we assessed kidney disease progression among women with glomerular disease with and without a history of a complicated pregnancy., Methods: Adult women enrolled in the Cure Glomerulonephropathy study (CureGN) were classified based on a history of a complicated pregnancy (defined by presence of worsening kidney function, proteinuria, or blood pressure; or a diagnosis of preeclampsia, eclampsia, or hemolysis, elevated liver enzymes, and low platelets [HELLP] syndrome), pregnancy without these complications, or no pregnancy history at CureGN enrollment. Linear mixed models were used to assess estimated glomerular filtration rate (eGFR) trajectories and urine protein-to-creatinine ratios (UPCRs) from enrollment., Results: Over a median follow-up period of 36 months, the adjusted decline in eGFR was greater in women with a history of a complicated pregnancy compared to those with uncomplicated or no pregnancies (-1.96 [-2.67, -1.26] vs. -0.80 [-1.19, -0.42] and -0.64 [-1.17, -0.11] ml/min per 1.73 m 2 per year, P  = 0.007). Proteinuria did not differ significantly over time. Among those with a complicated pregnancy history, eGFR slope did not differ by timing of first complicated pregnancy relative to glomerular disease diagnosis., Conclusions: A history of complicated pregnancy was associated with greater eGFR decline in the years following glomerulonephropathy (GN) diagnosis. A detailed obstetric history may inform counseling regarding disease progression in women with glomerular disease. Continued research is necessary to better understand pathophysiologic mechanisms by which complicated pregnancies contribute to glomerular disease progression., (.)

Introduction: Glomerulonephritis (GN) with crescents and IgA deposits in kidney biopsy poses a frequent diagnostic and therapeutic dilemma because of multiple possibilities., Methods: Native kidney biopsies showing glomerular IgA deposition and crescents (excluding lupus nephritis) were identified from our biopsy archives between 2010 and 2021. Detailed clinicopathologic features were assessed. One-year clinical follow-up on a subset of cases was obtained., Results: A total of 285 cases were identified, and these clustered into IgA nephropathy (IgAN, n  = 108), Staphylococcus or other infection-associated GN/infection-related GN (SAGN/IRGN, n  = 43), and antineutrophil cytoplasmic antibody-associated GN (ANCA-GN, n  = 26) based on a constellation of clinicopathologic features, but 101 cases (group X) could not be definitively differentiated. The reasons have been elucidated, most important being atypical combination of clinicopathologic features and lack of definitive evidence of active infection. Follow-up (on 72/101 cases) revealed that clinicians' working diagnosis was IgAN in 43%, SAGN/IRGN in 22%, ANCA-GN in 28%, and others in 7% of the cases, but treatment approach varied from supportive or antibiotics to immunosuppression in each subgroup. Comparing these cases as "received immunosuppression" versus "non-immunosuppression," only 2 features differed, namely C3-dominant staining, and possibility of recent infection (both higher in the no-immunosuppression group) ( P  < 0.05). Renal loss was higher in the non-immunosuppression subgroup, but not statistically significant ( P  = 0.11)., Conclusion: Diagnostic overlap may remain unresolved in a substantial number of kidney biopsies with glomerular crescents and IgA deposits. A case-by-case approach, appropriate antibiotics if infection is ongoing, and consideration for cautious immunosuppressive treatment for progressive renal dysfunction may be needed for best chance of renal recovery., (© 2022 Published by Elsevier Inc. on behalf of the International Society of Nephrology.)

The immune pathways that define treatment response and non-response in lupus nephritis (LN) are unknown. To characterize these intra-kidney pathways, transcriptomic analysis was done on protocol kidney biopsies obtained at flare (initial biopsy (Bx1)) and after treatment (second biopsy (Bx2)) in 58 patients with LN. Glomeruli and tubulointerstitial compartments were isolated using laser microdissection. RNA was extracted and analyzed by nanostring technology with transcript expression from clinically complete responders, partial responders and non-responders compared at Bx1 and Bx2 and to the healthy controls. Top transcripts that differentiate clinically complete responders from non-responders were validated at the protein level by confocal microscopy and urine ELISA. At Bx1, cluster analysis determined that glomerular integrin, neutrophil, chemokines/cytokines and tubulointerstitial chemokines, T cell and leukocyte adhesion genes were able to differentiate non-responders from clinically complete responders. At Bx2, glomerular monocyte, extracellular matrix, and interferon, and tubulointerstitial interferon, complement, and T cell transcripts differentiated non-responders from clinically complete responders. Protein analysis identified several protein products of overexpressed glomerular and tubulointerstitial transcripts at LN flare, recapitulating top transcript findings. Urine complement component 5a and fibronectin-1 protein levels reflected complement and fibronectin expression at flare and after treatment. Thus, transcript analysis of serial LN kidney biopsies demonstrated how gene expression in the kidney changes with clinically successful and unsuccessful therapy. Hence, these insights into the molecular landscape of response and non-response may help align LN management with the pathogenesis of kidney injury., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Beta-adrenergic antagonists or blockers (BB) are a cornerstone of cardiac therapy for multiple indications. However, BB are considered relatively contraindicated in amyloid cardiomyopathy due to poor tolerance. This intolerance is hypothesized to be due to concomitant neuropathy and significant restrictive cardiomyopathy. This study analyzes the incidence and characteristics of BB tolerance in patients with amyloid cardiomyopathy., Methods: Through a single-center retrospective chart review, patients with amyloid cardiomyopathy, confirmed by endomyocardial biopsy or technetium-99 pyrophosphate scan, were identified and clinical data was collected. Statistical methods included Chi-square test and two sample t -tests., Results: Of 135 cardiac amyloidosis patients, 27 patients (20.0%) had no BB use, 56 patients (41.5%) were current BB users, and 52 patients (38.5%) were prior BB users. The most frequent indications for BB use were heart failure, hypertension, coronary artery disease, and arrhythmia. The most common reason for stopping BB therapy was hypotension (62.8%) followed by fatigue, bradycardia, and orthostasis. Neurologic symptoms at the initial BB prescription or most recent evaluation were not significantly different between current and prior BB users. Their cardiovascular profiles were similar by ejection fraction, wall thickness, troponin I, and brain natriuretic peptide. There was no association for BB discontinuation based on amyloid subtype, sex, or race., Conclusion: The majority of patients with amyloid cardiomyopathy were prescribed BB, and over half of these patients still tolerated BB therapy. Current and prior BB users had similar profiles from a cardiovascular and neurologic perspective, with no association identified to predict BB discontinuation., Competing Interests: CC reports research support from Alnylam Pharmaceuticals, Akari Therapeutics, and Pfizer, Inc and consultant fees from Alnylam. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ramsell, Arias Bermudez, Takem Baiyee, Rodgers, Parikh, Almaani, Sharma, LoRusso, Freimer, Redder, Bumma, Vallkati, Efebera, Kahwash and Campbell.)

Background: Primary nephrotic syndromes are rare diseases which can impede adequate sample size for observational patient-oriented research and clinical trial enrollment. A computable phenotype may be powerful in identifying patients with these diseases for research across multiple institutions., Methods: A comprehensive algorithm of inclusion and exclusion ICD-9 and ICD-10 codes to identify patients with primary nephrotic syndrome was developed. The algorithm was executed against the PCORnet CDM at three institutions from January 1, 2009 to January 1, 2018, where a random selection of 50 cases and 50 noncases (individuals not meeting case criteria seen within the same calendar year and within 5 years of age of a case) were reviewed by a nephrologist, for a total of 150 cases and 150 noncases reviewed. The classification accuracy (sensitivity, specificity, positive and negative predictive value, F1 score) of the computable phenotype was determined., Results: The algorithm identified a total of 2708 patients with nephrotic syndrome from 4,305,092 distinct patients in the CDM at all sites from 2009 to 2018. For all sites, the sensitivity, specificity, and area under the curve of the algorithm were 99% (95% CI, 97% to 99%), 79% (95% CI, 74% to 85%), and 0.9 (0.84 to 0.97), respectively. The most common causes of false positive classification were secondary FSGS (nine out of 39) and lupus nephritis (nine out of 39)., Conclusion: This computable phenotype had good classification in identifying both children and adults with primary nephrotic syndrome utilizing only ICD-9 and ICD-10 codes, which are available across institutions in the United States. This may facilitate future screening and enrollment for research studies and enable comparative effectiveness research. Further refinements to the algorithm including use of laboratory data or addition of natural language processing may help better distinguish primary and secondary causes of nephrotic syndrome., Competing Interests: C. Tran reports being a scientific advisor or member of Frontiers in Pediatrics Review Editor on the Editorial Board of Pediatric Nephrology. D. Gipson reports having consultancy agreements, through the University of Michigan, with AstraZeneca, Boehringer Ingelheim, Roche/Genentech, and Vertex Pharmaceuticals; reports receiving research funding, through the University of Michigan, from Atrium Health Medical Foundation, Boehringer Ingelheim, Centers for Disease Control, Food and Drug Administration, Goldfinch Bio, National Institutes of Health, Novartis, Reata, and Travere; and reports being a scientific advisor or member of the American Society of Pediatric Nephrology, American Society of Nephrology, and International Society of Pediatric Nephrology. H. Desmond reports receiving research funding through a percentage of salary from the University of Michigan, funded by Boehringer Ingelheim. I. Ayoub reports receiving honoraria from the American College of Rheumatology; reports being a scientific advisor or member of the Journal of Clinical Nephrology (Editorial Board) and the Lupus Foundation of America (advisory board). L. Mariani reports having consultancy agreements with, and receiving honoraria from, Calliditas Therapeutics Advisory Board, CKD Advisory Committee, Reata Pharmaceuticals, and Travere Therapeutics Advisory Board; reports receiving research funding from Boehringer Ingelheim; reports receiving honoraria from American Society of Nephrology Board Review Course and Update; and reports being a scientific advisor or member of Calliditas Therapeutics, Reata Pharmaceuticals, and Travere Therapeutics. M. Denburg reports having consultancy agreements with Trisalus Life Sciences (spouse); reports having an ownership interest in In-Bore LLC (spouse) and Precision Guided Interventions LLC (spouse); reports receiving research funding from Mallinckrodt; reports being a scientific advisor or member of NKF Delaware Valley Medical Advisory Board and Trisalus Life Sciences Scientific Advisory Board (spouse); and reports other interests/relationships with the American Society of Pediatric Nephrology Research and Program Committees and the National Kidney Foundation Pediatric Education Planning Committee. M. Matheny reports consultancy agreements with National Institutes of Health- Veterans Affairs- Department of Defense Pain Management Grant Consortium (PMC3); reports being a scientific advisor or member of Scientific Merit Review Board Study Section, VA Health Services Research and Development (HSR&D), Informatics and Methods Section, the Steering Committee of Indianapolis VA HSR&D Center of Innovation; and the Steering Committee of VA HSR&D VA Information Resource Center. S. Almaani reports having consultancy agreements with Aurinia Pharmaceuticals and Kezar Life Sciences; reports receiving research funding from Gilead Sciences; reports being a scientific advisor or member Clinical Nephrology Editorial Board; and reports speakers bureau from Aurinia Pharmaceuticals. S. Massengill reports having consultancy agreements with Guidepoint Group; reports being a scientific advisor or member of the Editorial Board of online Glomerular Disease Journal (Karger Publishers). All remaining authors have nothing to disclose., (Copyright © 2021 by the American Society of Nephrology.)

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 between 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; 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% versus 16-23% in the other three groups, p=0.04), and had the worst self-reported global physical health (median score 44.1 versus 48.0-48.2, p<0.001) and fatigue (53.8 versus 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 were 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., Competing Interests: Conflicts of Interest: Dr. Greenbaum reports receiving research support from Vertex Pharmaceuticals, Apellis Pharmaceuticals, Reata Pharmaceuticals, Alexion Pharmaceuticals and an honorarium from Alexion Pharmaceuticals. Dr. Almaani is a consultant for Aurinia Pharmaceuticals Inc. Dr. Reidy is a primary investigator for Complexa and Advicenne studies unrelated to this current manuscript. Dr. Gibson holds advisory roles for Aurinia Inc., Reata Inc., and Retrophin, Inc. Dr. Tuttle has received research support from Goldfinch Bio and Travere/Retrophin and holds an advisory role for Goldfinch Bio. Dr. Sperati reports receiving research support for clinical trials from Alexion Pharmaceuticals and Alnylam, and honoraria for serving as chair of DSMB. All other authors declare that they have no known competing financial interests personal relationships that could appear to influence the work reported in this paper. Results of this paper have not been published previously in whole or part, with the exception of abstract format (ASN Kidney Week 2019).

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) represents a group of small vessel vasculitides characterized by granulomatous and neutrophilic tissue inflammation, often associated with the production of antibodies that target neutrophil antigens. The two major antigens targeted by ANCAs are leukocyte proteinase 3 (PR3) and myeloperoxidase (MPO). AAV can be classified into 3 categories based on patterns of clinical involvement: namely, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic GPA (EGPA). Clinically, AAV involves many organ systems including the lungs, kidneys, skin, and nervous system. The prognosis of AAV has improved dramatically due to advances in the understanding of its pathogenesis and treatment modalities. This review will highlight some of the recent updates in our understanding of the pathogenesis, clinical manifestations, and treatment options in patients with AAV focusing on kidney involvement.

Background: Microscopic analysis of urine sediment is probably the most commonly used diagnostic procedure in nephrology. The urinary cells, however, have not yet undergone careful unbiased characterization., Methods: Single-cell transcriptomic analysis was performed on 17 urine samples obtained from five subjects at two different occasions, using both spot and 24-hour urine collection. A pooled urine sample from multiple healthy individuals served as a reference control. In total 23,082 cells were analyzed. Urinary cells were compared with human kidney and human bladder datasets to understand similarities and differences among the observed cell types., Results: Almost all kidney cell types can be identified in urine, such as podocyte, proximal tubule, loop of Henle, and collecting duct, in addition to macrophages, lymphocytes, and bladder cells. The urinary cell-type composition was subject specific and reasonably stable using different collection methods and over time. Urinary cells clustered with kidney and bladder cells, such as urinary podocytes with kidney podocytes, and principal cells of the kidney and urine, indicating their similarities in gene expression., Conclusions: A reference dataset for cells in human urine was generated. Single-cell transcriptomics enables detection and quantification of almost all types of cells in the kidney and urinary tract., (Copyright © 2021 by the American Society of Nephrology.)

Introduction: Although diabetic kidney disease (DKD) is responsible for more than half of all chronic and end-stage kidney disease (ESKD), the association of light (LM) and electron microscopic (EM) structural changes with clinical parameters and prognosis in DKD is incompletely understood., Methods: This is an interim analysis of 62 patients diagnosed with biopsy-confirmed DKD from the multicenter TRIDENT (Transformative Research in Diabetic Nephropathy) study. Twelve LM and 8 EM descriptors, representing changes in glomeruli, tubulointerstitium, and vasculature were analyzed for their relationship with clinical measures of renal function. Patients were followed every 6 months., Results: Multivariable linear regression analysis revealed that estimated glomerular filtration rate (eGFR) upon enrollment correlated the best with interstitial fibrosis. On the other hand, the rate of kidney function decline (eGFR slope) correlated the most with glomerular lesions including global glomerulosclerosis and mesangiolysis. Unbiased clustering analysis based on histopathologic data identified 3 subgroups. The first cluster, encompassing subjects with the mildest histologic lesions, had the most preserved kidney function. The second and third clusters had similar degrees of kidney dysfunction and structural damage, but differed in the degree of glomerular epithelial cell and podocyte injury (podocytopathy DKD subtype). Cox proportional hazard analysis showed that subjects in cluster 2 had the highest risk to reach ESKD (hazard ratio: 17.89; 95% confidence interval: 2.13-149.79). Glomerular epithelial hyperplasia and interstitial fibrosis were significant predictors of ESKD in the multivariate model., Conclusion: The study highlights the association between fibrosis and kidney function and identifies the role of glomerular epithelial changes and kidney function decline., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)

Background: Systemic light chain (AL) amyloidosis is a clonal plasma-cell neoplasm that carries a poor prognosis. Although AL amyloidosis and Multiple Myeloma (MM) can co-exist and share various cytogenetic chromosomal abnormalities, little is known about Fluorescent in situ hybridization (FISH) and its prognostic relevance in AL amyloidosis., Aim: The study aims to evaluate the most prevalent FISH cytogenetic abnormalities in AL patients as independent prognostic factors, and assess the impact of cytogenetics on the survival of high-risk cardiac AL patients., Materials & Methods: This retrospective study reviewed 113 consecutive AL patients treated at The Ohio State University (OSU). Patients were divided into subgroups based on FISH data obtained within 90 days of diagnosis. Hyperdiploidy was defined as trisomies of at least 2 chromosomal loci. Primary endpoints were progression free survival (PFS) and overall survival (OS). Kaplan Meier curves were used to calculate PFS and OS. The log-rank test and Cox proportional hazard models were used to test the equality of survival functions and further evaluate the differences between groups., Results: FISH abnormalities were detected in 76% of patients. Patients with abnormal FISH trended toward lower overall survival (OS) (p=0.06) and progression free survival (PFS) (p=0.06). The two most prevalent aberrations were translocation t(11;14) (39%) and hyperdiploidy-overall (38%). Hyperdiploidy-overall was associated with worsening PFS (p=0.018) and OS (p=0.03), confirmed in multivariable analysis. Patients with del 13q most frequently had cardiac involvement (p=0.006) and was associated with increased bone marrow plasmacytosis (p=0.02). Cardiac AL patients with no FISH abnormalities had much improved OS (p=0.012) and PFS (p=0.018) CONCLUSIONS: Our findings ultimately reveal the association of hyperdiploidy on survival in AL amyloidosis patients, including the high-risk cardiac AL population., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: Membranous nephropathy (MN) is a common cause of adult nephrotic syndrome that progresses to end-stage kidney disease in up to 40% of cases. It is an autoimmune disease characterized by glomerular subepithelial deposits containing IgG. In experimental MN, these deposits activate complement and cause kidney damage. The role of complement in human MN is less clearly defined. To address this, the current study focused on the role of complement in 2 independent primary (p) MN cohorts., Methods: Glomeruli were isolated by laser capture microdissection and analyzed by mass spectrometry, focusing on complement proteins, from kidney biopsy specimens from a pMN cohort (n = 11) and from normal controls (n = 5). Immunohistological staining of kidney biopsy specimens for complement proteins was also done. In a second pMN cohort (n = 13), urine levels of Ba, C5a, and C5b-9 (membrane attack complex [MAC]) were measured., Results: Mass spectrometry identified 8 complement pathway components (C1q, C3, C4, C5, C6, C7, C8, and C9) and 5 complement regulators (complement receptor type 1 [CR1], factor H [FH], FH-related protein 2 [FHR2], vitronectin, and clusterin). All complement levels were significantly higher in the MN groups than in the control group, except the level of CR1, which was lower. All pMN biopsy specimens showed negative or trace staining for C1q, positive staining for C3 and C4, and positive staining for at least 1 component of the lectin pathway. Urine Ba, C5a, and MAC were present in pMN, and their levels correlated ( r Ba,C5a  = 0.87, r Ba,MAC  = 0.89, and r C5a,MAC  = 0.97, P  = .001 for each correlation)., Conclusion: Elevated glomerular levels of C3, C4, and components of MAC (C5b-9) and absent or decreased levels of the complement regulator CR1, along with increased levels of complement activation products in the urine, support the involvement of complement in the pathogenesis of MN. These data raise the possibility that anti-complement therapies may be effective in some forms of MN., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)

Background: Autologous stem cell transplantation (ASCT) remains an effective treatment option for many patients with systemic light chain (AL) amyloidosis. While maintenance post ASCT in multiple myeloma is now standard, the decision to utilize maintenance in AL amyloidosis remains largely unexplored. The present study aims to determine the prognostic significance of utilizing maintenance therapy following ASCT and assess the impact of fluorescent in situ hybridization (FISH) abnormalities, bone marrow plasma cell burden (BMPC), and degree of organ involvement on this decision., Methods and Results: This is a retrospective analysis of fifty AL amyloidosis patients who underwent ASCT at The Ohio State University. Twenty-eight patients received maintenance and twenty-two did not. Kaplan-Meier survival analysis was used to compare the effect of maintenance therapy with no significant difference in PFS ( p = 0.66) and OS ( p = 0.32) between the two groups. There was no difference in survival based on maintenance when further categorized by FISH, PFS ( p = 0.15), and OS ( p = 0.65); BMPC ≥ 10%, PFS ( p = 0.49), and OS ( p = 0.32); or with 2 or more organs involved, PFS ( p = 0.34) and OS ( p = 0.80)., Conclusion: Maintenance therapy post ASCT did not impact PFS or OS when categorized by FISH abnormalities, increasing BMPC, or ≥2 organs involved in AL amyloidosis patients.

Systemic lupus erythematosus is a multisystem autoimmune disease that commonly affects the kidneys. Lupus nephritis (LN) is the most common cause of kidney injury in systemic lupus erythematosus and a major risk factor for morbidity and mortality. The pathophysiology of LN is heterogeneous. Genetic and environmental factors likely contribute to this heterogeneity. Despite improved understanding of the pathogenesis of LN, treatment advances have been few and risk for kidney failure remains unacceptably high. This installment in the Core Curriculum of Nephrology provides an up-to-date review of the current understanding of LN epidemiology, pathogenesis, diagnosis, and treatment. Challenging issues such as the management of LN in pregnancy, timing of transplantation, and the evolving role of corticosteroid use in the management of LN are discussed. We review the currently accepted approach to care for patients with LN and highlight deficiencies that need to be addressed to better preserve long-term kidney health and improve outcomes in LN., (Copyright © 2020 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

The International Society of Nephrology/Renal Pathology Society (ISN/RPS) lupus nephritis (LN) classification is under reconsideration, given challenges with inter-rater reliability and resultant inconsistent relationship with treatment response. Integration of molecular classifiers into histologic evaluation can improve diagnostic precision and identify therapeutic targets. This study described the relationship between histological and molecular phenotypes and clinical responses in LN. Renal compartmental mRNA abundance was measured in 54 biopsy specimens from LN patients and correlated to ISN/RPS classification and individual histologic lesions. A subset of transcripts was also evaluated in sequential biopsies of a separate longitudinal cohort of 36 patients with paired samples obtained at the time of flare and at follow up. Unsupervised clustering based on mRNA abundance did not demonstrate a relationship with the (ISN/RPS) classification, nor did univariate statistical analysis. Exploratory analyses suggested a correlation with individual histologic lesions. Glomerular FN1 (fibronectin), SPP1 (secreted phosphoprotein 1), and LGALS3 (galectin 3) abundance correlated with disease activity and changed following treatment. Exploratory analyses suggested relationships between specific transcripts and individual histologic lesions, with the important representation of interferon-regulated genes. Our findings suggested that the current LN classification could be refined by the inclusion of molecular descriptors. Combining molecular and pathologic kidney biopsy phenotypes may hold promise to better classify disease and identify actionable treatment targets and merits further exploration in larger cohorts.

The kidney biopsy advanced our understanding of kidney disease in systemic lupus erythematosus. It allowed for better recognition and classification of lupus nephritis (LN). Several LN classifications have been devised in an effort to inform treatment decision and predict prognosis, and these are being further updated. In this review, we will examine the role of diagnostic as well as repeat kidney biopsy in the management of LN, including the potential role of molecular interrogation as a step forward beyond conventional histology to guide the discovery of novel biomarkers and a precision medicine approach to the management of LN., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Membranous lupus nephritis (MLN) (Class V lupus nephritis [LN]) is a distinct form of LN defined by the presence of subepithelial immune complex deposits seen on kidney biopsy. MLN is often associated with the nephrotic syndrome. The histology of MLN closely resembles that of idiopathic (primary) membranous nephropathy (pMN). However, MLN typically has abundant mesangial deposits that are absent in primary membranous nephropathy. The clinical presentation, management, and prognosis of MLN differ from that of the proliferative forms of LN (Class III, IV, or Mixed III/IV + V). Although immunosuppressive therapy is often warranted in MLN, the optimal treatment regimen remains unclear. Here we describe the clinical presentation, histologic features, and natural history of MLN. We also review the role of supportive treatment and discuss when to deploy immunosuppressive management in MLN., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Anti-phospholipase A2 receptor (PLA2R) antibody is a specific biomarker for primary membranous nephropathy (MN). Testing positive for anti-PLA2R has been postulated to establish a diagnosis of MN in the absence of a kidney biopsy. Bobart et al. tested this hypothesis and concluded that anti-PLA2R positivity is sufficient to diagnose primary MN and initiate treatment in a subset of patients with nephropathy. This biomarker, however, does not render the kidney biopsy obsolete, but encourages the application of molecular analyses to renal pathology to keep the biopsy relevant., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Systemic lupus erythematosus (SLE) is an autoimmune multisystem disease that commonly affects the kidneys. It is characterized by persistent autoantibody production that targets a multitude of self-antigens. B-cells, plasmablasts and plasma cells, as the source of these autoantibodies, play a major role in the development of lupus nephritis (LN), and are therefore promising therapeutic targets. To date, however, randomized clinical trials of B-cell therapies in LN have not lived up to expectations, whereas uncontrolled cohort and observational studies of B-cell antagonists have been more promising. In this article, we will review the current experience with B-cell therapy in LN and highlight the pitfalls that may have limited their success. We will conclude by suggesting B-cell-centric approaches to the management of LN based on what has been learned from the overall B-cell experience in SLE.

SLE is a chronic inflammatory disease that affects the kidneys in about 50% of patients. Lupus nephritis is a major risk factor for overall morbidity and mortality in SLE, and despite potent anti-inflammatory and immunosuppressive therapies still ends in CKD or ESRD for too many patients. This review highlights recent updates in our understanding of disease epidemiology, genetics, pathogenesis, and treatment in an effort to establish a framework for lupus nephritis management that is patient-specific and oriented toward maintaining long-term kidney function in patients with lupus., (Copyright © 2017 by the American Society of Nephrology.)

Patients enrolled in the African American Study of Kidney Disease and Hypertension (AASK) Cohort Study who exhibited overt proteinuria have been reported to show high nonalbumin proteinuria (NAP), which is characteristic of a tubulopathy. To determine whether African American Study of Kidney Disease and Hypertension nephropathy (AASK-N) is a tubulopathy, we obtained urine samples of 37 patients with AASK-N, with 24-hour protein-to-creatinine ratios (milligrams per milligram) ranging from 0.2 to 1.0, from the National Institute of Diabetes and Digestive Kidney Diseases repository and tested for seven markers of tubular proteinuria. By protocol, each sample had been collected in acetic acid (0.5%; mean final concentration). Compared with samples from patients with lupus nephritis or healthy black controls, AASK-N samples had lower amounts of six markers. Four markers (albumin, β -2-microglobulin, cystatin C, and osteopontin) were undetectable in most AASK-N samples. Examination by SDS-PAGE followed by protein staining revealed protein profiles indicative of severe protein degradation in 34 of 37 AASK-N urine samples. Treatment of lupus nephritis urine samples with 0.5% acetic acid produced the same protein degradation profile as that of AASK-N urine. We conclude that the increased NAP in AASK-N is an artifact of acetic acid-mediated degradation of albumin. The AASK-N repository urine samples have been compromised by the acetic acid preservative., (Copyright © 2017 by the American Society of Nephrology.)

Background: It is well-established from autopsy studies that gouty tophi can form in the kidney, particularly in the renal medulla. Recently hyperuricemia has been identified as a risk factor for progression of chronic kidney disease (CKD). Because each collecting duct serves more than 2,000 nephrons, we postulated that obstruction or disruption of collecting ducts by medullary tophi may explain, at least in part, the association between hyperuricemia and progressive CKD. This work was done to determine the prevalence of medullary tophi in CKD patients., Methods: We queried our nephropathology database over the last 10 years for native kidney biopsies that had medullary tophi. The presence or absence of CKD and uric acid levels around the time of biopsy were determined by chart review., Results: Predominant medullary tissue was reported in 796 of 7,409 total biopsies, and 572 of these were from patients with established CKD. Medullary tophi were seen in 36 patients, 35 of whom had CKD, suggesting a minimum prevalence of tophi in CKD and no-CKD of 6.11 and 0.45%, respectively Medullary tophi occurred with and without hyperuricemia or a history of gout., Conclusion: Medullary tophi appear to be far more likely to occur in CKD compared to no-CKD patients. This cross-sectional study cannot determine whether medullary tophi are a cause or consequence of CKD. However, given their location and bulk, it is possible that medullary tophi contribute to progression of established CKD by causing upstream nephron damage.

Objective: Hyperphosphatemia in end-stage renal disease is associated with significant morbidity and mortality. Because phosphorus is not effectively dialyzed, dietary adherence remains a significant problem. Previous studies have examined the health belief model, but none have looked at stages of change and dietary adherence in patients undergoing hemodialysis (HD)., Design: Cross-sectional survey., Setting: Three dialysis centers in Columbus, Ohio, between August 2012 and March 2013., Subjects: English-speaking patients age 18 or older on HD without dementia or developmental delay., Intervention: None., Main Outcome Measure: Associations between dietary adherence based on the Precaution Adoption Process Model (stages of change) and serum phosphorus levels via a conceptual model incorporating modifying factors and individual health beliefs., Results: Ninety-five patients completed the survey; 59 (62%) endorsed adherence to a low-phosphorus diet and 32 (34%) had phosphorus values ≤5.5 mg/dL. Modifying factors associated with diet adherence included nonminority status odds ratio (OR), 95%CI 8.99 (1.08-74.60), greater level of education OR 18.23 (1.62-205.00), better quality of life OR 9.28 (1.35-63.71), and time on dialysis OR 1.04 (1.01-1.07). Individual health beliefs associated with diet adherence included perceived benefits OR 3.18 (1.47-6.88) and self-efficacy OR 1.22 (1.09-1.38). Modifying factors associated with phosphorus control included: age OR 0.94 (0.90-0.99), minority status OR 0.11 (0.02-0.68), greater level of education OR 6.60 (1.41-31.04), knowledge about chronic kidney disease OR 1.48 (1.03-2.13), and time on dialysis OR 0.98 (0.96-0.99). Individual health beliefs associated with phosphorus control included self-efficacy OR 1.08 (1.01-1.16)., Conclusion: HD clinicians and educators may obtain better results with dietary adherence and phosphorus control if they focus not only toward disease and dietary education but also on understanding modifying factors and individual health beliefs. Assessing where the patient is with regard to stages of change may assist health care providers in better matching interventions that build patients' self-efficacy., (Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)