Browsing by Author "Mariani, Laura H."

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    An atlas of healthy and injured cell states and niches in the human kidney
    (Springer Nature, 2023) Lake, Blue B.; Menon, Rajasree; Winfree, Seth; Hu, Qiwen; Ferreira, Ricardo Melo; Kalhor, Kian; Barwinska, Daria; Otto, Edgar A.; Ferkowicz, Michael; Diep, Dinh; Plongthongkum, Nongluk; Knoten, Amanda; Urata, Sarah; Mariani, Laura H.; Naik, Abhijit S.; Eddy, Sean; Zhang, Bo; Wu, Yan; Salamon, Diane; Williams, James C.; Wang, Xin; Balderrama, Karol S.; Hoover, Paul J.; Murray, Evan; Marshall, Jamie L.; Noel, Teia; Vijayan, Anitha; Hartman, Austin; Chen, Fei; Waikar, Sushrut S.; Rosas, Sylvia E.; Wilson, Francis P.; Palevsky, Paul M.; Kiryluk, Krzysztof; Sedor, John R.; Toto, Robert D.; Parikh, Chirag R.; Kim, Eric H.; Satija, Rahul; Greka, Anna; Macosko, Evan Z.; Kharchenko, Peter V.; Gaut, Joseph P.; Hodgin, Jeffrey B.; KPMP Consortium; Eadon, Michael T.; Dagher, Pierre C.; El-Achkar, Tarek M.; Zhang, Kun; Kretzler, Matthias; Jain, Sanjay; Medicine, School of Medicine
    Understanding kidney disease relies on defining the complexity of cell types and states, their associated molecular profiles and interactions within tissue neighbourhoods1. Here we applied multiple single-cell and single-nucleus assays (>400,000 nuclei or cells) and spatial imaging technologies to a broad spectrum of healthy reference kidneys (45 donors) and diseased kidneys (48 patients). This has provided a high-resolution cellular atlas of 51 main cell types, which include rare and previously undescribed cell populations. The multi-omic approach provides detailed transcriptomic profiles, regulatory factors and spatial localizations spanning the entire kidney. We also define 28 cellular states across nephron segments and interstitium that were altered in kidney injury, encompassing cycling, adaptive (successful or maladaptive repair), transitioning and degenerative states. Molecular signatures permitted the localization of these states within injury neighbourhoods using spatial transcriptomics, while large-scale 3D imaging analysis (around 1.2 million neighbourhoods) provided corresponding linkages to active immune responses. These analyses defined biological pathways that are relevant to injury time-course and niches, including signatures underlying epithelial repair that predicted maladaptive states associated with a decline in kidney function. This integrated multimodal spatial cell atlas of healthy and diseased human kidneys represents a comprehensive benchmark of cellular states, neighbourhoods, outcome-associated signatures and publicly available interactive visualizations.
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    Association of COVID-19 Versus COVID-19 Vaccination With Kidney Function and Disease Activity in Primary Glomerular Disease: A Report of the Cure Glomerulonephropathy Study
    (Elsevier, 2024) Wang, Chia-shi; Glenn, Dorey A.; Helmuth, Margaret; Smith, Abigail R.; Bomback, Andrew S.; Canetta, Pietro A.; Coppock, Gaia M.; Khalid, Myda; Tuttle, Katherine R.; Bou-Matar, Raed; Greenbaum, Larry A.; Robinson, Bruce M.; Holzman, Lawrence B.; Smoyer, William E.; Rheault, Michelle N.; Gipson, Debbie; Mariani, Laura H.; Cure Glomerulonephropathy (CureGN) Study Consortium; Pediatrics, School of Medicine
    Rationale & objective: Patients with glomerular disease (GN) may be at increased risk of severe COVID-19, yet concerns over vaccines causing disease relapse may lead to vaccine hesitancy. We examined the associations of COVID-19 with longitudinal kidney function and proteinuria and compared these with similar associations with COVID-19 vaccination. Study design: Observational cohort study from July 1, 2021, to January 1, 2023. Setting & participants: A prospective observational study network of 71 centers from North America and Europe (CureGN) with children and adults with primary minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy. Exposure: COVID-19 and COVID-19 vaccination. Outcome: Repeated measure of estimated glomerular filtration rate (eGFR); recurrent time-to-event outcome of GN disease worsening as defined by doubling of the urinary protein-creatinine ratio (UPCR) to at least 1.5g/g or increase in dipstick urine protein by 2 ordinal levels to 3+(300mg/dL) or above. Analytical approach: Interrupted time series analysis for eGFR. Prognostic matched sequential stratification recurrent event analysis for GN disease worsening. Results: Among 2,055 participants, 722 (35%) reported COVID-19 infection; of these, 92 (13%) were hospitalized, and 3 died (<1%). The eGFR slope before COVID-19 infection was-1.40mL/min/1.73m2 (± 0.29 SD); within 6 months after COVID-19 infection, the eGFR slope was-4.26mL/min/1.73m2 (± 3.02 SD), which was not significantly different (P=0.34). COVID-19 was associated with increased risk of worsening GN disease activity (HR, 1.35 [95% CI, 1.01-1.80]). Vaccination was not associated with a change in eGFR (-1.34mL/min/1.73m2±0.15 SD vs-2.16mL/min/1.73m2±1.74 SD; P=0.6) or subsequent GN disease worsening (HR 1.02 [95% CI, 0.79-1.33]) in this cohort. Limitations: Infrequent or short follow-up. Conclusions: Among patients with primary GN, COVID-19 infection was severe for 1 in 8 cases and was associated with subsequent worsening of GN disease activity, as defined by proteinuria. By contrast, vaccination against COVID-19 was not associated with change in disease activity or kidney function decline. These results support COVID-19 vaccination for patients with GN. Plain-language summary: In this cohort study of 2,055 patients with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy, COVID-19 resulted in hospitalization or death for 1 in 8 cases and was associated with a 35% increase in risk for worsening proteinuria. By contrast, vaccination did not appear to adversely affect kidney function or proteinuria. Our data support vaccination for COVID-19 in patients with glomerular disease.
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    Effects of Bardoxolone Methyl in Alport Syndrome
    (Wolters Kluwer, 2022-12) Warady, Bradley A.; Pergola, Pablo E.; Agarwal, Rajiv; Andreoli, Sharon; Appel, Gerald B.; Bangalore, Sripal; Block, Geoffrey A.; Chapman, Arlene B.; Chin, Melanie P.; Gibson , Keisha L.; Goldsberry, Angie; Iijima, Kazumoto; Inker, Lesley A.; Kashtan, Clifford E.; Knebelmann, Bertrand; Mariani, Laura H.; Meyer, Colin J.; Nozu, Kandai; O’Grady, Megan; Rheault, Michelle N.; Silva, Arnold L.; Stenvinkel, Peter; Torra, Roser; Chertow, Glenn M.; Medicine, School of Medicine
    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
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    Rationale and design of the Kidney Precision Medicine Project
    (Elsevier, 2021) de Boer, Ian H.; Alpers, Charles E.; Azeloglu, Evren U.; Balis, Ulysses G. J.; Barasch, Jonathan M.; Barisoni, Laura; Blank, Kristina N.; Bomback, Andrew S.; Brown, Keith; Dagher, Pierre C.; Dighe, Ashveena L.; Eadon, Michael T.; El-Achkar, Tarek M.; Gaut, Joseph P.; Hacohen, Nir; He, Yongqun; Hodgin, Jeffrey B.; Jain, Sanjay; Kellum, John A.; Kiryluk, Krzysztof; Knight, Richard; Laszik, Zoltan G.; Lienczewski, Chrysta; Mariani, Laura H.; McClelland, Robyn L.; Menez, Steven; Moledina, Dennis G.; Mooney, Sean D.; O'Toole, John F.; Palevsky, Paul M.; Parikh, Chirag R.; Poggio, Emilio D.; Rosas, Sylvia E.; Rosengart, Matthew R.; Sarwal, Minnie M.; Schaub, Jennifer A.; Sedor, John R.; Sharma, Kumar; Steck, Becky; Toto, Robert D.; Troyanskaya, Olga G.; Tuttle, Katherine R.; Vazquez, Miguel A.; Waikar, Sushrut S.; Williams, Kayleen; Wilson, Francis Perry; Zhang, Kun; Iyengar, Ravi; Kretzler, Matthias; Himmelfarb, Jonathan; Kidney Precision Medicine Project; Medicine, School of Medicine
    Chronic kidney disease (CKD) and acute kidney injury (AKI) are common, heterogeneous, and morbid diseases. Mechanistic characterization of CKD and AKI in patients may facilitate a precision-medicine approach to prevention, diagnosis, and treatment. The Kidney Precision Medicine Project aims to ethically and safely obtain kidney biopsies from participants with CKD or AKI, create a reference kidney atlas, and characterize disease subgroups to stratify patients based on molecular features of disease, clinical characteristics, and associated outcomes. An additional aim is to identify critical cells, pathways, and targets for novel therapies and preventive strategies. This project is a multicenter prospective cohort study of adults with CKD or AKI who undergo a protocol kidney biopsy for research purposes. This investigation focuses on kidney diseases that are most prevalent and therefore substantially burden the public health, including CKD attributed to diabetes or hypertension and AKI attributed to ischemic and toxic injuries. Reference kidney tissues (for example, living-donor kidney biopsies) will also be evaluated. Traditional and digital pathology will be combined with transcriptomic, proteomic, and metabolomic analysis of the kidney tissue as well as deep clinical phenotyping for supervised and unsupervised subgroup analysis and systems biology analysis. Participants will be followed prospectively for 10 years to ascertain clinical outcomes. Cell types, locations, and functions will be characterized in health and disease in an open, searchable, online kidney tissue atlas. All data from the Kidney Precision Medicine Project will be made readily available for broad use by scientists, clinicians, and patients.
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    Scaffold protein SH3BP2 signalosome is pivotal for immune activation in nephrotic syndrome
    (American Society for Clinical Investigation, 2024-02-08) Srivastava, Tarak; Garola, Robert E.; Zhou, Jianping; Boinpelly, Varun C.; Rezaiekhaligh, Mohammad H.; Joshi, Trupti; Jiang, Yuexu; Ebadi, Diba; Sharma, Siddarth; Sethna, Christine; Staggs, Vincent S.; Sharma, Ram; Gipson, Debbie S.; Hao, Wei; Wang, Yujie; Mariani, Laura H.; Hodgin, Jeffrey B.; Rottapel, Robert; Yoshitaka, Teruhito; Ueki, Yasuyoshi; Sharma, Mukut; Biomedical and Applied Sciences, School of Dentistry
    Despite clinical use of immunosuppressive agents, the immunopathogenesis of minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) remains unclear. Src homology 3-binding protein 2 (SH3BP2), a scaffold protein, forms an immune signaling complex (signalosome) with 17 other proteins, including phospholipase Cγ2 (PLCγ2) and Rho-guanine nucleotide exchange factor VAV2 (VAV2). Bioinformatic analysis of human glomerular transcriptome (Nephrotic Syndrome Study Network cohort) revealed upregulated SH3BP2 in MCD and FSGS. The SH3BP2 signalosome score and downstream MyD88, TRIF, and NFATc1 were significantly upregulated in MCD and FSGS. Immune pathway activation scores for Toll-like receptors, cytokine-cytokine receptor, and NOD-like receptors were increased in FSGS. Lower SH3BP2 signalosome score was associated with MCD, higher estimated glomerular filtration rate, and remission. Further work using Sh3bp2KI/KI transgenic mice with a gain-in-function mutation showed ~6-fold and ~25-fold increases in albuminuria at 4 and 12 weeks, respectively. Decreased serum albumin and unchanged serum creatinine were observed at 12 weeks. Sh3bp2KI/KI kidney morphology appeared normal except for increased mesangial cellularity and patchy foot process fusion without electron-dense deposits. SH3BP2 co-immunoprecipitated with PLCγ2 and VAV2 in human podocytes, underscoring the importance of SH3BP2 in immune activation. SH3BP2 and its binding partners may determine the immune activation pathways resulting in podocyte injury leading to loss of the glomerular filtration barrier.
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    Study Design and Baseline Characteristics of the CARDINAL Trial: A Phase 3 Study of Bardoxolone Methyl in Patients with Alport Syndrome
    (Karger, 2021) Chertow, Glenn M.; Appel, Gerald B.; Andreoli, Sharon; Bangalore, Sripal; Block, Geoffrey A.; Chapman, Arlene B.; Chin, Melanie P.; Gibson, Keisha L.; Goldsberry, Angie; Iijima, Kazumoto; Inker, Lesley A.; Knebelmann, Bertrand; Mariani, Laura H.; Meyer, Colin J.; Nozu, Kandai; O'Grady, Megan; Silva, Arnold L.; Stenvinkel, Peter; Torra, Roser; Warady, Bradley A.; Pergola, Pablo E.; Pediatrics, School of Medicine
    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.
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    Using Electronic Health Record Data to Rapidly Identify Children with Glomerular Disease for Clinical Research
    (American Society of Nephrology, 2019-12) Denburg, Michelle R.; Razzaghi, Hanieh; Bailey, L. Charles; Soranno, Danielle E.; Pollack, Ari H.; Dharnidharka, Vikas R.; Mitsnefes, Mark M.; Smoyer, William E.; Somers, Michael J. G.; Zaritsky, Joshua J.; Flynn, Joseph T.; Claes, Donna J.; Dixon, Bradley P.; Benton, Maryjane; Mariani, Laura H.; Forrest, Christopher B.; Furth, Susan L.; Pediatrics, School of Medicine
    Background: The rarity of pediatric glomerular disease makes it difficult to identify sufficient numbers of participants for clinical trials. This leaves limited data to guide improvements in care for these patients. Methods: The authors developed and tested an electronic health record (EHR) algorithm to identify children with glomerular disease. We used EHR data from 231 patients with glomerular disorders at a single center to develop a computerized algorithm comprising diagnosis, kidney biopsy, and transplant procedure codes. The algorithm was tested using PEDSnet, a national network of eight children's hospitals with data on >6.5 million children. Patients with three or more nephrologist encounters (n=55,560) not meeting the computable phenotype definition of glomerular disease were defined as nonglomerular cases. A reviewer blinded to case status used a standardized form to review random samples of cases (n=800) and nonglomerular cases (n=798). Results: The final algorithm consisted of two or more diagnosis codes from a qualifying list or one diagnosis code and a pretransplant biopsy. Performance characteristics among the population with three or more nephrology encounters were sensitivity, 96% (95% CI, 94% to 97%); specificity, 93% (95% CI, 91% to 94%); positive predictive value (PPV), 89% (95% CI, 86% to 91%); negative predictive value, 97% (95% CI, 96% to 98%); and area under the receiver operating characteristics curve, 94% (95% CI, 93% to 95%). Requiring that the sum of nephrotic syndrome diagnosis codes exceed that of glomerulonephritis codes identified children with nephrotic syndrome or biopsy-based minimal change nephropathy, FSGS, or membranous nephropathy, with 94% sensitivity and 92% PPV. The algorithm identified 6657 children with glomerular disease across PEDSnet, ≥50% of whom were seen within 18 months. Conclusions: The authors developed an EHR-based algorithm and demonstrated that it had excellent classification accuracy across PEDSnet. This tool may enable faster identification of cohorts of pediatric patients with glomerular disease for observational or prospective studies.