Browsing by Author "Sedor, John R."

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    A Participant-Centered Approach to Understanding Risks and Benefits of Participation in Research Informed by the Kidney Precision Medicine Project
    (Elsevier, 2022) Butler, Catherine R.; Appelbaum, Paul S.; Ascani, Heather; Aulisio, Mark; Campbell, Catherine E.; de Boer, Ian H.; Dighe, Ashveena L.; Hall, Daniel E.; Himmelfarb, Jonathan; Knight, Richard; Mehl, Karla; Murugan, Raghavan; Rosas, Sylvia E.; Sedor, John R.; O'Toole, John F.; Tuttle, Katherine R.; Waikar, Sushrut S.; Freeman, Michael; Kidney Precision Medicine Project; Medicine, School of Medicine
    An understanding of the ethical underpinnings of human subjects research that involves some risk to participants without anticipated direct clinical benefit-such as the kidney biopsy procedure as part of the Kidney Precision Medicine Project (KPMP)-requires a critical examination of the risks as well as the diverse set of countervailing potential benefits to participants. This kind of deliberation has been foundational to the development and conduct of the KPMP. Herein, we use illustrative features of this research paradigm to develop a more comprehensive conceptualization of the types of benefits that may be important to research participants, including respecting pluralistic values, supporting the opportunity to act altruistically, and enhancing benefits to a participant's community. This approach may serve as a model to help researchers, ethicists, and regulators to identify opportunities to better respect and support participants in future research that entails some risk to these participants as well as to improve the quality of research for people with kidney disease.
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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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    Multi-Scalar Data Integration Links Glomerular Angiopoietin-Tie Signaling Pathway Activation With Progression of Diabetic Kidney Disease
    (American Diabetes Association, 2022) Liu, Jiahao; Nair, Viji; Zhao, Yi-yang; Chang, Dong-yuan; Limonte, Christine; Bansal, Nisha; Fermin, Damian; Eichinger, Felix; Tanner, Emily C.; Bellovich, Keith A.; Steigerwalt, Susan; Bhat, Zeenat; Hawkins, Jennifer J.; Subramanian, Lalita; Rosas, Sylvia E.; Sedor, John R.; Vasquez, Miguel A.; Waikar, Sushrut S.; Bitzer, Markus; Pennathur, Subramaniam; Brosius, Frank C.; De Boer, Ian; Chen, Min; Kretzler, Matthias; Ju, Wenjun; Kidney Precision Medicine Project; Michigan Translational Core C-PROBE Investigator Group; Medicine, School of Medicine
    Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD). Prognostic biomarkers reflective of underlying molecular mechanisms are critically needed for effective management of DKD. A three-marker panel was derived from a proteomics analysis of plasma samples by an unbiased machine learning approach from participants (N = 58) in the Clinical Phenotyping and Resource Biobank study. In combination with standard clinical parameters, this panel improved prediction of the composite outcome of ESKD or a 40% decline in glomerular filtration rate. The panel was validated in an independent group (N = 68), who also had kidney transcriptomic profiles. One marker, plasma angiopoietin 2 (ANGPT2), was significantly associated with outcomes in cohorts from the Cardiovascular Health Study (N = 3,183) and the Chinese Cohort Study of Chronic Kidney Disease (N = 210). Glomerular transcriptional angiopoietin/Tie (ANG-TIE) pathway scores, derived from the expression of 154 ANG-TIE signaling mediators, correlated positively with plasma ANGPT2 levels and kidney outcomes. Higher receptor expression in glomeruli and higher ANG-TIE pathway scores in endothelial cells corroborated potential functional effects in the kidney from elevated plasma ANGPT2 levels. Our work suggests that ANGPT2 is a promising prognostic endothelial biomarker with likely functional impact on glomerular pathogenesis in DKD.
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    Plasma apolipoprotein L1 levels do not correlate with CKD
    (American Society of Nephrology, 2014-03) Bruggeman, Leslie A.; O'Toole, John F.; Ross, Michael D.; Madhavan, Sethu M.; Smurzynski, Marlene; Wu, Kunling; Bosch, Ronald J.; Gupta, Samir; Pollak, Martin R.; Sedor, John R.; Kalayjian, Robert C.; Department of Medicine, IU School of Medicine
    Polymorphisms in APOL1 are associated with CKD, including HIV-related CKD, in individuals of African ancestry. The apolipoprotein L1 (APOL1) protein circulates and is localized in kidney cells, but the contribution of APOL1 location to CKD pathogenesis is unclear. We examined associations of plasma APOL1 levels with plasma cytokine levels, dyslipidemia, and APOL1 genotype in a nested case-control study (n=270) of HIV-infected African Americans enrolled in a multicenter prospective observational study. Patients were designated as having CKD when estimated GFR (eGFR) decreased to <60 ml/min per 1.73 m(2) (eGFR<60 cohort) or protein-to-creatinine ratios became >3.5 g/g (nephrotic proteinuria cohort). Circulating APOL1 levels did not associate with APOL1 genotype, CKD status, or levels of proinflammatory cytokines, but did correlate with fasting cholesterol, LDL cholesterol, and triglyceride levels. At ascertainment, CKD-associated polymorphisms (risk variants) in APOL1 associated with the eGFR<60 cohort, but not the nephrotic-range proteinuria cohort. Of note, in both the eGFR<60 and nephrotic proteinuria cohorts, CKD cases with two APOL1 risk variants had significant declines in eGFR over a median of 4 years compared with individuals with one or no risk variants. APOL1 risk genotype was not associated with changes in proteinuria. Higher circulating proinflammatory cytokine levels were independently associated with CKD but not APOL1 genotype. In conclusion, the function of variant APOL1 proteins derived from circulation or synthesized in the kidney, but not the level of circulating APOL1, probably mediates APOL1-associated kidney disease in HIV-infected African Americans.
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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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    Severe vascular calcification and tumoral calcinosis in a family with hyperphosphatemia: a fibroblast growth factor 23 mutation identified by exome sequencing
    (Oxford University Press, 2014-12) Shah, Anuja; Miller, Clinton J.; Nast, Cynthia C.; Adams, Mark D.; Truitt, Barbara; Tayek, John A.; Tong, Lili; Mehtani, Parag; Monteon, Francisco; Sedor, John R.; Clinkenbeard, Erica L.; White, Kenneth; Mehrotra, Rajnish; LaPage, Janine; Dickson, Patricia; Adler, Sharon G.; Iyengar, Sudha K.; Department of Medical & Molecular Genetics, IU School of Medicine
    BACKGROUND: Tumoral calcinosis is an autosomal recessive disorder characterized by ectopic calcification and hyperphosphatemia. METHODS: We describe a family with tumoral calcinosis requiring amputations. The predominant metabolic anomaly identified in three affected family members was hyperphosphatemia. Biochemical and phenotypic analysis of 13 kindred members, together with exome analysis of 6 members, was performed. RESULTS: We identified a novel Q67K mutation in fibroblast growth factor 23 (FGF23), segregating with a null (deletion) allele on the other FGF23 homologue in three affected members. Affected siblings had high circulating plasma C-terminal FGF23 levels, but undetectable intact FGF23 or N-terminal FGF23, leading to loss of FGF23 function. CONCLUSIONS: This suggests that in human, as in experimental models, severe prolonged hyperphosphatemia may be sufficient to produce bone differentiation proteins in vascular cells, and vascular calcification severe enough to require amputation. Genetic modifiers may contribute to the phenotypic variation within and between families.