1,721,007 research outputs found
Precision Medicine in Nephrology: An Integrative Framework of Multidimensional Data in the Kidney Precision Medicine Project
Get PDFChronic kidney disease (CKD) and acute kidney injury (AKI) are heterogeneous syndromes defined clinically by serial measures of kidney function. Each condition possesses strong histopathologic associations, including glomerular obsolescence or acute tubular necrosis, respectively. Despite such characterization, there remains wide variation in patient outcomes and treatment responses. Precision medicine efforts, as exemplified by the Kidney Precision Medicine Project (KPMP), have begun to establish evolving, spatially anchored, cellular and molecular atlases of the cell types, states, and niches of the kidney in health and disease. The KPMP atlas provides molecular context for CKD and AKI disease drivers and will help define subtypes of disease that are not readily apparent from canonical functional or histopathologic characterization but instead are appreciable through advanced clinical phenotyping, pathomic, transcriptomic, proteomic, epigenomic, and metabolomic interrogation of kidney biopsy samples. This perspective outlines the structure of the KPMP, its approach to the integration of these diverse datasets, and its major outputs relevant to future patient care
Rationale and design of the Kidney Precision Medicine Project.
No full textChronic 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
Kidney Biopsy Utility: Patient and Clinician Perspectives from the Kidney Precision Medicine Project
No full textRATIONALE & OBJECTIVE: Limited data exist on patient perspectives of the implications of kidney biopsies. We explored patients\u27 perspectives alongside those of clinicians to better understand how kidney biopsies affect patients\u27 viewpoints and the clinical utility of biopsies.
STUDY DESIGN: Prospective Cohort Study.
SETTING & PARTICIPANTS: Patient participants and clinicians in the Kidney Precision Medicine Project, a prospective cohort study of patients who undergo a research protocol biopsy, at 9 recruitment sites across the United States. Surveys were completed at enrollment before biopsy and additional timepoints after biopsy (participants: 28 days, 6 months; clinicians: 2 weeks).
ANALYTICAL APPROACH: Kappa statistics assessed prebiopsy etiology concordance between clinicians and participants. Participant perspectives after biopsy were analyzed using a thematic approach. Clinician ratings of clinical management value were compared to prebiopsy ratings with Wilcoxon matched-pairs signed-rank tests and paired
RESULTS: A total of 167 participants undergoing biopsy (124 participants with chronic kidney disease [CKD], 43 participants with acute kidney injury [AKI]) and 58 clinicians were included in this study. CKD participants and clinicians had low etiology concordance for the 2 leading causes of CKD: diabetes (k = 0.358) and hypertension (k = 0.081). At 28 days postbiopsy, 46 (84%) participants reported that the biopsy affected their understanding of their diagnosis, and 21 (38%) participants reported that the results of the biopsy affected their medications. Participants also shared biopsy impressions in free-text responses, including impacts on lifestyle and concurrent condition management. The biopsy positively shifted clinician perceptions of the procedure\u27s clinical management benefits, while perceptions of prognostic value decreased and diagnostic ratings remained unchanged.
LIMITATIONS: Our study did not have demographic data of clinicians and could not provide insight into postbiopsy experiences for participants who did not respond to follow-up surveys.
CONCLUSIONS: Participant perspectives of the personal implications of kidney biopsy can be integrated into shared decision-making between clinicians and patients. Enhanced biopsy reports and interactions between nephrologists and pathologists could augment the management and prognostic value of kidney biopsies.
PLAIN-LANGUAGE SUMMARY: The utility of kidney biopsy is debated among clinicians, and patients\u27 perspectives are even less explored. To address these gaps, we synthesized perspectives from clinicians and patient participants of the Kidney Precision Medicine Project (KPMP). Both before and after biopsy, clinicians were surveyed on how the procedure affected their clinical management, diagnosis, and prognosis. After biopsy, participants shared how the procedure affected their diagnosis, medication, and lifestyle changes. Clinicians and patients shared an appreciation for the biopsy\u27s impact on medical management but diverged in their takeaways on diagnosis and prognosis. These findings highlight the need for greater collaboration between patients and clinicians, particularly as they navigate shared decision-making when considering kidney biopsy
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Rationale and design of the Kidney Precision Medicine Project
Get PDFChronic 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
A Participant-Centered Approach to Understanding Risks and Benefits of Participation in Research Informed by the Kidney Precision Medicine Project
No full textAn 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
A Participant-Centered Approach to Understanding Risks and Benefits of Participation in Research Informed by the Kidney Precision Medicine Project.
No full textAn 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 risks as well as a 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\u27s 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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Patient perspectives and involvement in precision medicine research.
No full textThe Kidney Precision Medicine Project will advance understanding of chronic kidney disease attributed to diabetes or hypertension and acute kidney injury through a protocol kidney biopsy used for deep phenotyping with state-of-the-art methodology. To guide scientific inquiry toward clinically meaningful benefit, patients are equal partners for priority setting, study design and conduct, and dissemination of findings. Patients from stakeholder organizations, recruitment sites, tissue interrogation sites, and the Central Hub are represented on the Community Engagement Committee. This unique collaboration between patients and scientists has set a new standard for inclusion in precision medicine research
Modelling kidney disease using ontology: insights from the Kidney Precision Medicine Project.
Get PDFAn important need exists to better understand and stratify kidney disease according to its underlying pathophysiology in order to develop more precise and effective therapeutic agents. National collaborative efforts such as the Kidney Precision Medicine Project are working towards this goal through the collection and integration of large, disparate clinical, biological and imaging data from patients with kidney disease. Ontologies are powerful tools that facilitate these efforts by enabling researchers to organize and make sense of different data elements and the relationships between them. Ontologies are critical to support the types of big data analysis necessary for kidney precision medicine, where heterogeneous clinical, imaging and biopsy data from diverse sources must be combined to define a patient\u27s phenotype. The development of two new ontologies - the Kidney Tissue Atlas Ontology and the Ontology of Precision Medicine and Investigation - will support the creation of the Kidney Tissue Atlas, which aims to provide a comprehensive molecular, cellular and anatomical map of the kidney. These ontologies will improve the annotation of kidney-relevant data, and eventually lead to new definitions of kidney disease in support of precision medicine
Integrating Patient Priorities with Science by Community Engagement in the Kidney Precision Medicine Project
No full textThe Kidney Precision Medicine Project (KPMP) is a multisite study designed to improve understanding of CKD attributed to diabetes or hypertension and AKI by performing protocol-driven kidney biopsies. Study participants and their kidney tissue samples undergo state-of-the-art deep phenotyping using advanced molecular, imaging, and data analytical methods. Few patients participate in research design or concepts for discovery science. A major goal of the KPMP is to include patients as equal partners to inform the research for clinically relevant benefit. The purpose of this report is to describe patient and community engagement and the value they bring to the KPMP. Patients with CKD and AKI and clinicians from the study sites are members of the Community Engagement Committee, with representation on other KPMP committees. They participate in KPMP deliberations to address scientific, clinical, logistic, analytic, ethical, and community engagement issues. The Community Engagement Committee guides KPMP research priorities from perspectives of patients and clinicians. Patients led development of essential study components, including the informed consent process, no-fault harm insurance coverage, the ethics statement, return of results plan, a Patient Primer for scientists and the public, and Community Advisory Boards. As members across other KPMP committees, the Community Engagement Committee assures that the science is developed and conducted in a manner relevant to study participants and the clinical community. Patients have guided the KPMP to produce research aligned with their priorities. The Community Engagement Committee partnership has set new benchmarks for patient leadership in precision medicine research
Metagenomic Profiling of Gut Microbiota in Kidney Precision Medicine Project Participants With CKD and AKI
No full textBACKGROUND: The gut microbiome plays an important role in human health and disease. Kidney Precision Medicine Project (KPMP) is a well-phenotyped, kidney biopsy-proven cohort of AKI and CKD patients. Comprehensive profiling of gut microbiota can uncover novel mechanistic, diagnostic, and therapeutic strategies for CKD and AKI patients. METHODS: We performed metagenomic whole genome sequencing (mWGS; \u3e 25 million reads) on KPMP stool samples. mWGS data of healthy controls from 4 published studies was used. Kraken2 and MetaPhlAn3 were used for taxonomic assignment, and HUMAnN3 for functional annotation. RESULTS: Kraken2 analysis showed significantly higher abundance of Ruminococcus bicirculans in CKD (6.47) compared to AKI (1.82) and healthy individuals (2.42; p = 0.01). Furthermore, the abundance of Gordonibacter pamelaeae increased in CKD (0.30) compared to AKI (0.07; p = 0.05) and healthy individuals (0.03). The percent mean abundance of genus Chryseobacterium was slightly higher in CKD (0.07) compared to AKI (0.05; p = 0.05) but reduced compared to healthy individuals (0.20; p \u3c 0.001). MetaPhlAn3 identified alterations in Gordonibacter, Bacteroides, and Faecalibacterium with a significant increase in Clostridium asparagiforme in AKI (11.68) compared to CKD (0.03; p = 0.06) and healthy (0.01; p = 0.001) individuals. Roseburia hominis, Roseburia intestinalis, Dorea longicatena, and Gemmiger formicilis were significantly reduced in AKI compared to CKD and healthy individuals. LDA/HUMAnN3 analysis showed a significant correlation between several metabolites and bacterial species in this KPMP population. CONCLUSION: Kidney biopsy-proven CKD and AKI patients show a distinct gut microbiota profile compared to healthy individuals. This high-quality dataset is a valuable resource for developing microbiome-based diagnostics and therapies for CKD and AKI
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